JP5918894B1 - Nalfurafine hydrochloride-containing capsule formulation - Google Patents

Abstract

Disclosed is a capsule preparation containing nalflaphine hydrochloride in a stable state and a method for producing such capsule preparation. A capsule preparation is produced by coating a capsule content solution containing nalfurafine hydrochloride, a base such as polyethylene glycol or propylene glycol, and a stabilizer with a film. The stabilizers include lidocaine, a local anesthetic, thioctic acid (α-lipoic acid), a vitamin-like substance that acts as a coenzyme, meglumine, an amino sugar derived from sorbitol, and tripeptide as an antioxidant. At least one selected from the group consisting of known reduced glutathione, amphoteric surfactant lauryldiaminoethylglycine sodium solution, and L-methionine which is a hydrophobic amino acid containing sulfur in the side chain, in particular lauryldiaminoethyl A glycine sodium solution can be mentioned. Moreover, the said stabilizer can be used together with a tocopherol. [Selection figure] None

Description

  The present invention relates to a capsule preparation containing nalfurafine hydrochloride, and more specifically, a capsule preparation in which a capsule content liquid containing nalfurafine hydrochloride, a base, and a stabilizer is coated with a film, It relates to a capsule preparation in which the agent is at least one selected from the group consisting of lidocaine, thioctic acid (α-lipoic acid), meglumine, glutathione, lauryldiaminoethylglycine sodium solution and L-methionine, particularly lauryldiaminoethylglycine sodium solution. .

  Conventionally, internal preparations such as antihistamines and antiallergic agents, and external preparations such as corticosteroids and nonsteroidal anti-inflammatory agents have been used for the treatment of pruritus. However, in the case of the above-mentioned internal preparation, side effects such as drowsiness, dullness, dry mouth and dysuria are likely to occur, and in the case of an external preparation, there are problems that side effects such as skin contraction and capillary vasodilation are likely to occur. There was a need to develop a new antipruritic agent.

  In recent years, it has become clear that opioid receptors are involved in itching and that endogenous opioids cause itching (see Patent Documents 1 and 2). There are mainly three subtypes of such opioid receptors: μ receptor, κ receptor, and δ receptor. Nalfurafine hydrochloride selectively acts on the kappa receptor that regulates the μ receptor, and can suppress the itch caused through the stimulation of endogenous opioids. At present, narfrafin hydrochloride is sold by Torii Pharmaceutical Co., Ltd. as Remitch (registered trademark) capsules, and is used as an remedy for pruritus that occurs during dialysis therapy. Nalfurafine hydrochloride is chemically unstable to heat, light, oxygen and the like. Therefore, in a capsule preparation containing nalfurafine hydrochloride, a method of stabilizing nalfurafine hydrochloride using an antioxidant, synergist, saccharide, or surfactant has been proposed (see Patent Document 3).

  On the other hand, lidocaine (hydrochloride) is the most widely used local anesthetic in the world and is also known as an antiarrhythmic agent. Thioctic acid is also called α-lipoic acid and is a vitamin-like substance that acts as a coenzyme. It is known that meglumine is an amino sugar derived from sorbitol and is used as an excipient or contrast agent in pharmaceutical preparations, and reduced glutathione (GSH) is a tripeptide consisting of three amino acids Known as an oxidant, sodium lauryldiaminoethylglycine solution is an amphoteric surfactant, known as a mouthwash other than iodine, and L-methionine is a hydrophobic essential amino acid containing sulfur in the side chain Known as.

International Publication No. 1998/23290 Pamphlet JP 2013-147459 A International Publication No. 1999/02158 Pamphlet

  An object of the present invention is to provide a capsule preparation containing nalflaphine hydrochloride in a stable state for a long period of time, a method for producing such a capsule preparation, and the like.

  As a result of repeating various studies to solve the above-mentioned problems, the present inventors can produce a capsule preparation containing nalfrafin hydrochloride in a stable state for a long period of time by using a specific stabilizer. I found something and completed the present invention.

That is, the present invention is as follows.
(1) A capsule formulation in which a capsule content liquid containing nalfurafine hydrochloride, a base, and a stabilizer is coated with a film,
A capsule preparation wherein the stabilizer is a sodium lauryldiaminoethylglycine solution.
(2) The above base is at least one selected from the group consisting of polyethylene glycol, propylene glycol, ethanol, glycerin monocaprylate, propylene glycol monooleate, propylene glycol monocaprylate (1) Capsule formulation.
(3) The capsule preparation according to (1) or (2) above, wherein the capsule content liquid further contains tocopherol and / or sodium thiosulfate.
(4) A method for producing a capsule preparation comprising the following steps (a) to (c).
(A) a step of preparing a nalfurafine hydrochloride stock solution by dissolving nalfurafine hydrochloride in a buffer or water;
(B) a step of preparing a capsule content solution by mixing the nalfurafine hydrochloride stock solution, a base, and a sodium lauryldiaminoethylglycine solution as a stabilizer;
(C) coating the capsule content liquid with a film;
(5) A method for stabilizing nalfurafine hydrochloride in a capsule preparation, wherein nalfurafine hydrochloride is brought into contact with sodium lauryldiaminoethylglycine as a stabilizer in the presence of a base.

  ADVANTAGE OF THE INVENTION According to this invention, it becomes possible to provide the capsule formulation which contains a narfrafin hydrochloride in a stable state for a long period of time.

It is a figure which shows the result of the residual rate (upper) of the main ingredient (nalfuraphine hydrochloride) when using reduced glutathione as a stabilizer, and the main degradation product (N-Oxide) content (lower). It is a figure which shows the result of the residual rate (top) of a main ingredient when using meglumine as a stabilizer, and the main degradation product content (bottom). It is a figure which shows the result of the residual rate (upper) of a main ingredient when a thioctic acid is used as a stabilizer, and the main degradation product content (lower). It is a figure which shows the result of the residual rate (top) of a main ingredient when a lidocaine is used as a stabilizer, and the main degradation product content (bottom). It is a figure which shows the result of the residual rate (upper) of a main ingredient when a lauryl diaminoethylglycine sodium solution is used as a stabilizer, and the main degradation product content (lower). It is a figure which shows the result of the residual rate (upper) of a main ingredient when a methionine is used as a stabilizer, and the main degradation product content (lower). It is a figure which shows the result of the residual rate (top) of a main ingredient, and the main degradation product content (bottom) when meglumine and / or a lauryl diaminoethylglycine sodium solution are used as a stabilizer. It is a figure which shows the result of the residual rate (top) of a main ingredient when using meglumine as a stabilizer, and the main degradation product content (bottom). It is a figure which shows the result of the residual rate (top) of a main ingredient, and the main degradation product content (bottom) when meglumine and / or a lauryl diaminoethylglycine sodium solution are used as a stabilizer. It is a figure which shows the result of the residual rate (top) of a main ingredient, and the main degradation product content (bottom) when meglumine and / or a lauryl diaminoethylglycine sodium solution are used as a stabilizer.

  The capsule preparation of the present invention is a capsule preparation in which a capsule content liquid containing nalfrafin hydrochloride, a base, and a stabilizer is coated with a film, wherein the stabilizer is a sodium lauryl diaminoethylglycine solution. There is no particular limitation as long as it is a capsule preparation, and the method for stabilizing nalfurafine hydrochloride in the capsule preparation of the present invention includes nalfurafine hydrochloride in the presence of a base and lauryl diaminoethylglycine as a stabilizer. Although it will not restrict | limit especially if it is a method of making a sodium solution contact, Meglumine can be used together in addition to a sodium lauryl diaminoethylglycine solution as said stabilizer. As a use density | concentration of a lauryl diamino ethylglycine sodium liquid, 0.05 to 0.5% can be illustrated. The capsule preparation is preferably a soft capsule preparation.

  Nalfurafine hydrochloride ((2E) -N-[(5R, 6R) -17- (cyclopropylmethyl) -4,5-epoxy-3,14-dihydroxymorphinan-6-yl] -3- () in the present invention Furan-3-yl) -N-methyl-2-propenamide hydrochloride; (2E) -N-[(5R, 6R) -17- (Cyclopropylmethyl) -4, 5-epoxy-3, 14-dihydroxymorphinan- 6-yl] -3- (furan-3-yl) -N-methyl-2-propenamide monohydrochloride) can be obtained by purchasing a commercial product.

  The content of nalflaphine hydrochloride in the capsule content liquid is not particularly limited, but may be 0.01 to 10,000 μg, preferably 0.1 to 1000 μg, in the capsule content liquid corresponding to one capsule.

  Examples of the base in the present invention include polyethylene glycol (PEG), propylene glycol, ethanol, glycerin monocaprylate, propylene glycol monooleate, propylene glycol monocaprylate.

  In the base in the present invention, two or more kinds may be combined. For example, polyethylene glycol (PEG) and glycerol monocaprylate, polyethylene glycol (PEG) and propylene glycol monooleate, polyethylene glycol (PEG) and propylene Glycol monocaprylate, polyethylene glycol (PEG) and propylene glycol, polyethylene glycol (PEG) and ethanol, glycerin monocaprylate and propylene glycol monooleate, glycerin monocaprylate and propylene glycol monocapryl Acid esters, glycerol monocaprylate and propylene glycol, glycerol monocaprylate and ethanol, Pyrene glycol monooleate and propylene glycol monocaprylate, propylene glycol monooleate and propylene glycol, propylene glycol monooleate and ethanol, propylene glycol monocaprylate and propylene glycol, propylene glycol mono A combination of caprylic acid ester and ethanol can be mentioned.

  In the present invention, in addition to sodium lauryldiaminoethylglycine solution, at least one other stabilizer selected from the group consisting of lidocaine, thioctic acid, meglumine, reduced glutathione, and L-methionine can be used in combination. , Sodium thiosulfate, n-propyl gallate, sodium bisulfite, L-ascorbic acid, butylhydroxyanisole (BHA), dibutylhydroxytoluene (BHT), tocopherol, L-ascorbic acid stearate, etc. are added to the capsule content liquid. In particular, tocopherol and sodium thiosulfate can be preferably exemplified. When tocopherol and / or sodium thiosulfate is used in combination with sodium lauryldiaminoethylglycine solution, the use concentration of tocopherol is 0.05 to 0.2%, preferably 0.075 to 0.15%. Examples of suitable concentrations of sodium sulfate include 0.01 to 0.04%, preferably 0.03 to 0.04%.

  The capsule content liquid in the present invention contains nalfurafine hydrochloride, a base, and a stabilizer. In addition to nalfurafine hydrochloride, a base, and a stabilizer, oils and fats, surfactants, buffers It may contain other substances such as liquid, water, gelling agent, pH adjusting agent, porous fine particle powder, flavoring agent such as sweetener, flavoring agent, dissolution aid, viscosity adjusting agent. A preferable example of the buffer is an acetate buffer.

  The pH of the capsule content liquid in the present invention is preferably 5.0 to 8.6, more preferably 7.0 to 8.2, and still more preferably 7.1 to 7.6. Examples of the pH adjustment include a method of adjusting depending on the type or amount of the base or stabilizer used, and a method of adjusting using a buffer solution. By preparing the solution while adjusting the pH of the capsule content solution or the solution being prepared at each stage to neutral to weakly acidic, it becomes possible to further improve the stability of nalfurafine hydrochloride.

  In the present invention, the film is not particularly limited, and may be a hydrophobic film or a hydrophilic film, but is preferably a hydrophilic film.

  Materials for the hydrophilic film include gelatin, modified gelatin such as succinated gelatin, carrageenan, agar, sodium alginate, pullulan, glucomannan, gum arabic, fur cerelan, Eugema algae, gellan gum, hydroxypropylmethylcellulose, hydroxypropylcellulose, polyvinylpyrrolidone In addition, one or a combination of two or more hydrophilic polymers such as polyvinyl alcohol and starch can be used, and gelatin or modified gelatin can be preferably used.

  When manufacturing the film, the film material is made of plasticizer such as glycerin, light-shielding agent such as titanium dioxide, pH adjuster such as sodium phosphate, chelating agent such as trisodium citrate and sodium metaphosphate, calcium lactate, chloride A gelling accelerator such as potassium, a surfactant such as polyglycerin fatty acid ester and lecithin, a flavoring agent, a fragrance, a preservative, a coloring agent, a dissolution aid and the like may be added.

The method for producing the capsule preparation of the present invention is not particularly limited as long as it comprises the following steps (a) to (c), and nalfrafin hydrochloride is buffered or water, preferably buffered, more preferably acetate buffered. It becomes possible to further improve the stability of nalfurafine hydrochloride by mixing with a base or a stabilizer after being dissolved in the liquid.
(A) a step of preparing a nalfurafine hydrochloride stock solution by dissolving nalfurafine hydrochloride in a buffer or water;
(B) A step of preparing a capsule content solution by mixing the nalfurafine hydrochloride stock solution, a base, and a lauryl diaminoethyl glycine sodium solution or a meglumine and lauryl diaminoethyl glycine sodium solution as a stabilizer;
(C) coating the capsule content liquid with a film;

As another aspect of the manufacturing method of the capsule formulation of this invention, the method provided with the process of following (d)-(f) can be mentioned.
(D) Nalfurafine hydrochloride is dissolved in at least one base selected from the group consisting of polyethylene glycol (PEG), propylene glycol, glycerin monocaprylate, propylene glycol monooleate, propylene glycol monocaprylate. Preparing a nalfurafine hydrochloride stock solution;
(E) A step of preparing a capsule content solution by mixing the nalfurafine hydrochloride stock solution and a lauryl diaminoethyl glycine sodium solution, or meglumine and lauryl diaminoethyl glycine sodium solution as a stabilizer; (f) the capsule content Coating the liquid with a film;

  When a buffer solution is used in the method for producing the capsule preparation of the present invention, the pH of the buffer solution may be 4.5 to 5.5, preferably 4.8 to 5.2.

  In the capsule preparation of the present invention and the method for producing the capsule preparation of the present invention, known methods such as a flat plate method, a rotary die method, and a seamless method can be used as a method for coating the capsule content liquid with a film.

(Test materials and abbreviations)
Nalfurafine hydrochloride as the active ingredient in the capsule content liquid, and reduced glutathione (Gl), meglumine (Mg), sodium lauryldiaminoethylglycine (An; manufactured by NOF Corporation “Nissan Anon [registered trademark]” as the active ingredient stabilizer LG-R), thioctic acid (SA), lidocaine (Ld), and L-methionine (Mt), sodium thiosulfate (St) and tocopherol (VE) as antioxidants, polyethylene glycol 400 (PEG400) as a base In addition, succinylated gelatin, concentrated glycerin, and titanium dioxide were used as the capsule film, in which the main degradation product represents N-Oxide, NN: not added, X.XX%; Concentration of additives contained in the liquid (w / w), +: Succinic gelatin film is immersed,-; It is shown click gelatin film without immersion, respectively.

(Preparation of capsule content liquid)
The fat-soluble solid additives thioctic acid and lidocaine and the fat-soluble liquid additive tocopherol are mixed and dissolved with PEG400 after weighing, and the water-soluble solid additives sodium thiosulfate, reduced glutathione, and L-methionine are After weighing, it was mixed and dissolved with water, and the lauryl diaminoethylglycine sodium solution, which is a water-soluble liquid additive, was mixed and dissolved with propylene glycol after weighing. The additive lysate is mixed and dissolved in PEG400, and each of the mixture and solution is mixed with an aqueous solution of nalflaphine hydrochloride. (+) The specimen is obtained by immersing 1 g of a succinylated gelatin film piece in 2 g of each mixture. The mixture was sealed in a glass vial, and the (-) specimen was sealed in a glass vial as it was to prepare each capsule content solution. For each capsule content solution, one vial was prepared for each storage period.

(Storage and stabilization analysis of capsule contents)
One vial was stored in a 4 ° C. refrigerator as a sample with a storage period of 0 weeks (at the start of storage), and the remaining vial containing the capsule content solution was stored in a 50 ° C. thermostat. The storage period was 1 to 8 weeks, and when the storage period at 50 ° C. was completed, the vial was taken out of the thermostatic bath. The (+) specimen was taken out of the immersed film, and the (-) specimen was stored as it was at 4 ° C. until the day of analysis. Further, in order to determine the residual rate of nalflaphine hydrochloride as the main drug, about 200 mg of the collected capsule content liquid was diluted about 5 times with water and subjected to high performance liquid chromatography (HPLC) analysis. HPLC analysis was performed according to the following conditions according to Horikiri et al. (Horikiri H. et al., Chem. Pharm. Bull. 52 (6): 664-669 (2004)). Moreover, the peak of the relative retention time 1.13 when the retention time of the nalfurafine active agent was set to 1 was analyzed as a main decomposition product (N-Oxide).

Analytical column: YMC-Pack ODS-AM 5μm
Column temperature: 40 ° C
Flow rate: 1.0 mL / min
Injection volume: 50 μL
Detection wavelength: 280 nm
Mobile phase A solution 50 mM sodium dihydrogen phosphate solution / acetonitrile = 95/5 (V /
V)
Mobile phase B solution 50 mM sodium dihydrogen phosphate solution / acetonitrile = 60/40 (V / V)

  The gradient conditions were the same as those shown in [Table 1] below.

(Reduced glutathione; stabilization by Gl)
The formulation of each capsule content solution is shown in [Table 2], and the results of the stabilization test up to 4 weeks later are shown in FIG.

(Meglumine; stabilization by Mg)
The formulation of each capsule content solution is shown in [Table 3], and the results of the stabilization test up to 8 weeks later are shown in FIG.

(Thioctic acid; stabilization by SA)
The formulation of each capsule content solution is shown in [Table 4], and the results of the stabilization test up to 8 weeks later are shown in FIG.

(Lidocaine; stabilization by Ld)
The formulation of each capsule content solution is shown in [Table 5], and the results of the stabilization test up to 8 weeks later are shown in FIG.

(Lauryldiaminoethylglycine sodium solution; stabilization by An)
The formulation of each capsule content liquid is shown in [Table 6], and the results of the stabilization test up to 8 weeks later are shown in FIG.

(Methionine; Stabilization with Mt)
The formulation of each capsule content solution is shown in [Table 7], and the results of the stabilization test after one week are shown in FIG. In FIG. 6, EMt represents VE + Mt, EMtM represents VE + Mt + Mg, EMtA represents VE + Mt + An, and EMMA represents VE + Mt + Mg + An.

(Preparation of capsule formulation)
According to the film formulation and capsule content liquid formulation described in [Table 8] below, 5 types of capsule formulations with different stabilizers were prepared. Specifically, glutathione, meglumine, and nalflavine hydrochloride were each dissolved in water and added to polyethylene glycol 400. Tocopherol, thioctic acid, and lidocaine were each dissolved in polyethylene glycol 400 divided into small portions and charged into the original polyethylene glycol 400. Nissan Anon LG-R was dissolved in propylene glycol and charged into polyethylene glycol 400. By stirring, uniform mixing was performed to obtain each capsule content solution. The prepared capsule content solution was filled into a film made of succinated gelatin, glycerin and titanium dioxide by a rotary die method to obtain an Oval3 type soft capsule preparation.

(Stabilization with meglumine and / or lauryldiaminoethylglycine sodium solution)
A stabilization test of nalfurafine hydrochloride with meglumine and / or lauryldiaminoethylglycine sodium solution was performed. The prescription of each capsule content liquid is shown in [Table 9] to [Table 12]. In [Table 9] to [Table 12], (+) indicates succinated gelatin film immersion, and (+ g) indicates gelatin film immersion. About each prescription of [Table 9]-[Table 11], the result of the stabilization test to 4 weeks after is shown in FIGS. 7-9, respectively. Moreover, about the prescription of [Table 12], the result of the stabilization test to 8 weeks after is shown in FIG. Preparation of the capsule content liquid and stabilization analysis of the capsule content liquid were performed in the same manner as in Example 1 except that the storage temperature was changed to 60 ° C.

  Based on the formulation of nalfurafine hydrochloride soft capsule formulation shown in [Table 13] below, four kinds of nalfurafine hydrochloride soft capsule formulations were filled into a film composed of succinated gelatin, glycerin and titanium dioxide by the rotary die method, and Oval type 3 A soft capsule formulation was obtained.

  As shown in the said patent document 1 (patent 3743449 gazette), 0.05%-1% of sodium thiosulfate is added as a stabilizer in the capsule formulation containing a narfrafin hydrochloride. Therefore, a product containing 0.15% sodium thiosulfate was adopted as a positive control. From FIG. 5 (samples “An 0.05% (+)” and “An 0.1% (+)”), the addition of 0.05% or more of lauryldiaminoethylglycine sodium solution is equivalent to or greater than the positive control remaining as the positive control. A certain stability effect was observed. Furthermore, by combining with tocopherol (sample “VE 0.1% + An 0.01% (+)” to “VE 0.1% + An 0.1% (+)”), the residual ratio of the main drug is higher and the main degradation It was found that the content was kept lower and the stability was extremely excellent. In addition, from FIG. 9, the remaining ratio of the main drug and the main degradation in the combination of sodium thiosulfate, tocopherol and / or meglumine and sodium lauryldiaminoethylglycine solution (samples “SE'M” A ”” to “SE'A ′”). A favorable result was obtained for both the product content and the stabilizing effect of lauryl diaminoethylglycine sodium solution on narfrafin hydrochloride was observed.

  The capsule preparation of the present invention can be used as a capsule preparation capable of holding nalfurafine hydrochloride in a stable state for a long period of time in the fields of medicine, quasi drugs and the like.

Claims (4)

Capsule formulation in which a capsule content liquid containing nalfrafin hydrochloride, a base, and a stabilizer is coated with a film, wherein the base is polyethylene glycol, propylene glycol, ethanol, glycerin monocaprylate, propylene A capsule preparation which is at least one selected from the group consisting of glycol monooleate and propylene glycol monocaprylate, and the stabilizer is a sodium lauryldiaminoethylglycine solution. The capsule preparation according to claim 1 , wherein the capsule content liquid further contains tocopherol and / or sodium thiosulfate. The manufacturing method of a capsule formulation provided with the process of (a)-(c) shown below.
(A) a step of preparing a nalfurafine hydrochloride stock solution by dissolving nalfurafine hydrochloride in a buffer or water;
(B) at least one base selected from the group consisting of the above-described nalfurafine hydrochloride stock solution, polyethylene glycol, propylene glycol, ethanol, glycerin monocaprylate, propylene glycol monooleate, propylene glycol monocaprylate , Mixing the sodium lauryldiaminoethylglycine solution as a stabilizer to prepare a capsule content solution;
(C) coating the capsule content liquid with a film; In a capsule preparation containing a capsule content liquid containing nalfurafine hydrochloride, a base, and a stabilizer, polyethylene glycol, propylene glycol, ethanol, glycerin monocaprylate, propylene glycol monooleate, propylene glycol monocapryl Nalfurafine hydrochloride in a capsule preparation characterized by contacting nalfurafine hydrochloride with sodium lauryl diaminoethylglycine as a stabilizer in the presence of at least one base selected from the group consisting of acid esters Stabilization method.