JP2015218153A - Quickly-soluble film preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide a quickly-soluble film preparation that is made from serotonin (5-HT) receptor agonist, particularly zolmitriptan, wherein the quickly-soluble film preparation has an improved feeling when taking it and has excellent storage stability.SOLUTION: A quickly-soluble film preparation comprises (A) serotonin (5-HT) receptor agonist, (B) highly-sweet sweetener, (C) organic acid with its content of 20-40 pts. mass relative to serotonin (5-HT) receptor agonist 100 pts. mass, (D) alkaline earth metal salt and (E) citrus flavor component.

Description

The present invention relates to a fast-dissolving film containing a serotonin (5-HT ₁ ) receptor agonist, which is a therapeutic agent for migraine.

Serotonin (5-HT ₁ ) receptor agonists, such as zolmitriptan, are migraine treatments that are used orally when migraine headache develops. As a preparation containing zolmitriptan, it is commercially available as a fast-dissolving tablet in the oral cavity because it is necessary to take it when migraine develops to exert its effect (Non-patent Document 1).

  Migraine headache attacks may occur during meetings or during classes, and migraine treatment drugs must be taken promptly without water and must be highly portable. From this point of view, a fast-dissolving film is preferable as a formulation of zolmitriptan. For example, a film containing a film-forming agent, a gel-forming agent and an anti-migraine agent (Patent Document 1), a water-soluble polymer, a pharmaceutically active ingredient An oral fast-dissolving film containing a stevioside sweetener and a first sweetener (Patent Document 2) has been reported.

Special table 2009-501751 gazette Special table 2012-528854

Zomig (registered trademark) RM lock package insert

However, serotonin (5-HT ₁ ) receptor agonists, particularly zolmitriptan, have a unique bitter taste, and when used as a fast-dissolving film agent, as in Patent Document 2, for the purpose of masking the bitter taste. It has been found that when a high-sweetness sweetener is added, the sweetness that continues after taking is sustained, and the feeling of taking is conversely reduced. On the other hand, it has been found that when zolmitriptan is blended and stored in an edible film base such as a water-soluble polymer, an N-oxidant is produced and the stability of zolmitriptan is lowered.
Accordingly, an object of the present invention is to improve the feeling of administration and storage stability when a serotonin (5-HT ₁ ) receptor agonist such as zolmitriptan is used as a fast-dissolving film agent.

The present inventors have, serotonin (5-HT ₁₎ result of various studies to achieve both ingestion feeling and stability of rapidly soluble film containing a receptor agonist, serotonin (5-HT ₁₎ receptor agonist By blending high-sweetness sweeteners, specific amounts of organic acids, alkaline earth metal salts and citrus flavor ingredients in the medicine, there is no bitterness and no sweetness to pull back, and a refreshing feeling is obtained, and serotonin ( The present inventors have found that a fast-dissolving film agent in which the stability of a 5-HT ₁ ) receptor agonist is remarkably improved can be obtained.

  That is, the present invention provides the following [1] to [10].

[1] (A) Serotonin (5-HT ₁ ) receptor agonist, (B) High sweetness sweetener, (C) Organic acid Serotonin (5-HT ₁ ) receptor agonist A fast-dissolving film agent containing 40 parts by mass, (D) an alkaline earth metal salt, and (E) a citrus flavor component.
[2] The fast-dissolving film agent according to [1], wherein the (A) serotonin (5-HT ₁ ) receptor agonist is zolmitriptan or a salt thereof.
[3] (B) The fast solubility according to [1] or [2], wherein the high-sweetness sweetener is one or more selected from aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, and saccharin. Film agent.
[4] The content of (B) high-potency sweetener is 10 to 50 parts by mass with respect to 100 parts by mass of (A) serotonin (5-HT ₁ ) receptor agonist [1] to [3] The fast-dissolving film agent according to any one of the above.
[5] (C) The fast dissolving film agent according to any one of [1] to [4], wherein the organic acid is a hydroxy acid having 3 to 8 carbon atoms.
[6] The fast dissolving film agent according to any one of [1] to [5], wherein the organic acid is anhydrous citric acid.
[7] The fast-dissolving film agent according to any one of [1] to [6], wherein the (D) alkaline earth metal salt is calcium chloride.
[8] The content of (D) alkaline earth metal salt is 10 to 40 parts by mass with respect to 100 parts by mass of (A) serotonin (5-HT ₁ ) receptor agonist [1] to [7] The fast-dissolving film agent according to any one of the above.
[9] The fast-dissolving film agent according to any one of [1] to [8], wherein (E) the citrus flavor component is a citrus-derived essential oil selected from orange, mandarin orange, lemon and grapefruit, or an essential oil component thereof.
[10] The content of (E) citrus flavor component is 0.1 to 20 parts by mass with respect to 100 parts by mass of (A) serotonin (5-HT ₁ ) receptor agonist [1] to [9 ] The fast-dissolving film agent in any one of.

The fast-dissolving film preparation of the present invention rapidly disintegrates in the oral cavity without water, so it can be taken when migraine headache develops and can be treated quickly, and is taken despite the rapid disintegration in the oral cavity. sensitive is good and long term serotonin during preparation storage (5-HT ₁₎ receptor agonist is maintained stably.

The fast dissolving film of the present invention comprises (A) a serotonin (5-HT ₁ ) receptor agonist, (B) a high sweetness sweetener, (C) an organic acid serotonin (5-HT ₁ ) receptor agonist 100 20-40 mass parts with respect to mass parts, (D) alkaline-earth metal salt, and (E) citrus flavor component are contained.

Examples of (A) serotonin (5-HT ₁ ) receptor agonists include zolmitriptan or a salt thereof, sumatriptan or a salt thereof, eletriptan or a salt thereof, naratriptan or a salt thereof, and rizatriptan or a salt thereof. . Of these serotonin (5-HT ₁ ) receptor agonists, zolmitriptan or a salt thereof is preferable because of its solubility in water and ethanol and a small single dose unit.
Zolmitriptan is the chemical name (S) -4-([3- [2- (dimethylamino) ethyl] -1H-indol-5-yl] methyl) -2-oxazolidinone, human 5-HT _1B and It shows high affinity for the 5-HT _1D receptor and is an active ingredient of a migraine therapeutic agent. Examples of the salt of zolmitriptan include inorganic acid salts such as hydrochloride and sulfate, and organic acid salts such as acetate and citrate.
The content of zolmitriptan or a salt thereof is preferably 1 to 10 mg, and particularly preferably 2.5 mg, per dosage unit.

(B) As a high sweetness sweetener, aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium, and saccharin can be mentioned, and one or more of these are used. Among these high-sweetness sweeteners, aspartame, sucralose, acesulfame potassium and thaumatin are preferred from the viewpoint of the masking effect and aftertaste of serotonin (5-HT ₁ ) receptor agonists, particularly zolmitriptan. It is more preferable to use one type or two or more types.
The content of the high sweetness sweetener is preferably (A) a serotonin (5-HT ₁ ) receptor agonist, particularly 10 to 50 parts by mass with respect to 100 parts by mass of zolmitriptan, and serotonin (5-HT ₁ ). 20-40 mass parts is more preferable from the point of the masking of bitterness of a receptor agonist, especially zolmitriptan, and aftertaste, and 25-30 mass parts is further more preferable.

(C) The organic acid not only suppresses the persistence of the aftertaste due to the blending of the high sweetness sweetener, but also contributes to the improvement of the stability of the serotonin (5-HT ₁ ) receptor agonist, particularly zolmitriptan. The organic acid may be an edible organic acid, but is preferably a hydroxy acid having 3 to 8 carbon atoms, more preferably citric acid, tartaric acid, malic acid, or lactic acid, and further preferably citric acid. Further, as citric acid, anhydrous citric acid is more preferable.
The content of the organic acid, aftertaste suppression and serotonin (5-HT ₁₎ receptor agonists, in particular in terms of improving the stability of zolmitriptan, serotonin (5-HT ₁₎ receptor agonists, in particular Zorumi It is important that it is 20-40 mass parts with respect to 100 mass parts of triptan, 22-35 mass parts is preferable, 23-30 mass parts is more preferable, and 24-30 mass parts is further more preferable.

(D) Alkaline earth metal salt is a component that exerts a stabilizing effect on serotonin (5-HT ₁ ) receptor agonists, particularly zolmitriptan. Alkaline earth metal halides are preferred and alkaline earth metal chlorides. More preferred. Specifically, calcium chloride is more preferable, calcium chloride hydrate is more preferable, and calcium chloride dihydrate is particularly preferable in terms of less exotherm and endotherm during preparation preparation.
The content of the alkaline earth metal salts, serotonin (5-HT ₁₎ receptor agonist, particularly in view of the stabilizing effect of zolmitriptan, serotonin (5-HT ₁₎ receptor agonists, in particular zolmitriptan 10-40 mass parts is preferable with respect to 100 mass parts, and 10-30 mass parts is more preferable.

(E) The citrus flavor component is a component that improves the aftertaste of serotonin (5-HT ₁ ) receptor agonist, particularly zolmitriptan, and the high sweetness sweetener, and further improves the feeling of dosing, It does not adversely affect the stability of serotonin (5-HT ₁ ) receptor agonists, especially zolmitriptan. Examples of the citrus flavor component include citrus-derived essential oils selected from orange, mandarin orange, lemon and grapefruit, or essential oil components thereof. More specifically, orange oil, orange flavor, mandarin oil, mandarin flavor, lemon oil, lemon flavor, lemon powder, grapefruit flavor, grapefruit oil and the like can be mentioned.
The content of the citrus flavor component is preferably 0.1 to 20 parts by mass with respect to a serotonin (5-HT ₁ ) receptor agonist, particularly 100 parts by mass of zolmitriptan, from the viewpoint of ingestion. A mass part is more preferable, and 1-5 mass parts is still more preferable.

The fast-dissolving film agent of the present invention uses an edible water-soluble polymer for the film base because it is fast-dissolving, that is, dissolves within 50 seconds, more preferably within 25 seconds in the oral cavity. Examples of the edible water-soluble polymer include hydroxypropylcellulose (HPC), hydroxypropylmethylcellulose (HPMC), polyvinylpyrrolidone (PVP), hydroxypropylmethylcellulose phthalate (HPMCP), ethylcellulose (EC), methylcellulose (MC), and hydroxypropylmethylcellulose. Acetate succinate (HPMCAS), hydroxyethyl cellulose (HEC) and the like can be used.
In particular, HPC and HPMC are preferable from the viewpoints of solubility or disintegration of the preparation due to moisture in the oral cavity, improvement of the appearance of the preparation, and provision of preparation strength. The viscosity of HPC and HPMC is not particularly limited. For example, in the case of HPC, the kinematic viscosity of a 2% aqueous solution at 20 ° C. is 2.0 to 10 mPa · s, particularly 2.0 to 2.9 mPa · s. In the case of HPMC, a 2% aqueous solution having a kinematic viscosity of 3.0 to 10 mPa · s, particularly 3.0 to 6 mPa · s at 20 ° C. is preferable. Such kinematic viscosity is a value based on the test method described in the 16th revised Japanese Pharmacopoeia.
The content of the edible water-soluble polymer is preferably 10 to 80% by mass and more preferably 20 to 75% by mass with respect to the total amount of the fast-dissolving film agent.

  Moreover, a plasticizer, a stabilizer, a pH adjuster, a corrigent, a disintegrant, an excipient, a colorant and the like can be blended in the fast-dissolving film of the present invention.

  Examples of the plasticizer include triethyl citrate, glycerin, sesame oil, sorbitol, castor oil, propylene glycol, polyoxyethylene polyoxypropylene glycol, polysorbate 80 (polyoxyethylene sorbitan monooleate (20EO)), polyethylene glycol [especially macro Goal 400 (polymerization degree n of oxyethylene unit is 7-9, hereinafter the same), macrogol 600 (n is 11-13), macrogol 1500 (n is 5-6, n is 28-36, etc.) ), Macrogol 4000 (n is 59 to 84), macrogol 6000 (n is 165 to 210)].

  Examples of the corrigent include fennel oil, camphor, peppermint oil, peppermint water, mint, peppermint, menthol and the like.

  The disintegrant is not particularly limited as long as it is commonly used in the technical field and is edible. For example, sugars, carmellose and salts thereof, cellulose, starch, sucrose fatty acid ester, gelatin, sodium bicarbonate , Dextrin, dehydroacetic acid and its salts, povidone, polyoxyethylene hydrogenated castor oil, polyoxyethylene polyoxypropylene glycol, polyoxyethylene sorbitan monooleate (eg, polysorbate), polyethylene glycol (eg, macrogol), anhydrous citric acid An acid etc. are mentioned. These can be used alone or in combination. Among these, saccharides and macrogol are preferably used from the viewpoint of improving disintegration of the preparation and imparting plasticity. The saccharide herein refers to a synthetic or natural sugar substitute having a sweetness level less than 50 times that of sucrose. Examples thereof include sugar, fructose, sorbitol, sucrose, and lactose. These can be used alone or in combination. Among these, mannitol, maltose, maltitol, trehalose, and reduced maltose starch syrup are preferably used from the viewpoint of improving the disintegration property of the preparation.

  The excipient is not particularly limited as long as it is commonly used in the art and is edible. For example, candy powder, starch, fructose, caramel, agar, xylitol, glycerin, paraffin, cellulose, oxidized Examples include titanium, sorbitol, lactose, sucrose, glucose, pullulan, propylene glycol, polyoxyethylene hydrogenated castor oil, polyethylene glycol (for example, macrogol), maltitol, maltose, mannitol, trehalose, malic acid, and the like. These can be used alone or in combination. Among these, titanium oxide, trehalose, and macrogol are preferably used from the viewpoint of improving the appearance of the product and workability during production.

  The colorant is not particularly limited as long as it is commonly used in the technical field and is edible. However, yellow iron sesquioxide, brown iron oxide, caramel, black iron oxide, titanium oxide, iron sesquioxide, tar Examples thereof include dyes, aluminum lake dyes, and copper chlorophyllin sodium. These can be used alone or in combination. Among these, titanium oxide is preferably used from the viewpoint of improving the appearance of the product and the product image.

The structure of the fast dissolving film agent of the present invention may be either a single layer preparation or a multilayer preparation. However, a multilayer preparation in which one or more layers are provided on both sides of the drug layer is preferable in order to suppress the influence of moisture (moisture) and oxygen on the drug.
In particular, a three-layer type preparation in which a coating layer mainly composed of HPMC is provided on both sides of a drug layer mainly composed of HPC is preferable.
The fast-dissolving film agent of the present invention is, for example, a solution prepared by adding an edible polymer to a solution obtained by dissolving or dispersing a drug and other additives in an appropriate solvent such as ethanol, water, and a mixed solvent thereof (preparation solution). ) Is dried to produce an edible film, which is cut into an appropriate size to produce a fast-dissolving film agent.
In the case of a multilayer preparation, a laminated coating drying method in which a preparation solution corresponding to the next layer is coated and dried on a previously prepared edible film, a laminating method in which a separately prepared edible film is bonded, and A multilayer edible film produced by combining these methods can be cut into an appropriate size and produced.
In addition, when layers having the same composition are bonded, one layer is used.

  EXAMPLES Next, an Example is given and this invention is demonstrated still in detail.

(1) Sample preparation Macrogol, acesulfame potassium, aspartame, trehalose hydrate, and orange oil as needed were added to purified water and stirred and dissolved in a solution in which titanium oxide was dispersed in ethanol. Subsequently, hydroxypropyl methylcellulose (HPMC) and orange oil as necessary were added and dissolved by stirring to obtain a coating layer preparation solution.
Zolmitriptan and, if necessary, anhydrous citric acid and calcium chloride dihydrate were added to purified water and dissolved by stirring. Ethanol and hydroxypropyl cellulose (HPC) were added to this solution and dissolved by stirring to obtain a drug layer preparation solution.
On the polyester film, the coating layer preparation liquid was applied and dried to produce a coating layer. Next, the drug layer preparation solution was applied onto the coating layer and dried to produce a two-layer film comprising the coating layer / drug layer.
After making two sets of the two-layer film, they were bonded so that the drug layers were in contact with each other. The bonded material was cut into a predetermined size and used as a sample.
The coating amount of each preparation solution was adjusted so that each component amount in one sample (2.8 cm ² ) was a predetermined amount (mg).

(2) Evaluation of taking feeling One sample was put in the oral cavity and evaluated according to the following score.
That is, two types of unpleasant tastes, i.e., bitterness of the drug (feeling of taking 1) and sweetness (feeling of taking 2) following the taking, were evaluated separately. Furthermore, taking into consideration taking feeling 1 and taking feeling 2 comprehensively, it was evaluated whether or not the preparation was satisfactory.
Satisfaction with a score of “feeling of taking 3” of “◯” or “Δ”.

(3) Stability evaluation Each sample was packaged in aluminum and stored at 60 ° C. for 3 weeks.
The content of zolmitriptan in the preparation after storage was quantified by HPLC method. Further, the amount of N-oxidized product, which is the main decomposition product of zolmitriptan, was also measured as required.
It is desirable that the residual rate of zolmitriptan after storage at 60 ° C. for 3 weeks exceeds 95%.

Test example 1
Table 4 shows the formulation of the preparation examples 1 to 3 (amount in one sheet: mg) and the test results.

  The stability of zolmitriptan was improved by the addition of anhydrous citric acid (Formulation Example 2). Furthermore, the amount of N-oxidant, which is the main decomposition product, was greatly suppressed by adding calcium chloride (Formulation Example 3). However, the feeling of taking these preparations was not satisfactory.

Test example 2
Table 5 shows the formulation of Formulation Examples 4 to 7 (amount in one sheet: mg) and test results.

When orange oil was added as a flavoring agent to Formulation Example 3, the feeling of dosing 1 was improved. This is thought to be due to the slight bitterness of the drug being masked by the flavor of orange oil.
Furthermore, by adjusting the amount of citric anhydride added, a preparation satisfying the feeling of medication and drug stability was obtained.

Claims (10)

(A) Serotonin (5-HT ₁ ) receptor agonist, (B) High sweetness sweetener, (C) Organic acid 20 to 40 parts by mass with respect to 100 parts by mass of serotonin (5-HT ₁ ) receptor agonist , (D) Alkaline earth metal salt and (E) Fast dissolving film agent containing citrus flavor component. (A) The fast dissolving film agent according to claim 1, wherein the serotonin (5-HT ₁ ) receptor agonist is zolmitriptan or a salt thereof.   (B) The fast-soluble film agent according to claim 1 or 2, wherein the high-sweetness sweetener is one or more selected from aspartame, stevia, sucralose, glycyrrhizic acid, thaumatin, acesulfame potassium and saccharin. The content of (B) high-potency sweetener is 10 to 50 parts by mass with respect to 100 parts by mass of (A) serotonin (5-HT ₁ ) receptor agonist. Fast-dissolving film.   (C) Organic acid is a C3-C8 hydroxy acid, The fast-dissolving film agent in any one of Claims 1-4.   (C) Organic acid is anhydrous citric acid, The fast-dissolving film agent in any one of Claims 1-5.   (D) Alkaline earth metal salt is calcium chloride, The fast-dissolving film agent in any one of Claims 1-6. The content of (D) an alkaline earth metal salt, according to any one of the preceding claims from 10 to 40 parts by weight with respect to (A) Serotonin (5-HT ₁₎ receptor agonists 100 parts by Fast-dissolving film.   (E) The fast-dissolving film agent according to any one of claims 1 to 8, wherein the citrus flavor component is a citrus-derived essential oil selected from orange, mandarin orange, lemon and grapefruit or an essential oil component thereof. The content of (E) citrus flavor component is 0.1 to 20 parts by mass with respect to 100 parts by mass of (A) serotonin (5-HT ₁ ) receptor agonist. The fast-dissolving film agent described.