JP2012136512A - Liquid medicine for oral dosing - Google Patents

Abstract

PROBLEM TO BE SOLVED: To prevent stability reduction of triptane caused by blending an acidulant in a liquid medicine for oral dosing containing triptane.SOLUTION: The liquid medicine for oral dosing is obtained by blending triptane or a pharmacologically acceptable salt thereof, at least one acidulant selected from the group consisting of citric acid, malic acid, tartaric acid, lactic acid, and salts thereof, and further tryptophan.

Description

  The present invention relates to an internal liquid preparation containing triptan.

  Triptan is a group of triptan-based serotonin-1 (5-HT1) receptor agonists known as rizatriptan, zolmitriptan, sumatriptan, eletriptan, naratriptan, etc., for the treatment of migraine Excellent effect.

  Among these triptans, immediate effects, efficacy, persistence, etc. differ depending on the pharmacokinetics, and they are properly used for treatment. Here, when compared with the same tablet, Rizatriptan is superior in terms of immediate effect and effectiveness compared to Sumatriptan, which has been used since the oldest, and zolmitriptan is effective at a small dose. It has the feature of exhibiting (Non-Patent Document 1).

  To date, these triptans have been provided as tablets, nasal drops, injections, and the like (Non-Patent Documents 2 to 4), but have not been provided as internal solutions. Therefore, there is a need for an internal liquid preparation containing triptan that is easy to take due to the characteristics of migraine.

  On the other hand, citric acid or a salt thereof, malic acid or a salt thereof, and the like are blended in the internal liquid preparation from the viewpoint of improving the ingestibility, and it is necessary to add these acidulants.

Drugs for migraine (triptan drugs) Pharmaceutical Affairs March 2007 (vol. 49 No. 3) Imigran (registered trademark) 50 Pharmaceutical Interview Form, GlaxoSmithKline Co., Ltd. Published September 2007 (4th revised edition) http://glaxosmithkline.co.jp/club_GSK/if/pdf/imigran_tab.pdf Immigration (registered trademark) Nasal Solution 20 Pharmaceutical Interview Form, GlaxoSmithKline Co., Ltd. Published April 2007 (2nd revised edition) http://glaxosmithkline.co.jp/club_GSK/if/pdf/imigran_nas20.pdf Immigrant (registered trademark) Note 3 Pharmaceutical interview form, GlaxoSmithKline Co., Ltd. Published March 2008 (7th revised edition) http://glaxosmithkline.co.jp/club_GSK/if/pdf/imigran_kit_sci.pdf

  The inventors of the present invention have confirmed that the stability of triptan is reduced when an acidulant such as citric acid is blended with an internal solution containing triptan.

  Therefore, the present invention suppresses a decrease in the stability of triptan that occurs in a triptan-containing oral solution containing one or more acidulants selected from the group consisting of citric acid, malic acid, tartaric acid, lactic acid and salts thereof. Is an issue.

  As a result of intensive studies to solve the above-mentioned problems, the inventors have formulated tryptophan in a triptan-containing internal liquid containing a sour agent, so that the stability of triptan is not mixed with a sour agent. The present inventors have found that the stability is similar to that of an internal solution, and have completed the present invention.

That is, the present invention comprises (1) one or more acidulants selected from the group consisting of triptan or a pharmacologically acceptable salt thereof, citric acid, malic acid, tartaric acid, lactic acid and salts thereof, and tryptophan. A featured oral solution,
(2) The internal liquid preparation according to (1), wherein the triptan is selected from rizatriptan, zolmitriptan, sumatriptan, eletriptan, and naratriptan,
(3) One or more acidulants selected from the group consisting of citric acid, malic acid, tartaric acid, lactic acid and salts thereof are produced when blended into an internal solution containing triptan or a pharmacologically acceptable salt thereof. A method for suppressing a decrease in the stability of triptan by adding tryptophan,
It is.

  By this invention, the fall of the stability of the triptan which arises when an acidulant was mix | blended with the internal use liquid agent containing a triptan was able to be suppressed.

  The triptan in the present invention is a migraine treatment agent Rizatriptan (that is, 3- [2- (dimethylamino) ethyl] -5- (1H-1,2,4-thiazole-1-methyl) indole), migraine Therapeutic agent zolmitriptan (that is, (S) -4-({3- [2- (dimethylaminoethyl)]-1H-indol-5-yl} methyl) -2-oxazolidinone), migraine therapeutic agent sumatriptan (I.e. 3- [2- (dimethylamino) ethyl] -N-methylindole-5-methanesulfonamide), migraine treatment eletriptan (i.e. (+)-(R) -3- (1-methyl) Pyrrolidin-2-ylmethyl) -5- (2-phenylsulfonylethyl) -1H-indole), a migraine treatment agent naratriptan (ie, N-methyl-2- [3- (1-methylpiperidin-4-yl) − H- indol-5-yl] ethanesulfonamide), and the like.

  The pharmacologically acceptable salt in the present invention is acetate, calcium salt, citrate, diethanolamine salt, hydrobromide, hydrochloride, lysine salt, potassium salt, sodium salt, succinate, benzoate. And so on.

  The content (formulation) of triptan or a pharmacologically acceptable salt thereof in the present invention can be appropriately selected and used according to the purpose. For example, it is preferable to contain triptan or a pharmacologically acceptable salt thereof in the range of 0.01 mg / mL to 10 mg / mL.

  The acidulant used in the present invention is a substance used to give acidity in food processing and cooking, and refers to various organic acids and salts thereof. Examples thereof include citric acid, malic acid, tartaric acid and lactic acid, and citric acid, malic acid and tartaric acid are preferred.

  Tryptophan used in the present invention is classified as an aromatic amino acid and is one of essential amino acids.

  The tryptophan used in the present invention is usually a natural L-form, but a non-natural D-form or a mixture of L-form and D-form can also be used.

  The content (mixing) of tryptophan of the present invention is not particularly limited as long as it has an effect of suppressing the decrease in stability of triptan that occurs when the sour agent is blended, but the stability of triptan is maintained. Then, it is 0.05 mass% or more with respect to 1 mass part of triptan, More preferably, it is 0.1 mass part or more.

  The preferred pH of the internal liquid preparation of the present invention is 2.5 to 7.0, more preferred pH is 2.5 to 5.0, and most preferred pH is 2.5 to 4.0. If the pH is less than 2.5, the acidity is too strong, which is not preferable from the standpoint of ingestion, and in the region where the pH exceeds 7.0, the taste is poor and unfavorable in terms of commercial properties. For adjusting the pH, for example, an organic acid such as acetic acid or a salt of the organic acid, an inorganic acid such as phosphoric acid or hydrochloric acid, or an inorganic base such as sodium hydroxide or potassium hydroxide can be used.

  Vitamins, minerals, herbal medicines, herbal extracts and the like can be appropriately added to the internal liquid preparation of the present invention as long as the effects of the present invention are not impaired. In addition, additives such as sweeteners, colorants, fragrances, surfactants, solubilizing agents, preservatives and the like can be appropriately blended as necessary so long as the effects of the present invention are not impaired. These additives and the like may be blended singly or in combination of two or more.

  The method for preparing the internal liquid preparation of the present invention is not particularly limited as long as the effects of the present invention are exhibited. Usually, after dissolving each component with an appropriate amount of purified water, the pH and volume are adjusted to the remaining purified water. It is the method of adding and adjusting, and filtering and sterilizing as needed. However, in order to maintain the stability of triptan, it is a method of adding an aqueous solution in which acidulant is dissolved in an aqueous solution in which triptan and tryptophan are dissolved, and then mixing to prepare an internal solution, or dissolving tryptophan and acidulant. A method in which an aqueous solution in which triptan is dissolved is added to the prepared aqueous solution and then mixed is preferable.

  The internal use liquid preparation of the present invention can be provided as, for example, pharmaceutical products such as syrups and drinks and designated quasi drugs.

  Hereinafter, the present invention will be described in more detail with reference to test examples and the like, but the present invention is not limited to these examples and the like.

Test Example (1) Preparation of each internal liquid solution Each component of the formulation described in Tables 1 to 3 was weighed and dissolved in purified water so that the pH was 2.5, 4.0 and 5.0, and The total amount of liquid for internal use was adjusted to 10 mL. Then, it filled into the glass bottle, the cap was given, and the internal use liquid agent of Examples 1-9 of this invention and Comparative Examples 1-12 was obtained.

(2) Test method Rizatriptan-containing oral solution containing the compositions shown in Examples 1 to 9 and Comparative Examples 1 to 10 described in Tables 1 and 2 was stored in a thermostatic bath at 65 ° C. for 14 days, and the reza in the internal solution. Triptan content was measured by HPLC. Risatriptan content (residual rate) in the internal liquid after storage at 65 ° C. for 14 days was calculated with respect to the content of rizatriptan in the internal liquid immediately after dissolving rizatriptan benzoate. Moreover, the sumatriptan and the zolmitriptan containing internal solution containing the composition shown in Examples 10 to 11 and Comparative Examples 11 to 12 in Table 3 were stored in a thermostatic bath at 65 ° C. for 14 days, and the sumatriptan and sol in the internal solution were used. Mittriptan content was measured by HPLC. Sumatriptan and zolmitriptan content in internal solution after storage at 65 ° C. for 14 days, compared to the content of sumatriptan and zolmitriptan in internal solution immediately after dissolving sumatriptan and zolmitriptan succinate (Remaining rate) was calculated. The results are shown in Tables 1-3.

(3) Results From the experimental results shown in Tables 1 and 2, it was found that in Comparative Example 1 in which citric acid was blended, the residual rate of rizatriptan in the oral solution after storage at 65 ° C. for 14 days was low. However, in Examples 1-5 which mix | blended tryptophan, it turned out that the fall of the stability of the rizatriptan in the internal use liquid agent which arises when a citric acid is mix | blended can be suppressed.

  In Comparative Examples 2 to 6 in which amino acids other than tryptophan were blended, it was not possible to suppress a decrease in the stability of rizatriptan in the oral solution. That is, it has been found that not all amino acids suppress the decrease in the stability of rizatriptan in the oral solution.

  In Comparative Examples 7 to 8 in which malic acid or tartaric acid was blended, it was found that the residual rate of rizatriptan in the internal solution after storage at 65 ° C. for 14 days was low. However, in Examples 6-7 which mix | blended tryptophan, it turned out that the fall of the stability of the rizatriptan in the internal use liquid agent which arises when malic acid or tartaric acid is mix | blended can be suppressed.

  Also in Comparative Examples 9 to 10 in which citric acid was blended and the pH was adjusted to 2.5 and 5.0, respectively, it was found that the residual ratio of rizatriptan in the oral solution after storage at 65 ° C. for 14 days was low. It was. However, in Examples 8 to 9 in which tryptophan was blended, it was found that the decrease in the stability of rizatriptan in the internal liquid preparation that occurs when citric acid was blended could be suppressed even at the corresponding pH.

  From the experimental results shown in Table 3, from the results of Comparative Examples 11-12, the sumatriptan and zolmitriptan compounded internal solution containing citric acid were stored at 65 ° C. for 14 days, and then the sumatriptan and zolmi in the internal solution were used. It was found that the residual rate of triptan was lowered. However, in Examples 10 to 11 using tryptophan, it was found that the decrease in the residual ratio of sumatriptan and zolmitriptan in the oral solution was suppressed despite the addition of citric acid.

  According to the present invention, it has become possible to produce a triptan-containing internal liquid preparation that can be stored for a long period of time. Therefore, it is expected that a triptan-containing internal liquid preparation with high commercial properties will be provided in the fields of pharmaceuticals and designated quasi drugs. The

Claims (3)

  An internal liquid preparation comprising triptan or a pharmacologically acceptable salt thereof, one or more acidulants selected from the group consisting of citric acid, malic acid, tartaric acid, lactic acid and salts thereof, and tryptophan.   The internal liquid preparation according to claim 1, wherein the triptan is selected from rizatriptan, zolmitriptan, sumatriptan, eletriptan, and naratriptan.   Stabilization of triptan that occurs when one or more acidulants selected from the group consisting of citric acid, malic acid, tartaric acid, lactic acid and salts thereof are added to an internal solution containing triptan or a pharmacologically acceptable salt thereof. The method of suppressing a fall of property by mix | blending tryptophan.