JP2015229664A - Meclizine-containing pharmaceutical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To improve the storage stability of a composition comprising a combination of meclizine hydrochloride and antacid.SOLUTION: An oral composition comprises (A) meclizine hydrochloride, (B) hydrogencarbonate and/or carbonate, and (C) at least one selected from the group consisting of citric acid, succinic acid, adipic acid, malic acid and salts thereof.

Description

  The present invention relates to a pharmaceutical composition containing meclizine hydrochloride.

Meclizine hydrochloride is a known antihistamine represented by the following formula (I), and exhibits antiallergic action and the like based on its H1 receptor antagonistic action. In addition, meclizine hydrochloride is widely used as an antipruritic agent because it is thought to prevent or alleviate symptoms such as nausea, vomiting, and dizziness in motion sickness by inhibiting the vestibule-autonomic nerve reflex in the inner ear and the central inhibitory effect on vomiting. (Non-Patent Document 1).

  In the case of meclizine hydrochloride, which is an antipruritic agent, in order to complement the action of meclizine hydrochloride, antacids such as bicarbonates and carbonates that are expected to help reduce stomach discomfort such as nausea and vomiting are further added. Formulated formulations are also being considered.

Pharmaceutical Manual 5th edition, Osaka Hospital Pharmacists Association, Pharmaceutical Industry Times, April 1992

  An object of the present invention is to improve the stability which is a concern with a pharmaceutical composition containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate, and is excellent in stability over a long period of time. Is to provide.

  The present inventor tried a short-term storage stability test under accelerated conditions in a mixed composition of (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate. Compared to a single product, it was found that the mixed composition deteriorated in properties and the like and significantly decreased the content of meclizine, which is an active ingredient. As a result of diligent studies to suppress such a decrease in stability, (C) ciclic acid, succinic acid, adipic acid, (C) ciclic acid, succinic acid, adipic acid, By containing one or more selected from the group consisting of malic acid and their salts, a pharmaceutical composition containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate can be used for a long time. The present invention has been completed.

  That is, the present invention provides a pharmaceutical composition listed below, or (A) a stability improving agent for a pharmaceutical composition containing meclizine hydrochloride and (B) bicarbonate and / or carbonate, and (A) meclizine hydrochloride. (B) It relates to a method for improving the stability of a pharmaceutical composition containing hydrogen carbonate and / or carbonate.

The present invention provides the following compositions, methods and the like.
[Item 1] One selected from the group consisting of (A) meclizine hydrochloride, (B) bicarbonate and / or carbonate, and (C) citric acid, succinic acid, adipic acid, malic acid and salts thereof, or An oral composition containing two or more kinds.

  [Item 2] Item (B) wherein the bicarbonate and / or carbonate is magnesium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, and / or ammonium carbonate. The oral composition according to 1.

  [Item 3] Item 1 or Item 2, wherein the total amount of (B) bicarbonate and / or carbonate is 0.1 to 20 parts by weight per 1 part by weight of (A) meclizine hydrochloride Oral composition.

  [Claim 4] (A) The total amount of one or more selected from the group consisting of (C) citric acid, succinic acid, adipic acid, malic acid and salts thereof is 0. Item 4. The oral composition according to any one of Items 1 to 3, wherein the composition is 02 to 4 parts by weight.

  [Item 5] The oral composition according to any one of Items 1 to 4, wherein the daily dose is (A) 15 to 75 mg of meclizine hydrochloride.

  [Item 6] The daily dose is (A) meclizine hydrochloride 15 to 75 mg, (B) bicarbonate and / or carbonate total amount 5 to 1000 mg, (C) citric acid, succinic acid, adipic acid, Item 6. The oral composition according to any one of Items 1 to 5, wherein the total amount is 1 to 200 mg of one or more selected from the group consisting of malic acid and salts thereof.

  [Item 7] The oral composition according to any one of Items 1 to 6, wherein the oral composition is a tablet (including chewable tablets), a powder, a granule, or a capsule.

  [Item 8] (C) Citric acid, succinic acid, adipic acid used to suppress discoloration of a pharmaceutical composition containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate Discoloration inhibitor consisting of one or more selected from the group consisting of malic acid and salts thereof.

  [Item 9] (C) Citric acid, succinic acid, adipine used to improve the fluidity of a pharmaceutical composition containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate A fluidity improver comprising one or more selected from the group consisting of acids, malic acid and salts thereof.

  [Item 10] (C) Citric acid, succinic acid, adipic acid used for suppressing the odor of a pharmaceutical composition containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate An odor suppressor comprising one or more selected from the group consisting of malic acid and salts thereof.

  [Item 11] A method for improving the stability of a pharmaceutical composition containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate, wherein (C) citric acid, succinic acid, adipic acid 1 or 2 or more types chosen from the group which consists of malic acid and those salts are added.

  The pharmaceutical composition of the present invention suppresses changes in the color, odor, and fluidity of a pharmaceutical composition containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate as shown in Examples below. It is useful as a pharmaceutical composition containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate that can be stored for a long period of time.

  “Meclizine hydrochloride” used in the present invention is a compound known as an antihistamine, and may be synthesized by a known method or obtained as a commercial product. The content of meclizine hydrochloride per dosage unit is 10 to 50 mg, and the daily dosage is 15 to 75 mg.

The “bicarbonate” used in the present invention is also referred to as bicarbonate, and refers to a pharmaceutically acceptable salt obtained from bicarbonate ion and alkali metal ion, alkaline earth metal ion, ammonium ion and the like. Specific examples include sodium hydrogen carbonate, potassium hydrogen carbonate, calcium hydrogen carbonate (Ca (HCO ₃ ) ₂ ), ammonium hydrogen carbonate (NH ₄ HCO ₃ ), and preferably sodium hydrogen carbonate and potassium hydrogen carbonate. Can be mentioned.

The “carbonate” used in the present invention refers to a pharmaceutically acceptable salt obtained from carbonate ion and alkali metal ion, alkaline earth metal ion, ammonium ion or the like. Specific examples include magnesium carbonate, sodium carbonate, potassium carbonate, calcium carbonate, ammonium carbonate ((NH ₄ ) ₂ CO ₃ ), and preferably magnesium carbonate and calcium carbonate.

  The “salts” in the “citric acid, succinic acid, adipic acid, malic acid and salts thereof” used in the present invention means the pharmaceuticals of the acids mentioned here and alkali metals or alkaline earth metals. In particular, sodium salts, potassium salts, calcium salts, and magnesium salts are preferable, and sodium salts are preferable.

  The “oral composition” used in the present invention intends a pharmaceutical composition including a solid pharmaceutical preparation for oral use, and specifically, powders, powders, fine granules, granules, dry syrups. Pills, troches, tablets [including plain tablets, sugar-coated tablets, intraoral quick disintegrating tablets, chewable tablets (chewable tablets), effervescent tablets, film-coated tablets, etc.], capsules, etc., preferably tablets (chewable Tablets), powders, granules, capsules (including hard capsules and soft capsules).

  In the present invention, the blending amount of (B) bicarbonate and / or carbonate is not particularly limited as long as it is a pharmaceutically used amount, but with respect to 1 part by weight of meclizine hydrochloride, (B) bicarbonate and / or The total amount of carbonate is 0.1 to 20 parts by weight, preferably 0.1 to 5 parts by weight, and more preferably 0.1 to 1 part by weight.

  In the present invention, (C) the amount of one or more selected from the group consisting of citric acid, succinic acid, adipic acid, malic acid and salts thereof is not particularly limited as long as it is a pharmaceutically used amount. However, the total amount of one or more selected from the group consisting of (C) citric acid, succinic acid, adipic acid, malic acid and salts thereof is 0.02 to 4 wt. Parts, preferably 0.02-2 parts by weight, more preferably 0.02-1 parts by weight. Moreover, (B) 1 type or 2 types chosen from the group which consists of (C) citric acid, succinic acid, adipic acid, malic acid, and those salts with respect to 1 weight part of total amounts of hydrogencarbonate and / or carbonate The total amount is 0.001 to 40 parts by weight, preferably 0.008 to 40 parts by weight, and more preferably 0.01 to 5 parts by weight.

  The daily dose of the oral composition in the present invention is determined by the dose of meclizine hydrochloride, and is appropriately set depending on the form, administration method, administration purpose, and age, weight, and symptom of the recipient of the composition. Is done. In addition, the oral administration of the pharmaceutical composition of the present invention may be performed once per day or divided into several times within a desired dose range, and administered before meals, between meals, after meals, or simultaneously with meals. May be. When the oral composition is used as an antipruritic agent, it is particularly preferable to administer the composition before boarding a ship (particularly between 1 hour before the boarding ship and the boarding ship), during the boarding ship, or when drunk on a vehicle. In addition, the term “administration” in the present specification is intended to include “taking”. The terms in this specification may be used interchangeably with “oral administration” and “internal use”. Preferably, it is selected from the group consisting of (A) meclizine hydrochloride 15 to 75 mg, (B) bicarbonate and / or carbonate 5 to 1000 mg, (C) citric acid, succinic acid, adipic acid, malic acid and salts thereof. The total amount of one or two or more is 1 to 200 mg, more preferably (B) bicarbonate and / or carbonate 5 to 250 mg, (C) citric acid, succinic acid, adipic acid, malic acid and salts thereof The total amount of one or more selected from the group consisting of 2 to 200 mg.

The present invention may further contain other medicinal ingredients. The kind of such component is not particularly limited, and examples thereof include parasympathetic blockade, antispasmodic, antiemetic, sedative, and cardiotonic diuretic. Examples of suitable components in the present invention include the following components. Two or more of these may be included.
Parasympathetic blockade: for example, scopolamine hydrobromide, oxyphencyclimine hydrochloride, dicyclomine hydrochloride, methixene hydrochloride, methyl atropine bromide, methyl anisotropine bromide, methyl-1-hyostiamine bromide, methyl benactyl bromide Palladium, belladonna extract, isopropamide iodide, diphenylpiperidinomethyldioxolane iodide, funnel extract, etc.
Antispasmodic: for example, papaverine hydrochloride.
Antiemetics: for example, ethyl aminobenzoate, cerium oxalate, piperidylacetylaminoethyl ethylbenzoate and the like.
Sedatives: for example, allyl isopropyl acetylurea, bromovalerylurea, etc.
Cardiac diuretics: For example, caffeine, citrate caffeine, anhydrous caffeine, aminophylline, diprofylline, theophylline and the like.

  In the present invention, a sweetening component and a refreshing component may be contained to alleviate the bitterness. Examples of the sweetening component and the refreshing component include sugar, sugar alcohol, mint oil, mint water, dl-menthol, and l-menthol, and may contain two or more thereof.

The oral composition of the present invention is a conventional ingredient used for quasi-drugs, pharmaceuticals, foods, etc. as other pharmaceutical ingredients other than those described above, such as disintegrants, excipients, binders, lubricants. , Antioxidants, coating agents, coloring agents, flavoring agents, plasticizers, sweeteners, fragrances, solvents, pH adjusters, suspending agents, antifoaming agents, thickening agents, solubilizing agents, sustaining agents, stability A (chemical) agent, a chelating agent, a reducing agent, a fluidizing agent, a brightening agent, a surfactant, a solubilizing (chemical) agent, and the like may be contained.
Specific examples of conventional components that can be arbitrarily blended are shown below, but the components used in the present invention are not limited thereto.

  Disintegrators: starches (corn starch, potato starch, hydroxypropyl starch, sodium carboxymethyl starch, partially pregelatinized starch, etc.), celluloses (carboxymethylcellulose calcium, crystalline cellulose, hydroxypropylcellulose, low-substituted hydroxypropylcellulose, carmellose) , Carmellose calcium, croscarmellose sodium, etc.) and plasma silicic acid. In the present invention, corn starch, hydroxypropyl cellulose, crystalline cellulose, light anhydrous silicic acid and the like are preferably used.

  Excipients: sugars such as glucose, sucrose, lactose, fructose, crystalline cellulose, carmellose sodium, calcium hydrogen phosphate, wheat starch, rice starch, corn starch, potato starch, dextrin, β-cyclodextrin, light anhydrous silicic acid , Titanium oxide, magnesium aluminate metasilicate, talc, kaolin, etc.

  Binder: Cellulose derivatives (methylcellulose, ethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, etc.), polyvinylpyrrolidone, polyvinyl alcohol, acrylic polymer, gelatin, gum arabic, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, Alginic acid propylene glycol ester and the like.

Lubricant: stearic acid, magnesium stearate, calcium stearate, polyoxyl stearate, cetanol, talc, hydrogenated oil, sucrose fatty acid ester, dimethylpolysiloxane, beeswax, beeswax, etc.
Antioxidants: Dibutylhydroxytoluene (BHT), propyl gallate, butylhydroxyanisole (BHA), tocopherol, citric acid and the like.

  Coating agent: Hydroxypropyl methylcellulose, hydroxypropylcellulose, methylcellulose, ethylcellulose, hydroxypropylmethylcellulose phthalate, hydroxypropylmethylcellulose acetate succinate, carboxymethylethylcellulose, cellulose acetate phthalate, polyvinyl acetal diethylaminoacetate, aminoalkyl methacrylate copolymer, hydroxypropylmethylcellulose Acetate succinate, methacrylic acid copolymer, polyvinyl acetate diethylaminoacetate, shellac, etc.

Colorant: Food Red No. 2, Food Red No. 3, Food Red No. 102, Food Yellow No. 4, Food Yellow No. 5, Food Blue No. 1, Food Yellow No. 4, Metal Lake, Copper Chlorofin Sodium, Riboflavin, Turmeric Extract Carotene solution.
Flavoring agents: aspartame, ascorbic acid, stevia, menthol, licorice crude extract, simple syrup, etc.

Plasticizer: Triethyl citrate, polyethylene glycol, triacetin, cetanol and the like.
Sweetener: Natural or synthetic sweeteners such as sucrose and aspartame.
Fragrance: camphor, borneol, cinnamaldehyde, etc.

  Solvent: water, ethanol, isopropanol, lauryl alcohol, cetanol, stearyl alcohol, oleyl alcohol, lanolin alcohol, behenyl alcohol, 2-hexyl decanol, isostearyl alcohol, 2-octyldodecanol and the like.

pH adjuster: sodium hydrogen phosphate, dipotassium phosphate, etc.
Suspending agents: kaolin, carmellose sodium, xanthan gum, methylcellulose, tragacanth, etc.
Antifoaming agent: dimethylpolysiloxane, silicon antifoaming agent, etc.
Thickener: xanthan gum, tragacanth, methylcellulose, dextrin, etc.
Solubilizer: ethanol, sucrose fatty acid ester, macrogol, etc.

  The blending ratio of the conventional ingredients as described above can be appropriately selected depending on the dosage form, size, use and the like of the oral composition. It may be weight percent.

The oral composition of the present invention is used as a drug based on the medicinal properties of meclizine hydrochloride, which is its medicinal component, and can be used, for example, for prevention and alleviation of dizziness due to motion sickness, nausea and headache.
The oral composition of the present invention can be administered in the same manner as a normal pharmaceutical composition.

Hereinafter, the present invention will be described based on examples, but the present invention is not limited to these examples.
Test Example 1 (Influence on stability by mixing meclizine hydrochloride and antacid)
According to the composition described in Table 1 below, each component was weighed and mixed in a mortar. The obtained mixed powder was filled in 200 mg each in a 10 mL vial (main body: clear glass, lid: none), stored at 40 ° C. and RH 75% for 24 hours, and then observed for properties.
In the property observation, color, fluidity and odor were used as indices, and fluidity was evaluated according to the following criteria. The color difference was measured by SPECTROPHOTOMETER CM-5 (KONICA MINOLTA) to measure the difference between the sample before the start of storage and the sample after storage. The residual ratio of meclizine hydrochloride was calculated by formula 1 after quantifying meclizine hydrochloride in the sample by liquid chromatography.
<Fluidity evaluation criteria>
-: Good fluidity (no caking)
+: Fluidity generally good (slight caking)
++: Can be solved by vibration (caking)
++++: Cannot be solved by vibration (caking)

The results are shown in Table 1. (A) Meclizine hydrochloride and (B) heavy magnesium carbonate alone were odorless and white after storage at 40 ° C./RH 75% / 24 hours, respectively, and were odorless and white (Comparative Examples 1 and 2). ). However, when (A) meclizine hydrochloride and (B) heavy magnesium carbonate were combined, an odor was produced, the color became yellowish and light yellow, and the fluidity also deteriorated (Comparative Example 3).
On the other hand, when diphenidol hydrochloride, which is another drug with the same antihistamine drug, was used instead of meclizine hydrochloride, there was no problem regarding stability even when combined with (B) heavy magnesium carbonate (Comparative Example 4). ). This suggests that the problem caused by the combination with (B) heavy magnesium carbonate does not occur with any antihistamine, but is (A) specific to meclizine hydrochloride.

＜色差変化改善率（％）＞
色差変化改善率（％）は、式３により算出した。

Test Example 2 (Effect of addition of citric acid etc.)
As shown in Table 2 below, a mixture prepared by adding various organic acids to a mixed formulation of meclizine hydrochloride and heavy magnesium carbonate similar to those in Comparative Example 3 was prepared, and the same stability test as in Test Example 1 was performed. The degree of improvement with respect to Comparative Example 3 was evaluated for each of color (visual observation), odor, color difference, and meclizine residual ratio, and the results are shown in Table 2.
<Increase rate of residual rate of meclizine hydrochloride (%)>
Meclizine hydrochloride was quantified by liquid chromatography, the residual ratio of meclizine hydrochloride was calculated by the above formula 1, and the increase rate (%) of the residual ratio of meclizine hydrochloride was calculated by the following formula 2.

<Color difference change improvement rate (%)>
The color difference change improvement rate (%) was calculated by Equation 3.

(A) In response to stability problems caused by combining meclizine hydrochloride and (B) heavy magnesium carbonate, as component (C), citric acid, succinic acid, adipic acid, trisodium citrate, malic acid It was shown that any change in color, fluidity, odor, and meclizine hydrochloride residual ratio was significantly reduced by adding any of (Examples 1 to 5). Moreover, when tartaric acid is blended in place of the component (C) (Comparative Example 4), any change in color, fluidity and odor is not reduced, and (A) meclizine hydrochloride and (B) heavy Stability issues arising from the combination with magnesium carbonate are not simply improved with organic acids, but are specific to citric acid, succinic acid, adipic acid, citric acid, malic acid or salts thereof. It has been suggested.

Test example 3
As shown in Table 3, potassium hydrogen carbonate, which is a component (B) different from Test Examples 1 and 2, was combined with (A) meclizine hydrochloride, and Test Example 2 had an effect of contributing to stability (C). A composition with / without one malic acid component was prepared and tested in the same manner as in Test Example 1 with a storage time of 85 hours. The results are shown in Table 3.
(B) When potassium hydrogen carbonate is blended as the component (Comparative Example 5), the color, fluidity, odor and color difference are changed as in the case of blending magnesium carbonate (Comparative Example 3). It has been suggested that the occurrence of problems related to stability due to the combination with component A) is a common characteristic of carbonates and / or bicarbonates.
The change in color, fluidity and odor caused by the combination of (A) meclizine hydrochloride and (B) potassium bicarbonate is similar to that of (B) magnesium carbonate, in combination with (C) malic acid. It was shown to be significantly reduced (Example 6).

In the following, formulation examples of the present invention according to formulation examples shown in Table 4 below are listed, but the present invention is not limited thereto.

Formulation Examples 1-10
About the prescription examples 1-10 of Table 4, a tablet is manufactured with the direct compression method.

Formulation Examples 11-20
About the prescription examples 1-10 of Table 4, according to a conventional method, a powder is manufactured.

Formulation Examples 21-30
About the formulation examples 1-10 of Table 4, a granule is manufactured with a dry granulation method and it fills with a capsule.

Claims (11)

  (A) meclizine hydrochloride, (B) bicarbonate and / or carbonate, and (C) one or more selected from the group consisting of citric acid, succinic acid, adipic acid, malic acid and salts thereof A composition for oral use.   (B) The bicarbonate and / or carbonate is magnesium carbonate, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, calcium carbonate, and / or ammonium carbonate. Oral composition.   The oral dose according to claim 1 or 2, wherein the total amount of (B) bicarbonate and / or carbonate is 0.1 to 20 parts by weight per 1 part by weight of (A) meclizine hydrochloride. Composition.   (A) The total amount of one or more selected from the group consisting of (C) citric acid, succinic acid, adipic acid, malic acid and salts thereof is 0.02 to 4 wt. The composition for oral administration according to any one of claims 1 to 3, wherein the composition is a part.   The oral dose according to any one of claims 1 to 4, wherein the daily dose is (A) 15 to 75 mg of meclizine hydrochloride.   The daily dose is (A) 15 to 75 mg of meclizine hydrochloride, (B) a total amount of bicarbonate and / or carbonate of 5 to 1000 mg, (C) citric acid, succinic acid, adipic acid, malic acid and those The oral composition according to any one of claims 1 to 5, wherein the total amount is 1 to 200 mg of one or more selected from the group consisting of these salts.   The oral composition according to any one of claims 1 to 6, wherein the oral composition is any one of tablets (including chewable tablets), powders, granules, and capsules.   (C) citric acid, succinic acid, adipic acid, malic acid, and (C) used to inhibit discoloration of pharmaceutical compositions containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate The discoloration inhibitor which consists of 1 type, or 2 or more types chosen from the group which consists of those salts.   (C) Citric acid, succinic acid, adipic acid, malic acid used to improve the fluidity of pharmaceutical compositions containing (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate And a fluidity improver comprising one or more selected from the group consisting of salts thereof.   (C) citric acid, succinic acid, adipic acid, malic acid, and (C) used to suppress the odor of meclizine hydrochloride and (B) pharmaceutical compositions containing bicarbonate and / or carbonate An odor suppressor comprising one or more selected from the group consisting of those salts.   A method for improving the stability of a pharmaceutical composition comprising (A) meclizine hydrochloride and (B) bicarbonate and / or carbonate, comprising (C) citric acid, succinic acid, adipic acid, malic acid and A method comprising adding one or more selected from the group consisting of salts thereof.