JP2007269786A - Pantethine-containing oral liquid preparation - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a new oral liquid preparation containing pantethine. <P>SOLUTION: It has been newly found that a stable pantethine-containing oral liquid preparation can be obtained by adding a specific pH adjuster to a pantethine-containing solution to adjust the pH of the solution to 4-6. Thereby, such stable pantethine-containing oral liquid preparations, for example, nutritional fortifier can be provided. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

The present invention relates to an oral liquid preparation containing pantethine.

Pantethine is (1) prevention and treatment of pantothenic acid deficiency, (2) consumable diseases, hyperthyroidism, maternal and breastfeeding demand for pantothenic acid is increased, and intake from the diet is insufficient Supplementation, (3) hyperlipidemia, flaccid constipation, prevention and treatment of side effects caused by streptomycin and kanamycin, acute / chronic eczema, improvement in platelet count and bleeding tendency in blood disorders, pantothenic acid deficiency or metabolic disorder It is a useful drug used at 30 to 600 mg (in the case of internal use) per day when it is estimated to be involved. (See Non-Patent Document 1)
Panthetin is an amorphous powder if it is in an anhydrous state at room temperature. However, since it has high hygroscopicity, it cannot maintain the powder state and is in the form of a bowl. For this reason, pantethine is provided as a viscous liquid, and panthetin in the Japanese Pharmacopoeia is an aqueous solution containing 80% pantethine and is a colorless to slightly yellow clear viscous liquid. However, the 80% pantethine solution is an aqueous solution, and thus has a known problem that it is not always good in storage stability.

  For this reason, most of the preparations containing pantethine are conventionally solid preparations not affected by moisture. For solid preparation of pantethine, 80% pantethine aqueous solution is used, mixed with a large amount of excipients such as saccharides, starches, celluloses, etc., dried, and then powdered, fine granules, granules, tablets, capsules Attempts have been made to use it as an agent.

However, these solid preparations have a problem that they are difficult to take in children, elderly people and the like. For this reason, there has been a strong demand for the development of oral liquids or syrups containing pantethine from the standpoint of immediate effect and ease of taking, but there is no satisfactory oral liquid at present.
So far, a liquid preparation containing pantethine, a pH adjusting agent added, and an injection having a pH of 4.2 to 5.2 has been disclosed (see Non-Patent Document 2), but it is not an oral preparation. It is not something that can be taken.
An oral solution containing pantethine and pravastatin is disclosed (see Patent Document 1 (Table 7)), but does not contain a pH adjuster or the organic acid of the present invention.

JP 2002-249431 A Japan Pharmaceutical Information Center, Japan Medical Drug Collection 2006, pages 1708 to 1709 10% of pantethine injection "Kobayashi" package insert

The present invention relates to an oral solution that is easy to take and contains pantethine stably, and a method for stabilizing pantethine in an oral solution.

  As a result of diligent research, the present inventors can obtain a pantetin-containing oral liquid that is easy to take and is stable by adding a specific pH adjuster to a solution containing pantethine and adjusting the pH to 4 to 6. The present invention has been completed by finding out what can be done.

That is,
1. A pantethine-containing oral solution characterized by containing a specific pH regulator;
2. A pantethine-containing oral solution characterized by containing a specific pH regulator and being adjusted to pH 4-6,
3. The pantethine-containing oral solution according to 1 or 2, wherein the specific pH adjuster is an edible acid or a salt thereof,
4). The pantethine-containing oral solution according to 3, wherein the edible acid or a salt thereof is an organic acid or a salt thereof,
5). The pantethine-containing oral solution according to 4, wherein the organic acid or a salt thereof is an oxyacid or a salt thereof,
6). The pantethine-containing oral solution according to 5, wherein the oxyacid or a salt thereof is one or more selected from the group consisting of citric acid, tartaric acid, malic acid and salts thereof,
7). The pantethine-containing oral solution according to any one of 1 to 6, wherein the pantethine content is 30 to 600 mg,
8). A method for stabilizing a pantethine-containing oral solution characterized by adding a pH regulator and adjusting the pH to 4 to 6.

  According to the present invention, a stable pantethine-containing oral solution can be provided. For example, it is possible to provide a prophylactic and / or therapeutic drug containing pantethine for patients with pantothenic acid deficiency or metabolic disorders.

  The pantethine ((R, R) -bis (N-pantothenyl-2-aminoethyl) disulfide) according to the present invention is a known compound, and as a method for obtaining it, a commercially available product may be used. It is also possible to manufacture based on the method.

  In general, the dose of pantethine according to the present invention may be appropriately determined depending on the sex, age, symptoms, etc. of the patient to be administered, and the daily dose of pantethine is preferably 5-1200 mg, more preferably 30-600 mg. 60 to 600 mg is particularly preferable. Therefore, the pantethine-containing oral solution of the present invention may be formulated so that preferably 5 to 1200 mg, more preferably 30 to 600 mg, particularly preferably 60 to 600 mg per day as pantethine can be taken. The concentration of pantethine in the containing oral solution is not particularly limited. However, the pantethine-containing oral liquid of the present invention is preferably 10 to 200 mL, more preferably 30 to 100 mL, as the amount of liquid taken per day.

  The specific pH adjuster according to the present invention is preferably an edible acid or a salt thereof. Examples of the edible acid or salt thereof according to the present invention include an organic acid or a salt thereof, or an inorganic acid or a salt thereof.

  Examples of the organic acid according to the present invention include oxyacids such as citric acid, tartaric acid, malic acid, lactic acid, and glycolic acid, mono- or dicarboxylic acids such as acetic acid, adipic acid, succinic acid, maleic acid, and fumaric acid, ascorbic acid Erythorbic acid or a salt thereof. Moreover, as an inorganic acid concerning this invention, hydrochloric acid, phosphoric acid, etc. can be mentioned, for example. The specific pH adjuster according to the present invention is preferably an organic acid or a salt thereof, more preferably an oxyacid or a salt thereof, and one or more selected from the group consisting of citric acid, tartaric acid and malic acid. Particularly preferred. Examples of the salts of organic acids and inorganic acids listed above include pharmaceutically acceptable salts such as alkali metal salts such as sodium and potassium, and alkaline earth metal salts such as calcium and magnesium. . Among these, sodium salt or potassium salt is preferable. The specific pH adjuster according to the present invention can be used alone or in combination.

  Further, the content of the specific pH adjuster in the pantethine-containing oral liquid preparation of the present invention is not particularly limited, but when the pH adjuster is an edible acid or a salt thereof, it is 0.01 in terms of edible acid. It is preferable that it is -20W / W%, and it is more preferable that it is 0.1-5W / W%. It is possible to stabilize the pantethine-containing oral solution by adding the pH regulator to the pantethine-containing oral solution and adjusting the pH of the pantethine-containing oral solution to preferably 3 to 7, more preferably 4 to 6. it can.

  Moreover, what adjusted the pH of the solution containing pantethine to 4-6 also has the effect that it becomes easy to drink, without feeling the gut taste and strong acidity in the case of an oral liquid preparation.

  The pantethine-containing oral liquid preparation of the present invention can contain a medicinal component other than pantethine depending on the application. Medicinal active ingredients that can be added to the pantethine-containing oral drug of the present invention include, for example, vitamins, antihistamines, antitussives, antipyretic analgesics, sympathomimetic drugs, central nervous stimulants, anti-inflammatory drugs, local anesthetics, bactericides Include, but are not limited to, antacids, antacids, digestives, gastric mucosal repairs, analgesics and antispasmodics, constipation, psychotropic, ulcer, and herbal medicines. The medicinal component is not particularly limited as long as it does not affect the effects of the present invention, and a taste component, health food component, dietary supplement component and the like may be blended in place of the medicinal component.

  Further, in the present invention, additives usually added to oral liquids, such as stabilizers, antioxidants, colorants, surfactants, fragrances / fragrances, emulsifiers, solubilizers, preservatives, sweeteners An agent, a corrigent, a preservative, a refreshing agent, a solubilizing agent, a solvent, a buffering agent, a suspending agent, a thickening agent, a bitterness masking agent and the like can be blended as necessary. These additives may be used alone or in combination of two or more.

  There is no restriction | limiting in particular as a preparation method of the pantethine containing oral solution of this invention, It can prepare using a well-known means. Usually, each component and a part of a solvent such as purified water are mixed and dissolved, and the remaining solvent is added to adjust the liquid volume. In addition, when the liquid agent of the present invention contains a component hardly soluble in water or a component insoluble in water, the above-mentioned appropriate surfactant, solubilizer, emulsifier, suspending agent, etc. should be added. Can be solubilized, emulsified, suspended or the like. In addition, if necessary, a solvent such as purified water may be heated at the time of dissolution in accordance with a known method for preparing an oral solution. In the preparation, the fragrance and fragrance may be added at the final stage of preparation so as not to impair the flavor, and the preparation liquid may be subjected to filtration and sterilization treatment. The present invention can be used as various beverages such as drinks, syrups, extracts, elixirs, limonades and functional beverages.

  Hereinafter, the present invention will be described with reference to examples and test examples.

(Test Example 1) (Panthetin stability)
1. 1. Preparation of pH buffer 1-1. Preparation of pH 1.5 and 2.0 Buffer Solutions Each buffer solution was prepared by adjusting to pH 1.5 and pH 2.0 using 0.2 mol / L hydrochloric acid and 0.2 mol / L potassium chloride.

1-2. Preparation of pH 3.0, 4.0, 5.0, 6.0, 7.0 Buffers Using 0.1 mol / L citric acid and 0.5 mol / L disodium hydrogen phosphate, pH 3.0, pH 4 The pH was adjusted to 0.0, pH 5.0, pH 6.0, and pH 7.0 to prepare respective buffers.

2. Preparation of sample solution About 50 mg of 80 W / W% pantethine solution was accurately weighed and dissolved by adding the above pH 1.5 buffer solution, and further pH 1.5 buffer solution was added to make exactly 100 ml. About 20 ml of the obtained solution was filled in a 20 ml ampule and melted to prepare a pH 1.5 sample solution. Sample solutions of pH 2.0, pH 3.0, pH 4.0, pH 5.0, pH 6.0, and pH 7.0 were similarly prepared.

3. Storage conditions, storage period and panthetin content measurement method Each sample solution is stored at 40 ° C. for 7 days, 14 days, 1 month, 2 months, 6 months, and at 50 ° C. for 7 days, 14 days. The sample was stored for 1 month, and the content of pantethine in the sample solution after the storage period was measured by liquid chromatography.

Test conditions Detector: Ultraviolet absorptiometer Column: A stainless tube having an inner diameter of 4.6 mm and a length of 15 cm is filled with 5 μm of octadecylsilylated silica gel for liquid chromatography.
Column temperature: constant temperature around 40 ° C. Mobile phase: 0.05 mol / L potassium dihydrogen phosphate solution / acetonitrile mixture (6: 1) at pH 3.5
Flow rate: Adjusted so that the retention time of pantethine is about 13 minutes.

4). Stability of pantethine in each pH sample solution Table 1 shows the pantethine content in each pH sample solution stored at 40 ° C and Table 2 shows the case stored at 50 ° C.
In addition, since pantethine decomposition | disassembly follows a primary reaction, the reaction rate constant (k) was computed by the following primary reaction rate formula, and also the logarithm value (log (k)) of the reaction rate constant was computed.

k = 2.303 / t × logC ₀ / C
t: days elapsed (days)
C ₀ : Content at start (%)
C: Content at the start of time (%)

ND: Below content detection limit k: Reaction rate constant-: Not measured or not calculated

5). pH Profile FIG. 1 shows the relationship between logk representing the degradation rate of pantethine in the sample solution and pH of the sample solution described in Tables 1 and 2. From FIG. 1, it was found that the stability of pantethine in an aqueous solution depends on pH, and the most stable pH range is pH 4-6.

(Test Example 2) (Sensory test)
1. Preparation of sample solution 1) 0.1 mol / L organic acid solution of pH 5.0 (1) Acetic acid-sodium acetate, (2) Citric acid-sodium citrate, (3) DL-malic acid-DL-sodium malate, (4) Using tartaric acid-sodium tartrate, a 0.1 mol / L organic acid solution having a pH of 5.0 was prepared.

2) Organic acid solution containing pantethine 75 mg of 80 W / W% pantethine solution (60 mg as pantethine) was added to each 0.1 mol / L organic acid solution of pH 5.0 to make 50 ml.

2. Test Method Sensory tests were conducted on odor and taste in 2 healthy adult men and 3 women. After rinsing the oral cavity with water, the sample solution was included in the oral cavity and evaluated for odor and taste.

3. Test results The test results are shown in Table 3.

  From Table 3, it was found that the solution obtained by adding acetic acid to pantethine has a strong acetic acid odor and is not preferable as an oral solution. Although citric acid and malic acid feel a slight odor, it was found from the results of comprehensive judgment that citric acid, malic acid and tartaric acid are preferable as an oral solution. As a result, it was found that adding citric acid, malic acid or tartaric acid to the pantethine-containing oral solution is preferable as an oral solution.

(Formulation example)
The following components and amounts were taken and mixed and dissolved to obtain a pantethine oral-containing solution.
80W / W% pantethine solution 75mg
(60mg as pantethine)
Koujin extract 240mg
(1000mg as the drug substance)
Gourd tincture 0.5mL
(5mg as the drug substance)
Hampi tincture 0.5mL
(100mg as the drug substance)
Ikari grass extract 50mg
(500mg as an active ingredient)
Pyridoxine hydrochloride 50mg
Nicotinamide 30mg
Honey 2500mg
Glycerin 800mg
Powdered reduced maltose water candy 2500mg
dl-malic acid 80mg
Sodium citrate proper amount sodium benzoate 21mg
Butyl paraoxybenzoate 3.5mg
Alginate propyl glycol ester 60mg
Polyoxyethylene hydrogenated castor oil 60 150 mg
Fragrance Trace purified water Total volume 30mL
pH 5.0

  According to the present invention, a stable pantethine-containing oral solution can be provided. For example, it is possible to provide a preventive and / or therapeutic solution that is easy to take for patients with pantothenic acid deficiency or metabolic disorders.

It is the graph which showed the relationship between logk showing the degradation rate of pantethine, and pH of a pantethine containing oral solution.

Claims (8)

A pantethine-containing oral solution characterized by containing a specific pH regulator. A pantethine-containing oral liquid preparation characterized by containing a specific pH regulator and being adjusted to pH 4-6. The pantethine-containing oral solution according to claim 1 or 2, wherein the specific pH adjusting agent is an edible acid or a salt thereof. The pantethine-containing oral solution according to claim 3, wherein the edible acid or a salt thereof is an organic acid or a salt thereof. The pantethine-containing oral solution according to claim 4, wherein the organic acid or a salt thereof is an oxyacid or a salt thereof. The pantethine-containing oral solution according to claim 5, wherein the oxyacid or a salt thereof is one or more selected from the group consisting of citric acid, tartaric acid, malic acid and salts thereof. The pantethine-containing oral solution according to any one of claims 1 to 6, wherein the pantethine content is 30 to 600 mg. A method for stabilizing a pantethine-containing oral solution, characterized by adding a pH regulator and adjusting the pH to 4-6.