JP2011246407A - Oral jelly formulation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To provide an oral jelly formulation having sufficiently high antiseptic properties, a good taste and texture and excellent administration properties.SOLUTION: The oral jelly formulation contains: a gelling agent; 0.005-0.1 wt.% of parabens; and 0.02-0.5 wt.% of benzoic acid or a salt thereof, and has 1,000-3,500 mOsm of an osmotic pressure.

Description

  The present invention relates to an oral jelly agent having excellent antiseptic power and good taste and texture.

Oral jelly preparations do not adhere to the oral cavity or esophagus unlike tablets and capsules, and do not require water at the time of taking, and are excellent in dosage form. In addition, like a powder, it can be taken smoothly without scattering. Furthermore, since the weight and volume can be significantly reduced as compared with so-called drinks, it is excellent in portability.
Oral jelly is a dosage form that can be easily taken even by consumers who have difficulty swallowing solids and liquids due to reduced swallowing function. With the progress of physiological and pathological aging, the elderly suffer a decrease in swallowing function, resulting in trouble when taking medicine (Non-patent Document 1). In addition, a decrease in swallowing function is directly related to prognosis of life such as pneumonia due to aspiration (a part or all of food and drink flows into the airways below the glottis) (Non-patent Document 2). Japanese pneumonia is the fourth most common cause of death by cause of death in Japan, and it is thought that one third to half of this is due to aspiration (Non-patent Document 3).
It is said that in order to prevent aspiration of solid matter or liquid, it is necessary to devise such as adding a thickening or making it into a jelly (Non-Patent Document 4). In medical institutions, it has been reported that jelly-form preparations are useful for improving medication compliance (Non-patent Document 5).

  However, the oral jelly preparation has a problem that its preservative power against various bacteria and molds is weak because the water content is high in order to ensure good dosing from the viewpoint of texture and hardness.

  As a technique related to an oral jelly agent, it contains (a) a sugar, (b) a protein, a peptide or an amino acid, and (c) an electrolyte, substantially does not contain fat, and has an amino acid score of 90 to 100, NPC In nutrition drinks or jelly characterized by having an / N value of 50 to 180, it is known that the osmotic pressure is 200 to 440 mOsm, so that the intestinal tract is not stimulated and the occurrence of diarrhea can be avoided (patent) Reference 1). Moreover, by using sodium-type carrageenan as a jelly agent, a semi-raw jelly with a low water content (water activity of 0.8 or less) and a high sugar concentration (sugar concentration of 70 ° or more) can be obtained (Patent Document 2). By using seed gum as a jelly agent, a gummy jelly having a water activity of 0.6 to 0.8 and a sugar content of 70 to 95 ° can be obtained (Patent Document 3). It is known that a gummy preparation with no fear of microbial growth can be obtained by making gelatin into gelatin, having a water content of 10 to 25% by weight and a water activity at 20 ° C. of 0.7 or less (Patent Document 4) Yes.

  However, regarding the osmotic pressure among the above-mentioned techniques, even if the osmotic pressure of the oral jelly agent is adjusted to 200 to 440 mOsm, sufficient antiseptic power against fungi and mold cannot be obtained. In addition, all other jelly agents fall within the category of gummy preparations having a low water content, and do not have good dosing properties as jelly agents.

On the other hand, for an internal liquid containing an acidic and decomposing drug such as diphenhydramine hydrochloride, the pH is 4 or more, and at least one of benzoic acid and benzoate is 0.01 to 0.5 W / V% (g / 100 mL), By containing 0.005 to 0.05 W / V% (g / 100 mL) of paraoxybenzoic acid alkyl ester having 4 to 6 carbon atoms in the alkyl ester, it has excellent antiseptic power against various fungi and molds and is stable. It is known that it is possible to obtain an internal liquid preparation composition having a high taste and flavor (Patent Document 5).
In addition, it is known that the growth of fermentable yeast is suppressed when the total osmotic pressure of salt, sugar, etc. is about 120 atmospheres or more (about 4800 mOsm or more in terms of ozmol concentration) (Non-patent Document 6). .

JP 2002-315548 A JP 2001-252027 A JP 2001178831 A JP 09-52850 A JP 2003-95933 A

Geriatric Dentistry, 20, 25-33 (2005) BRAIN and NERVE, 591, 1149-1154 (2007) Ms. Nohara, “Recommendations for Food Clinic Diagnosis and Treatment of Ingestion and Swallowing Disorders Useful for Daily Clinical Practice” (2), Osaka Dental Insurance Newspaper, May 15, 2008 Akihiko Ito Masayasu Sugihara, Formulation for the elderly, Monthly Pharmaceutical Affairs, Vol. 37, no. 11 (1995) Kimiko Uchida Hisayo Ota Arisa Matsumoto Hideo Shimohira Hiroshi Uchida, Investigation of dosage forms in Kampo preparations, 1st report, Pharmacy, Vol. 42, no. 11 (1991) Supervised by Taizo Ishii, Practical Encyclopedia of Microorganism Control, First Edition, 1st Edition, P29, 744 (1993)

However, in the oral jelly preparation, at least one of benzoic acid and benzoate is 0.01 to 0.5 W / V% (g / 100 mL), and the alkyl ester alkyl alkyl having 4 to 6 carbon atoms. It has been found that the preservative power against fungi and mold cannot be sufficiently obtained only by adding 0.005 to 0.05 W / V% (g / 100 mL) of the ester. In addition, when the osmotic pressure is increased to 4800 mOsm or more in order to improve the antiseptic power in the oral jelly preparation, it influences the gel structure forming the jelly preparation, resulting in a large amount of water separation, and a texture as a jelly preparation. It turned out to be worse.
Accordingly, an object of the present invention is to provide an oral jelly agent having a sufficiently high antiseptic power, good taste and texture, and good dosing properties.

  Therefore, as a result of various studies to solve the above problems, the present inventor has a high antiseptic power by using parabens and benzoic acid or a salt thereof in combination and adjusting the osmotic pressure to 1000 to 3500 mOsm. The present invention was completed by finding that an oral jelly preparation having good taste, texture and ingestibility can be obtained.

  That is, the present invention contains a gelling agent, 0.005 to 0.1% by weight of parabens, and 0.02 to 0.5% by weight of benzoic acid or a salt thereof, and has an osmotic pressure of 1000 to 3500 mOsm. A jelly agent is provided.

  The oral jelly preparation of the present invention has a high water content, has an excellent antiseptic power against not only bacteria but also fungi and fungi, has a good taste and texture, and has a reduced swallowing function It has a hardness that can be taken even by a person. Therefore, elderly people can take it with peace of mind.

  The oral jelly preparation of the present invention is a gel-form preparation (Nippon Pharmacy Forum JP Forum Vol. 18, No. 4) which is orally administered and has no fluidity. It is a jelly-like preparation that is softer than a so-called gummy and easily breaks in the mouth when it is put in the mouth.

  The oral jelly preparation of the present invention includes (A) a gelling agent, (B) parabens, and (C) benzoic acid or a salt thereof.

  The gelling agent used in the present invention refers to an additive that solidifies a fluid material in a jelly form. A gelling agent added with a gelling agent has elasticity against external stress, and collapses when a stronger stress is applied.

Examples of the gelling agent used in the present invention include agar (including agar powder containing agar powder), carrageenan, carob bean gum (also known as locust bean gum), pullulan, pectin, gelatin, xanthan gum, alginic acid or a salt thereof, gellan gum, Examples include native gellan gum, glucomannan, tara gum, tamarind gum, guar gum, starch phosphate, gum arabic, curdlan, gati gum and the like. Among these, agar, alginic acid or a salt thereof, carob bean gum, xanthan gum and pullulan are preferable from the viewpoint of imparting a good texture and hardness. Furthermore, agar, alginic acid or a salt thereof and carob bean gum are particularly preferable because an oral jelly agent having a good texture and hardness can be easily produced as compared with other gelling agents.
These gelling agents can be compounded by mixing one kind or two or more kinds.

  These gelling agents are contained in the oral jelly preparation of the present invention in an amount of 0.15 to 5% by weight, more preferably 0.3 to 3% by weight, particularly 0.4 to 2 in terms of food texture, feeling of taking and antiseptic power. It is preferable to contain by weight.

  The oral jelly preparation of the present invention contains 0.005 to 0.1% by weight of (B) parabens from the viewpoint of obtaining sufficient antiseptic power. When the content of parabens exceeds 0.1% by weight in an oral jelly preparation, the bitterness becomes remarkably strong, and there is irritation in the oral cavity, and the taste is impaired. On the other hand, if it exceeds 0.1% by weight, a large amount of solubilizers and solubilizing agents are required, leading to a further decrease in taste. Further, when the content of parabens is less than 0.005% by weight, the antiseptic power is remarkably weakened. A more preferable content of parabens is 0.005 to 0.05% by weight.

Parabens used in the present invention are not particularly limited as long as they are used in ordinary foods, pharmaceuticals, or quasi drugs. For example, methyl paraoxybenzoate and paraoxybenzoic acid listed in Japanese Pharmacopoeia Examples include ethyl, propyl paraoxybenzoate, and butyl paraoxybenzoate.
Moreover, it is desirable that the parabens used in the present invention be added after being dissolved by heating in advance. Methyl paraoxybenzoate and ethyl paraoxybenzoate have a relatively good solubility in water compared to propyl paraoxybenzoate and butyl paraoxybenzoate, and the dissolution time during production is propyl paraoxybenzoate and butyl paraoxybenzoate. Compared to, it has advantages such as being short, and is widely used as a preservative for foods, pharmaceuticals or quasi drugs. However, methyl paraoxybenzoate and ethyl paraoxybenzoate have less antibacterial activity than propyl paraoxybenzoate and butyl paraoxybenzoate. In the oral jelly preparation of the present invention, propyl paraoxybenzoate and butyl paraoxybenzoate have strong antibacterial activity and can reduce the amount of addition compared to methyl paraoxybenzoate or ethyl paraoxybenzoate, so there is no bitterness. The feeling of taking is good.

In the oral jelly preparation of the present invention, in addition to parabens, (C) benzoic acid or a salt thereof in an amount of 0.02 to 0.5% by weight can be used to obtain excellent antiseptic power. In the oral jelly preparation of the present invention, when the content of benzoic acid and / or a salt thereof exceeds 0.5% by weight, the taste is impaired. On the other hand, when the content is less than 0.02% by weight, the antiseptic power is remarkably weak. A more preferable content of benzoic acid or a salt thereof is 0.05 to 0.3% by weight.
As a salt of benzoic acid used in the oral jelly preparation of the present invention, sodium benzoate is preferable.

  In addition, the content weight ratio (B: C) of (B) parabens and (C) benzoic acid or a salt thereof in the oral jelly preparation of the present invention is from 1: 100 to the effect of improving antiseptic power and taste. 5: 1 is preferable, and 1: 100 to 2: 1 is more preferable.

The osmotic pressure of the oral jelly preparation of the present invention is 1000 to 3500 mOsm, preferably 1000 to 2500 mOsm, from the viewpoint of antiseptic power against fungi, fungi and the like.
In general, it is known that in a composition having a high osmotic pressure, microbial cells cannot survive and growth is suppressed. For example, the practical use of these techniques is vegetable pickles. It is said that the growth of yeasts (including those with osmotic pressure) is remarkably inhibited when the osmotic pressure is about 120 atmospheres or higher, that is, about 4800 mOsm or higher (Non-patent Document 6).
However, in the case of an oral jelly preparation, when the osmotic pressure is set to 4800 mOsm or more, there is a problem that the gel structure forming the jelly preparation is affected and the texture becomes worse.
If the osmotic pressure is less than 1000 mOsm, sufficient antiseptic power cannot be obtained. On the other hand, when the osmotic pressure exceeds 3500 mOsm, the jelly agent becomes hard and the ingestion property is lowered.
The osmotic pressure is measured according to the 15th revision Japanese Pharmacopoeia General Test Method, Osmotic Pressure Measurement Method (Osmolality Measurement Method). However, the oral jelly agent for measuring the osmotic pressure was dissolved in pre-warmed purified water and diluted 10 times so as not to be affected by the gelling agent.
The osmotic pressure can be adjusted by adjusting the amount of water, sugars, polyhydric alcohols and other components.

  The water content in the oral jelly preparation of the present invention is preferably from 50 to 90% by weight, more preferably from 70 to 90% by weight, particularly preferably from 70 to 80% by weight, from the viewpoint of antiseptic power, ingestibility and texture. . In particular, it is surprising that sufficient antiseptic power can be obtained even with a jelly agent having a high water content of 70% by weight or more.

The oral jelly preparation of the present invention preferably contains a saccharide and / or a polyhydric alcohol from the viewpoints of adjustment of osmotic pressure, adjustment of hardness, taste and texture. Examples of the saccharide include purified sucrose, xylitol, D-sorbitol, dextrin, glucose, fructose-glucose liquid sugar, reduced maltose water candy, maltitol, erythritol and the like. Polyhydric alcohol refers to those excluding sugar alcohols classified as saccharides, and includes glycerin, propylene glycol and the like. In the oral jelly preparation of the present invention, it is particularly preferable to contain both saccharide and polyhydric alcohol from the viewpoint of adjustment of osmotic pressure, adjustment of hardness, taste and texture. Among these, from the viewpoint of the taste and texture of oral jelly, in particular, as sugars, one or more kinds selected from purified sucrose, fructose-glucose liquid sugar and reduced maltose water candy, and as polyhydric alcohol, glycerin It is desirable to use either or both propylene glycol and both.
In addition, 10-40 weight% is preferable in an oral jelly agent from the point of the taste and food texture of an oral jelly agent, and, as for content of saccharides, 10-30 weight% is especially preferable. The content of the polyhydric alcohol is preferably 2 to 15% by weight, particularly preferably 2 to 10% by weight in the oral jelly from the viewpoint of taste and texture.

  The oral jelly preparation of the present invention can contain a medicinal component. Such medicinal ingredients include vitamins and other ingredients. Examples of vitamins include thiamine nitrate, thiamine chloride hydrochloride, fursultiamine hydrochloride, riboflavin phosphate sodium, pyridoxine hydrochloride, cyanocobalamin, nicotinamide, and tocopherol acetate. Other ingredients include Yokuinin extract, Toki-style extract, carrot extract, processed sea bream (aka oxoamidine), kokushi-style extract, guarana extract, royal jelly, seisei-style extract, acetaminophen, chlorpheniramine maleate, lysozyme. Examples include hydrochloride, licorice extract and anhydrous caffeine.

  In addition, the oral jelly preparation of the present invention includes a stabilizer such as sodium edetate, sodium sulfite, and erythorbic acid; a surfactant such as polyoxyethylene polyoxypropylene glycol, polyoxyethylene fatty acid ester, sorbitan fatty acid ester; Solubilizers such as oxyethylene hydrogenated castor oil, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester; buffers such as lactic acid, sodium citrate hydrate, L-glutamic acid; acesulfame potassium, saccharin, stevia extract, sucralose, etc. Sweeteners; citric acid hydrate, DL-malic acid and other sour agents, caramel, chili tincture and other flavoring agents; food red No. 3, coloring agents such as turmeric extract; orange flavor, grapefruit flavor, strawberry flavor, Peach flavor Perfumes such as lemon flavor and yogurt flavor; pH regulators such as phosphoric acid and salts thereof, hydrochloric acid, sodium hydroxide, sodium carbonate hydrate, lactic acid and salts thereof; and dispersants such as ethanol and dextrin .

  The pH of the oral jelly preparation of the present invention is preferably from 3.0 to 7.0, particularly preferably from 3.5 to 5.5, from the viewpoint of stability in the gel state.

In order to produce the oral jelly preparation of the present invention, the above components are usually added and mixed, gelled by an appropriate method, and formed into a certain shape.
The oral jelly preparation of the present invention is dissolved, for example, by adding parabens, sodium benzoate, polyhydric alcohol, saccharide and gelling agent in heated water, and further adding a buffer such as citric acid to dissolve it, After adjusting to the designated pH with a pH adjuster such as sodium hydroxide, make up the volume and mix thoroughly. It can be manufactured by molding it into a certain shape. The temperature of the heated water for dissolving the gelling agent or the like may be 80 ° C. or higher, for example, about 90 ° C.

As described above, the oral jelly preparation of the present invention has good dosing properties and excellent antiseptic power. Here, the oral jelly agent having a good texture in the present invention refers to an oral jelly agent that does not cause water separation upon storage and has good elasticity and hardness when taken.
Oral at 20 ° C ± 2 ° C with reference to the standard value of hardness of Standard Standard II for food for people with difficulty in swallowing as set forth in “No. When the resistance when compressing the jelly agent is 1 × 10 ^{3 to} 1.5 × 10 ⁵ N / m ² , it is an oral jelly agent with good hardness that can be taken with peace of mind even by a consumer with reduced swallowing function .
Although the container filled with the oral jelly agent of the present invention is not particularly limited, an airtight container is usually preferable.
A potion type container, a pouch type container, a three-side seal container, etc. are mentioned. Among these, a small-capacity stick-shaped three-side sealed container is particularly easy to open, easy to take, and the amount remaining in the container after taking is extremely small. Furthermore, it has advantages such as excellent portability.

  EXAMPLES Next, although an Example is given and this invention is demonstrated in detail, this invention is not limited to this.

Examples 1-27 and Comparative Examples 1-18
Parabens were dissolved in purified water heated to about 90 ° C. according to the formulations described in Examples 1 to 26 and Comparative Examples 1 to 18 in Tables 1 to 5. Thereafter, each component was added, dissolved and mixed thoroughly, filled in a single-dose stick-shaped three-sided sealed container, sealed, and cooled to room temperature.
Moreover, about Example 27 of Table 3, it did not melt | dissolve parabens (butyl paraoxybenzoate) in the heated purified water, but it melt | dissolved in the normal temperature propylene glycol. The other components were dissolved in purified water heated to about 90 ° C. These were combined and mixed thoroughly, filled in a single-dose stick-shaped three-sided sealed container, sealed, and cooled to room temperature.
The obtained oral jelly preparation was evaluated as follows. The results are shown in Tables 1-5.
Evaluation Method Preservation Efficacy Test Preservation Efficacy Test for Oral Jelly Agents of Examples 1-27 and Comparative Examples 1-18 in accordance with Fifteenth Revised Japanese Pharmacopoeia Reference Information "Preservation Efficacy Test Method" did. The test bacteria are Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus bacteria and Aspergillus niger, Candida albicans fungi, and the number of viable bacteria at the time of inoculation, after 14 days and after 28 days, The antiseptic power was judged according to the standard. In addition, the viable count at the time of ingestion was 10 ⁵ to 10 ⁶ per 1 g.

Determination of bacteria A: The viable cell count after 14 days decreased to 1% or less of the viable cell count at the time of ingestion, and the viable cell count after 28 days decreased to a level equal to or less than the level after 14 days.
○: The viable cell count after 14 days decreased to 10% or less of the viable cell count at the time of ingestion, and the viable cell count after 28 days decreased to a level equal to or less than the level after 14 days.
(Triangle | delta): Although the viable count after 14 days fell to 50% or less of the viable count at the time of ingestion, it did not fall to 10% or less.
X: The viable count after 14 days did not decrease to 50% or less of the viable count at the time of ingestion. Or it increased more than the number of viable bacteria at the time of ingestion.

Determination of fungi A: The viable cell count after 14 days decreased to 10% or less of the viable cell count at the time of ingestion, and the viable cell count after 28 days decreased to a level equal to or less than the level after 14 days.
○: The number of viable bacteria after 14 days and 28 days decreased to the same level or lower than that at the time of ingestion.
(Triangle | delta): Although the viable count after 14 days fell to the same level or less than the viable count at the time of ingestion, the viable count after 28 days increased from the time of ingestion.
X: The viable cell count after 14 days or 28 days increased from the viable cell count at the time of ingestion.

Evaluation of taste Five well-trained evaluation panelists took the oral jelly preparations of Examples 1 to 27 and Comparative Examples 1 to 18, and evaluated bitterness and feeling of taking according to the following evaluation criteria. The degree of bitterness was determined by the value. Before taking each oral jelly, always rinsed the mouth with normal water so that the bitter taste of the oral jelly taken before was not affected.
Evaluation criteria Score 3: Although there was very slight bitterness, it was able to be taken deliciously.
Score 2: Slightly bitter, but delicious.
Score 1: It had a bitter taste and could not be taken deliciously.
Score 0: There was a strong bitterness and it was very bad.

Judgment of degree of bitterness ○○: Average score of 5 people is 2.3 or more and less than 3.0 ○: Average score of 5 people is 1.5 or more and less than 2.3 Δ: Score of 5 people Average value of 0.8 or more and less than 1.5 ×: Average value of 5 scores is 0 to less than 0.8

Evaluation of texture The oral jelly preparations of Examples 1 to 27 and Comparative Examples 1 to 18 were stored in a temperature-controlled room at 40 ° C. for one month, and these were taken by five well-trained evaluation panelists and evaluated as follows. The texture was evaluated according to the criteria, and whether the texture was good or bad was determined by the average value of the scores of the five people.
Evaluation criteria Score 4: The texture as a jelly agent was extremely good.
Score 3: The texture as a jelly agent was good.
Score 2: The texture as a jelly agent was slightly good.
Score 1: The texture as a jelly agent was poor.
Score 0: The texture as a jelly agent was remarkably bad.
Judgment of good or bad texture OO: Average score of 5 people is 3.2 or more to 4.0
◯: Average score of 5 people is 2.4 or more and less than 3.2 ○: Average score of 5 people is 1.6 or more and less than 2.4 △: Average score of 5 people is 0 .8 or more to less than 1.6 ×: Average value of 5 scores is less than 0 to less than 0.8

Hardness ○: Resistance when compressed at 20 ° C. ± 2 ° C. 1 × 10 ^{3 to} 1.5 × 10 ⁵ N / m ²
X: Resistance when compressed at 20 ° C. ± 2 ° C. is higher than 1.5 × 10 ⁵ N / m ²

  As apparent from Tables 1 to 5, it contains a gelling agent, 0.005 to 0.1% by weight of parabens, and 0.02 to 0.5% by weight of benzoic acid or a salt thereof, and has an osmotic pressure of 1000. The jelly agent of ˜3500 mOsm had sufficient antiseptic power against bacteria and fungi, had no bitter taste, and had good texture and hardness.

Claims (7)

  An oral jelly agent containing a gelling agent, 0.005 to 0.1% by weight of parabens, and 0.02 to 0.5% by weight of benzoic acid or a salt thereof and having an osmotic pressure of 1000 to 3500 mOsm.   The oral jelly preparation according to claim 1, wherein the parabens are propyl paraoxybenzoate and / or butyl paraoxybenzoate.   The oral jelly agent of Claim 1 or 2 containing 1 type, or 2 or more types chosen from saccharides and a polyhydric alcohol.   The oral jelly preparation according to claim 3, wherein the polyhydric alcohol is propylene glycol and / or glycerin.   The oral jelly agent according to any one of claims 1 to 4, comprising 10 to 40% by weight of a saccharide and / or 2 to 15% by weight of a polyhydric alcohol.   The oral jelly preparation according to any one of claims 1 to 5, wherein the gelling agent is one or more selected from agar, alginic acid or a salt thereof, carob bean gum, xanthan gum and pullulan.   The oral jelly preparation according to any one of claims 1 to 6, which has a pH of 3.0 to 7.0.