JPH10130140A - Production of gummy pharmaceutical preparation - Google Patents

Abstract

PROBLEM TO BE SOLVED: To obtain a gummy pharmaceutical preparation, containing a medicine having large difference in specific gravity from gummy base in uniform concentration by ethanol dissolution method. SOLUTION: This gummy pharmaceutical preparation is obtained by dissolving a medicine in ethanol, adding the solution to gummy base, mixing the solution with the gummy base and cooling and solidifying gummy base. The gummy base is obtained by mixing saccharide with water, adding a gelling agent consisting essentially of gelatin n thereto, further as necessary, adding a flavoring agent, coloring agent and an acidifier thereto. When ethanol in which a medicine is dissolved is added to gummy base, ethanol is evaporated by heat of the gummy base. Therefore, ethanol is added thereto while rapidly stirring. Since the left medicine is dispersed in gummy base as fine particles when the medicine has water-insoluble property or slightly insoluble property, the preparation does not cause floating or precipitation due to the difference in specific gravity. Thereby, when the medicine is soluble in ethanol, gummy preparation, in which medicine is dispersed in fine state, having uniform composition, is obtained and ethanol residual amount can be suppressed in low level.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

The present invention relates to a method for producing a gummy preparation which is a special dosage form of an oral preparation or an extraoral preparation.

[0002]

2. Description of the Related Art Oral medicines are generally taken with water in principle. However, in the case of children and elderly people, when taking powders, tablets, and the like with water, the medicine is left in the mouth only by drinking water, and there are many cases where the medicine cannot be taken as instructed by a doctor. Also, if you want to take medicine due to sudden fever in children or sudden pain when going out, but you do not have water or if you have restricted water intake due to other diseases, oral medicine that can be taken without water is clinical. It is considered to be useful.
In addition, pharmaceuticals are often accompanied by bitterness and unpleasant odor. These may also be obstacles to taking them, which may lead to a decrease in compliance (certainty of taking the medicine).

[0003] An ointment is generally used as an external medicine for the affected part of the mouth. However, the base of the ointment often has an unpleasant taste and is easily dissolved in saliva and removed, so that it may be inadequate in permeability and efficacy to the affected part. Therefore, it can be said that there has been a need for a formulation that exerts sufficient efficacy when applied to an affected area in the mouth and has good flavor.

[0004] The present inventors have studied a pharmaceutical composition which can be easily taken even without water and has a bitter taste or an unpleasant odor, particularly an oral preparation and an oral preparation. As a result, a gummy composition, which is a confectionery that is favored by a wide range of ages from children to adults, and a so-called "gummy formulation" obtained by combining a medicinal product, are found to be extremely effective. (Japanese Patent Application No. 8-147575). In this production method, the drug to be used is water-soluble and does not inhibit gelation of gelatin, or if the effect is minimal, the drug to be used is water-insoluble and does not inhibit gelation of gelatin. Use if the effect is minor, or if a drug is used that has some inhibitory effect on gelatin gelation, regardless of whether the drug is water-soluble or water-insoluble. It is possible.
In the case of, the drug may be added as an aqueous solution during the manufacturing process. In the case of, the drug may be added by a method called a solid dispersion method.

[0005]

According to the solid dispersion method, according to the usual method for producing a gummy composition, after mixing all the ingredients except for the medicine, the dough is cooled to the gelation start temperature and held for a certain time. This is a method in which a drug is charged in a solid state, mixed, and sufficiently dispersed at a stage where gelatin forms a hydrogen bond and thickens. According to this method, a hydrogen bond of gelatin is formed before mixing the medicine, so that a solidified gummy composition can be obtained by cooling as it is. In addition, by lowering the temperature of the gummy dough before the introduction of the medicine, there is also an effect of suppressing the dissolution of the medicine. However, it has been found that in the solid dispersion method, when the specific gravity difference between the drug and the gummy dough is large, the drug floats or sediments in the gummy dough due to the specific gravity difference, and it is not possible to obtain a uniform composition.

[0006]

Means for Solving the Problems The present inventors have proposed a production method capable of solving the above-mentioned problems, that is, a gummy substitute for a solid dispersion method containing a drug having a large specific gravity difference from gummy dough in a uniform concentration. We worked diligently to develop a manufacturing method for the formulation. As a result, the method of the present invention that enables this for ethanol-soluble drugs, that is, an ethanol dissolution method has been completed.

The gummy composition used in the present invention is a gel-like composition obtained by gelling a composition mainly composed of carbohydrate and water with a gelling agent mainly composed of gelatin, preferably a gelling agent mainly composed of gelatin. Refers to a composition, which is widely known as a confectionary generally called gummy, gummy candy and the like. More specifically, the main component of the gelling agent is gelatin, the water content is about 10 to 25% by weight, preferably about 20% by weight, and the Aw (water activity, 20 ° C.) is 0.7%. Less than
It is a confectionery composition to be kept for a long time without fear of propagation of microorganisms. Here, Aw is an index representing free water contained in food, that is, the amount of water available to microorganisms. It is empirically known that if this is about 0.7 or less, there is no fear of propagation of microorganisms in the gummy composition.

The gelling agent may contain other gelling agents such as starch, pectin, carrageenan, agar and the like in addition to gelatin, and preferably consists of gelatin alone.

Examples of carbohydrates which are the main raw materials of the gel composition include sugar, starch syrup, glucose, fructose, lactose, palatinose, and sugar alcohols (eg, sorbitol, maltitol, lactitol, xylitol, erythritol, reduced palatinose). , Reduced starch saccharified products), oligosaccharides (for example, fructooligosaccharides, inulooligosaccharides, galactooligosaccharides, isomaltooligosaccharides, maltooligosaccharides, lactosucrose, xylooligosaccharides, soybean oligosaccharides, palatinose oligosaccharides), and polydextrose. In particular, the use of non-fermentable or hardly carious carbohydrates such as sugar alcohols can be said to be preferable because gummy compositions that do not easily become caries can be produced.

According to a preferred embodiment of the present invention, the basic composition is such that 65 to 87% by weight of a saccharide as a main raw material and a gelling agent mainly composed of gelatin, preferably 3% by mass of gelatin. 10 to 10% by weight, moisture of 10 to 2
5% by weight, and, if necessary, an acidulant, a fragrance, a colorant and other auxiliary materials.

The medicine contained in the gummy preparation according to the present invention is a commonly used oral medicine or an extraoral medicine, and is not particularly limited as long as it is an ethanol-soluble medicine. Specific examples of the medicament used in the present invention include antiepileptic agents (eg, sodium valproate,
Phenobarbital), antipyretic analgesics (eg, acetaminophen, ibuprofen, ketoprofen, aspirin, isopropylantipyrine, diclofenac sodium, emorfazone, salicylamide, sazapyrine), drugs for psychiatric nerves (eg, perphenazine, chlorpromazine hydrochloride, hydroxyzine hydrochloride) , Isopramine hydrochloride, clothiazepam), antispasmodics (eg, flopropion, timepidium bromide), cardiotonic agents (eg, ethyrefrin hydrochloride), arrhythmic drugs (eg, disopyramide, mexiletine hydrochloride, aprindine hydrochloride), blood pressure lowering agents (eg, Captopril), drugs for hyperlipidemia (eg, simvastatin, probucol), antitussives (eg, pentoxiverine citrate, dextromethorphan hydrobromide, guaifene) Gout), gout remedies (eg, colchicine), diabetes drugs (eg, buformin hydrochloride), antihistamines (eg, diphenhydramine hydrochloride, d-chlorpheniramine maleate, chlorpheniramine maleate, triplozine hydrochloride, dimenhydrinate, hydrochloride) Promethazine), allergic drug (for example, methoxyphenamine), dental oral agent (for example, cetylpyridinium chloride), gastrointestinal function regulator (for example, bedanecol hydrochloride),
Laxatives (eg, dioctyl sodium sulfosuccinate), vitamins (eg, ergocalciferol, alphacalcidol, fursultiamine, tocopherol acetate) and the like.

The gummy preparation according to the present invention can contain a coloring agent, a flavor, an acidulant and the like, if necessary. In particular, in the case of fragrances, if the medicines have bitterness or an unpleasant odor, they are masked to make them easier to take. Also,
Regarding the colorant, it is advantageous to change the color of the colorant depending on the type of medicine, so that even if a plurality of gummy preparations are carried at the same time, accidental ingestion during taking can be prevented. Specific examples of the coloring agent include red cabbage (red), red flower yellow (yellow), gardenia blue (blue), and the like. Further, specific examples of the fragrance include an orange flavor, a grape flavor, and a muscat flavor. Examples of the sour agent include citric acid, malic acid, phosphoric acid, and the like. In addition, it is desirable to select and use the components of these gummy compositions that do not adversely affect the contained medicine.

Further, according to a preferred embodiment of the present invention,
The gummy preparation is coated on its surface. The coating is advantageous because it prevents photodegradation and denaturation of the drug in the gummy composition. Preferred examples of the coating include sugar coating and chocolate hanging. By changing the color of the coating with a medicine containing the color, it is advantageous since accidental ingestion during taking can be prevented.

[0014]

BEST MODE FOR CARRYING OUT THE INVENTION The method of the present invention, that is, the ethanol dissolving method will be described in detail in comparison with a conventional gummy production method and a solid dispersion method.

(1) Normal Gummy Production Method Conventionally, gummy gum production is carried out by boiling sugar and syrup together with charging water, adding a gelatin solution prepared in advance, mixing, and, if necessary, sour taste. Ingredients and some amount of auxiliary materials such as pigments and fragrances are added to prepare gummy dough, and this gummy dough is deposited on a starch mold, and then aged for about 24 hours to transfer moisture released from the gummy dough to the starch mold. Has been done by solidifying the gummy dough while demolding, destarching and then oil coating (R. Lees et al., “Sugar
Cofectionary and Chocolate Manufacture, "p. 226, 1
973, published by Leonard Hill Scotland). In addition, instead of depositing on a starch mold, edible oil or fat which is liquid at normal temperature is applied to the inner surface of a plastic tray such as vinyl chloride in advance, and gummy dough is deposited on this.

Starch mold, plastic tray,
The meanings of deposit, aging, demold, destarch, and oil coating are as follows. Starch mold: refers to a cavity formed by filling a tray with starch, flattening the surface thereof, and then pressing a convex mold against the starch layer. Plastic tray: Refers to a container made by molding plastic such as vinyl chloride. Deposit: Refers to an operation of pouring or pouring gummy dough into a starch mold or a plastic tray coated with edible oil and fat. Aging: In the case of using a starch mold, the deposited gummy dough is left as it is stored in the starch mold, and moisture released from the confectionery dough is transferred to the starch layer, whereby Bx reaches a predetermined value. Together with the storage process until it becomes removable. In the case of using a plastic tray, it refers to a storage process in which the deposited gummy dough is left in a state of being stored in the plastic tray until the confectionery dough is solidified and can be removed from the mold. Demolding: removing a product from a mold. When using a starch mold, it is usually performed by inverting the entire tray. When using a plastic tray, it refers to removing the product from the plastic tray by hand or using an instrument. Destarch: When using a starch mold, removing the starch remaining on the surface of the demolded gummy. Usually, starch is scattered and removed by passing it through a rotating cylindrical sieve and then blowing compressed air onto the surface. Oil coating: The surface of gummy degummed from a starch mold and destarched or demolded from a plastic tray is coated with edible fat. This prevents the destarched products from binding to each other. Ordinarily, destarch gummy is placed in a rotating drum, and a liquid and edible oily fat is dropped at room temperature, and the drum is rotated to form a thin and uniform oil and fat film on the surface of the gummy.

In order to improve the taste of gummy, fruit juice,
The problem of adding an auxiliary material such as pulp has been solved in Japanese Patent Application Laid-Open No. 3-83550. Further, with respect to the prevention of deterioration of flavor and the adverse effect of texture during the production process and storage of jelly confectionery, see Japanese Unexamined Patent Publication No.
No. 56 discloses this. These techniques can also be appropriately used in the practice of the present invention.

(2) Solid dispersion method In the case of using a medicine which exerts some inhibitory action on gelation of gelatin, a gummy composition which forms a good gel cannot be obtained by an ordinary method. As a result of intensive studies to overcome this, the present applicant has previously developed a manufacturing method called an individual dispersion method and filed a patent application (Japanese Patent Application No. Hei 8-1475).
75). This is the stage in which, after mixing all ingredients other than medicines according to the normal gummy manufacturing method, the dough is cooled to the gelation start temperature and held for a certain period of time, and gelatin forms hydrogen bonds and thickens. In this method, the drug is charged in a solid state, mixed, and sufficiently dispersed. According to this method, a hydrogen bond of gelatin is formed before mixing the medicine, so that a solidified gummy composition can be obtained by cooling as it is. In addition, by lowering the temperature of the gummy dough before the introduction of the medicine, there is also an effect of suppressing the dissolution of the medicine. At this time, the drug may be used as it is in a solid or powder state, but it may be coated with sugar, gelatin or the like to be microencapsulated, or once the drug is made into an aqueous solution, dextrin or the like is used as a binder. May be granulated. Alternatively, the drug may be once prepared as an aqueous solution, then impregnated in a water-insoluble matrix, dried, and dispersed in gummy dough. By these operations, the effect of further suppressing the dissolution of the medicine in the gummy dough can be obtained. When the medicine is insoluble in water such as essential oil, the treatment described above can be prevented from separating and floating in the gummy dough, and can be uniformly dispersed. This is important in keeping the potency of the gummy preparation constant.

However, in the above-mentioned method, when the specific gravity of the medicine dispersed as the solid phase and the gummy dough are significantly different, the medicine may float or settle in the gummy preparation and the concentration distribution of the medicine in the gummy preparation may not be uniform. found. If such a distribution of the drug concentration occurs due to the difference in specific gravity before the dough is poured into the mold, there is a possibility that the drug content of each gummy preparation may vary. Further, even when the drug occurs after pouring into a mold, there is a possibility that a portion where the medicine is locally concentrated occurs in the gummy preparation, the palatability is lost, and the intended purpose of improving compliance may not be achieved.

(3) Method of the Present Invention (Ethanol Dissolving Method) In the method of the present invention, a drug is dissolved in ethanol and added at the time of addition of an auxiliary material such as fruit juice in a usual method for producing gummy gum. At this time, since the ethanol is scattered by the heat of the dough, if the drug is not added while stirring rapidly, the drug will precipitate on the gummy dough surface if the drug is insoluble or poorly soluble. The residual amount of ethanol in the gummy preparation can be controlled by adjusting the temperature of the gummy dough at the time of addition, the intensity of stirring after the addition, the atmospheric pressure of the atmosphere, and the like. When giving gummy preparations to children and patients who are vulnerable to alcohol, it is desirable that the residual amount of ethanol in the gummy preparations is as small as possible,
In this case, the temperature of the gummy dough at the time of adding the pharmaceutical ethanol solution may be increased (100 to 120 ° C) and the mixture may be stirred vigorously. It is more effective to put under reduced pressure during stirring.

In the method of the present invention, the ethanol in which the medicine is dissolved is scattered by heat when added to gummy dough. Therefore, if the stirring is performed promptly, the remaining medicine will be dispersed in the gummy dough as fine particles when it is insoluble or hardly soluble in water. Even when the drug is water-soluble, the gummy dough to which the drug is added is already a solution of a supersaturated sugar, and the drug to be added does not contain water, so it hardly dissolves in the gummy dough. Further, the drug dispersed in such a fine state no longer floats or sinks due to a difference in specific gravity. Therefore, according to the method of the present invention, a gummy preparation having a uniform composition in which the drug is finely dispersed can be obtained as long as the drug is ethanol-soluble.

[0022]

The present invention will be described more specifically with reference to the following examples, which do not limit the present invention.

EXAMPLE 1 Gummy made by ethanol dissolution method
Preparation of Agent (1) Preparation of Dough for Gummy Formulation According to the composition shown in Table 1, sugar was mixed in a starch syrup, 1/3 the amount of water in sugar was added, and the mixture was boiled down to 125 ° C. On the other hand, gelatin was swollen with 1.5 times the amount of water and then heated and dissolved at about 60 ° C., and this was quickly mixed with the boiled sugar. This was added together with a separately prepared mixed solution of fruit juice, citric acid, pigment, and flavor, followed by stirring to prepare a gummy dough having a water content of about 19%. Meanwhile, 12.5 g of 95% ethanol was added to 5 g of acetaminophen in another container,
Dissolve in hot water. 975 g of this gummy dough
, And the mixture was quickly stirred, hydrated to a total of 1000 g, and mixed well to prepare a gummy preparation dough.

[0024]

(2) Deposit The oil is preliminarily placed on a plastic tray molded so that about 5 g of gummy dough can be poured, and the gummy dough is deposited on the plastic tray by 5 g, and immediately covered with a greased vinyl sheet. And cool at 10 ° C. (3) Demold After aging at room temperature for about 24 hours to solidify, the gummy preparation was removed from the plastic tray. Acetaminophen content per obtained gummy preparation is 25 mg
(Theoretical value). In addition, the Aw of the gummy preparation was 0.68 at 20 ° C., which was a value that would cause no problem even when distributed and stored at room temperature.

Comparative Example 1 Preparation of gummy preparation by solid dispersion method
According formulations shown in concrete (1) Preparation Table 2 gummy formulation dough, sugar mixed with syrup, boiled down to 130 ° C. by the addition of 1/3 volume of water of sugar. On the other hand, gelatin was swollen with 1.5 times the amount of water and then heated and dissolved at about 60 ° C., and this was quickly mixed with the boiled sugar. To this, a separately prepared mixed solution of fruit juice, citric acid, pigment, and flavor was added, stirred, mixed, and then watered to prepare a gummy dough having a water content of 21% by weight. Immediately before the temperature of the gummy dough lowers (about 40 ° C.) and solidifies, acetaminophen previously finely powdered is quickly added at the ratio shown in Table 3 to uniformly disperse the medicine in a solid state, and the gummy dough is mixed. Was prepared.

[0027]

[0028]

(2) Deposit The oil is previously put on a plastic tray molded so that about 5 g of gummy dough can be poured, and the gummy dough is deposited on the plastic tray by 5 g, and immediately covered with a greased vinyl sheet. And cool at 10 ° C.

(3) Demolding After aging at room temperature for about 24 hours to solidify, the gummy preparation was removed from the plastic tray. Acetaminophen content per obtained gummy preparation is 25 mg
(Theoretical value). In addition, the Aw of the gummy preparation was 0.68 at 20 ° C., which was a value that would cause no problem even when distributed and stored at room temperature.

Test Example 1 Analysis of Acetaminophen Content Table 4 shows the results of analyzing the acetaminophen content of the gummy preparation produced by the ethanol dissolution method of Example 1. Table 5 shows the results of analyzing the acetaminophen content of the gummy preparation manufactured by the solid dispersion method of Comparative Example 1. Compared with the gummy preparation manufactured by the solid dispersion method, it was confirmed that the medicine was very uniformly dispersed in the gummy preparation manufactured by the ethanol dissolution method of the present invention. Further, the result of measuring the residual amount of ethanol in the gummy preparation produced by the ethanol dissolution method by gas chromatography was 0.35%.

[0032] (In the table, medicine represents acetaminophen)

[0033] (In the table, medicine represents acetaminophen)

Examples 2 to 4
Production of gummi preparation (1) Preparation of gummy dough According to the composition shown in Table 6, sugar was mixed in a syrup, water was added to one-third of the amount of sugar, boiled down to 125 ° C, and water was added.
x81. On the other hand, gelatin was swollen with 1.5 times the amount of water and then heated and dissolved at about 60 ° C., and this was quickly mixed with the boiled sugar. A gummy dough was prepared by adding the mixture together with a separately prepared solution of fruit juice, citric acid, pigment, and flavor, followed by stirring.

[0035]

On the other hand, ethanol is added to the medicine in a separate container in the composition shown in Table 7, and the medicine is dissolved by boiling in water at 60 ° C. This was added to 195 g of the gummy dough, stirred quickly, hydrated to a total of 200 g, and mixed well to prepare a gummy dough.

[0037]

(2) Deposit The oil is previously put on a plastic tray molded so that about 5 g of gummy dough can be poured, and the above gummy dough is deposited on the plastic tray by 5 g, and immediately covered with a greased vinyl sheet. And cool at 10 ° C. (3) Demold After aging at room temperature for about 24 hours to solidify, the gummy preparation was removed from the plastic tray. The drug content (theoretical value) per obtained gummy preparation is 10 mg in Example 2, 2 mg in Example 3, and 50 mg in Example 4. In addition, the Aw of the gummy preparation was 0.68 at 20 ° C., which was a value that would cause no problem even when distributed and stored at room temperature.

Test Example 2 Content of diphenhydramine hydrochloride
Table 8 shows the result of analyzing the diphenhydramine hydrochloride content of the gummy preparation produced in Analysis Example 2. It was confirmed that the gummy preparation produced by the method of the present invention had the drug dispersed very uniformly. The residual amount of ethanol of this preparation was measured by gas chromatography to be 0.81%.

[0040] (In the table, medicine represents diphenhydramine hydrochloride)

Test Example 3 Chlorpheniramine maleate
Analysis of Content Table 9 shows the results of analyzing the chlorpheniramine maleate content of the gummy preparation prepared in Example 3. It was confirmed that the gummy preparation produced by the method of the present invention had the drug dispersed very uniformly. The residual amount of ethanol of this preparation was measured by gas chromatography to be 0.50%.

[0042] (In the table, medicine represents chlorpheniramine maleate)

Test Example 4 Analysis of Tocopherol Acetate Content The results of analysis of the tocopherol acetate content of the gummy preparation prepared in Example 4 are shown in Table 10. It was confirmed that the gummy preparation produced by the method of the present invention had the drug dispersed very uniformly. The residual amount of ethanol of this preparation was measured by gas chromatography to be 0.55%.

[0044] (In the table, the medicine represents tocopherol acetate)

[0045]

According to the method of the present invention, as long as the drug is ethanol-soluble, a gummy preparation having a uniform composition in which the drug is dispersed in a fine state can be obtained. It is also possible to keep the residual amount of ethanol low.

Claims (3)

[Claims] 1. A method for producing a gummy preparation having a uniform concentration of the medicine, comprising dissolving the medicine in ethanol, adding the mixture to the gummy dough, mixing the mixture, and then cooling and solidifying the gummy preparation dough. 2. The drug is an ethanol-soluble drug,
The method of claim 1. 3. Gummy dough is obtained by mixing and heating a saccharide with water, adding a gelling agent mainly composed of gelatin, and optionally adding a flavor, a colorant or an acidulant. The method according to claim 1.