WO2015064680A1 - Pharmaceutical composition in easy-to-take jelly form - Google Patents
Pharmaceutical composition in easy-to-take jelly form Download PDFInfo
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- WO2015064680A1 WO2015064680A1 PCT/JP2014/078859 JP2014078859W WO2015064680A1 WO 2015064680 A1 WO2015064680 A1 WO 2015064680A1 JP 2014078859 W JP2014078859 W JP 2014078859W WO 2015064680 A1 WO2015064680 A1 WO 2015064680A1
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- pharmaceutical composition
- sodium
- jelly
- gelling agent
- fatty acid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
- A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P33/00—Antiparasitic agents
- A61P33/10—Anthelmintics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/16—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing nitrogen, e.g. nitro-, nitroso-, azo-compounds, nitriles, cyanates
- A61K47/18—Amines; Amides; Ureas; Quaternary ammonium compounds; Amino acids; Oligopeptides having up to five amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
Definitions
- the present invention relates to a jelly-like pharmaceutical composition that is easy to take.
- Fleas, ticks and filaria are well known as parasites common in dogs.
- filaria is a kind of endoparasite and parasitizes in the host body by being mediated by mosquitoes.
- Filaria also known as dog filamentous insects, parasitize organs such as the intestinal tract, absorbs the nutrients digested by the host, and continues to live in the body. The disease is asymptomatic in the early stages of infection, but eventually suffers from symptoms similar to heart disease, such as coughing and dyspnea, and eventually death.
- prophylactic use with drugs is mainly used. In particular, once a month is indispensable when mosquitoes occur.
- the drug used include milbemycin oxime, praziquantel, moxidectin, ivermectin, pirantel, and selamectin.
- milbemycin oxime is a commonly used drug, and many products are on sale.
- Product forms include tablets and granules.
- microspheres Patent Document 1
- chewable tablets Patent Document 2
- jelly agents Patent Document 3
- transmucosal absorbents Patent Document 4
- An object of the present invention is to solve the above-mentioned problems, and an object of the present invention is to realize a chemically stable jelly-like pharmaceutical composition while having a high water content.
- the present invention is chemically stable by having a dispersing agent that makes the medicinal component uniform in the composition and a stabilizer that suppresses deterioration of the medicinal component against heat. It provides a preparation that is easy to take.
- composition of the present invention is [1] A jelly-form pharmaceutical composition comprising a medicinal ingredient, a gelling agent, and purified water, [2] The pharmaceutical composition according to [1] above, wherein the medicinal component is milbemycin oxime, moxidectin, ivermectin, abamectin, emamectin, doramectin, or a derivative thereof, or a pharmaceutically usable salt thereof.
- the medicinal component is milbemycin oxime, moxidectin, ivermectin, abamectin, emamectin, doramectin, or a derivative thereof, or a pharmaceutically usable salt thereof.
- the gelling agent is pectin, agar powder, carrageenan, gellan gum, gelatin, xanthan gum, locust bean gum, guar gum, tara gum, alginic acid or a sodium salt thereof, or mannans.
- the pharmaceutical composition described, [4] The pharmaceutical composition according to any one of the above [1] to [3], further comprising a dispersant, [5]
- the dispersant is sucrose fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene (105) polyoxypropylene (5) glycol, or sodium alkyl sulfate.
- the pharmaceutical composition according to the above [4], [6] The pharmaceutical composition according to the above [5], wherein the fatty acid moiety in the fatty acid ester is a saturated fatty acid having 10 to 16 carbon atoms, [7]
- composition [9] The pharmaceutical composition according to any one of [1] to [8] above, wherein the pH of the pharmaceutical composition is 5 or more, [10] The pharmaceutical composition according to any one of the above [1] to [9], further comprising an excipient, a suspending agent, or a solubilizing agent, [11] A method for producing a jelly-form pharmaceutical composition comprising at least a medicinal ingredient, a gelling agent, a dispersant, and purified water, A step of heating and dissolving a solution obtained by adding a gelling agent to purified water as necessary, A step of cooling the obtained solution to a temperature at which the medicinal component is not decomposed and the gelling agent can be dissolved; The production method comprising a step of adding a medicinal component and a dispersant after the cooling step; [12] A method for producing a jelly-form pharmaceutical composition comprising at least a medicinal component, a gelling agent that requires heating for dissolution, a dispersant, and purified water, Adding at least a gelling
- the pharmaceutical composition of the present invention it is possible to provide a jelly-like composition having a high water content, fluidity, easy to take, chemically stable and uniform content.
- Milbemycin oxime that can be used as a medicinal component in the present invention has the following chemical structural formula: A white to yellowish white tasteless powder represented by the formula, having no odor or a slightly unique odor. Moreover, it hardly dissolves in water.
- the medicinal ingredient may consist of a mixture of milbemycin A 3 oxime and milbemycin A 4 oxime, the ratio milbemycin A 3 oxime 20% or less, milbemycin A 4 oxime is 80% or more.
- R is a methyl group
- it is milbemycin A 3 oxime
- R is an ethyl group
- it is milbemycin A 4 oxime.
- macrolide antibiotics and derivatives thereof can be used in the pharmaceutical composition of the present invention.
- macrolide antibiotics and derivatives thereof can be used, and these compounds can be used in free form or in the form of pharmaceutically available salts. can do.
- Cyclic peptide antibiotics can also be used in the pharmaceutical composition of the present invention. Specific examples include cyclosporine, vancomycin, erythromycin and the like.
- the dose of the medicinal component (especially milbemycin oxime) in the present invention can be administered while appropriately adjusting, but is preferably a dose of 0.1 to 1.5 mg per kg body weight, more preferably body weight.
- the dosage is 0.25 to 1.0 mg per kg.
- the content of the medicinal component is preferably 0.0125 to 1.25% by weight, more preferably 0.025 to 0.625% by weight, per unit preparation.
- purified water As the solvent in the present invention, purified water, ethanol or the like can be used.
- the pharmaceutical composition of the present invention is a jelly-like composition and contains water.
- the content is not particularly limited, but is preferably 50 to 95% by weight per unit preparation.
- Pharmacologically acceptable additives can be appropriately added to the pharmaceutical composition of the present invention.
- Specific additives include, for example, excipients, gelling agents, dispersing agents, suspending agents, solubilizing agents, sweetening agents, stabilizing agents, pH adjusting agents, fragrances, preservatives, coloring agents and the like. It is done.
- the pharmaceutical composition of this invention does not contain fats and oils (a vegetable oil and animal fats and oils).
- Sugar alcohol can be used as an excipient in the present invention.
- sugar alcohol for example, maltitol, lactitol, mannitol, erythritol, xylitol, trehalose, or sorbitol can be used. These sugar alcohols may be used alone or in combination of two or more as appropriate.
- the gelling agent in the present invention for example, pectin, agar powder, carrageenan, gellan gum, gelatin, xanthan gum, locust bean gum, guar gum, tara gum, alginic acid or its sodium salt, or mannans can be used.
- the dissolution temperature of these gelling agents is shown in Table 1. These gelling agents may use only 1 type and may use 2 or more types together suitably.
- the content of the gelling agent is preferably 0.01 to 5% by weight, more preferably 0.1 to 3% by weight, per unit preparation.
- the main component may not be dispersed, and conversely, agglomeration may occur to form a lump, so it is important to use an optimal dispersant.
- dispersant in the present invention examples include sucrose fatty acid ester, glycerin fatty acid ester (including fatty acid and glycerin or polyglycerin ester and derivatives thereof), polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene. (105) Polyoxypropylene (5) glycol, sodium alkyl sulfate, or the like can be used.
- the fatty acid constituting these esters is preferably a saturated fatty acid having 10 to 16 carbon atoms.
- Specific fatty acids include capric acid (C 10 ), undecyl acid (C 11 ), lauric acid (C 12 ), tridecyl acid (C 13 ), myristic acid (C 14 ), pentadecylic acid (C 15 ), palmitic acid. acid (C 16) and the like.
- the fatty acid which comprises is not only 1 type, but 2 or more types may be contained. Further, the average degree of polymerization of glycerin fatty acid ester is preferably 6-15, more preferably 8-10.
- dispersants may be used alone or in combination of two or more.
- Specific dispersants include, for example, sucrose laurate, sucrose myristate, sucrose palmitate, decaglycerin caprylate, decaglycerin laurate, decaglycerin myristate, sodium lauryl sulfate, etc. Is mentioned. Among them, sucrose palmitic acid ester, decaglycerin lauric acid ester, decaglycerin myristic acid ester, and sodium lauryl sulfate are more preferable.
- suspending agent in the present invention for example, carmellose sodium, xanthan gum, methylcellulose, tragacanth and the like can be used. These suspending agents may use only 1 type and may use 2 or more types together suitably.
- solubilizer in the present invention for example, propylene glycol, glycerol, polyethylene glycol and the like can be used. These solubilizers may use only 1 type and may use 2 or more types together suitably.
- sucrose reduced maltose starch syrup
- artificial sweeteners acesulfame potassium, sucralose, aspartame, saccharin, saccharin sodium, stevia, thaumatin and the like can be used.
- sweeteners may use only 1 type and may use 2 or more types together suitably.
- the pharmaceutical composition of the present invention has a high water content, the main component becomes unstable when exposed to dissolved oxygen, so it is important to increase the stability with a stabilizer.
- the stabilizer in the present invention include tocopherol, alkyl gallate, butylhydroxyanisole, butylhydroxytoluene, sodium sulfite, edetic acid, sodium edetate, erythorbic acid, sodium erythorbate, ascorbic acid, and sodium ascorbate. Can be used. Among these, ascorbic acid and sodium ascorbate are preferable.
- the amount of the stabilizer used in the present invention is not particularly limited, but it is preferably added at a concentration of 1 to 6% by weight with respect to the total amount of the composition of the present invention. Only one type of stabilizer may be used, or two or more types may be used in combination as appropriate.
- Examples of the pH adjuster in the present invention include citric acid (including hydrate), sodium citrate, potassium citrate, sodium hydroxide, monoethanolamine, diethanolamine, tartaric acid, propionic acid, lactic acid, malic acid, and succinic acid.
- Sodium phosphate, monosodium glutamate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, or the like can be used.
- These pH regulators can be added to the composition in the form of a solution or as they are so that the pH can be adjusted to a predetermined pH. These pH regulators may be used alone or in combination of two or more as appropriate.
- the pH of the pharmaceutical composition of the present invention is stable as long as the pH is 5 or more, and preferably within the range of pH 5-7.
- fragrance in the present invention for example, apple flavor, acerola flavor, orange flavor, grape flavor, strawberry flavor, sweet potato flavor, chocolate flavor, beef flavor, peach flavor, maple flavor, or tomato flavor can be used. .
- peach flavor and tomato flavor are preferable.
- flavors may use only 1 type and may use 2 or more types together suitably.
- preservative in the present invention for example, potassium sorbate, sorbic acid, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, or butyl paraoxybenzoate can be used. Of these, methyl paraoxybenzoate and ethyl paraoxybenzoate are preferable.
- These preservatives may be used alone or in combination of two or more as appropriate in order to further enhance the antiseptic effect.
- colorant in the present invention food colors, ⁇ -carotene, caramel and the like can be used in addition to general synthetic colorants. Only 1 type may be used for these coloring agents, and 2 or more types may be used together suitably.
- the container for storing the pharmaceutical composition of the present invention is not particularly limited.
- the container may be filled with a cup container, a Cheapack (registered trademark) -like container, a bottle shape, a stick shape, or the like to obtain a product. it can.
- a stick-shaped container is preferable.
- the material of the container is not particularly limited, an aluminum laminate capable of maintaining the stability of the drug is preferable.
- the oxygen in the jelly is removed with a laminate sheet mixed with an oxygen scavenger, and the drug is stored. It may be one that prevents oxidation.
- the pharmaceutical composition of the present invention can be produced by a usual method for producing a jelly preparation. For example, after adding an appropriate amount of purified water as a solvent, a gelling agent is added and dissolved. Various other additives are added by heating the liquid as necessary while stirring, or after completely dissolving the gelling agent at room temperature. The melting temperature of the gelling agent can be appropriately determined according to the type of the gelling agent to be selected. Thereafter, a medicinal component is added, stirred well, homogenized in a dispersed / suspended state, and the suspension is cooled as necessary to obtain a jelly composition.
- the addition temperature or addition timing of the dispersant, stabilizer, or medicinal component is important. If the stabilizer or medicinal component itself is not very stable against heat, it is better to add it as late as possible, and the liquid temperature should be low. In this case, it is more preferable that the medicinal component is added after being dispersed in a solubilizer. Moreover, since a dispersing agent becomes easy to foam by stirring if a liquid temperature is high, it is better to lower a liquid temperature to predetermined temperature as much as possible.
- the temperature at which the dispersant is added can be appropriately determined according to the type of the dispersant selected, but it is a temperature at which the medicinal component does not decompose during the preparation and the dissolved state of the gelling agent can be maintained. Preferably there is.
- agar powder is used as the gelling agent and a fatty acid ester is used as the dispersing agent, it is preferably lowered to 85 ° C. or lower.
- the component is added and further cooled to obtain a jelly-like composition.
- the composition may be obtained by adding a component that is not preferable to be exposed to high temperature immediately before cooling.
- the packaging form of the pharmaceutical composition thus obtained is not particularly limited, but it is preferable to fill a single stick with a single dose of the medicinal component as described above.
- the filling and sealing methods here are performed in a conventional manner.
- the pharmaceutical composition of the present invention is a jelly, has a high water content of 50% or more, contains an effective dispersant, can ensure the stability of medicinal ingredients, is easy to drink, It has the feature that there is no bias. Furthermore, the pharmaceutical composition of the present invention has a feature that water is not required for oral administration.
- the temperature was lowered to 85 ° C., and a predetermined concentration of glycerin fatty acid ester (decaglycerin myristic acid ester) was added thereto. Furthermore, a predetermined concentration of sodium ascorbate was added. Thereto, a solution of milbemycin oxime previously dissolved in propylene glycol was added to the preparation solution and uniformly dispersed. Finally, caramel and peach flavor were added.
- the prepared solution 50 kg was sterilized at 85 ° C. for 30 minutes and then cooled to 55 ° C. Thereafter, the prepared solution was filled into an aluminum laminate tube to obtain a product.
- Production Example (2) A glycerin fatty acid ester (decaglycerin myristic acid ester) in Production Example (1) was changed to a sucrose fatty acid ester (sucrose palmitic acid ester) and produced in the same manner to obtain a product.
- the temperature was lowered to 85 ° C. and a predetermined concentration of sodium ascorbate was added.
- a solution of milbemycin oxime previously dissolved in propylene glycol was added to the preparation solution and uniformly dispersed.
- caramel and peach flavor were added.
- the prepared solution 50 kg was sterilized at 85 ° C. for 30 minutes and then cooled to 55 ° C. Thereafter, the prepared solution was filled into an aluminum laminate tube to obtain a product.
- pH stability test (1) Citric acid hydrate and anhydrous disodium hydrogen phosphate were dissolved in a solution in which 0.1% xanthan gum and 0.05% ethyl paraoxybenzoate were dissolved in purified water. By changing the ratio of these solutions and mixing them, a buffer solution having a pH of 2.6 to 7 was prepared. On the other hand, a liquid in which 2.5 g of milbemycin oxime, a medicinal component, was dispersed in 97.5 g of propylene glycol was prepared. 5 g of this dispersion and 95 g of each of the above buffers were mixed to prepare a milbemycin oxime suspension. These suspensions were filled in glass vials and plugged with rubber stoppers, and stored for 1 week at 60 ° C. and 75% RH, and then the content of medicinal components was measured to confirm the stability due to pH.
- Thermal stability test (1) The formulation described in Table 6 below and the formulation in which 1% of trehalose in this formulation is replaced with sodium ascorbate are stored at 60 ° C. and 75% RH for 3 weeks to improve the stability of the medicinal ingredients. confirmed. As shown in Table 7, it was confirmed that the one added with 1% sodium ascorbate maintained excellent stability even when stored at 60 ° C. and 75% RH for 3 weeks.
- Production Example (3) Powder mixed with a predetermined concentration of agar powder, xanthan gum, sucralose, and ethyl paraoxybenzoate in Table 8 was added to purified water in the tank. While stirring this mixed liquid, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved. Next, the temperature was lowered to 85 ° C., and anhydrous sodium monohydrogen phosphate, citric acid hydrate, and polyoxyethylene (105) polyoxypropylene (5) glycol were added thereto. Furthermore, a predetermined concentration of sodium ascorbate was added.
- pH stability test (2) A 0.1M citric acid hydrate aqueous solution containing a predetermined concentration of ethyl paraoxybenzoate in Table 9 and a 0.2M aqueous sodium monohydrogen phosphate aqueous solution were mixed at different ratios, and a buffer solution having a pH of 2.6 to 7 was added. Prepared. A predetermined concentration of xanthan gum and polyoxyethylene (105) polyoxypropylene (5) glycol were dissolved in this buffer solution. On the other hand, a solution was prepared by dissolving 30 mg of ivermectin, a medicinal component, in 30 g of propylene glycol.
- Production Example (4) Powder mixed with a predetermined concentration of agar powder, xanthan gum, sucralose and ethyl paraoxybenzoate in Table 10 was added to purified water in the tank. This mixed solution was dispersed while stirring, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved. Next, the temperature was lowered to 85 ° C., and anhydrous sodium monohydrogen phosphate, citric acid hydrate, and polyoxyethylene (105) polyoxypropylene (5) glycol were added thereto. Furthermore, a predetermined concentration of sodium ascorbate was added.
- pH stability test (3) A 0.1M citric acid hydrate aqueous solution containing a predetermined concentration of ethyl paraoxybenzoate in Table 11 and a 0.2M aqueous sodium monohydrogen phosphate aqueous solution were mixed at different ratios, and a buffer solution having a pH of 2.6 to 7 was added. Prepared. A predetermined concentration of xanthan gum and polyoxyethylene (105) polyoxypropylene (5) glycol were dissolved in this buffer solution. On the other hand, a solution was prepared by dissolving 10 mg of moxidectin as a medicinal component in 10 g of propylene glycol.
- polyoxyethylene (105) polyoxypropylene (5) glycol was dissolved in purified water, cyclosporine was added and dispersed uniformly. This dispersion was added to the preparation liquid, sterilized at 85 ° C. for 30 minutes, and then filled into an aluminum laminate tube to obtain a product.
- pH stability test (4) The predetermined concentrations of ethyl paraoxybenzoate, sodium lauryl sulfate, citric acid hydrate, and anhydrous sodium monohydrogen phosphate in Table 13 were dissolved. A cyclosporin having a predetermined concentration was dissolved therein to prepare a cyclosporine solution having a predetermined pH. These solutions were filled in glass vials and stored at 60 ° C. and 75% RH for 1 week, and then the content of medicinal components was measured to confirm the stability due to pH. As a result, as shown in FIG. 4, it was confirmed that the pH became unstable on the acidic side, but stable at pH 4-7.
- the present invention can be used to provide a jelly preparation that is chemically stable and easy to take.
- this invention was demonstrated along the specific aspect, the deformation
Abstract
Jelly formulations are problematic in that although a jelly formulation having good fluidity is obtained by increasing the water content, an increase in the water content leads to deterioration of drug stability and poor long-term shelf life. The present invention provides a pharmaceutical preparation that is chemically stable and easy to take as a result of including a dispersant for uniform dispersion of the drug active ingredient in the composition and a stabilizer that prevents degradation of the drug active ingredient due to exposure to heat.
Description
本発明は、服用し易いゼリー状医薬組成物に関する。
The present invention relates to a jelly-like pharmaceutical composition that is easy to take.
イヌに多い寄生虫としては、ノミ、マダニ、フィラリアなどがよく知られている。この中でフィラリアは内部寄生虫の一種であり、蚊が媒介することにより、宿主の体内に寄生する。フィラリアは犬糸状虫とも呼ばれ、腸管などの臓器に寄生し、宿主が消化した栄養を吸収して体内で生き続ける。感染初期は無症状だが、やがて咳や呼吸困難など心臓病と似た症状があらわれ、やがて死に至る病気である。
Fleas, ticks and filaria are well known as parasites common in dogs. Among these, filaria is a kind of endoparasite and parasitizes in the host body by being mediated by mosquitoes. Filaria, also known as dog filamentous insects, parasitize organs such as the intestinal tract, absorbs the nutrients digested by the host, and continues to live in the body. The disease is asymptomatic in the early stages of infection, but eventually suffers from symptoms similar to heart disease, such as coughing and dyspnea, and eventually death.
フィラリア症への対処としては、主に薬剤による予防的な使用が行われている。特に、蚊が発生する時期には月１回の投与が欠かせない。使用される薬剤としては、ミルベマイシンオキシム、プラジカンテル、モキシデクチン、イベルメクチン、ピランテル、セラメクチンなどが挙げられる。
予 防 As a countermeasure against filariasis, prophylactic use with drugs is mainly used. In particular, once a month is indispensable when mosquitoes occur. Examples of the drug used include milbemycin oxime, praziquantel, moxidectin, ivermectin, pirantel, and selamectin.
この中でもミルベマイシンオキシムはよく使用される薬剤であり、多くの製品が発売されている。製品の形態としては、錠剤や顆粒があり、その他にマイクロスフェア（特許文献１）、チュアブル錠（特許文献２）、ゼリー剤（特許文献３）、経粘膜吸収剤（特許文献４）なども検討されている。
Among them, milbemycin oxime is a commonly used drug, and many products are on sale. Product forms include tablets and granules. In addition, microspheres (Patent Document 1), chewable tablets (Patent Document 2), jelly agents (Patent Document 3), transmucosal absorbents (Patent Document 4), etc. are also considered. Has been.
しかし、動物に薬剤を与える場合、錠剤や顆粒などの固形の剤型では、食べ残しがあり、完全に服用できない場合がある。また、ゼリー剤であっても、前記特許文献３に記載の、最高でも９％の水を含むゼリー剤のように、水分含量の少ないものであれば、固形の剤型と同様に服用しにくい。そこで、ゼリー剤で水分含量が多くすることで、流動性のよいものが得られるが、一方で水分含量が多くなることで薬剤の安定性が悪くなるため、長期保存に耐えられないことがある。
However, when drugs are given to animals, solid dosage forms such as tablets and granules have leftovers and may not be taken completely. Moreover, even if it is a jelly agent, as long as it is a thing with little water content like the jelly agent containing the water of 9% at the maximum as described in the said patent document 3, it is hard to take like a solid dosage form. . Therefore, by increasing the water content with a jelly agent, a product with good fluidity can be obtained, but on the other hand, increasing the water content may deteriorate the stability of the drug and may not withstand long-term storage. .
そのため、服用し易く、且つ、化学的に安定性が高いゼリー状の医薬組成物が望まれる。本発明は、上記の課題を解決しようとするものであり、水分含量の高い製剤でありながら、化学的に安定なゼリー状の医薬組成物を実現することを目的とするものである。
Therefore, a jelly-like pharmaceutical composition that is easy to take and has high chemical stability is desired. An object of the present invention is to solve the above-mentioned problems, and an object of the present invention is to realize a chemically stable jelly-like pharmaceutical composition while having a high water content.
そして、本発明は、上記目的を達成するために、組成物の中に薬効成分を均一にする分散剤や、熱に対する薬効成分の劣化を抑える安定化剤を有することによって、化学的に安定で服用しやすい製剤を提供するものである。
In order to achieve the above object, the present invention is chemically stable by having a dispersing agent that makes the medicinal component uniform in the composition and a stabilizer that suppresses deterioration of the medicinal component against heat. It provides a preparation that is easy to take.
すなわち、本発明の組成物は、
［１］薬効成分、ゲル化剤、及び精製水を含んでなるゼリー状医薬組成物、
［２］薬効成分が、ミルベマイシンオキシム、モキシデクチン、イベルメクチン、アバメクチン、エマメクチン、若しくはドラメクチン、若しくはそれらの誘導体、又はそれらの製剤学的に利用可能な塩である、上記［１］に記載の医薬組成物、
［３］ゲル化剤が、ペクチン、カンテン末、カラギーナン、ジェランガム、ゼラチン、キサンタンガム、ローカストビーンガム、グアガム、タラガム、アルギン酸若しくはそのナトリウム塩、又はマンナン類である、上記［１］又は［２］に記載の医薬組成物、
［４］さらに分散剤を含んでなる、上記［１］～［３］のいずれかに記載の医薬組成物、
［５］分散剤が、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール、又はアルキル硫酸ナトリウムである、上記［４］に記載の医薬組成物、
［６］上記脂肪酸エステルにおける脂肪酸部分が、炭素数１０～１６の飽和脂肪酸である、上記［５］に記載の医薬組成物、
［７］さらに安定化剤を含んでなる、上記［１］～［６］のいずれかに記載の医薬組成物、
［８］安定化剤が、トコフェロール、没食子酸アルキル、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、亜硫酸ナトリウム、エデト酸、エデト酸ナトリウム、アスコルビン酸、又はアスコルビン酸ナトリウムである、上記［７］に記載の医薬組成物、
［９］医薬組成物のｐＨが５以上である、上記［１］～［８］のいずれかに記載の医薬組成物、
［１０］さらに賦形剤、懸濁剤、又は可溶化剤を含んでなる、上記［１］～［９］のいずれかに記載の医薬組成物、
［１１］薬効成分、ゲル化剤、分散剤、精製水を少なくとも含むゼリー状医薬組成物の製造方法であって、
ゲル化剤を精製水に添加した液を必要に応じて加熱して溶解する工程、
得られた溶液を、薬効成分が分解せず、且つ、ゲル化剤の溶解状態を維持できる温度まで冷却する工程、
前記冷却工程の後に、薬効成分および分散剤を添加する工程
を含む、前記製造方法、
［１２］薬効成分、溶解に加熱が必要なゲル化剤、分散剤、精製水を少なくとも含むゼリー状医薬組成物の製造方法であって、
薬効成分および分散剤を除く、少なくともゲル化剤を精製水に添加し、この分散液を前記ゲル化剤の溶解温度以上に加熱してゲル化剤を溶解する工程、
得られた溶液を、薬効成分が分解せず、且つ、ゲル化剤の溶解状態を維持できる温度まで冷却する工程、
前記冷却工程の後に、薬効成分および分散剤を添加する工程
を含む、前記製造方法、
［１３］薬効成分、常温で溶解するゲル化剤、分散剤、精製水を少なくとも含むゼリー状医薬組成物の製造方法であって、
薬効成分および分散剤を除く、少なくともゲル化剤を精製水に添加し、ゲル化剤を溶解する工程、
前記溶解工程の後に、薬効成分および分散剤を添加する工程
を含む、前記製造方法、
［１４］上記［１１］～［１３］のいずれかに記載の製造方法で得られる、ゼリー状医薬組成物
に関するものである。 That is, the composition of the present invention is
[1] A jelly-form pharmaceutical composition comprising a medicinal ingredient, a gelling agent, and purified water,
[2] The pharmaceutical composition according to [1] above, wherein the medicinal component is milbemycin oxime, moxidectin, ivermectin, abamectin, emamectin, doramectin, or a derivative thereof, or a pharmaceutically usable salt thereof. ,
[3] In the above [1] or [2], the gelling agent is pectin, agar powder, carrageenan, gellan gum, gelatin, xanthan gum, locust bean gum, guar gum, tara gum, alginic acid or a sodium salt thereof, or mannans. The pharmaceutical composition described,
[4] The pharmaceutical composition according to any one of the above [1] to [3], further comprising a dispersant,
[5] The dispersant is sucrose fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene (105) polyoxypropylene (5) glycol, or sodium alkyl sulfate. The pharmaceutical composition according to the above [4],
[6] The pharmaceutical composition according to the above [5], wherein the fatty acid moiety in the fatty acid ester is a saturated fatty acid having 10 to 16 carbon atoms,
[7] The pharmaceutical composition according to any one of [1] to [6], further comprising a stabilizer,
[8] The medicament according to [7] above, wherein the stabilizer is tocopherol, alkyl gallate, butylhydroxyanisole, butylhydroxytoluene, sodium sulfite, edetic acid, sodium edetate, ascorbic acid, or sodium ascorbate. Composition,
[9] The pharmaceutical composition according to any one of [1] to [8] above, wherein the pH of the pharmaceutical composition is 5 or more,
[10] The pharmaceutical composition according to any one of the above [1] to [9], further comprising an excipient, a suspending agent, or a solubilizing agent,
[11] A method for producing a jelly-form pharmaceutical composition comprising at least a medicinal ingredient, a gelling agent, a dispersant, and purified water,
A step of heating and dissolving a solution obtained by adding a gelling agent to purified water as necessary,
A step of cooling the obtained solution to a temperature at which the medicinal component is not decomposed and the gelling agent can be dissolved;
The production method comprising a step of adding a medicinal component and a dispersant after the cooling step;
[12] A method for producing a jelly-form pharmaceutical composition comprising at least a medicinal component, a gelling agent that requires heating for dissolution, a dispersant, and purified water,
Adding at least a gelling agent to purified water, excluding medicinal ingredients and a dispersing agent, and heating the dispersion above the melting temperature of the gelling agent to dissolve the gelling agent;
A step of cooling the obtained solution to a temperature at which the medicinal component is not decomposed and the gelling agent can be dissolved;
The production method comprising a step of adding a medicinal component and a dispersant after the cooling step;
[13] A method for producing a jelly-like pharmaceutical composition comprising at least a medicinal component, a gelling agent that dissolves at room temperature, a dispersant, and purified water,
Adding at least a gelling agent to purified water, excluding medicinal ingredients and a dispersant, and dissolving the gelling agent;
The production method comprising a step of adding a medicinal ingredient and a dispersant after the dissolution step,
[14] The present invention relates to a jelly-like pharmaceutical composition obtained by the production method according to any one of [11] to [13].
［１］薬効成分、ゲル化剤、及び精製水を含んでなるゼリー状医薬組成物、
［２］薬効成分が、ミルベマイシンオキシム、モキシデクチン、イベルメクチン、アバメクチン、エマメクチン、若しくはドラメクチン、若しくはそれらの誘導体、又はそれらの製剤学的に利用可能な塩である、上記［１］に記載の医薬組成物、
［３］ゲル化剤が、ペクチン、カンテン末、カラギーナン、ジェランガム、ゼラチン、キサンタンガム、ローカストビーンガム、グアガム、タラガム、アルギン酸若しくはそのナトリウム塩、又はマンナン類である、上記［１］又は［２］に記載の医薬組成物、
［４］さらに分散剤を含んでなる、上記［１］～［３］のいずれかに記載の医薬組成物、
［５］分散剤が、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール、又はアルキル硫酸ナトリウムである、上記［４］に記載の医薬組成物、
［６］上記脂肪酸エステルにおける脂肪酸部分が、炭素数１０～１６の飽和脂肪酸である、上記［５］に記載の医薬組成物、
［７］さらに安定化剤を含んでなる、上記［１］～［６］のいずれかに記載の医薬組成物、
［８］安定化剤が、トコフェロール、没食子酸アルキル、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、亜硫酸ナトリウム、エデト酸、エデト酸ナトリウム、アスコルビン酸、又はアスコルビン酸ナトリウムである、上記［７］に記載の医薬組成物、
［９］医薬組成物のｐＨが５以上である、上記［１］～［８］のいずれかに記載の医薬組成物、
［１０］さらに賦形剤、懸濁剤、又は可溶化剤を含んでなる、上記［１］～［９］のいずれかに記載の医薬組成物、
［１１］薬効成分、ゲル化剤、分散剤、精製水を少なくとも含むゼリー状医薬組成物の製造方法であって、
ゲル化剤を精製水に添加した液を必要に応じて加熱して溶解する工程、
得られた溶液を、薬効成分が分解せず、且つ、ゲル化剤の溶解状態を維持できる温度まで冷却する工程、
前記冷却工程の後に、薬効成分および分散剤を添加する工程
を含む、前記製造方法、
［１２］薬効成分、溶解に加熱が必要なゲル化剤、分散剤、精製水を少なくとも含むゼリー状医薬組成物の製造方法であって、
薬効成分および分散剤を除く、少なくともゲル化剤を精製水に添加し、この分散液を前記ゲル化剤の溶解温度以上に加熱してゲル化剤を溶解する工程、
得られた溶液を、薬効成分が分解せず、且つ、ゲル化剤の溶解状態を維持できる温度まで冷却する工程、
前記冷却工程の後に、薬効成分および分散剤を添加する工程
を含む、前記製造方法、
［１３］薬効成分、常温で溶解するゲル化剤、分散剤、精製水を少なくとも含むゼリー状医薬組成物の製造方法であって、
薬効成分および分散剤を除く、少なくともゲル化剤を精製水に添加し、ゲル化剤を溶解する工程、
前記溶解工程の後に、薬効成分および分散剤を添加する工程
を含む、前記製造方法、
［１４］上記［１１］～［１３］のいずれかに記載の製造方法で得られる、ゼリー状医薬組成物
に関するものである。 That is, the composition of the present invention is
[1] A jelly-form pharmaceutical composition comprising a medicinal ingredient, a gelling agent, and purified water,
[2] The pharmaceutical composition according to [1] above, wherein the medicinal component is milbemycin oxime, moxidectin, ivermectin, abamectin, emamectin, doramectin, or a derivative thereof, or a pharmaceutically usable salt thereof. ,
[3] In the above [1] or [2], the gelling agent is pectin, agar powder, carrageenan, gellan gum, gelatin, xanthan gum, locust bean gum, guar gum, tara gum, alginic acid or a sodium salt thereof, or mannans. The pharmaceutical composition described,
[4] The pharmaceutical composition according to any one of the above [1] to [3], further comprising a dispersant,
[5] The dispersant is sucrose fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene (105) polyoxypropylene (5) glycol, or sodium alkyl sulfate. The pharmaceutical composition according to the above [4],
[6] The pharmaceutical composition according to the above [5], wherein the fatty acid moiety in the fatty acid ester is a saturated fatty acid having 10 to 16 carbon atoms,
[7] The pharmaceutical composition according to any one of [1] to [6], further comprising a stabilizer,
[8] The medicament according to [7] above, wherein the stabilizer is tocopherol, alkyl gallate, butylhydroxyanisole, butylhydroxytoluene, sodium sulfite, edetic acid, sodium edetate, ascorbic acid, or sodium ascorbate. Composition,
[9] The pharmaceutical composition according to any one of [1] to [8] above, wherein the pH of the pharmaceutical composition is 5 or more,
[10] The pharmaceutical composition according to any one of the above [1] to [9], further comprising an excipient, a suspending agent, or a solubilizing agent,
[11] A method for producing a jelly-form pharmaceutical composition comprising at least a medicinal ingredient, a gelling agent, a dispersant, and purified water,
A step of heating and dissolving a solution obtained by adding a gelling agent to purified water as necessary,
A step of cooling the obtained solution to a temperature at which the medicinal component is not decomposed and the gelling agent can be dissolved;
The production method comprising a step of adding a medicinal component and a dispersant after the cooling step;
[12] A method for producing a jelly-form pharmaceutical composition comprising at least a medicinal component, a gelling agent that requires heating for dissolution, a dispersant, and purified water,
Adding at least a gelling agent to purified water, excluding medicinal ingredients and a dispersing agent, and heating the dispersion above the melting temperature of the gelling agent to dissolve the gelling agent;
A step of cooling the obtained solution to a temperature at which the medicinal component is not decomposed and the gelling agent can be dissolved;
The production method comprising a step of adding a medicinal component and a dispersant after the cooling step;
[13] A method for producing a jelly-like pharmaceutical composition comprising at least a medicinal component, a gelling agent that dissolves at room temperature, a dispersant, and purified water,
Adding at least a gelling agent to purified water, excluding medicinal ingredients and a dispersant, and dissolving the gelling agent;
The production method comprising a step of adding a medicinal ingredient and a dispersant after the dissolution step,
[14] The present invention relates to a jelly-like pharmaceutical composition obtained by the production method according to any one of [11] to [13].
本発明の医薬組成物によれば、水分含量が高く、流動性があって服用しやすく、化学的に安定で含量の均一なゼリー状の組成物を提供することができる。
According to the pharmaceutical composition of the present invention, it is possible to provide a jelly-like composition having a high water content, fluidity, easy to take, chemically stable and uniform content.
以下では、本発明について、更に詳細に説明する。
本発明における薬効成分として用いることのできるミルベマイシンオキシムは、下記の化学構造式：
で示される白色～帯黄白色の無味の粉末であり、においはないか、又はわずかに特異なにおいがある。また、水にはほとんど溶けない。この薬効成分は、ミルベマイシンＡ３オキシムとミルベマイシンＡ４オキシムの混合物からなり、その比率はミルベマイシンＡ３オキシムが２０％以下、ミルベマイシンＡ４オキシムは８０％以上である。上記構造式において、Ｒがメチル基であるとき、ミルベマイシンＡ３オキシムであり、Ｒがエチル基であるとき、ミルベマイシンＡ４オキシムである。
Hereinafter, the present invention will be described in more detail.
Milbemycin oxime that can be used as a medicinal component in the present invention has the following chemical structural formula:
A white to yellowish white tasteless powder represented by the formula, having no odor or a slightly unique odor. Moreover, it hardly dissolves in water. The medicinal ingredient may consist of a mixture of milbemycin A 3 oxime and milbemycin A 4 oxime, the ratio milbemycin A 3 oxime 20% or less, milbemycin A 4 oxime is 80% or more. In the above structural formula, when R is a methyl group, it is milbemycin A 3 oxime, and when R is an ethyl group, it is milbemycin A 4 oxime.
本発明における薬効成分として用いることのできるミルベマイシンオキシムは、下記の化学構造式：
Milbemycin oxime that can be used as a medicinal component in the present invention has the following chemical structural formula:
また、これ以外の薬効成分として、マクロライド系の抗生物質およびこれらの誘導体を本発明の医薬組成物に使用することができる。具体的には、例えば、モキシデクチン、イベルメクチン、アバメクチン、エマメクチン、若しくはドラメクチン、若しくはそれらの誘導体を使用することができ、これらの化合物は、遊離の形または製剤学的に利用可能な塩の形で使用することができる。また、本発明の医薬組成物に環状ペプチド抗生物質を使用することもできる。具体的には、シクロスポリン、バンコマイシン、エリスロマイシンなどが挙げられる。
In addition, as other medicinal ingredients, macrolide antibiotics and derivatives thereof can be used in the pharmaceutical composition of the present invention. Specifically, for example, moxidectin, ivermectin, abamectin, emamectin, or doramectin, or derivatives thereof can be used, and these compounds can be used in free form or in the form of pharmaceutically available salts. can do. Cyclic peptide antibiotics can also be used in the pharmaceutical composition of the present invention. Specific examples include cyclosporine, vancomycin, erythromycin and the like.
本発明における薬効成分（特にミルベマイシンオキシム）の投与量は、適宜調整しながら、投与することができるが、好ましくは、体重１ｋｇ当たり０．１～１．５ｍｇの投与量であり、より好ましくは体重１ｋｇ当たり０．２５～１．０ｍｇの投与量である。また、薬効成分の含有量は、単位製剤当たり、好ましくは０．０１２５～１．２５重量％であり、より好ましくは０．０２５～０．６２５重量％である。
The dose of the medicinal component (especially milbemycin oxime) in the present invention can be administered while appropriately adjusting, but is preferably a dose of 0.1 to 1.5 mg per kg body weight, more preferably body weight. The dosage is 0.25 to 1.0 mg per kg. Further, the content of the medicinal component is preferably 0.0125 to 1.25% by weight, more preferably 0.025 to 0.625% by weight, per unit preparation.
本発明における溶剤としては、精製水やエタノールなどを使用することができる。
As the solvent in the present invention, purified water, ethanol or the like can be used.
本発明の医薬組成物はゼリー状の組成物であり、水分を含有している。その含有量は特に限定されるものではないが、単位製剤当たり５０～９５重量％であることが好ましい。
The pharmaceutical composition of the present invention is a jelly-like composition and contains water. The content is not particularly limited, but is preferably 50 to 95% by weight per unit preparation.
本発明の医薬組成物には、製薬学的に許容される添加剤を適宜添加することができる。具体的な添加剤としては、例えば、賦形剤、ゲル化剤、分散剤、懸濁剤、可溶化剤、甘味剤、安定化剤、ｐＨ調節剤、香料、防腐剤、着色剤などが挙げられる。なお、本発明の医薬組成物は油脂（植物油脂および動物油脂）を含まない。
Pharmacologically acceptable additives can be appropriately added to the pharmaceutical composition of the present invention. Specific additives include, for example, excipients, gelling agents, dispersing agents, suspending agents, solubilizing agents, sweetening agents, stabilizing agents, pH adjusting agents, fragrances, preservatives, coloring agents and the like. It is done. In addition, the pharmaceutical composition of this invention does not contain fats and oils (a vegetable oil and animal fats and oils).
本発明における賦形剤としては、糖アルコールを使用することができる。糖アルコールとしては、例えば、マルチトール、ラクチトール、マンニトール、エリスリトール、キシリトール、トレハロース、又はソルビトールなどを使用することができる。これらの糖アルコールは、１種類のみを用いてもよく、適宜２種以上を併用してもよい。
Sugar alcohol can be used as an excipient in the present invention. As the sugar alcohol, for example, maltitol, lactitol, mannitol, erythritol, xylitol, trehalose, or sorbitol can be used. These sugar alcohols may be used alone or in combination of two or more as appropriate.
本発明におけるゲル化剤としては、例えば、ペクチン、カンテン末、カラギーナン、ジェランガム、ゼラチン、キサンタンガム、ローカストビーンガム、グアガム、タラガム、アルギン酸若しくはそのナトリウム塩、又はマンナン類などを使用することができる。これらのゲル化剤の溶解温度を表１に示す。これらのゲル化剤は、１種類のみを用いてもよく、適宜２種以上を併用してもよい。ゲル化剤の含有量は、単位製剤当たり、好ましくは０．０１～５重量％であり、より好ましくは０．１～３重量％である。
As the gelling agent in the present invention, for example, pectin, agar powder, carrageenan, gellan gum, gelatin, xanthan gum, locust bean gum, guar gum, tara gum, alginic acid or its sodium salt, or mannans can be used. The dissolution temperature of these gelling agents is shown in Table 1. These gelling agents may use only 1 type and may use 2 or more types together suitably. The content of the gelling agent is preferably 0.01 to 5% by weight, more preferably 0.1 to 3% by weight, per unit preparation.
本発明の医薬組成物では、薬効成分を均一に分散させることが均一な品質を維持するためには重要である。分散剤によっては、主成分を分散させずに、逆に凝集を起こさせて塊になる場合もあるため、最適な分散剤を使用することが大切である。
In the pharmaceutical composition of the present invention, it is important to uniformly disperse medicinal ingredients in order to maintain uniform quality. Depending on the dispersant, the main component may not be dispersed, and conversely, agglomeration may occur to form a lump, so it is important to use an optimal dispersant.
本発明における分散剤としては、例えば、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル（脂肪酸とグリセリン又はポリグリセリンのエステル及びその誘導体を含む）、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール、又はアルキル硫酸ナトリウムなどを使用することができる。これらのエステルを構成する脂肪酸は、炭素数１０～１６の飽和脂肪酸を使用することが好ましい。具体的な脂肪酸としては、カプリン酸（Ｃ１０）、ウンデシル酸（Ｃ１１）、ラウリン酸（Ｃ１２）、トリデシル酸（Ｃ１３）、ミリスチン酸（Ｃ１４）、ペンタデシル酸（Ｃ１５）、パルミチン酸（Ｃ１６）が挙げられる。構成する脂肪酸は１種類のみではなく、２種以上が含まれていてもよい。また、ポリグリセリン脂肪酸エステルのグリセリンの平均重合度は６～１５が好ましく、８～１０がより好ましい。
Examples of the dispersant in the present invention include sucrose fatty acid ester, glycerin fatty acid ester (including fatty acid and glycerin or polyglycerin ester and derivatives thereof), polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene. (105) Polyoxypropylene (5) glycol, sodium alkyl sulfate, or the like can be used. The fatty acid constituting these esters is preferably a saturated fatty acid having 10 to 16 carbon atoms. Specific fatty acids include capric acid (C 10 ), undecyl acid (C 11 ), lauric acid (C 12 ), tridecyl acid (C 13 ), myristic acid (C 14 ), pentadecylic acid (C 15 ), palmitic acid. acid (C 16) and the like. The fatty acid which comprises is not only 1 type, but 2 or more types may be contained. Further, the average degree of polymerization of glycerin fatty acid ester is preferably 6-15, more preferably 8-10.
これらの分散剤は、１種類のみを用いてもよく、また２種以上を併用してもよい。具体的な分散剤としては、例えば、ショ糖ラウリン酸エステル、ショ糖ミリスチン酸エステル、ショ糖パルミチン酸エステル、デカグリセリンカプリル酸エステル、デカグリセリンラウリン酸エステル、デカグリセリンミリスチン酸エステル、ラウリル硫酸ナトリウム等が挙げられる。それらの中で、ショ糖パルミチン酸エステル、デカグリセリンラウリン酸エステル、デカグリセリンミリスチン酸エステル、ラウリル硫酸ナトリウムがより好ましい。
These dispersants may be used alone or in combination of two or more. Specific dispersants include, for example, sucrose laurate, sucrose myristate, sucrose palmitate, decaglycerin caprylate, decaglycerin laurate, decaglycerin myristate, sodium lauryl sulfate, etc. Is mentioned. Among them, sucrose palmitic acid ester, decaglycerin lauric acid ester, decaglycerin myristic acid ester, and sodium lauryl sulfate are more preferable.
本発明における懸濁剤としては、例えば、カルメロースナトリウム、キサンタンガム、メチルセルロース、トラガントなどを使用することができる。これらの懸濁剤は、１種類のみを用いてもよく、適宜２種以上を併用してもよい。
As the suspending agent in the present invention, for example, carmellose sodium, xanthan gum, methylcellulose, tragacanth and the like can be used. These suspending agents may use only 1 type and may use 2 or more types together suitably.
本発明における可溶化剤としては、例えば、プロピレングリコール、グリセロール、ポリエチレングリコールなどを使用することができる。これらの可溶化剤は、１種類のみを用いてもよく、適宜２種以上を併用してもよい。
As the solubilizer in the present invention, for example, propylene glycol, glycerol, polyethylene glycol and the like can be used. These solubilizers may use only 1 type and may use 2 or more types together suitably.
本発明における甘味剤としては、例えば、ショ糖、還元麦芽糖水飴、人工甘味料であるアセスルファムカリウム、スクラロース、アスパルテーム、サッカリン、サッカリンナトリウム、ステビア、ソーマチンなどを使用することができる。これらの甘味剤は、１種類のみを用いてもよく、適宜２種以上を併用してもよい。
As the sweetener in the present invention, for example, sucrose, reduced maltose starch syrup, artificial sweeteners acesulfame potassium, sucralose, aspartame, saccharin, saccharin sodium, stevia, thaumatin and the like can be used. These sweeteners may use only 1 type and may use 2 or more types together suitably.
本発明の医薬組成物は、高い水分含量を有していることから、溶存酸素に晒されることにより、主成分が不安定になることから、安定化剤により安定性を高めることが重要である。本発明における安定化剤としては、例えば、トコフェロール、没食子酸アルキル、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、亜硫酸ナトリウム、エデト酸、エデト酸ナトリウム、エリソルビン酸、エリソルビン酸ナトリウム、アスコルビン酸、又はアスコルビン酸ナトリウムなどを使用することができる。その中でもアスコルビン酸、アスコルビン酸ナトリウムが好ましい。本発明における安定化剤の使用量は特に制限されないが、本発明の組成物の全量に対して、１～６重量％の濃度で添加することが好ましい。安定化剤は、１種類のみを用いてもよく、適宜２種以上を併用してもよい。
Since the pharmaceutical composition of the present invention has a high water content, the main component becomes unstable when exposed to dissolved oxygen, so it is important to increase the stability with a stabilizer. . Examples of the stabilizer in the present invention include tocopherol, alkyl gallate, butylhydroxyanisole, butylhydroxytoluene, sodium sulfite, edetic acid, sodium edetate, erythorbic acid, sodium erythorbate, ascorbic acid, and sodium ascorbate. Can be used. Among these, ascorbic acid and sodium ascorbate are preferable. The amount of the stabilizer used in the present invention is not particularly limited, but it is preferably added at a concentration of 1 to 6% by weight with respect to the total amount of the composition of the present invention. Only one type of stabilizer may be used, or two or more types may be used in combination as appropriate.
本発明におけるｐＨ調節剤としては、例えば、クエン酸（水和物を含む）、クエン酸ナトリウム、クエン酸カリウム、水酸化ナトリウム、モノエタノールアミン、ジエタノールアミン、酒石酸、プロピオン酸、乳酸、リンゴ酸、コハク酸ナトリウム、グルタミン酸一ナトリウム、リン酸ナトリウム、リン酸水素二ナトリウム、リン酸二水素ナトリウム、リン酸カリウム、リン酸水素二カリウム、又はリン酸二水素カリウムなどを使用することができる。これらのｐＨ調節剤は、所定のｐＨに調整できるように、溶液にして、あるいはそのまま組成物に添加することができる。これらのｐＨ調節剤は、１種類のみを用いてもよく、適宜２種以上を併用してもよい。本発明の医薬組成物のｐＨとしては、ｐＨ５以上であれば、組成物は安定であり、好ましくはｐＨ５～７の範囲内であればよい。
Examples of the pH adjuster in the present invention include citric acid (including hydrate), sodium citrate, potassium citrate, sodium hydroxide, monoethanolamine, diethanolamine, tartaric acid, propionic acid, lactic acid, malic acid, and succinic acid. Sodium phosphate, monosodium glutamate, sodium phosphate, disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, or the like can be used. These pH regulators can be added to the composition in the form of a solution or as they are so that the pH can be adjusted to a predetermined pH. These pH regulators may be used alone or in combination of two or more as appropriate. The pH of the pharmaceutical composition of the present invention is stable as long as the pH is 5 or more, and preferably within the range of pH 5-7.
本発明における香料としては、例えば、アップルフレーバー、アセロラフレーバー、オレンジフレーバー、グレープフレーバー、ストロベリーフレーバー、スイートポテトフレーバー、チョコレートフレーバー、ビーフフレーバー、ピーチフレーバー、メイプルフレーバー、又はトマトフレーバーなどを使用することができる。その中でも、ピーチフレーバー、トマトフレーバーが好ましい。これらの香料は、１種類のみを用いてもよく、適宜２種以上を併用してもよい。
As the fragrance in the present invention, for example, apple flavor, acerola flavor, orange flavor, grape flavor, strawberry flavor, sweet potato flavor, chocolate flavor, beef flavor, peach flavor, maple flavor, or tomato flavor can be used. . Among these, peach flavor and tomato flavor are preferable. These fragrance | flavors may use only 1 type and may use 2 or more types together suitably.
本発明における防腐剤としては、例えば、ソルビン酸カリウム、ソルビン酸、安息香酸ナトリウム、パラオキシ安息香酸メチル、パラオキシ安息香酸エチル、パラオキシ安息香酸プロピル、又はパラオキシ安息香酸ブチルなどを使用することができる。その中でも、好ましくは、パラオキシ安息香酸メチル、パラオキシ安息香酸エチルである。これらの防腐剤は、１種類のみを用いてもよく、防腐効果をより高めるために、適宜２種以上を組み合わせて使用することもできる。
As the preservative in the present invention, for example, potassium sorbate, sorbic acid, sodium benzoate, methyl paraoxybenzoate, ethyl paraoxybenzoate, propyl paraoxybenzoate, or butyl paraoxybenzoate can be used. Of these, methyl paraoxybenzoate and ethyl paraoxybenzoate are preferable. These preservatives may be used alone or in combination of two or more as appropriate in order to further enhance the antiseptic effect.
本発明における着色料としては、一般的な合成着色料に加え、食用色素、β－カロチン、カラメルなどを使用することができる。これらの着色料は、１種類のみを用いてもよく、適宜２種以上を併用してもよい。
As the colorant in the present invention, food colors, β-carotene, caramel and the like can be used in addition to general synthetic colorants. Only 1 type may be used for these coloring agents, and 2 or more types may be used together suitably.
本発明の医薬組成物を保存する容器は特に限定されるものではなく、例えば、カップ容器、チアパック（登録商標）類似容器、ボトル状やスティック状などの容器に充填して、製品とすることができる。携帯性や服用性などの利便性を考慮した場合、スティック状の容器が好ましい。
The container for storing the pharmaceutical composition of the present invention is not particularly limited. For example, the container may be filled with a cup container, a Cheapack (registered trademark) -like container, a bottle shape, a stick shape, or the like to obtain a product. it can. In consideration of convenience such as portability and administration, a stick-shaped container is preferable.
また、容器の材質も特に限定されないが、薬物の安定性を保持できるアルミラミネートが好ましく、場合によっては、脱酸素剤が混ぜ込まれたようなラミネートシートで、ゼリー中の酸素を除去し、薬物の酸化を防ぐようなものでも良い。
Further, although the material of the container is not particularly limited, an aluminum laminate capable of maintaining the stability of the drug is preferable. In some cases, the oxygen in the jelly is removed with a laminate sheet mixed with an oxygen scavenger, and the drug is stored. It may be one that prevents oxidation.
本発明の医薬組成物は、通常のゼリー製剤の製造方法により製造することができる。例えば、溶剤である精製水を適量加えた後、ゲル化剤を添加して溶解させる。この液を撹拌しながら必要に応じて加熱することにより、あるいは、常温において、ゲル化剤を完全に溶解させた後、他の種々の添加剤を加える。ゲル化剤の溶解温度は、選択するゲル化剤の種類に応じて適宜決定することができるが、例えば、カンテン末では９５℃以上で溶解する。その後、薬効成分を添加し、良く撹拌して、分散・懸濁状態として均質化し、必要に応じてその懸濁液を冷却することにより、ゼリー組成物を得ることができる。
The pharmaceutical composition of the present invention can be produced by a usual method for producing a jelly preparation. For example, after adding an appropriate amount of purified water as a solvent, a gelling agent is added and dissolved. Various other additives are added by heating the liquid as necessary while stirring, or after completely dissolving the gelling agent at room temperature. The melting temperature of the gelling agent can be appropriately determined according to the type of the gelling agent to be selected. Thereafter, a medicinal component is added, stirred well, homogenized in a dispersed / suspended state, and the suspension is cooled as necessary to obtain a jelly composition.
本発明の医薬組成物の製造において、より品質を安定させるためには、分散剤、安定化剤、または薬効成分の添加温度または添加時期が重要である。安定化剤や薬効成分はそれ自体が熱に対してあまり安定性が高くない場合には、出来るだけ、製造工程の後半で添加するほうがよく、また液温は低いほうがよい。この場合、薬効成分は可溶化剤に分散させて添加するほうがより好ましい。また、分散剤は液温が高いと撹拌することにより発泡しやすくなるため、出来るだけ、所定温度まで液温を下げたほうがよい。分散剤を添加する際の温度は、選択する分散剤の種類に応じて適宜決定することができるが、調製中に薬効成分が分解せず、且つ、ゲル化剤の溶解状態を維持できる温度であることが好ましい。例えば、ゲル化剤としてカンテン末を使用し、分散剤として脂肪酸エステルを用いる場合、８５℃以下に下げることが好ましい。高温に曝すことが好ましくない成分を配合する場合においては、上記で得られる溶液または懸濁液が適当な温度になるまで放置した後に、当該成分を添加し、さらに冷却してゼリー状組成物を得てもよく、あるいは高温に曝すのが好ましくない成分を冷却直前に添加して組成物を得てもよい。
In the production of the pharmaceutical composition of the present invention, in order to stabilize the quality, the addition temperature or addition timing of the dispersant, stabilizer, or medicinal component is important. If the stabilizer or medicinal component itself is not very stable against heat, it is better to add it as late as possible, and the liquid temperature should be low. In this case, it is more preferable that the medicinal component is added after being dispersed in a solubilizer. Moreover, since a dispersing agent becomes easy to foam by stirring if a liquid temperature is high, it is better to lower a liquid temperature to predetermined temperature as much as possible. The temperature at which the dispersant is added can be appropriately determined according to the type of the dispersant selected, but it is a temperature at which the medicinal component does not decompose during the preparation and the dissolved state of the gelling agent can be maintained. Preferably there is. For example, when agar powder is used as the gelling agent and a fatty acid ester is used as the dispersing agent, it is preferably lowered to 85 ° C. or lower. In the case of blending a component that is not preferable to be exposed to a high temperature, after allowing the solution or suspension obtained above to reach an appropriate temperature, the component is added and further cooled to obtain a jelly-like composition. The composition may be obtained by adding a component that is not preferable to be exposed to high temperature immediately before cooling.
このようにして得られる医薬組成物の包装形態は、特に限定されないが、先に示したように薬効成分の１回投与量を１つのスティックに充填することが好ましい。ここでの充填およびシールの方法は、常法により行なわれる。
The packaging form of the pharmaceutical composition thus obtained is not particularly limited, but it is preferable to fill a single stick with a single dose of the medicinal component as described above. The filling and sealing methods here are performed in a conventional manner.
本発明の医薬組成物は、ゼリー化している点、水分含量が５０％以上と高く、且つ有効な分散剤を含有する点、しかも薬効成分の安定性が確保できる点、飲みやすい点、薬剤の偏りがない点といった特徴を有する。更に、本発明の医薬組成物は、経口投与の際に水を要しないという特徴も有する。
The pharmaceutical composition of the present invention is a jelly, has a high water content of 50% or more, contains an effective dispersant, can ensure the stability of medicinal ingredients, is easy to drink, It has the feature that there is no bias. Furthermore, the pharmaceutical composition of the present invention has a feature that water is not required for oral administration.
以下に、実施例を挙げて、本発明をさらに具体的に説明するが、これらの実施例は、例示であって、本発明を限定するものではない。また、本発明のゼリー状医薬組成物中の添加物は、日本薬局方、医薬品添加物規格、食品添加物等の公定書に適合したものを使用した。
Hereinafter, the present invention will be described more specifically with reference to examples. However, these examples are illustrative and do not limit the present invention. In addition, as the additive in the jelly-like pharmaceutical composition of the present invention, an additive that conforms to official documents such as Japanese Pharmacopoeia, Pharmaceutical Additive Standard, Food Additive, etc. was used.
１．製造実施例（１）
表２の所定濃度のカンテン末、カルメロースナトリウム、トレハロース、スクラロース、クエン酸、無水リン酸水素二ナトリウム、及びパラオキシ安息香酸エチルを混合した粉末をタンク内の精製水に添加した。この混合液を撹拌しながら分散させ、９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。 1. Manufacturing Example (1)
Powder containing a mixture of agar powder, carmellose sodium, trehalose, sucralose, citric acid, anhydrous disodium hydrogen phosphate, and ethyl paraoxybenzoate in Table 2 was added to purified water in the tank. This mixed liquid was dispersed while stirring, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
表２の所定濃度のカンテン末、カルメロースナトリウム、トレハロース、スクラロース、クエン酸、無水リン酸水素二ナトリウム、及びパラオキシ安息香酸エチルを混合した粉末をタンク内の精製水に添加した。この混合液を撹拌しながら分散させ、９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。 1. Manufacturing Example (1)
Powder containing a mixture of agar powder, carmellose sodium, trehalose, sucralose, citric acid, anhydrous disodium hydrogen phosphate, and ethyl paraoxybenzoate in Table 2 was added to purified water in the tank. This mixed liquid was dispersed while stirring, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
次に８５℃まで温度を下げ、そこへ所定濃度のグリセリン脂肪酸エステル（デカグリセリンミリスチン酸エステル）を添加した。さらに、所定濃度のアスコルビン酸ナトリウムを添加した。そこへ、あらかじめプロピレングリコールに溶解させたミルベマイシンオキシムの溶液を調製液に添加し、均一分散化させた。最後にカラメルおよびピーチフレーバーを投入した。この調製液５０ｋｇを８５℃で３０分間殺菌を行った後、５５℃まで冷却した。その後、調製液をアルミラミネートのチューブに充てんし、製品を得た。
Next, the temperature was lowered to 85 ° C., and a predetermined concentration of glycerin fatty acid ester (decaglycerin myristic acid ester) was added thereto. Furthermore, a predetermined concentration of sodium ascorbate was added. Thereto, a solution of milbemycin oxime previously dissolved in propylene glycol was added to the preparation solution and uniformly dispersed. Finally, caramel and peach flavor were added. The prepared solution 50 kg was sterilized at 85 ° C. for 30 minutes and then cooled to 55 ° C. Thereafter, the prepared solution was filled into an aluminum laminate tube to obtain a product.
２．製造実施例（２）
製造実施例（１）のグリセリン脂肪酸エステル（デカグリセリンミリスチン酸エステル）をショ糖脂肪酸エステル（ショ糖パルミチン酸エステル）へ変更して、同様に製造し、製品を得た。 2. Production Example (2)
A glycerin fatty acid ester (decaglycerin myristic acid ester) in Production Example (1) was changed to a sucrose fatty acid ester (sucrose palmitic acid ester) and produced in the same manner to obtain a product.
製造実施例（１）のグリセリン脂肪酸エステル（デカグリセリンミリスチン酸エステル）をショ糖脂肪酸エステル（ショ糖パルミチン酸エステル）へ変更して、同様に製造し、製品を得た。 2. Production Example (2)
A glycerin fatty acid ester (decaglycerin myristic acid ester) in Production Example (1) was changed to a sucrose fatty acid ester (sucrose palmitic acid ester) and produced in the same manner to obtain a product.
３．製造比較例
表２の所定濃度のグリセリン脂肪酸エステル（デカグリセリンミリスチン酸エステル）をタンク内の精製水に添加し溶解させた後、所定濃度のカンテン末、カルメロースナトリウム、トレハロース、スクラロース、クエン酸、無水リン酸水素二ナトリウム、及びパラオキシ安息香酸エチルを混合した粉末を更に添加した。この混合液を撹拌しながら分散させ、９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。 3. Production Comparative Example After adding a predetermined concentration of glycerin fatty acid ester (decaglycerin myristic acid ester) in Table 2 to purified water in the tank and dissolving it, a predetermined concentration of agar powder, carmellose sodium, trehalose, sucralose, citric acid, A powder mixed with anhydrous disodium hydrogen phosphate and ethyl parahydroxybenzoate was further added. This mixed liquid was dispersed while stirring, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
表２の所定濃度のグリセリン脂肪酸エステル（デカグリセリンミリスチン酸エステル）をタンク内の精製水に添加し溶解させた後、所定濃度のカンテン末、カルメロースナトリウム、トレハロース、スクラロース、クエン酸、無水リン酸水素二ナトリウム、及びパラオキシ安息香酸エチルを混合した粉末を更に添加した。この混合液を撹拌しながら分散させ、９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。 3. Production Comparative Example After adding a predetermined concentration of glycerin fatty acid ester (decaglycerin myristic acid ester) in Table 2 to purified water in the tank and dissolving it, a predetermined concentration of agar powder, carmellose sodium, trehalose, sucralose, citric acid, A powder mixed with anhydrous disodium hydrogen phosphate and ethyl parahydroxybenzoate was further added. This mixed liquid was dispersed while stirring, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
次に８５℃まで温度を下げ、所定濃度のアスコルビン酸ナトリウムを添加した。そこへ、あらかじめプロピレングリコールに溶解させたミルベマイシンオキシムの溶液を調製液に添加し、均一分散化させた。最後にカラメルおよびピーチフレーバーを投入した。この調製液５０ｋｇを８５℃で３０分間殺菌を行った後、５５℃まで冷却した。その後、調製液をアルミラミネートのチューブに充てんし、製品を得た。
Next, the temperature was lowered to 85 ° C. and a predetermined concentration of sodium ascorbate was added. Thereto, a solution of milbemycin oxime previously dissolved in propylene glycol was added to the preparation solution and uniformly dispersed. Finally, caramel and peach flavor were added. The prepared solution 50 kg was sterilized at 85 ° C. for 30 minutes and then cooled to 55 ° C. Thereafter, the prepared solution was filled into an aluminum laminate tube to obtain a product.
４．タンク内の含量均一性試験
製造実施例（１）及び製造比較例に基づきゼリー液を調製し、調製タンクTZY-100-03184型（ユニコントロールズ株式会社製）の上層、中層、及び下層の薬効成分の含量を測定した。 4). Content uniformity test in tank Prepare jelly liquid based on production example (1) and production comparative example, and effect on upper layer, middle layer and lower layer of preparation tank TZY-100-03184 type (manufactured by Unicontrols Co., Ltd.) The content of the components was measured.
製造実施例（１）及び製造比較例に基づきゼリー液を調製し、調製タンクTZY-100-03184型（ユニコントロールズ株式会社製）の上層、中層、及び下層の薬効成分の含量を測定した。 4). Content uniformity test in tank Prepare jelly liquid based on production example (1) and production comparative example, and effect on upper layer, middle layer and lower layer of preparation tank TZY-100-03184 type (manufactured by Unicontrols Co., Ltd.) The content of the components was measured.
その結果、表３に示したように、製造実施例（１）では、タンク内のどの部分においてもすべて含量は１００％程度得られており、含量が均一であることが確認されたが、製造比較例においては、タンク上層で含量が著しく高くなり、含量が不均一になることが分かった。これは調製液の温度を下げずに、分散剤を添加したために、分散剤が泡立ち、その泡に薬効成分が抱き込まれたことに起因するものである。
As a result, as shown in Table 3, in the production example (1), it was confirmed that the content was about 100% in any part of the tank, and the content was uniform. In the comparative example, it was found that the content was remarkably high in the upper layer of the tank, and the content became non-uniform. This is due to the fact that the dispersant was foamed without lowering the temperature of the preparation liquid, so that the dispersant foamed and the medicinal component was entrapped in the foam.
５．分散性試験
表４の原料を使用して、製造実施例（１）と同様の方法により、分散剤の種類が異なるゼリー状の組成物を調製した。なお、製造実施例（１）では、５５℃まで冷却した後、調製液をアルミラミネートチューブに充てんしたが、本試験では、５５℃まで冷却した調製液を、それぞれ１０ｍＬずつ容器（約２６ｍＬ容量のプラスチック容器：上部直径４０ｍｍ、底部直径３５ｍｍ、高さ３０ｍｍのテーパー容器）に充填し、自然冷却して固化させた後、容器から水平に広げたペーパータオル上にゼリーを静かに取り出して底面を上にして観察した。また、試験に用いた分散剤は、表５に示した。 5. Dispersibility test Using the raw materials shown in Table 4, jelly-like compositions having different types of dispersants were prepared in the same manner as in Production Example (1). In Production Example (1), after cooling to 55 ° C., the prepared solution was filled in an aluminum laminate tube. In this test, 10 mL each of the prepared solution cooled to 55 ° C. was added to each container (approximately 26 mL capacity). Plastic container: taper container (top diameter 40mm, bottom diameter 35mm, height 30mm), and after natural cooling and solidification, gently take out the jelly on a paper towel spread horizontally from the container, with the bottom face up And observed. The dispersant used in the test is shown in Table 5.
表４の原料を使用して、製造実施例（１）と同様の方法により、分散剤の種類が異なるゼリー状の組成物を調製した。なお、製造実施例（１）では、５５℃まで冷却した後、調製液をアルミラミネートチューブに充てんしたが、本試験では、５５℃まで冷却した調製液を、それぞれ１０ｍＬずつ容器（約２６ｍＬ容量のプラスチック容器：上部直径４０ｍｍ、底部直径３５ｍｍ、高さ３０ｍｍのテーパー容器）に充填し、自然冷却して固化させた後、容器から水平に広げたペーパータオル上にゼリーを静かに取り出して底面を上にして観察した。また、試験に用いた分散剤は、表５に示した。 5. Dispersibility test Using the raw materials shown in Table 4, jelly-like compositions having different types of dispersants were prepared in the same manner as in Production Example (1). In Production Example (1), after cooling to 55 ° C., the prepared solution was filled in an aluminum laminate tube. In this test, 10 mL each of the prepared solution cooled to 55 ° C. was added to each container (approximately 26 mL capacity). Plastic container: taper container (top diameter 40mm, bottom diameter 35mm, height 30mm), and after natural cooling and solidification, gently take out the jelly on a paper towel spread horizontally from the container, with the bottom face up And observed. The dispersant used in the test is shown in Table 5.
目視で確認した結果、表５に示すように、実施例１～３では、薬効成分が均一に分散されていることが確認された。しかし、エステルの脂肪酸がステアリン酸の分散剤（比較例１～２）は、薬効成分が均一に分散されず、凝集して塊になっていることが確認された。
As a result of visual confirmation, as shown in Table 5, in Examples 1 to 3, it was confirmed that the medicinal components were uniformly dispersed. However, it was confirmed that in the dispersant (Comparative Examples 1 and 2) in which the fatty acid of the ester is stearic acid, the medicinal components are not uniformly dispersed but aggregated into a lump.
６.ｐＨ安定性試験（１）
精製水に０．１％キサンタンガム、０．０５％パラオキシ安息香酸エチルを溶解させた溶液に、クエン酸水和物、無水リン酸水素二ナトリウムをそれぞれ溶解させた。これらの溶液の比率を変えて混合し、ｐＨ２．６～７の緩衝液を調製した。他方、薬効成分のミルベマイシンオキシム２．５ｇをプロピレングリコール９７．５ｇに分散させた液を調製した。この分散液５ｇと前記の各緩衝液９５ｇを混合し、ミルベマイシンオキシム懸濁液を調製した。これらの懸濁液をガラスバイアルに充填し、ゴム栓で栓をしたものを、６０℃、７５％ＲＨで１週間保存した後、薬効成分の含量を測定し、ｐＨによる安定性を確認した。 6. pH stability test (1)
Citric acid hydrate and anhydrous disodium hydrogen phosphate were dissolved in a solution in which 0.1% xanthan gum and 0.05% ethyl paraoxybenzoate were dissolved in purified water. By changing the ratio of these solutions and mixing them, a buffer solution having a pH of 2.6 to 7 was prepared. On the other hand, a liquid in which 2.5 g of milbemycin oxime, a medicinal component, was dispersed in 97.5 g of propylene glycol was prepared. 5 g of this dispersion and 95 g of each of the above buffers were mixed to prepare a milbemycin oxime suspension. These suspensions were filled in glass vials and plugged with rubber stoppers, and stored for 1 week at 60 ° C. and 75% RH, and then the content of medicinal components was measured to confirm the stability due to pH.
精製水に０．１％キサンタンガム、０．０５％パラオキシ安息香酸エチルを溶解させた溶液に、クエン酸水和物、無水リン酸水素二ナトリウムをそれぞれ溶解させた。これらの溶液の比率を変えて混合し、ｐＨ２．６～７の緩衝液を調製した。他方、薬効成分のミルベマイシンオキシム２．５ｇをプロピレングリコール９７．５ｇに分散させた液を調製した。この分散液５ｇと前記の各緩衝液９５ｇを混合し、ミルベマイシンオキシム懸濁液を調製した。これらの懸濁液をガラスバイアルに充填し、ゴム栓で栓をしたものを、６０℃、７５％ＲＨで１週間保存した後、薬効成分の含量を測定し、ｐＨによる安定性を確認した。 6. pH stability test (1)
Citric acid hydrate and anhydrous disodium hydrogen phosphate were dissolved in a solution in which 0.1% xanthan gum and 0.05% ethyl paraoxybenzoate were dissolved in purified water. By changing the ratio of these solutions and mixing them, a buffer solution having a pH of 2.6 to 7 was prepared. On the other hand, a liquid in which 2.5 g of milbemycin oxime, a medicinal component, was dispersed in 97.5 g of propylene glycol was prepared. 5 g of this dispersion and 95 g of each of the above buffers were mixed to prepare a milbemycin oxime suspension. These suspensions were filled in glass vials and plugged with rubber stoppers, and stored for 1 week at 60 ° C. and 75% RH, and then the content of medicinal components was measured to confirm the stability due to pH.
その結果、図１に示す通り、ｐＨが酸性側では不安定になるが、ｐＨ５～７では安定であることが確認された。
As a result, as shown in FIG. 1, it was confirmed that the pH became unstable on the acidic side, but stable at pH 5-7.
７．熱安定性試験（１）
下記に示す表６に記載の処方と、この処方の中のトレハロース１％分をアスコルビン酸ナトリウムに置き換えた処方とを、６０℃、７５％ＲＨで３週間保存して、薬効成分の安定性を確認した。
その結果を表７に示した通り、アスコルビン酸ナトリウムを１％添加したものは、６０℃、７５％ＲＨで３週間保存しても、優れた安定性を維持することが確認された。 7). Thermal stability test (1)
The formulation described in Table 6 below and the formulation in which 1% of trehalose in this formulation is replaced with sodium ascorbate are stored at 60 ° C. and 75% RH for 3 weeks to improve the stability of the medicinal ingredients. confirmed.
As shown in Table 7, it was confirmed that the one added with 1% sodium ascorbate maintained excellent stability even when stored at 60 ° C. and 75% RH for 3 weeks.
下記に示す表６に記載の処方と、この処方の中のトレハロース１％分をアスコルビン酸ナトリウムに置き換えた処方とを、６０℃、７５％ＲＨで３週間保存して、薬効成分の安定性を確認した。
その結果を表７に示した通り、アスコルビン酸ナトリウムを１％添加したものは、６０℃、７５％ＲＨで３週間保存しても、優れた安定性を維持することが確認された。 7). Thermal stability test (1)
The formulation described in Table 6 below and the formulation in which 1% of trehalose in this formulation is replaced with sodium ascorbate are stored at 60 ° C. and 75% RH for 3 weeks to improve the stability of the medicinal ingredients. confirmed.
As shown in Table 7, it was confirmed that the one added with 1% sodium ascorbate maintained excellent stability even when stored at 60 ° C. and 75% RH for 3 weeks.
８．製造実施例（３）
表８の所定濃度のカンテン末、キサンタンガム、スクラロース、及びパラオキシ安息香酸エチルを混合した粉末をタンク内の精製水に添加した。この混合液を撹拌しながら９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。
次に８５℃まで温度を下げ、そこへ所定濃度の無水リン酸一水素ナトリウム、クエン酸水和物、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを添加した。さらに、所定濃度のアスコルビン酸ナトリウムを添加した。そこへ、あらかじめプロピレングリコールに溶解させたイベルメクチンの溶液を調製液に添加し、均一分散化させた。この調製液３００ｇを８５℃で３０分間殺菌を行った後、５５℃まで冷却した。その後、調製液をガラスバイアルに充てんし、製品を得た。 8). Production Example (3)
Powder mixed with a predetermined concentration of agar powder, xanthan gum, sucralose, and ethyl paraoxybenzoate in Table 8 was added to purified water in the tank. While stirring this mixed liquid, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
Next, the temperature was lowered to 85 ° C., and anhydrous sodium monohydrogen phosphate, citric acid hydrate, and polyoxyethylene (105) polyoxypropylene (5) glycol were added thereto. Furthermore, a predetermined concentration of sodium ascorbate was added. Thereto, a solution of ivermectin previously dissolved in propylene glycol was added to the preparation solution and uniformly dispersed. 300 g of this preparation solution was sterilized at 85 ° C. for 30 minutes, and then cooled to 55 ° C. Thereafter, the preparation solution was filled into a glass vial to obtain a product.
表８の所定濃度のカンテン末、キサンタンガム、スクラロース、及びパラオキシ安息香酸エチルを混合した粉末をタンク内の精製水に添加した。この混合液を撹拌しながら９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。
次に８５℃まで温度を下げ、そこへ所定濃度の無水リン酸一水素ナトリウム、クエン酸水和物、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを添加した。さらに、所定濃度のアスコルビン酸ナトリウムを添加した。そこへ、あらかじめプロピレングリコールに溶解させたイベルメクチンの溶液を調製液に添加し、均一分散化させた。この調製液３００ｇを８５℃で３０分間殺菌を行った後、５５℃まで冷却した。その後、調製液をガラスバイアルに充てんし、製品を得た。 8). Production Example (3)
Powder mixed with a predetermined concentration of agar powder, xanthan gum, sucralose, and ethyl paraoxybenzoate in Table 8 was added to purified water in the tank. While stirring this mixed liquid, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
Next, the temperature was lowered to 85 ° C., and anhydrous sodium monohydrogen phosphate, citric acid hydrate, and polyoxyethylene (105) polyoxypropylene (5) glycol were added thereto. Furthermore, a predetermined concentration of sodium ascorbate was added. Thereto, a solution of ivermectin previously dissolved in propylene glycol was added to the preparation solution and uniformly dispersed. 300 g of this preparation solution was sterilized at 85 ° C. for 30 minutes, and then cooled to 55 ° C. Thereafter, the preparation solution was filled into a glass vial to obtain a product.
９．ｐＨ安定性試験（２）
表９の所定濃度のパラオキシ安息香酸エチルを含む０．１Ｍクエン酸水和物水溶液及び０．２Ｍ無水リン酸一水素ナトリウム水溶液をそれぞれ比率を変えて混合し、ｐＨ２．６～７の緩衝液を調製した。この緩衝液に所定濃度のキサンタンガム、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを溶解させた。他方、薬効成分のイベルメクチン３０ｍｇをプロピレングリコール３０ｇに溶解させた液を調製した。この溶液３．４ｇと前記の各緩衝液９６．６ｇを混合し、所定のｐＨとなるイベルメクチン溶液を調製した。これらの溶液をガラスバイアルに充填し、６０℃、７５％ＲＨで１週間保存した後、薬効成分の含量を測定し、ｐＨによる安定性を確認した。
その結果、図２に示す通り、ｐＨが酸性側では不安定になるが、ｐＨ４～６では安定であることが確認された。 9. pH stability test (2)
A 0.1M citric acid hydrate aqueous solution containing a predetermined concentration of ethyl paraoxybenzoate in Table 9 and a 0.2M aqueous sodium monohydrogen phosphate aqueous solution were mixed at different ratios, and a buffer solution having a pH of 2.6 to 7 was added. Prepared. A predetermined concentration of xanthan gum and polyoxyethylene (105) polyoxypropylene (5) glycol were dissolved in this buffer solution. On the other hand, a solution was prepared by dissolving 30 mg of ivermectin, a medicinal component, in 30 g of propylene glycol. 3.4 g of this solution and 96.6 g of each of the above buffers were mixed to prepare an ivermectin solution having a predetermined pH. These solutions were filled in glass vials and stored at 60 ° C. and 75% RH for 1 week, and then the content of medicinal components was measured to confirm the stability due to pH.
As a result, as shown in FIG. 2, it was confirmed that the pH was unstable on the acidic side, but stable atpH 4 to 6.
表９の所定濃度のパラオキシ安息香酸エチルを含む０．１Ｍクエン酸水和物水溶液及び０．２Ｍ無水リン酸一水素ナトリウム水溶液をそれぞれ比率を変えて混合し、ｐＨ２．６～７の緩衝液を調製した。この緩衝液に所定濃度のキサンタンガム、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを溶解させた。他方、薬効成分のイベルメクチン３０ｍｇをプロピレングリコール３０ｇに溶解させた液を調製した。この溶液３．４ｇと前記の各緩衝液９６．６ｇを混合し、所定のｐＨとなるイベルメクチン溶液を調製した。これらの溶液をガラスバイアルに充填し、６０℃、７５％ＲＨで１週間保存した後、薬効成分の含量を測定し、ｐＨによる安定性を確認した。
その結果、図２に示す通り、ｐＨが酸性側では不安定になるが、ｐＨ４～６では安定であることが確認された。 9. pH stability test (2)
A 0.1M citric acid hydrate aqueous solution containing a predetermined concentration of ethyl paraoxybenzoate in Table 9 and a 0.2M aqueous sodium monohydrogen phosphate aqueous solution were mixed at different ratios, and a buffer solution having a pH of 2.6 to 7 was added. Prepared. A predetermined concentration of xanthan gum and polyoxyethylene (105) polyoxypropylene (5) glycol were dissolved in this buffer solution. On the other hand, a solution was prepared by dissolving 30 mg of ivermectin, a medicinal component, in 30 g of propylene glycol. 3.4 g of this solution and 96.6 g of each of the above buffers were mixed to prepare an ivermectin solution having a predetermined pH. These solutions were filled in glass vials and stored at 60 ° C. and 75% RH for 1 week, and then the content of medicinal components was measured to confirm the stability due to pH.
As a result, as shown in FIG. 2, it was confirmed that the pH was unstable on the acidic side, but stable at
１０．製造実施例（４）
表１０の所定濃度のカンテン末、キサンタンガム、スクラロース、及びパラオキシ安息香酸エチルを混合した粉末をタンク内の精製水に添加した。この混合溶液を撹拌しながら分散させ９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。
次に８５℃まで温度を下げ、そこへ所定濃度の無水リン酸一水素ナトリウム、クエン酸水和物、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを添加した。さらに、所定濃度のアスコルビン酸ナトリウムを添加した。そこへ、あらかじめプロピレングリコールに溶解させたモキシデクチンの溶液を調製液に添加し、均一分散化させた。この調製液３００ｇを８５℃で３０分間殺菌を行った後、５５℃まで冷却した。その後、調製液をガラスバイアルに充てんし、製品を得た。 10. Production Example (4)
Powder mixed with a predetermined concentration of agar powder, xanthan gum, sucralose and ethyl paraoxybenzoate in Table 10 was added to purified water in the tank. This mixed solution was dispersed while stirring, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
Next, the temperature was lowered to 85 ° C., and anhydrous sodium monohydrogen phosphate, citric acid hydrate, and polyoxyethylene (105) polyoxypropylene (5) glycol were added thereto. Furthermore, a predetermined concentration of sodium ascorbate was added. Thereto, a solution of moxidectin dissolved in propylene glycol in advance was added to the preparation solution and uniformly dispersed. 300 g of this preparation solution was sterilized at 85 ° C. for 30 minutes, and then cooled to 55 ° C. Thereafter, the preparation solution was filled into a glass vial to obtain a product.
表１０の所定濃度のカンテン末、キサンタンガム、スクラロース、及びパラオキシ安息香酸エチルを混合した粉末をタンク内の精製水に添加した。この混合溶液を撹拌しながら分散させ９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。
次に８５℃まで温度を下げ、そこへ所定濃度の無水リン酸一水素ナトリウム、クエン酸水和物、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを添加した。さらに、所定濃度のアスコルビン酸ナトリウムを添加した。そこへ、あらかじめプロピレングリコールに溶解させたモキシデクチンの溶液を調製液に添加し、均一分散化させた。この調製液３００ｇを８５℃で３０分間殺菌を行った後、５５℃まで冷却した。その後、調製液をガラスバイアルに充てんし、製品を得た。 10. Production Example (4)
Powder mixed with a predetermined concentration of agar powder, xanthan gum, sucralose and ethyl paraoxybenzoate in Table 10 was added to purified water in the tank. This mixed solution was dispersed while stirring, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
Next, the temperature was lowered to 85 ° C., and anhydrous sodium monohydrogen phosphate, citric acid hydrate, and polyoxyethylene (105) polyoxypropylene (5) glycol were added thereto. Furthermore, a predetermined concentration of sodium ascorbate was added. Thereto, a solution of moxidectin dissolved in propylene glycol in advance was added to the preparation solution and uniformly dispersed. 300 g of this preparation solution was sterilized at 85 ° C. for 30 minutes, and then cooled to 55 ° C. Thereafter, the preparation solution was filled into a glass vial to obtain a product.
１１．ｐＨ安定性試験（３）
表１１の所定濃度のパラオキシ安息香酸エチルを含む０．１Ｍクエン酸水和物水溶液及び０．２Ｍ無水リン酸一水素ナトリウム水溶液をそれぞれ比率を変えて混合し、ｐＨ２．６～７の緩衝液を調製した。この緩衝液に所定濃度のキサンタンガム、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを溶解させた。他方、薬効成分のモキシデクチン１０ｍｇをプロピレングリコール１０ｇに溶解させた液を調製した。この溶液１．５ｇと前記の各緩衝液９８．５ｇを混合し、所定のｐＨとなるモキシデクチン溶液を調製した。これらの溶液をガラスバイアルに充填し、６０℃、７５％ＲＨで１週間保存した後、薬効成分の含量を測定し、ｐＨによる安定性を確認した。
その結果、図３に示す通り、ｐＨが酸性側では不安定になるが、ｐＨ４～６では安定であることが確認された。 11. pH stability test (3)
A 0.1M citric acid hydrate aqueous solution containing a predetermined concentration of ethyl paraoxybenzoate in Table 11 and a 0.2M aqueous sodium monohydrogen phosphate aqueous solution were mixed at different ratios, and a buffer solution having a pH of 2.6 to 7 was added. Prepared. A predetermined concentration of xanthan gum and polyoxyethylene (105) polyoxypropylene (5) glycol were dissolved in this buffer solution. On the other hand, a solution was prepared by dissolving 10 mg of moxidectin as a medicinal component in 10 g of propylene glycol. 1.5 g of this solution was mixed with 98.5 g of each of the above buffers to prepare a moxidectin solution having a predetermined pH. These solutions were filled in glass vials and stored at 60 ° C. and 75% RH for 1 week, and then the content of medicinal components was measured to confirm the stability due to pH.
As a result, as shown in FIG. 3, it was confirmed that the pH became unstable on the acidic side, but stable at pH 4-6.
表１１の所定濃度のパラオキシ安息香酸エチルを含む０．１Ｍクエン酸水和物水溶液及び０．２Ｍ無水リン酸一水素ナトリウム水溶液をそれぞれ比率を変えて混合し、ｐＨ２．６～７の緩衝液を調製した。この緩衝液に所定濃度のキサンタンガム、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを溶解させた。他方、薬効成分のモキシデクチン１０ｍｇをプロピレングリコール１０ｇに溶解させた液を調製した。この溶液１．５ｇと前記の各緩衝液９８．５ｇを混合し、所定のｐＨとなるモキシデクチン溶液を調製した。これらの溶液をガラスバイアルに充填し、６０℃、７５％ＲＨで１週間保存した後、薬効成分の含量を測定し、ｐＨによる安定性を確認した。
その結果、図３に示す通り、ｐＨが酸性側では不安定になるが、ｐＨ４～６では安定であることが確認された。 11. pH stability test (3)
A 0.1M citric acid hydrate aqueous solution containing a predetermined concentration of ethyl paraoxybenzoate in Table 11 and a 0.2M aqueous sodium monohydrogen phosphate aqueous solution were mixed at different ratios, and a buffer solution having a pH of 2.6 to 7 was added. Prepared. A predetermined concentration of xanthan gum and polyoxyethylene (105) polyoxypropylene (5) glycol were dissolved in this buffer solution. On the other hand, a solution was prepared by dissolving 10 mg of moxidectin as a medicinal component in 10 g of propylene glycol. 1.5 g of this solution was mixed with 98.5 g of each of the above buffers to prepare a moxidectin solution having a predetermined pH. These solutions were filled in glass vials and stored at 60 ° C. and 75% RH for 1 week, and then the content of medicinal components was measured to confirm the stability due to pH.
As a result, as shown in FIG. 3, it was confirmed that the pH became unstable on the acidic side, but stable at pH 4-6.
１２．製造実施例（５）
表１２の所定濃度のカンテン末、キサンタンガム及びスクラロースを混合した粉末をタンク内の精製水に添加した。この混合液を撹拌しながら９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。
次に８５℃まで温度を下げ、そこへ所定濃度のパラオキシ安息香酸エチル、無水リン酸一水素ナトリウム、クエン酸水和物、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールの所定の３分の１量を添加した。他方、残りの３分の２量のポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを精製水に溶解させた後、シクロスポリンを添加し、均一分散化させた。この分散液を調製液に加え、８５℃で３０分間殺菌を行った後、アルミラミネートのチューブに充てんし、製品を得た。 12 Production Example (5)
The powder mixed with a predetermined concentration of agar powder, xanthan gum and sucralose in Table 12 was added to purified water in the tank. While stirring this mixed liquid, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
Next, the temperature is lowered to 85 ° C., and there is a predetermined concentration of ethyl paraoxybenzoate, anhydrous sodium monohydrogen phosphate, citric acid hydrate, polyoxyethylene (105) polyoxypropylene (5) glycol for 3 minutes. One amount of was added. On the other hand, after the remaining two-thirds of polyoxyethylene (105) polyoxypropylene (5) glycol was dissolved in purified water, cyclosporine was added and dispersed uniformly. This dispersion was added to the preparation liquid, sterilized at 85 ° C. for 30 minutes, and then filled into an aluminum laminate tube to obtain a product.
表１２の所定濃度のカンテン末、キサンタンガム及びスクラロースを混合した粉末をタンク内の精製水に添加した。この混合液を撹拌しながら９５℃以上に液温を上げ、カンテン末が完全に溶解するまで温度を保持した。
次に８５℃まで温度を下げ、そこへ所定濃度のパラオキシ安息香酸エチル、無水リン酸一水素ナトリウム、クエン酸水和物、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールの所定の３分の１量を添加した。他方、残りの３分の２量のポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコールを精製水に溶解させた後、シクロスポリンを添加し、均一分散化させた。この分散液を調製液に加え、８５℃で３０分間殺菌を行った後、アルミラミネートのチューブに充てんし、製品を得た。 12 Production Example (5)
The powder mixed with a predetermined concentration of agar powder, xanthan gum and sucralose in Table 12 was added to purified water in the tank. While stirring this mixed liquid, the liquid temperature was raised to 95 ° C. or higher, and the temperature was maintained until the agar powder was completely dissolved.
Next, the temperature is lowered to 85 ° C., and there is a predetermined concentration of ethyl paraoxybenzoate, anhydrous sodium monohydrogen phosphate, citric acid hydrate, polyoxyethylene (105) polyoxypropylene (5) glycol for 3 minutes. One amount of was added. On the other hand, after the remaining two-thirds of polyoxyethylene (105) polyoxypropylene (5) glycol was dissolved in purified water, cyclosporine was added and dispersed uniformly. This dispersion was added to the preparation liquid, sterilized at 85 ° C. for 30 minutes, and then filled into an aluminum laminate tube to obtain a product.
１３．ｐＨ安定性試験（４）
表１３の所定濃度のパラオキシ安息香酸エチル、ラウリル硫酸ナトリウム、クエン酸水和物、無水リン酸一水素ナトリウムをそれぞれ溶解させた。そこへ所定濃度のシクロスポリンを溶解させ、所定のｐＨとなるシクロスポリンの溶液を調製した。これらの溶液をガラスバイアルに充填し、６０℃、７５％ＲＨで１週間保存した後、薬効成分の含量を測定し、ｐＨによる安定性を確認した。
その結果、図４に示す通り、ｐＨが酸性側では不安定になるが、ｐＨ４～７では安定であることが確認された。 13. pH stability test (4)
The predetermined concentrations of ethyl paraoxybenzoate, sodium lauryl sulfate, citric acid hydrate, and anhydrous sodium monohydrogen phosphate in Table 13 were dissolved. A cyclosporin having a predetermined concentration was dissolved therein to prepare a cyclosporine solution having a predetermined pH. These solutions were filled in glass vials and stored at 60 ° C. and 75% RH for 1 week, and then the content of medicinal components was measured to confirm the stability due to pH.
As a result, as shown in FIG. 4, it was confirmed that the pH became unstable on the acidic side, but stable at pH 4-7.
表１３の所定濃度のパラオキシ安息香酸エチル、ラウリル硫酸ナトリウム、クエン酸水和物、無水リン酸一水素ナトリウムをそれぞれ溶解させた。そこへ所定濃度のシクロスポリンを溶解させ、所定のｐＨとなるシクロスポリンの溶液を調製した。これらの溶液をガラスバイアルに充填し、６０℃、７５％ＲＨで１週間保存した後、薬効成分の含量を測定し、ｐＨによる安定性を確認した。
その結果、図４に示す通り、ｐＨが酸性側では不安定になるが、ｐＨ４～７では安定であることが確認された。 13. pH stability test (4)
The predetermined concentrations of ethyl paraoxybenzoate, sodium lauryl sulfate, citric acid hydrate, and anhydrous sodium monohydrogen phosphate in Table 13 were dissolved. A cyclosporin having a predetermined concentration was dissolved therein to prepare a cyclosporine solution having a predetermined pH. These solutions were filled in glass vials and stored at 60 ° C. and 75% RH for 1 week, and then the content of medicinal components was measured to confirm the stability due to pH.
As a result, as shown in FIG. 4, it was confirmed that the pH became unstable on the acidic side, but stable at pH 4-7.
本発明は、化学的に安定で服用しやすいゼリー製剤の提供に利用することができる。
以上、本発明を特定の態様に沿って説明したが、当業者に自明の変形や改良は本発明の範囲に含まれる。 The present invention can be used to provide a jelly preparation that is chemically stable and easy to take.
As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.
以上、本発明を特定の態様に沿って説明したが、当業者に自明の変形や改良は本発明の範囲に含まれる。 The present invention can be used to provide a jelly preparation that is chemically stable and easy to take.
As mentioned above, although this invention was demonstrated along the specific aspect, the deformation | transformation and improvement obvious to those skilled in the art are included in the scope of the present invention.
Claims (9)
- 薬効成分、ゲル化剤、及び精製水を含んでなるゼリー状医薬組成物。 A jelly-like pharmaceutical composition comprising a medicinal ingredient, a gelling agent, and purified water.
- ゲル化剤が、ペクチン、カンテン末、カラギーナン、ジェランガム、ゼラチン、キサンタンガム、ローカストビーンガム、グアガム、タラガム、アルギン酸若しくはそのナトリウム塩、又はマンナン類である、請求項１に記載の医薬組成物。 The pharmaceutical composition according to claim 1, wherein the gelling agent is pectin, agar powder, carrageenan, gellan gum, gelatin, xanthan gum, locust bean gum, guar gum, tara gum, alginic acid or a sodium salt thereof, or mannans.
- さらに分散剤を含んでなる、請求項１又は２に記載の医薬組成物。 The pharmaceutical composition according to claim 1 or 2, further comprising a dispersant.
- 分散剤が、ショ糖脂肪酸エステル、グリセリン脂肪酸エステル、ポリオキシエチレンソルビタン脂肪酸エステル、ポリオキシエチレン脂肪酸エステル、ポリオキシエチレン（１０５）ポリオキシプロピレン（５）グリコール、又はアルキル硫酸ナトリウムである、請求項３に記載の医薬組成物。 The dispersing agent is sucrose fatty acid ester, glycerin fatty acid ester, polyoxyethylene sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene (105) polyoxypropylene (5) glycol, or sodium alkyl sulfate. A pharmaceutical composition according to 1.
- さらに安定化剤を含んでなる、請求項１～４のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 4, further comprising a stabilizer.
- 安定化剤が、トコフェロール、没食子酸アルキル、ブチルヒドロキシアニソール、ブチルヒドロキシトルエン、亜硫酸ナトリウム、エデト酸、エデト酸ナトリウム、アスコルビン酸、又はアスコルビン酸ナトリウムである、請求項５に記載の医薬組成物。 The pharmaceutical composition according to claim 5, wherein the stabilizer is tocopherol, alkyl gallate, butylhydroxyanisole, butylhydroxytoluene, sodium sulfite, edetic acid, sodium edetate, ascorbic acid, or sodium ascorbate.
- 医薬組成物のｐＨが５以上である、請求項１～６のいずれか一項に記載の医薬組成物。 The pharmaceutical composition according to any one of claims 1 to 6, wherein the pH of the pharmaceutical composition is 5 or more.
- 薬効成分、ゲル化剤、分散剤、精製水を少なくとも含むゼリー状医薬組成物の製造方法であって、
ゲル化剤を精製水に添加した液を必要に応じて加熱して溶解する工程、
得られた溶液を、薬効成分が分解せず、且つ、ゲル化剤の溶解状態を維持できる温度まで冷却する工程、
前記冷却工程の後に、薬効成分および分散剤を添加する工程
を含む、前記製造方法。 A method for producing a jelly-like pharmaceutical composition comprising at least a medicinal component, a gelling agent, a dispersant, and purified water,
A step of heating and dissolving a solution obtained by adding a gelling agent to purified water as necessary,
A step of cooling the obtained solution to a temperature at which the medicinal component is not decomposed and the gelling agent can be dissolved;
The said manufacturing method including the process of adding a medicinal ingredient and a dispersing agent after the said cooling process. - 請求項８に記載の製造方法で得られる、ゼリー状医薬組成物。 A jelly-like pharmaceutical composition obtained by the production method according to claim 8.
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|---|---|---|---|---|
| JP2005533806A (en) * | 2002-06-21 | 2005-11-10 | メリアル リミテッド | Homogeneous oral paste for anthelmintic animals |
| WO2010070705A1 (en) * | 2008-12-17 | 2010-06-24 | 株式会社メドレックス | Aqueous oral preparation of stable amlodipine |
| JP2011503140A (en) * | 2007-11-15 | 2011-01-27 | ノバルティス アーゲー | Anthelmintic paste containing praziquantel, macrolide lactone, cyclodextrin and thickening agent |
| WO2012177151A1 (en) * | 2011-06-23 | 2012-12-27 | Bayer New Zealand Limited | Anti-parasitic composition comprising a macrocyclic lactone and levamisole and method of treatment of parasitic infestation |
| JP2013018752A (en) * | 2011-07-13 | 2013-01-31 | Nitto Denko Corp | Jelly-form preparation and method for producing jelly-form preparation |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2005533806A (en) * | 2002-06-21 | 2005-11-10 | メリアル リミテッド | Homogeneous oral paste for anthelmintic animals |
| JP2011503140A (en) * | 2007-11-15 | 2011-01-27 | ノバルティス アーゲー | Anthelmintic paste containing praziquantel, macrolide lactone, cyclodextrin and thickening agent |
| WO2010070705A1 (en) * | 2008-12-17 | 2010-06-24 | 株式会社メドレックス | Aqueous oral preparation of stable amlodipine |
| WO2012177151A1 (en) * | 2011-06-23 | 2012-12-27 | Bayer New Zealand Limited | Anti-parasitic composition comprising a macrocyclic lactone and levamisole and method of treatment of parasitic infestation |
| JP2013018752A (en) * | 2011-07-13 | 2013-01-31 | Nitto Denko Corp | Jelly-form preparation and method for producing jelly-form preparation |
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