JP7543175B2 - Solid pharmaceutical composition - Google Patents

Description

The present invention relates to a solid pharmaceutical composition such as an air freshener. In particular, the present invention relates to a solid pharmaceutical composition containing a solvent that is not a volatile organic compound (VOC) and a medicinal ingredient.

Air fresheners are widely used to eliminate unpleasant odors in indoor and storage spaces and create a comfortable environment.

Sold air fresheners include oil-based ones based on oily solvents and water-based ones in which fragrances are dispersed in water, but oil-based ones are preferred due to the ease of fragrance selection and the good scent release.

There are various types of volatilization devices for oil-based air fresheners, including reed diffusers that use natural wood chips such as rattan as the volatilization material to naturally evaporate the liquid, plug types that evaporate the composition by heating it with a heating element attached to the liquid-absorbing wick, and solid types that are solidified with metal soap, etc.

The types and blends of fragrances and solvents used in air freshener compositions vary depending on the volatilization device, but volatile hydrocarbon solvents such as glycol-based solvents, pinene, and paraffin-based hydrocarbons have been used mainly as solvents for solidified types (Patent Documents 1 and 2). However, recently, in accordance with regulations on "VOCs", the content of these solvents in air freshener compositions has been regulated. "VOC" is an abbreviation for "Volatile Organic Compounds" and is a term well known to those skilled in the art. An example of regulations on "VOCs" (hereinafter sometimes referred to as "VOC regulations") is the General Consumer Product Regulations (Section 2) in California, USA, which regulate the sale, supply, offer for sale, or manufacture of consumer products that contain "VOCs" in excess of the designated limit during sale or manufacture. In this regulation, "VOC" is defined in Article 2, §94508(a)(155) of the California Consumer Products Regulation, and includes isoparaffinic hydrocarbons.

In addition, because limonene and pinene are flammable liquids, when they are transported, especially when they are exported, various legal regulations must be met, such as restrictions on the amount that can be handled, leading to increased transportation costs.

Therefore, in order to avoid falling under VOC regulations, attempts have been made to reduce the VOC content below the specified limit and replace it with other low-volatility solvents such as water (Patent Document 4). However, as the fragrance content is reduced, the fragrance becomes weaker and the strength of the fragrance itself is insufficient, which can cause problems such as it crumbling during transportation.

Japanese Unexamined Patent Publication No. 59-77859 Japanese Unexamined Patent Publication No. 3-9758 JP 2002-102325 A WO2019/087840 publication

The present invention aims to provide a solid pharmaceutical composition that does not fall under the category of "VOCs," can stably volatilize the oily active ingredient used as a solvent in the solid pharmaceutical composition, and can fully demonstrate the product's functions.

As a result of intensive research, the inventors discovered that by using the above-mentioned oil-based active ingredient, benzylidene sorbitol, and a specific glycol ether, a solid pharmaceutical composition does not fall under VOC regulations, and thus completed the present invention.

（式中、ｎは１～３の整数を示し、Ｒ_１はＣ１～３のアルキル基を示し、Ｒ_２はＣ１～３のアルキレン基を示し、Ｒ_３はＣＨ_３－ＣＯＯ－またはＣ１～Ｃ３のアルキル基を示す）
で表されるグリコールエーテルアセテート、
２０℃での蒸気圧が２ｍｍＨｇ未満の油性有効成分、
を含有する固形状薬剤組成物を提供するものである。 That is, the present invention provides:
Benzylidene sorbitol,
The following formula (1)

(wherein n is an integer of 1 to 3, R ₁ is a C1 to 3 alkyl group, R ₂ is a C1 to 3 alkylene group, and R ₃ is CH ₃ -COO- or a C1 to C3 alkyl group).
Glycol ether acetates represented by the formula:
An oil-based active ingredient having a vapor pressure of less than 2 mmHg at 20°C;
The present invention provides a solid pharmaceutical composition comprising:

（式中、ｎは１～３の整数を示し、Ｒ_１はＣ１～３のアルキル基を示し、Ｒ_２はＣ１～３のアルキレン基を示し、Ｒ_３はＣＨ_３－ＣＯＯ－またはＣ１～Ｃ３のアルキル基を示す）
で表されるグリコールエーテルアセテート、
２０℃での蒸気圧が２ｍｍＨｇ未満の油性有効成分を溶解させた後、容器に充填して固化させることを特徴とする固形状薬剤組成物の製造方法である。 The present invention also relates to benzylidene sorbitol,
The following formula (1)

(wherein n is an integer of 1 to 3, R ₁ is a C1 to 3 alkyl group, R ₂ is a C1 to 3 alkylene group, and R ₃ is CH ₃ -COO- or a C1 to C3 alkyl group).
Glycol ether acetates represented by the formula:
This is a method for producing a solid pharmaceutical composition, which comprises dissolving an oily active ingredient having a vapor pressure of less than 2 mmHg at 20° C., filling the solution into a container, and allowing it to solidify.

According to the present invention, a solid pharmaceutical composition with high gel strength that is not subject to VOC regulations can be obtained. In addition, the solid pharmaceutical composition of the present invention can stably volatilize oily active ingredients and can be used safely because it uses a solvent that does not fall under the VOC category.

（式中、ｎは１～３の整数を示し、Ｒ_１はＣ（炭素数）１～３のアルキル基を示し、Ｒ_２はＣ１～３のアルキレン基を示し、Ｒ_３はＣＨ_３－ＣＯＯ－またはＣ１～Ｃ３のアルキル基を示す）
で表されるグリコールエーテルアセテート、
２０℃での蒸気圧が２ｍｍＨｇ未満の油性有効成分、
を含有するものである。 The solid pharmaceutical composition of the present invention (hereinafter referred to as "the composition of the present invention") contains benzylidene sorbitol,
The following formula (1)

(wherein n is an integer of 1 to 3, _R1 is an alkyl group having 1 to 3 carbon atoms, _R2 is an alkylene group having 1 to 3 carbon atoms, and _R3 is _CH3 -COO- or an alkyl group having 1 to 3 carbon atoms).
Glycol ether acetates represented by the formula:
An oil-based active ingredient having a vapor pressure of less than 2 mmHg at 20°C;
It contains:

The benzylidene sorbitol used in the composition of the present invention is a gelling agent, which is a chemically neutral, hydrophobic, and heat-resistant solid, and is usually in the form of a fine powder. This benzylidene sorbitol is a condensation product obtained by a condensation reaction between sorbitol and benzaldehyde, and includes monobenzylidene sorbitol, dibenzylidene sorbitol, tribenzylidene sorbitol, or derivatives thereof, and each of these alone or mixtures of these in any ratio. Examples of derivatives of dibenzylidene sorbitol include compounds in which the benzene nucleus in the benzylidene group of dibenzylidene sorbitol is substituted at any position with an alkyl group having 1 to 3 carbon atoms or a halogen atom, and specific examples include [di(p-methylbenzylidene)]sorbitol, [di(m-ethylbenzylidene)]sorbitol, and [di(p-chlorobenzylidene)]sorbitol. In addition, examples of derivatives of tribenzylidene sorbitol include compounds in which the benzene nucleus in the benzylidene group of tribenzylidene sorbitol is substituted at any position with an alkyl group having 1 to 3 carbon atoms or a halogen atom, and specific examples include [tri(p-methylbenzylidene)]sorbitol, [tri(m-ethylbenzylidene)]sorbitol, and [tri(p-chlorobenzylidene)]sorbitol. Among these benzylidene sorbitols, dibenzylidene sorbitol is preferred.

Benzylidene sorbitol may be synthesized according to known methods, but since it is commercially available under trade names such as "Gelol D" (dibenzylidene sorbitol) and "Gelol MD" [di(p-methylbenzylidene)] sorbitol (both trade names manufactured by New Japan Chemical Co., Ltd.), these may also be used.

The content of benzylidene sorbitol in the composition of the present invention is not particularly limited, but is 0.01 to 10% by mass (hereinafter simply referred to as "%"), preferably 0.1 to 7%, and more preferably 1 to 5%.

The glycol ether acetate represented by the following formula (1) used in the composition of the present invention is a volatile organic solvent that does not fall under the category of VOC.

In the formula, n is an integer of 1 to 3, preferably 2. _R1 is a C1 to 3 alkyl group, preferably a methyl group. _R2 is a C1 to 3 alkylene group, preferably a propylene group. _R3 is _CH3 -COO- or a C1 to C3 alkyl group, preferably a _CH3 -COO- group.

で表されるジプロピレングリコールメチルエーテルアセテートまたはジプロピレングリコール－ｎ－プロピルエーテルであり、より好ましくはジプロピレングリコールメチルエーテルアセテートである。本発明組成物におけるグリコールエーテルアセテートの含有量は、特に限定されないが、３０～９８％、好ましくは４０～８０％、さらに好ましくは５０～８０％である。 Among the glycol ether acetates represented by formula 1, those represented by the following formula (2) are preferred:

The glycol ether acetate content in the composition of the present invention is not particularly limited, but is 30 to 98%, preferably 40 to 80%, and more preferably 50 to 80%.

Oil-based active ingredients used in the composition of the present invention that have a vapor pressure of less than 2 mmHg at 20°C are not VOCs. Such oil-based active ingredients will gradually vaporize when the composition of the present invention is used at 20°C. There are no particular limitations on such oil-based active ingredients, but for example, fragrances prepared with fragrance raw materials that have a vapor pressure of less than 2 mmHg at 20°C are preferred.

Examples of fragrance raw materials having a vapor pressure of less than 2 mmHg at 20°C include animal fragrances such as musk, spirit cat's spice, and dragon's spice, and vegetable fragrances such as abies oil, acorn oil, almond oil, angelica root oil, peper oil, bergamot oil, perch oil, boerose oil, kayabuchi oil, gananga oil, capsicum oil, caraway oil, cardamom oil, cassia oil, celery oil, cinnamon oil, citronella oil, cognac oil, coriander oil, cumin oil, camphor oil, dill oil, estgolan oil, eucalyptus oil, fennel oil, garlic oil, ginger oil, grapefruit oil, hops oil, lemon oil, lemongrass oil, nutmeg oil, mandarin oil, peppermint oil, orange oil, sage oil, star anise oil, and turpentine oil. The fragrance may be an artificial fragrance such as a synthetic fragrance or an extracted fragrance, for example, terpene-based hydrocarbons such as limonene, terpinolene, dipentene, alcohol-based fragrances such as linalool, geraniol, citronellol, menthol, borneol, benzyl alcohol, anise alcohol, β-phenethyl alcohol, phenol-based fragrances such as anethole, eugenol, aldehyde-based fragrances such as citronellal, benzaldehyde, cinnamic aldehyde, cumin aldehyde, ketone-based fragrances such as carvone, menthone, camphor, acetophenone, ionone, lactone-based fragrances such as γ-butyrolactone, coumarin, cineol, ester-based fragrances such as octyl acetate, benzyl acetate, cinnamyl acetate, methyl benzoate, etc. Furthermore, a blended fragrance in which two or more of the above fragrances are mixed may also be used.

The content of the oily active ingredient having a vapor pressure of less than 2 mmHg at 20°C in the composition of the present invention is not particularly limited, but is 1 to 60%, preferably 1 to 30%, and more preferably 5 to 20%.

The composition of the present invention may further contain a syneresis inhibitor. The syneresis inhibitor used in the composition of the present invention is not particularly limited, but examples thereof include crystalline cellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, glycerin, talc, mica, zinc oxide, and hydroxyapatite. These syneresis inhibitors may be used alone or in combination of two or more, but it is preferable to use two types in terms of gel strength. The content of the syneresis inhibitor in the composition of the present invention is not particularly limited, but is 0.1 to 10%, preferably 0.1 to 5%, and more preferably 0.5 to 3%.

Various additives can be added to the composition of the present invention to the extent that they do not affect the formation of the gel. Examples of additives that can be added include other solvents, preservatives, antioxidants, UV absorbers, deodorants, dyes, oily components with 13 or more carbon atoms that are not VOCs or that are less than 0.1 mmHg at 20°C, etc.

A preferred embodiment of the composition of the present invention is one in which benzylidene sorbitol is 1-5%, glycol ether acetate represented by formula (1) is 30-98%, an oily active ingredient having a vapor pressure of less than 2 mmHg at 20°C is 1-60%, and, if necessary, a syneresis inhibitor is 0.1-10%.

The composition of the present invention can be produced by a conventional method, for example, by dissolving benzylidene sorbitol, glycol ether acetate represented by formula (1), and an oily active ingredient having a vapor pressure of less than 2 mmHg at 20°C (and, if necessary, a syneresis inhibitor and additives) by heating, filling the mixture into a container, and allowing it to cool at room temperature to solidify.

The composition of the present invention thus obtained does not fall under the "VOC" regulations, and is capable of stably volatilizing the oily active ingredient used as a solvent constituting the solid pharmaceutical composition, and can be used for applications such as fragrances and deodorants. The fact that the composition of the present invention does not fall under the "VOC" regulations means that the VOC component is less than 3 mass %, excluding oily active ingredients with a vapor pressure of less than 2 mmHg at 20°C and oily ingredients with 13 or more carbon atoms or less than 0.1 mmHg at 20°C.

The present invention will be described in detail below with reference to examples, but the present invention is not limited to these examples.

Example 1
Solid pharmaceutical compositions:
According to the recipes in Table 1, Example Products 1 to 6 and Comparative Products 1 to 3 were manufactured by the following manufacturing method. These were evaluated for syneresis, gel strength, compliance with VOC regulations, volatility, and compliance with UN GHS flammable solids according to the following standards. The results are also shown in Table 1.

<Production Method>
(1) Products 1 to 6
All the ingredients were mixed and dissolved by heating, then filled into a container, and allowed to cool at room temperature to solidify.
(2) Comparison product 1
After mixing the fragrance and limonene, the mixture was heated to 80° C., and sodium stearate was added and dissolved while stirring. The mixture was then poured into a container and allowed to cool at room temperature to solidify.
(3) Comparison product 2
The gelling agent, solvent and fragrance were mixed under heating in the ratios shown in Table 1 to dissolve, and then the mixture was poured into a container and allowed to cool at room temperature to solidify.
(4) Comparison product 3
Ethylene glycol monoethyl ether, 3-methoxy-3-methyl-1-butanol, dibenzylidene sorbitol and water were added and heated to 70°C to 80°C to dissolve, then cooled to 60°C, fragrance was added, stirred, and filled into a container, and allowed to cool at room temperature to solidify.

<Evaluation criteria>
(1) Syneresis Test method: The appearance of 20 g of the prepared gel was observed and evaluated. The same gel was also placed in a thermostatic chamber at 80° C. for 5 days, removed from the chamber, and left at room temperature for 24 hours, after which the appearance was observed and evaluated.
(Evaluation) (Content)
◎: No syneresis is observed. 〇: Very little syneresis is observed (weight of syneresis liquid is less than 1g).
△: Separation is visible (weight of serosal fluid is 3g or less)
×: Liquefied

(2) Gel strength:
Test method: 20 g of the prepared gel was left to stand in a thermostatic chamber at 80° C. for 5 days, then removed from the chamber and left at room temperature for 24 hours. The gel was then scooped up with a spoon and the gel strength was confirmed and evaluated.
(Evaluation) (Content)
◎: The gel created is strong and maintains its solid form. 〇: Slightly soft and in a sol state. ×: In a liquid state.

(3) Compliance with VOC regulations Products containing VOCs in excess of the specified limit (3 wt% of VOC substances other than fragrances) in the General Consumer Product Regulations (Section 2) (Regulations) in California, USA, were marked with an "X," and products not containing VOCs were marked with an "O."

(4) Volatility The prepared gels were left in an open space at room temperature for 30 days, and those in which the difference in weight after 30 days from the start was 40% or more of the start weight were rated as "good," and those in which the difference was less than 40% were rated as "poor."

(5) Response to UN GHS flammable solids According to the UN GHS criteria for flammable solids, substances that meet the criteria are marked with an "X" and substances that do not meet the criteria are marked with an "O".

As is clear from Table 1, none of the products of the present invention fall under VOC regulations or flammable solids, making them highly safe, and while they ensure sufficient volatility, they also have high gel strength and are unlikely to cause syneresis problems. On the other hand, comparison products 1 and 3 have safety issues, and comparison products 2 and 3 have problems with gel strength and syneresis.

The solid pharmaceutical composition of the present invention can be used as an air freshener, etc.

Claims (6)

Benzylidene sorbitol,
The following formula (1)

(wherein n is an integer of 1 to 3, R ₁ is a C1 to 3 alkyl group, R ₂ is a C1 to 3 alkylene group, and R ₃ is CH ₃ -COO- or a C1 to C3 alkyl group).
Glycol ether acetates represented by the formula:
An oil-based active ingredient having a vapor pressure of less than 2 mmHg at 20°C;
A solid pharmaceutical composition comprising: The solid pharmaceutical composition according to claim 1, wherein the glycol ether acetate represented by formula (1) is dipropylene glycol methyl ether acetate. The solid pharmaceutical composition according to claim 1 or 2, further comprising an anti-syringe agent. A solid pharmaceutical composition according to any one of claims 1 to 3, in which the benzylidene sorbitol is 1 to 5% by mass, the glycol ether acetate represented by formula (1) is 30 to 98% by mass, and the oily active ingredient is 1 to 60% by mass. A solid pharmaceutical composition according to any one of claims 1 to 4, in which the VOC content is less than 3% by mass. Benzylidene sorbitol,
The following formula (1)

(wherein n is an integer of 1 to 3, R ₁ is a C1 to 3 alkyl group, R ₂ is a C1 to 3 alkylene group, and R ₃ is CH ₃ -COO- or a C1 to C3 alkyl group).
Glycol ether acetates represented by the formula:
A method for producing a solid pharmaceutical composition, comprising dissolving an oily active ingredient having a vapor pressure of less than 2 mmHg at 20°C, filling the solution into a container and allowing it to solidify.