JP7576541B2 - Method for producing oil-in-water cream - Google Patents

Description

The present invention relates to a method for efficiently producing oil-in-water creams with uniform viscosity.

Carboxyvinyl polymers are known to thicken when neutralized with a basic substance (alkaline agent). Taking advantage of this property, carboxyvinyl polymers are used as thickeners for pharmaceuticals, cosmetics, etc. (Patent Document 1).

JP 2013-256472 A

In oil-in-water creams containing carboxyvinyl polymer as a thickener, uniformity of viscosity is required for commercial value.
The method for producing an oil-in-water cream requires a step of neutralizing a carboxyvinyl polymer and a step of emulsifying an oil phase in an aqueous phase, but in the prior art, the neutralization step was carried out after the emulsification step (Example 4 of Patent Document 1).
However, the present inventors have found that if a neutralization step is carried out after the emulsification step, it takes a long time to produce an oil-in-water cream having a uniform viscosity.

As a result of extensive research into improving the productivity of oil-in-water creams, the inventors discovered that adding an oil phase containing an alkaline agent to an aqueous phase simultaneously causes emulsification and neutralization of the carboxyvinyl polymer, thereby shortening the time required to produce an oil-in-water cream with a uniform viscosity. The present invention is based on this finding.

That is, the present invention relates to the following [1] to [6].
[1] A method for producing an oil-in-water cream, comprising the step of adding an oil phase containing an alkaline agent, an active ingredient, and an emulsifier to an aqueous phase containing a carboxyvinyl polymer to emulsify the oil phase.
[2] The method for producing the composition according to [1] above, wherein the active ingredient is one or more substances selected from the group consisting of antihistamines, antipruritics, anti-inflammatory analgesics and disinfectants.
[3] The manufacturing method described in [1] or [2] above, further comprising a step of adding a second oil phase containing a second active ingredient to the aqueous phase before adding the oil phase (first oil phase) containing an alkaline agent, an active ingredient and an emulsifier.
[4] The manufacturing method described in [3] above, wherein the second active ingredient is a liquid substance at 25°C and the active ingredient contained in the first oil phase is a solid substance at 25°C.
[5] The manufacturing method according to [3] or [4] above, wherein the second active ingredient is one or more substances selected from the group consisting of antihistamines, antipruritics, anti-inflammatory analgesics and disinfectants.
[6] The method according to any one of [1] to [5] above, wherein the alkaline agent is an amine.

As shown in the examples below, the manufacturing method of the present invention can shorten the time required to produce an oil-in-water cream with a uniform viscosity, thereby improving the productivity of oil-in-water cream.

The method for producing an oil-in-water cream of the present invention is characterized by including a step of emulsifying the oil by adding an oil phase containing an alkaline agent, an active ingredient and an emulsifier to an aqueous phase containing a carboxyvinyl polymer.

[Aqueous Phase]
The aqueous phase contains a carboxyvinyl polymer as an essential component. The carboxyvinyl polymer is blended as a thickening agent because it thickens when neutralized with an alkaline agent.
Any carboxyvinyl polymer that can be incorporated into an oil-in-water cream can be used without particular limitation as the carboxyvinyl polymer. For example, a polymer that satisfies the standards set forth in the "Carboxyvinyl Polymer" column of the Pharmaceutical Excipients Standards 2018 (Ministry of Health, Labour and Welfare) is preferred.
The amount of the carboxyvinyl polymer can be appropriately set depending on the intended viscosity of the oil-in-water cream, but is, for example, 0.1 to 3.0% by mass, preferably 0.5 to 1.5% by mass, based on the total mass of the oil-in-water cream. The amount is, for example, 0.3 to 3.0% by mass, preferably 0.5 to 2.0% by mass, based on the total mass of the aqueous phase. The amount is, for example, 0.5 to 5.0% by mass, preferably 1.0 to 3.0% by mass, based on the total mass of the premix described below when preparing the aqueous phase.

In order to disperse the carboxyvinyl polymer in water, a surfactant may be added to the aqueous phase. The surfactant may be any surfactant capable of dispersing the carboxyvinyl polymer, but is preferably a nonionic surfactant. Specific examples include sorbitan fatty acid esters such as sorbitan monoisostearate, sorbitan monolaurate, sorbitan monopalmitate, and sorbitan monostearate; propylene glycol fatty acid esters such as propylene glycol monostearate; polyoxyethylene hydrogenated castor oil; polyoxyethylene sorbitan fatty acid esters such as polyoxyethylene (20) sorbitan monolaurate (polysorbate 20), polyoxyethylene (20) sorbitan monostearate (polysorbate 60), and polyoxyethylene (20) sorbitan monooleate (polysorbate 80); polyoxyalkylene alkyl ethers, and the like, and preferably polyoxyethylene sorbitan fatty acid esters.
The amount of surfactant used when dispersing the carboxyvinyl polymer in the aqueous phase can be appropriately set depending on the amount of the carboxyvinyl polymer and the type of surfactant used, but is, for example, 0.02 to 0.2% by mass, preferably 0.05 to 0.2% by mass, based on the total mass of the aqueous phase. Also, the amount is, for example, 0.05 to 0.5% by mass, preferably 0.1 to 0.3% by mass, based on the total mass of the premix described below when preparing the aqueous phase.

The water constituting the aqueous phase can be any water that can be incorporated into an oil-in-water cream without any particular limitations. Specific examples include purified water, pure water, distilled water, ion-exchanged water, etc., and purified water is preferred.
The amount of water to be added is not particularly limited, and an appropriate amount can be added to achieve the desired component composition and viscosity.

In addition to the essential components described above, the aqueous phase may contain one or more optional components such as a chelating agent.
Chelating agents include sodium edetate and the like.

Each component of the aqueous phase is a known substance and is readily available on the market or can be prepared by known methods.

[Preparation of aqueous phase]
The method for preparing the aqueous phase is not particularly limited as long as it can provide a uniformly dispersed state of the carboxyvinyl polymer, but a method including the following steps (1) and (2) is preferred.

Step (1): Preparation of premix Pour water (preferably purified water at room temperature) into a preliminary blending tank equipped with a stirrer and start stirring. Add a surfactant, a chelating agent (optional), and a carboxyvinyl polymer in this order to the stirred water, and continue stirring until the carboxyvinyl polymer is dispersed to obtain a premix.
The carboxyvinyl polymer is preferably added in portions to prevent the polymer from forming lumps in the water.
The dispersion of the carboxyvinyl polymer in the aqueous phase can be confirmed by visually checking whether or not any lumps are formed. For example, a part of the dispersion is passed through a sieve having a nominal mesh size of 1.18 mm, and visually checked whether or not any lumps or undissolved residues are present on the sieve.

Step (2): Preparation of Water Phase (2-1): Water (preferably purified water) is charged into a blending vessel equipped with a steam jacket, a stirrer, and a homo (or ultra) mixer, and heated (preferably to 70 to 95° C.) with stirring.
The steam jacket is used to heat (sterilize) the inside of the blending tank by injecting steam. The agitator is preferably equipped with an agitating blade (scraping mixer) that can scrape off the raw materials adhering to the side and bottom of the blending tank. The homo (or ultra) mixer is used to atomize the droplets of the oil phase components added to the aqueous phase.

(2-2): The premix from step (1) (preferably adjusted to 26 to 30°C) and wash water (wash water from the tank in which the premix was prepared; preferably purified water; preferably adjusted to 10 to 30°C) are added in this order to heated water, and the mixture is stirred to obtain an aqueous phase.
It is preferable to carry out the step (2-2) after stopping the supply of steam to the steam jacket (i.e., without active heating operation) to prevent the formation of gel-like aggregates of the carboxyvinyl polymer, which is undesirable because it interferes with the uniformity of the viscosity of the oil-in-water cream.
The formation of the aqueous phase can be confirmed visually.

It is preferable that the blending tank in which step (2) is carried out is the main blending tank of a vacuum emulsification apparatus in which the emulsification step described below is carried out.

[Oil Phase]
The oil phase contains an alkaline agent, an active ingredient, and an emulsifier as essential components. By adding the oil phase containing the alkaline agent to the aqueous phase, emulsification and thickening due to neutralization of the carboxyvinyl polymer can be simultaneously performed.

The alkaline agent is not particularly limited as long as it can neutralize the carboxyvinyl polymer to thicken it. Specific examples include amines and inorganic bases, and among these, amines are preferred.
Examples of the amines include triethanolamine, diisopropanolamine, and triisopropanolamine, and these tertiary amines are preferably used.
Examples of the inorganic base include potassium hydroxide and sodium hydroxide, with potassium hydroxide being preferred.
The amount of alkaline agent to be added can be appropriately determined depending on the purpose of the addition, but is, for example, the amount necessary to adjust the pH of the oil-in-water cream to 3 to 10, preferably 4 to 8, and more preferably 4 to 6. The pH is measured by adding 2.0 g of the oil-in-water cream to 20 mL of deionized water and stirring to prepare a measurement sample, and measuring the value using a pH meter at a liquid temperature of 20 to 30° C.

The active ingredient can be appropriately selected depending on the application of the oil-in-water cream.
For example, active ingredients include antihistamines, antipruritics, anti-inflammatory analgesics, and disinfectants. Specific examples are listed below. Note that the indication of "liquid" or "solid" in parentheses after the substance name indicates the state at 25°C.
Antihistamines include diphenhydramine (liquid), diphenhydramine hydrochloride (solid), and chlorpheniramine maleate (solid).
Antipruritic agents include crotamiton (liquid).
Examples of anti-inflammatory analgesics include prednisolone valerate acetate (solid), ufenamate (liquid), dipotassium glycyrrhizinate (solid), and ibuprofen piconol (liquid).
Examples of the disinfectant include allantoin (solid), isopropylmethylphenol (IPMP) (solid), and benzethonium chloride (solid).
Among these, dipotassium glycyrrhizinate (solid), isopropylmethylphenol (IPMP) (solid), diphenhydramine (liquid), ufenamate (liquid), and ibuprofen piconol (liquid) are preferable.
The active ingredient may be used alone or in combination of two or more kinds.
The amount of the active ingredient can be appropriately determined depending on the application of the oil-in-water cream, but is, for example, 1.0 to 10.0% by mass, preferably 1.5 to 6.0% by mass, based on the total mass of the oil-in-water cream.

The emulsifier is added to emulsify the oil phase in the aqueous phase.
The emulsifier can be appropriately selected depending on the type of active ingredient, etc., and examples thereof include the above-mentioned surfactants to be added to the aqueous phase, and polyoxyethylene sorbitan fatty acid esters are preferably used.
The emulsifier may be the same as or different from the surfactant to be blended in the aqueous phase.
The amount of the emulsifier to be added can be appropriately set depending on the type and amount of the active ingredient; for example, the total amount of the emulsifier and the surfactant to be added to the aqueous phase is 0.1 to 2.0% by mass, and preferably 0.5 to 1.2% by mass, based on the total mass of the oil-in-water cream.

In addition to the essential components described above, the oil phase may contain one or more optional components such as bases, fragrances, preservatives, stabilizers, antioxidants, and colorants.

The base is blended as a solvent for the active ingredient. When the active ingredient is a solid substance at 25° C., it is preferable to use a base. The base can be appropriately selected depending on the type of active ingredient, and examples thereof include 2-octyldodecanol, 1,3-butylene glycol, etc.
The base may be used alone or in combination of two or more kinds.
The amount of the base can be appropriately set depending on the type and amount of the active ingredient, but is, for example, 11.0 to 18.5% by mass, preferably 12.0 to 16.0% by mass, based on the total mass of the oil-in-water cream.

Each component of the oil phase is a known substance and is readily available on the market or can be prepared by known methods.

[Preparation of oil phase]
The method for preparing the oil phase is not particularly limited as long as it can obtain a mixed state of each component, but for example, it can be carried out by putting the active ingredient, flavor (optional), base (optional), emulsifier, preservative (optional) and alkali agent into a blending tank equipped with a stirring device (stirring blade or pulsator) and continuing to stir until each component is dissolved. Note that the order of putting each component in may be different from that described above.
In order to promote dissolution of each component, it is preferable to carry out stirring under heating (preferably at 80 to 85° C.) after adding all the components.
The dissolution of each component can be confirmed visually.

When using multiple active ingredients with different amounts, multiple oil phases may be prepared. For example, an active ingredient with a relatively small amount may be blended into the oil phase (hereinafter also referred to as the "first oil phase") containing an alkaline agent and an emulsifier, and an active ingredient with a relatively large amount (hereinafter also referred to as the "second active ingredient") may be blended as another oil phase (hereinafter also referred to as the "second oil phase"). In this case, the second oil phase is added to the aqueous phase before the first oil phase is added. The second oil phase is added to the aqueous phase, and the aqueous phase in which the oil phase components of the second oil phase are dispersed is added under stirring, thereby simplifying the preparation of the first oil phase and obtaining an oil-in-water cream in which all active ingredients are uniformly dispersed.
The first and second oil phases may each contain one type of active ingredient or multiple types of active ingredients.

[Emulsification process]
The emulsification step is not particularly limited as long as an oil-in-water cream is obtained by emulsifying the oil phase in the aqueous phase. For example, the emulsification step can be carried out by adding the oil phase to the aqueous phase under stirring, and continuing to stir until an emulsion is produced.
The blending ratio of the oil phase to the aqueous phase can be appropriately set depending on the composition of the oil-in-water cream.
The emulsification step is preferably carried out in a vacuum emulsification device.
The resulting emulsion is an oil-in-water cream, and after the emulsion is produced, it may be stirred under cooling (for example, at 8 to 30° C.).

Oil-in-water creams can be used as medicines (for example, medicines for itching and rashes, medicines for dermatitis, etc.) or cosmetics depending on the type of active ingredient.

The present invention will be described in more detail below with reference to examples, but the present invention is not limited thereto. In the examples and comparative examples, the blending amount of each component is expressed as mass% (based on the pure content unless otherwise specified).

Example 1
An oil-in-water cream was prepared having the following composition:
In Example 1, a preparation was carried out using a first and a second oil phase.

[Preparation of aqueous phase]
An aqueous phase was prepared by a method including the following steps (1) and (2).
Step (1): Preparation of premix A surfactant, a chelating agent, and a carboxyvinyl polymer were added in this order to 40 parts by weight of purified water at room temperature being stirred in a preliminary blending tank equipped with a stirrer, and the stirring was continued until the carboxyvinyl polymer was dispersed to obtain a premix. The dispersion was confirmed by visual observation.
In addition, 10% of the total amount of polysorbate 60 used was used in the preparation of the premix as a surfactant for dispersing the carboxyvinyl polymer, and the remainder was used as an emulsifier.
The amount of the carboxyvinyl polymer was 2.4% by mass based on the total mass of the premix, and the amount of the surfactant was 0.24% by mass based on the total mass of the premix.

Step (2): Preparation of Water Phase (2-1): 31 parts by weight of purified water was charged into a main blending tank of a vacuum emulsifier equipped with a steam jacket, an agitator (scraping mixer), and a homomixer, and heated to 70 to 95° C. with stirring.
(2-2): The entire amount of the premix prepared in the above step (1) at 26 to 30°C and 12 parts by weight of purified water (washing water) at 10 to 30°C were added in this order to heated water and stirred to obtain an aqueous phase. The generation of the aqueous phase was confirmed by visual inspection. Step (2-2) was carried out after the introduction of steam into the steam jacket was stopped.
The amount of the carboxyvinyl polymer was 1.2% by mass based on the total mass of the aqueous phase, and the amount of the surfactant was 0.12% by mass based on the total mass of the aqueous phase.

[Preparation of the first oil phase]
The first active ingredient, the first base, the emulsifier, the preservative and the alkali agent were charged into a preliminary blending tank equipped with a stirrer, and stirring was continued at 80 to 85°C until each component was dissolved, to prepare a first oil phase. The dissolution of each component was confirmed by visual inspection.
Preparation of the second oil phase
The second active ingredient, the flavor, and the second base were added to a preliminary blending tank equipped with a stirrer, and the mixture was stirred until each ingredient was dissolved to prepare a second oil phase. The dissolution of each ingredient was confirmed by visual inspection.
[Emulsification]
The second oil phase was added to the stirred aqueous phase in the main blending tank of the vacuum emulsifier, followed by the first oil phase, and stirring was continued until an emulsion was formed, which was confirmed by visual inspection.
After the emulsion was produced, the mixture was further stirred under cooling (8 to 12° C.) to obtain an oil-in-water cream (pH 5.0, measured by the above-mentioned measuring method; the same applies to Example 2 and Comparative Example).

Example 2
An oil-in-water cream was prepared having the following composition:
Example 2 was prepared without a second oil phase.

[Preparation of aqueous phase]
The aqueous phase was prepared in the same manner as in Example 1. 38 parts by weight of purified water was used to prepare the premix.
The amount of the carboxyvinyl polymer was 2.6% by mass based on the total mass of the premix, and the amount of the surfactant was 0.26% by mass based on the total mass of the premix.
The amount of the carboxyvinyl polymer was 1.3% by mass based on the total mass of the aqueous phase, and the amount of the surfactant was 0.13% by mass based on the total mass of the aqueous phase.

[Preparation of oil phase]
The first active ingredient, the second active ingredient, the first base, the second base, the emulsifier, the preservative, the flavoring, and the alkali agent were added to a preliminary blending tank equipped with a stirrer, and the mixture was stirred at 80 to 85°C until each ingredient was dissolved to prepare an oil phase. The dissolution of each ingredient was confirmed by visual inspection.
[Emulsification]
The oil phase was added to the aqueous phase under stirring in the main blending tank of the vacuum emulsifier, and stirring was continued until an emulsion was formed. The formation of an emulsion was confirmed by visual observation.
After the emulsion was produced, it was further stirred under cooling (8 to 12° C.) to obtain an oil-in-water cream (pH 5.0).

Comparative Example
An oil-in-water cream (pH 5.0) was obtained according to the same procedure as in Example 2, except that an oil phase prepared without blending an alkaline agent was added to an aqueous phase, emulsified, and then the alkaline agent alone was added 15 minutes later.

〇：３カ所から採取したサンプル間の粘度差が３Ｐａ・ｓ未満
×：３カ所から採取したサンプル間の粘度差が３Ｐａ・ｓ以上

乳化物形成後にカルボキシビニルポリマーの中和を行った比較例では、粘度が均一な水中油型クリーム剤が得られるまでに２５分間を要した。一方、アルカリ剤を含む油相を水相に添加して乳化とカルボキシビニルポリマーの中和とを同時に行った実施例１及び２では、１５分間で粘度が均一な水中油型クリーム剤が得られた。 [Time required for a uniformly viscous oil-in-water cream (emulsion) to form]
For each of Examples 1 and 2 and Comparative Example, the time from the addition of the alkaline agent to the formation of an emulsion (500 kg) with a uniform viscosity was measured by the following procedure. First, samples were taken from three locations, the upper, middle, and lower parts of the main blending tank, every 5 minutes from the time the alkaline agent was added (Example 1: when the first oil phase was added; Example 2: when the oil phase was added; Comparative Example: when only the alkaline agent was added). The viscosity of each sample was measured with a BH viscometer (No. 7 rotor/20 rpm/1 min/20-30°C). When the viscosity difference between the samples taken from the three locations was less than 3 Pa·s, it was determined that an emulsion with a uniform viscosity had been formed. The measurement results are shown below.

◯: The viscosity difference between the samples taken from the three locations is less than 3 Pa·s. ×: The viscosity difference between the samples taken from the three locations is 3 Pa·s or more.

In the Comparative Example, where the carboxyvinyl polymer was neutralized after emulsion formation, it took 25 minutes to obtain an oil-in-water cream with a uniform viscosity, whereas in Examples 1 and 2, where the oil phase containing an alkaline agent was added to the aqueous phase to simultaneously perform emulsification and neutralization of the carboxyvinyl polymer, an oil-in-water cream with a uniform viscosity was obtained in 15 minutes.

The present invention can be used in the fields of pharmaceutical and cosmetic manufacturing.

Claims (6)

The method includes a step of emulsifying the aqueous phase containing a carboxyvinyl polymer by adding an oil phase containing an alkaline agent, an active ingredient, and an emulsifier,
The method for producing an oil-in-water cream further comprises a step of adding a second oil phase containing a second active ingredient to the aqueous phase before adding the oil phase (first oil phase) containing an alkaline agent, an active ingredient and an emulsifier. The method according to claim 1, wherein the active ingredient is one or more substances selected from the group consisting of antihistamines, antipruritics, anti-inflammatory analgesics, and bactericides. 2. The method according to claim 1 , wherein the second active ingredient is a substance that is liquid at 25°C, and the active ingredient contained in the first oil phase is a substance that is solid at 25°C. 4. The method according to claim 1 , wherein the second active ingredient is one or more substances selected from the group consisting of antihistamines, antipruritics, anti-inflammatory analgesics and disinfectants. The method according to any one of claims 1 to 4 , wherein the alkaline agent is an amine. The method according to any one of claims 1 to 5, wherein the emulsifier is a non-ionic surfactant.