KR20190013535A - Semisolid formulation containing ketoprofen and a process for the preparation thereof - Google Patents

Abstract

One aspect of the present invention is
A semi-solid preparation comprising ketoprofen and a gelling agent which comprises 25-35% by weight of ethanol as a solvent for ketoprofen and contains a physiologically compatible alkanolamine having a pH of 6.0 to 6.5 A solid preparation, and a preparation method thereof.

Description

TECHNICAL FIELD The present invention relates to a ketoprofen-containing semi-solid preparation and a preparation method thereof,

The present invention relates to a semi-solid preparation containing ketoprofen as a main component, and more particularly to a semi-solid preparation containing ketoprofen as a main ingredient, which is capable of securing stability over time of the main ingredient and improving the property stability of the preparation and the skin permeability of the main ingredient. And a production method thereof.

An antiinflammatory agent having an arylpropionic acid structure such as ibuprofen, naproxen, or ketoprofen is formulated as a semi-solid drug such as gel or cream due to ease of use and safety, and localized treatment such as pain control such as muscular pain and anti- Is widely used.

The polyacrylic gel of arylpropionic acid is prepared by dissolving polyacrylic gel as a starting material as a free acid in an appropriate solvent such as ethanol, adding this solution to an aqueous dispersion of a carboxyvinyl polymer, and finally adding triethanolamine, diethanolamine or tromethamine To a physiologically compatible amine compound, such that a desired gel can be prepared. The carboxyvinyl polymer acts as a gelling agent for preparing the gel, which must be neutralized as a base in order to increase the viscosity of the gel and ensure proper gelation, the base being capable of neutralizing both the gelling agent and the active ingredient do. Such neutralizing agents for neutralization may be physiologically compatible alkanolamines such as triethanolamine, diethanolamine, or tromethamine.

The keto-propene gel prepared by using the triethanolamine or diethanolamine as the alkanolamine at a concentration of about 1 to 3% by weight according to the above-mentioned method is precipitated as a salt with an alkanolamine, which is a neutralizing agent, The main component tends to precipitate. This precipitation is more pronounced at temperatures below 20 ° C, often corresponding to conventional storage conditions. This precipitation lowers the property stability of the semi-solid preparation, which lowers the skin permeability of the main ingredient and may lead to a reduction in the efficacy of the drug.

A semi-solid preparation for preventing the precipitation of a main component by salt formation with an amine neutralizing agent during the production of such a ketoprofen gel has been disclosed (Patent Document 1). It is described that the above semi-solid preparation can overcome the phenomenon of precipitation of the main component by using Dekkketpropentamol as ketoprofen. However, a semi-solid preparation having improved stability and skin permeability as in the present invention has not been studied.

Korean Patent Registration 0543558

An aspect of the present invention is to provide a semi-solid preparation containing ketoprofen having improved skin permeability of the main component, while ensuring stability of the formulation due to the absence of precipitation of the main ingredient and ensuring stability over time of the main ingredient.

Another aspect of the present invention is to provide a method for producing the above-mentioned semi-solid preparation containing ketoprofen.

One aspect of the present invention is

A semi-solid preparation comprising ketoprofen and a gelling agent, which comprises 25 to 35% by weight of ethanol as a solvent of ketoprofen and contains physiologically compatible alkanolamine having a pH of 6.0 to 6.5 A solid preparation is provided.

In another aspect of the present invention,

Mixing and homogenizing an aqueous dispersion of carboxyvinyl polymer, an ethanol solution containing ketoprofen and essence oil; And

And neutralizing the resulting mixture with a physiologically compatible alkanolamine to adjust the pH to 6.0-6.5 to form a gel. The present invention also provides a method for preparing a semi-solid preparation according to one aspect of the present invention.

It has been confirmed that the ketopropene-containing semi-solid preparation according to one aspect of the present invention can secure both the property stability of the preparation and the stability of the main ingredient because the main ingredient is not precipitated even during long-term storage, . In addition, the semi-solid preparation can be used as an effective keto-propene-containing semi-solid preparation because the skin permeability of the main ingredient is remarkably improved.

BRIEF DESCRIPTION OF THE DRAWINGS FIG. 1 is a process flow diagram of a method for producing a ketopropene-containing semi-solid preparation according to an embodiment of the present invention.
FIG. 2 is a photograph of the gels of Examples 1 to 5 and Comparative Examples 1 to 7, in which the pH and viscosity were measured and an appropriate amount (about 200 mg) was applied to the skin, .
Fig. 3 is a photograph of the gel of Example 1 and Comparative Examples 1 and 2, which was left for one month under the conditions of 25 캜 and 60% RH, and observed with naked eyes. Fig.
FIG. 4 is a graph comparing the ketopropene gels of Examples 1, 4, and 5 and Comparative Examples 5, 6, and 7 with those of (A) Ketoprofen Gel produced over time, And (B) the total amount of the flexible material.
FIG. 5 is a graph showing the skin permeability of the main component measured as a result of the skin permeability test using the gels of Examples 1, 3 and 5 and Comparative Examples 3 and 4. FIG.

All technical terms used in the present invention are used in the sense that they are generally understood by those of ordinary skill in the relevant field of the present invention unless otherwise defined. In addition, preferred methods or samples are described in this specification, but similar or equivalent ones are also included in the scope of the present invention. Also, the numerical values set forth herein are considered to include the meaning of " about " unless explicitly stated. The contents of all publications referred to in this specification are incorporated herein by reference in their entirety.

One aspect of the present invention is

A semi-solid preparation comprising ketoprofen and a gelling agent, which comprises 25 to 35% by weight of ethanol as a solvent of ketoprofen and contains physiologically compatible alkanolamine having a pH of 6.0 to 6.5 A solid preparation is provided.

In one embodiment, the semi-solid formulation is prepared by mixing a water dispersant containing a gellant in water and an ethanol solution of ketoprofen, and then adjusting the pH to 6.0 to 6.5 by adding physiologically compatible alkanolamine to form a gel . ≪ / RTI >

The ketoprofen may exist as an enantiomer due to the presence of chemically absent carbon, and may exist in the form of a racemic mixture or an S (+) - enantiomer (dexketopropene) with excellent pharmacological activity. In one embodiment, the keto propene is dexketopropene.

Also, in one embodiment, the ketoprofen may be present in the form of a pharmaceutically acceptable salt. The pharmaceutically acceptable salts refer to any salt suitable for formulation into a non-toxic, semi-solid formulation. Such pharmaceutically acceptable salts include, but are not limited to, ketoprofen lysine salts. In another embodiment, the ketoprofen may be a free ketoprofen.

The term "ketopropene" as used herein should be construed to encompass both racemic mixtures of ketoprofen, dexketoprofen, and pharmaceutically acceptable salts thereof.

The gelling agent may be any gelling agent capable of producing a keto-propene-containing semi-solid preparation. Examples of the gelling agent include carboxyvinyl polymer, methyl cellulose, xanthan gum, diphenhydramine, methyl cellulose, hydroxypropyl methylcellulose (HPMC), or any combination thereof. In one embodiment, the gelling agent is a carboxyvinyl polymer such as carbomer 941 (molecular weight about 1.25 million), carbomer 934 (molecular weight about 3 million), carbomer 940 (molecular weight about 4 million). The carboxyvinyl polymer may be contained in an amount of 0.5 to 3% by weight based on the total amount of the composition, and may have a different viscosity value depending on the amount used.

The physiologically compatible alkanolamine serves to neutralize both the gelling agent and the major component keto-propene, and by this neutralization, a semi-solid preparation (e.g., gel) having a sufficiently high viscosity of about 5,000 to 60,000 cps . The term "physiologically compatible alkanolamine" refers to an alkanolamine that serves to neutralize both the gelling agent and the major component ketoprofen, and does not have a deleterious effect on the human body. The physiologically compatible alkanolamine may be selected from the group consisting of triethanolamine, diethanolamine, tromethamine, and any combination thereof, but is not limited thereto.

Since the pH of the solution was 6.0 to 6.5 by the alkanolamine, the semi-solid preparation was found to be able to maintain proper viscosity and transparency without precipitation of the main component (see Test Examples 1 and 2).

In one embodiment, the semi-solid formulation may have a viscosity of from about 5,000 to about 60,000 cps. If it is below the above-mentioned range, the viscosity may be too low to flow down, and if it is excessive, the absorption rate of the main component may be lowered or the spreadability may be lowered.

In one embodiment, the semi-solid formulation comprises 1.0 to 3.0% by weight of Carbomer 940 as the carboxyvinyl polymer, 3.0 to 4.0% by weight of triethanolamine as the alkanolamine, a viscosity of about 5,000 to 60,000 cps, 0.0 > 6.5 < / RTI > to 6.5.

The semi-solid preparation is used in an amount of 1.0 to 2.0% by weight, more preferably 1.3 to 1.7% by weight, of Carbomer 940, 3.0 to 3.5% by weight of triethanolamine as an alkanolamine, cPs viscosity, and the content ratio of the carbomer and the alkanolamine may vary depending on the specific kind of the gelling agent and the alkanolamine, and thus the present invention is not limited thereto.

Ethanol contained in the semi-solid preparation is contained as a solvent of ketoprofen and may be contained in an amount of 25 to 35% by weight, specifically 27 to 33% by weight based on the total weight of the semi-solid preparation, more specifically, May contain 30 to 33% by weight. As a result of the test, when the pH of the semi-solid preparation was out of the range of 6.0 to 6.5, or when the content of ethanol was more than 35% by weight based on the total weight of the semi-solid preparation, the amount of the produced substance was significantly increased. Therefore, when the semi-solid preparation satisfies both the pH 6.0 to 6.5 and the ethanol content of 25 to 35% by weight, the degree of formation of the flexible substance of the main component keto-propene is remarkably low, so that the stability of the main component can be secured (See Test Example 3).

In one embodiment, the alkanolamine is triethanolamine.

In one embodiment, the semi-solid formulation may further comprise an oil, specifically the oil may be an essence oil.

As used herein, the term "essential oil" has volatility, which is the source of the odor emitted from the stem, leaf, rootstock, bark, fruit, bud, resin, etc. of the plant, It means oil component that is lighter than water, and it is also called plant essential oil. The essence oil may be any essential oil known to be applicable to topical preparations such as gels and creams in the pharmaceutical field. In one embodiment, the essence oil may comprise an oil comprising at least 50% terpene or an aromatic compound. For example, the essence oil may be lavender oil, neroli oil, rosemary oil, eucalyptus oil, or any mixture thereof. In one embodiment, skin permeability of the active ingredient can be significantly improved by including an oil containing 50% or more of the terpene or aromatic compound.

In one embodiment, the essence oil is an oil mixed with neroli oil and lavender oil in a weight ratio of 1: 1.

In one embodiment, the semi-solid formulation may contain from 0.5% to 3.0% by weight of the essence oil relative to the total amount of the semi-solid formulation. For example, the essence oil may contain 0.5 to 2.0% by weight based on the total amount of the semi-solid preparation. For example, the essence oil may contain 1.0 to 2.0% by weight based on the total amount of the semi-solid preparation.

Due to the inclusion of the essence oil, the semi-solid preparation containing the keto-propene as a main component can remarkably improve the skin permeability of the main ingredient, and thus can have improved drug efficacy, and the appearance, stability, The flavor can be increased. As a result of the test, when the pH of the semi-solid preparation was out of the range of 6.0 to 6.5 or the content of the essence oil was less than 0.5 wt% based on the total weight of the semi-solid preparation, the skin permeability of the main ingredient was remarkably lowered (Test Example 4) . In addition, it was confirmed that when the essence oil of more than 3.0% by weight with respect to the total weight of the semi-solid preparation, for example, 3.5% by weight of essence oil was used, the unknown softening material tended to increase by 0.2% or more in the severe stability test 3). In addition, when the essence oil is used in an amount exceeding 3.0% by weight based on the total weight of the semi-solid preparation, the odor of the essence oil is strong when the semi-solid preparation is topically applied, and the palatability may be deteriorated. The greater the increase, the lower the economic efficiency.

Therefore, when the semi-solid preparation satisfies both the pH 6.0 to 6.5 and the essential oil content of 0.5 to 3.0% by weight, the main ingredient is not precipitated and the stability of the preparation of the preparation can be maintained. In addition, It can have a medicinal effect. In addition, it is possible to provide a semi-solid preparation having excellent appearance, palatability and flavor of excellent products, and to reduce the production cost.

In one embodiment, the semi-solid formulation comprises from 1.0 to 3.0% by weight of a carboxyvinyl polymer and from 3.0 to 4.0% by weight of triethanolamine as an alkanolamine, based on the total weight of the composition, cps < / RTI > with a pH of 6.0 to 6.5.

The semi-solid preparation can be formulated as a gel or cream form and can be topically applied to the skin.

Such semi-solid formulations can be used in any indications of keto-propene known to be effective in topical applications in the art. In one embodiment, the semi-solid formulation may be used for analgesia or anti-inflammatory.

In one embodiment, the semi-solid preparation may contain from 1 to 5% by weight, more preferably from 1 to 3% by weight, based on the free acid, of the principal component ketoprofen.

The semi-solid preparation may further comprise a pharmaceutically acceptable additive in the semi-solid preparation. For example, it may further contain a preservative or a colorant, and it may be suitably selected by a person skilled in the art.

According to another aspect of the present invention,

Mixing and homogenizing an aqueous dispersion of carboxyvinyl polymer, an ethanol solution containing ketoprofen and essence oil; And

And neutralizing the resulting mixture with a physiologically compatible alkanolamine to adjust the pH to 6.0-6.5 to form a gel. The present invention also provides a method for preparing a semi-solid preparation according to one aspect of the present invention.

Details of the method for producing the semi-solid preparation can be applied as it is for the semi-solid preparation according to one aspect of the present invention.

The aqueous dispersion of the carboxyvinyl polymer may be prepared by heating the carboxyvinyl polymer to 90 ° C, adding the carboxyvinyl polymer to purified water cooled at 60 ° C and homogenizing the mixture at about 50-70 ° C.

The above-mentioned ethanol solution containing ketoprofen may be used. In addition, an essence oil may be added to prepare an ethanol solution containing ketoprofen and essence oil, which can be prepared by simple mixing.

Thereafter, an ethanol solution of ketopropene or an ethanol solution containing ketoprofen and essence oil is added to the aqueous dispersion of the carboxyvinyl polymer, and homogenization is performed at 25 to 35 ° C. Then, a physiologically compatible alkane The gel can be formed by adjusting the pH to 6.0 to 6.5 by neutralizing by adding olamine.

The gel formed can remove air in a gentle vacuum atmosphere, thereby reducing the stability due to oxidation during long-term storage and ensuring the uniformity of the container filling mass.

[Example]

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are for illustrative purposes only and are not intended to limit the scope of the present invention.

Example 1-5: Preparation of semi-solid preparation

The keto-propene gel of Example 1-5 was prepared according to the prescription of Table 1 below.

Concretely, the purified water was heated to 90 DEG C and then cooled to 60 DEG C. Carbomer 940 was added and homogenized at 60 DEG C for 30 minutes. Then, a mixture in which ketopropene and essence oil were dissolved in ethanol was added and the mixture was heated at 30 DEG C for 30 minutes After homogenization, the mixture was neutralized by adding triethanolamine while homogenizing at 30 DEG C for 120 minutes to form a gel. The obtained gel was degassed under a gentle vacuum atmosphere. A process flow chart of this manufacturing method is shown in Fig.

Unit: wt% Example 1 Example 2 Example 3 Example 4 Example 5 Ketoprofen 3.0 3.0 3.0 3.0 3.0 Carbomer 940 1.5 1.5 1.7 1.4 1.5 Triethanolamine 3.0 3.5 3.5 3.5 3.5 ethanol 30.0 30.0 35.0 25.0 30.0 Purified water 62.0 61.0 55.8 66.6 60.0 Essential oil (Neroli oil: Lavender oil = 1: 1) 0.5 1.0 1.0 0.5 2.0 Total amount 100.0 100.0 100.0 100.0 100.0

Comparative Example 1-7: Preparation of semi-solid preparation

Ketoprofen gel was prepared in the same manner as the preparation method of Example 1-5 according to the prescription of Table 2 below.

Unit: wt% Comparative Example 1 Comparative Example 2 Comparative Example 3 Comparative Example 4 Comparative Example 5 Comparative Example 6 Comparative Example 7 Ketoprofen 3.0 3.0 3.0 3.0 3.0 3.0 3.0 Carbomer 940 1.5 1.5 1.5 1.4 1.7 1.5 1.5 Triethanolamine 0.5 1.5 2.5 2.5 3.5 4.5 3.5 ethanol 30.0 30.0 30.0 30.0 40.0 30.0 30.0 Purified water 64.5 63.5 62.5 62.9 51.3 60.5 58.5 Essence oil 0.5 0.5 0.5 0.2 0.5 0.5 3.5 Total amount 100.0 100.0 100.0 100.0 100.0 100.0 100.0

Test Example 1: Confirmation of properties according to pH, viscosity and pH according to prescription

The prepared gel was measured with an Orion 3star pH meter (Thermo) according to the general method described in the Japanese Pharmacopoeia, and the viscosity was measured with a Brookfield viscometer RV DV-II + at 24 ° C, 6 times spindle, 30 rpm. Appearance was applied to the skin by taking an appropriate amount (about 200 mg) and visually observed at 1 minute after use.

The photographic images of the results of visual observation of the properties are shown in Fig. 2 together with the measured pH and viscosity values.

According to FIG. 2, when the pH was 5.0 or less, the viscosity of the sample was low, which was lowered during use. In the case of the sample having a pH of less than 5.5, precipitation of the main component occurred due to evaporation of the solvent. Under the condition of pH 6.0 or higher, transparent property was maintained without precipitation of the main component due to evaporation of the solvent.

Test Example 2: Stability test for long-term storage

The samples of Example 1 and Comparative Examples 1 and 2 were allowed to stand for one month at 25 DEG C and 60% RH, and visually observed, and the properties were confirmed in actual use. The results are shown in Fig.

As a result of the test, in Example 1, the main component precipitation did not occur after 1 month of standing, and the properties did not change even when used. In Comparative Examples 1 and 2, white precipitation occurred at 1 month, Crystallization.

Test Example 3: Harsh stability test according to prescription (flexible substance)

The flexural stability test for the gels of Examples 1, 4 and 5 and Comparative Examples 5, 6 and 7 was carried out at 60 ° C. (A) Unknown impurities and (B) total flexible substances were analyzed by HPLC with reference to the British Pharmacopoeia ("BP") "Ketoprofen Gel".

The results are shown in Figs. 4 (A) and 4 (B).

4 (A) and (B), the comparative example 5 in which the amount of ethanol was 40 wt% or more and the comparative example 6 in which the pH was 7 or more had a significantly higher increase rate of the flexural mass than the gel of Example 1, 4 or 5 It looked. In the case of Comparative Example 7 in which the amount of the essence oil is more than 3.0% by weight, for example, 3.5% by weight based on the total weight of the semi-solid preparation, Examples 1 and 4 , Or the amount of the essential oil was 2.0% by weight. Specifically, in Comparative Example 7 using 3.5% by weight of essence oil, (A) individual flexible substances and (B) total flexible substances increased by 0.2% or more when measured after one week in the severe stability test.

Test Example 4: Skin permeability test

The skin permeability test was carried out using the gels of Examples 1, 3 and 5 and Comparative Examples 3 and 4.

The skin permeability test was carried out using Franz cell and Ponzu, and the number of samples (n = 6) and the sampling time (six time points) were designed according to the in vitro skin absorption test guidelines. For the receptor media used in the Franz diffusion cell, a pH 7.4 phosphate buffer solution (PBS buffer) was used. The temperature was 32 ± 0.5 ° C. and 600 rpm, and the experiment was conducted ( International Journal of Pharmaceutical Compounding .16). The sample was analyzed by the BP Ketoprofen gel content test according to the conditions shown in Table 3 below.

HPLC conditions (see BP Content Test Method) Mobile phase DW: ACN (acetonitrile): pH 3.5 buffer = 55: 43: 2 Column Inertsil ODS-2 (250 mm x 4.6 mm, 5 um) Flow rate 1 mL / min UV (WL) 254 mm Injection volume (Injec. Vol.) 20uL

The results are shown in Fig. 5 and Table 4 below.

Time (hr) Example 1 Example 3 Example 5 Comparative Example 3 Comparative Example 4 One 0.01 0.02 0.03 0.01 0.00 3 0.09 0.13 0.15 0.08 0.02 6 0.37 0.46 0.57 0.32 0.15 9 0.75 0.91 1.04 0.61 0.34 12 1.16 1.33 1.49 0.87 0.54 24 2.61 2.81 3.20 1.83 1.12

As a result of the test, it was found that the skin permeability of Examples 1, 3 and 5 was about 140 to 285% as compared with Comparative Examples 3 and 4 from 6 hours after the initial absorption rate was similar. In Comparative Example 3 in which the content of the essence oil was 0.5% by weight or more, the permeability was remarkably higher than that in Comparative Example 4 which was 0.2% by weight. However, Comparative Example 3 showed significantly lower permeability than Examples 1 and 3. Specifically, in Comparative Example 3, the skin permeability was significantly lower than that of Example 1, in which the essence oil content was equal to 0.5% by weight and the ethanol content was 30.0% by weight. This means that a sufficient amount of the essence oil was used together with ethanol , The amount absorbed into the skin by the precipitation of the main component is reduced when the pH range is not satisfied. Examples 1 and 3, which contained 0.5% or more of essence oil at pH 6.0 to 6.5, showed higher skin permeability because there was no precipitation of main components. It was confirmed that the skin permeability was somewhat higher than that of Example 1 in which the content of the essence oil was 1.0%, which was 0.5% in the case of Example 3.

Therefore, the test results show that the skin permeability of the main component is significantly increased when the pH is in the range of 6.0 to 6.5 and the essence content is 0.5% or more.

The present invention has been described with reference to the preferred embodiments. It will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the spirit and scope of the invention as defined by the appended claims. Therefore, the above-described embodiments should be considered in an illustrative rather than a restrictive sense. The scope of the present invention is defined by the appended claims rather than by the foregoing description, and all differences within the scope of equivalents thereof should be construed as being included in the present invention.

Claims (12)

A semi-solid preparation comprising ketoprofen and a gelling agent, which comprises 25 to 35% by weight of ethanol as a solvent of ketoprofen and contains physiologically compatible alkanolamine having a pH of 6.0 to 6.5 Solid formulation. The semi-solid formulation according to claim 1, wherein the gelling agent is a carboxyvinyl polymer, methylcellulose, xanthan gum, diphenhydramine, methylcellulose, hydroxypropylmethylcellulose (HPMC), or any combination thereof. The semi-solid preparation according to claim 1, wherein the alkanolamine is selected from the group consisting of triethanolamine, diethanolamine, and tromethamine. The semi-solid preparation according to claim 1, wherein the alkanolamine is triethanolamine. The semi-solid preparation according to claim 1, further comprising 0.5 to 3.0% by weight of an essence oil. The semi-solid preparation according to claim 1, further comprising 0.5 to 2.0% by weight of an essence oil. The semi-solid preparation according to claim 5, wherein the essence oil comprises at least 50% of terpene or an aromatic compound. The semi-solid preparation according to claim 5, wherein the essence oil is neroli oil, lavender oil, rosemary oil, eucalyptus oil, or any mixture thereof. The semi-solid preparation according to claim 1, wherein the semi-solid preparation is gel or cream. The semi-solid preparation according to claim 1, wherein the ketoprofen is dexketoprofen. The semi-solid preparation according to claim 1, which is for pain or inflammation. Mixing and homogenizing an aqueous dispersion of carboxyvinyl polymer, an ethanol solution containing ketoprofen and essence oil; And
A process for preparing a gel according to any one of claims 1 to 11, comprising the step of neutralizing the resulting mixture with physiologically compatible alkanolamine to adjust the pH to 6.0-6.5 to form a gel.

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