JP5999875B2 - Gel-like pharmaceutical composition - Google Patents

Description

  The present invention relates to a gel pharmaceutical composition, specifically, a gel external anti-inflammatory analgesic. More specifically, a gel-like pharmaceutical composition suitable for an external anti-inflammatory analgesic comprising a salicylic acid ester derivative as an active ingredient, wherein the pharmaceutical is characterized by excellent stability over time of the active ingredient and the preparation Relates to the composition.

  Stiff shoulder is a symptom caused by muscle fatigue, muscle tone and blood circulation disorder due to static muscle work such as typing or reading or reduced shock absorption due to aging, and causes discomfort such as stiffness, fatigue and pain .

  Conventionally, for the symptoms of stiff shoulders, attention has been paid to inflammation occurring in the affected area, and various anti-inflammatory agents have been applied externally in order to suppress the inflammation. However, stiff shoulders are a symptom that feels muscle stiffness and stiffness, and there is a problem that the symptom is difficult to be alleviated by simply applying an anti-inflammatory agent, and the effect cannot be fully realized. For this reason, a semi-solid preparation that can be applied so as to rub into the affected area has been studied.

  Semi-solid preparations include ointments, creams and gels. Of these, gel agents are preferred in that they are less sticky and provide a sense of effectiveness when they are swallowed. The gel is usually produced by adding a water-soluble polymer compound to a base such as water to increase the viscosity. As such a water-soluble polymer compound, a carboxyvinyl polymer is suitably used because of its excellent dispersibility in water and the effect of thickening under conditions of pH 6-10.

  It has been conventionally known that the carboxyvinyl polymer has an action of inhibiting hydrolysis of salicylic acid ester derivatives such as glycol salicylate and methyl salicylate in the presence of water and transesterification reaction in the presence of ethanol (patent) It is a component that is preferably used as a stabilizer in anti-inflammatory analgesics containing salicylic acid ester derivatives as active ingredients.

JP-A-1-294625

  Based on the above prior art, the present inventor mixes a carboxyvinyl polymer with a salicylic acid ester derivative, adjusts the pH to pH 6-10 where the carboxyvinyl polymer exhibits a thickening effect, and prepares a gel-like preparation. When manufactured, salicylic acid ester is an active ingredient even if the properties of the preparation become unstable, such as deterioration of the shape retention over time and the occurrence of water separation, and the properties of the preparation become unstable. It has been found that there is a problem that the derivative is decomposed and the expected therapeutic effect cannot be obtained.

  Therefore, the present invention aims to solve the above-mentioned problems that the preparation stability (active ingredient stability, property stability) is lacking in preparing a gel-form preparation by mixing a carboxyvinyl polymer with a salicylic acid ester derivative. To do.

  That is, the present invention provides a salicylic acid ester derivative and a carboxyvinyl polymer that are free from problems such as decomposition of the salicylic acid ester derivative, which is an active ingredient, a decrease in shape retention, and generation of water separation. It aims at providing the gel-like pharmaceutical composition to contain and its manufacturing method. Another object of the present invention is to provide a method for suppressing the decomposition of salicylic acid ester derivatives, the decrease in shape retention or the occurrence of water separation in a gel-like pharmaceutical composition containing a salicylic acid ester derivative and a carboxyvinyl polymer. To do.

  The present inventor has intensively studied to solve the above-mentioned problems. As a result, a cellulose water-soluble polymer compound, a lower alcohol, and water are used in combination with a salicylic acid ester derivative and a carboxyvinyl polymer, and 1 part by weight of the water. By adjusting the ratio of the lower alcohol to 0.5 parts by weight or less and the pH in the range of 4 to 6, a gel-like pharmaceutical composition containing a salicylic acid ester derivative in which the above problems have been solved can be prepared. I found it.

  The present invention has been completed based on such findings and has the following aspects.

(I) Gel-like pharmaceutical composition (I-1 ) A gel-like pharmaceutical composition containing a salicylic acid ester derivative, a carboxyvinyl polymer, a cellulose-based water-soluble polymer compound, a lower alcohol and water,
The ratio of lower alcohol to 1 part by weight of water is 0.5 parts by weight or less,
A gel pharmaceutical composition having a pH of 4-6.
(I-2) The gel-like pharmaceutical composition described in (I-1), wherein the cellulose-based water-soluble polymer compound is hydroxypropyl cellulose.
(I-3) The gel pharmaceutical composition according to (I-1) or (I-2), wherein the salicylic acid ester derivative is glycol salicylate or methyl salicylate.
(I-4) The gel pharmaceutical composition according to any one of (I-1) to (I-3), which is an antiphlogistic analgesic for external use.

(II) Method for producing gel-like pharmaceutical composition (II-1) A method for producing a gel-like pharmaceutical composition containing a salicylic acid ester derivative, a carboxyvinyl polymer, a cellulose-based water-soluble polymer compound, a lower alcohol and water. A method for producing a gel-like pharmaceutical composition excellent in formulation stability, characterized in that the ratio of lower alcohol to 1 part by weight of water is adjusted to 0.5 parts by weight or less and the pH is adjusted to a range of 4-6.
(II-2) The production method according to (II-1), wherein the cellulose-based water-soluble polymer compound is hydroxypropyl cellulose.
(II-3) The gel pharmaceutical composition according to (II-1) or (II-2), wherein the salicylic acid ester derivative is glycol salicylate or methyl salicylate.
(II-4) The production method according to any one of (II-1) to (II-3), wherein the gel pharmaceutical composition is an external anti-inflammatory analgesic.

(III) Formulation Stabilization Method for Gelled Pharmaceutical Composition (III-1) Formulation stabilization method for gelled pharmaceutical composition containing salicylic acid ester derivative, carboxyvinyl polymer and water, comprising cellulose-based water A method comprising blending a functional polymer compound and a lower alcohol, and adjusting the ratio of the lower alcohol to 1 part by weight of water to 0.5 parts by weight or less and the pH to a range of 4-6.
(III-2) The method according to (III-1), wherein the preparation stabilization method is a method for suppressing the decomposition of a salicylic acid ester derivative.
(III-3) The method according to (III-1), wherein the preparation stabilization method is a method for suppressing a decrease in the shape retention of the preparation.
(III-4) The method according to (III-1), wherein the preparation stabilization method is a method for suppressing water separation of the preparation.
(III-5) The method according to any one of (III-1) to (III-4), wherein the gel pharmaceutical composition is an external anti-inflammatory analgesic.
(III-6) The method according to any one of (III-1) to (III-5), wherein the cellulose-based water-soluble polymer compound is hydroxypropylcellulose.
(III-7) The method according to any one of (III-1) to (III-6), wherein the salicylic acid ester derivative is glycol salicylate or methyl salicylate.

  According to the present invention, in addition to the salicylic acid ester derivative and the carboxyvinyl polymer, a cellulose-based water-soluble polymer compound, a lower alcohol, and water are blended, and the ratio of the lower alcohol to 1 part by weight of water is 0.5 parts by weight or less. And adjusting the pH of the final formulation to 4 to 6, preferably 4 to 5.5, the decomposition of salicylic acid ester derivatives, the decrease in shape retention or / and water separation are significantly suppressed, and the formulation It is possible to produce and provide a gel-like pharmaceutical composition having excellent stability over time.

  That is, the present invention provides a gel-like pharmaceutical composition prepared by using a salicylic acid ester derivative and a carboxyvinyl polymer in combination with the stability over time of the preparation (decomposition suppression of salicylic acid ester derivative, maintenance of shape retention, suppression of water separation). This is useful for providing an excellent gel-like pharmaceutical composition.

I. Gel-like pharmaceutical composition and preparation method thereof The gel-like pharmaceutical composition of the present invention comprises (a) a salicylic acid ester derivative (hereinafter also referred to as “(a) component”), (b) a carboxyvinyl polymer (hereinafter referred to as “(b ) Component ”), (c) cellulose-based water-soluble polymer compound (hereinafter also referred to as“ (c) component ”), (d) lower alcohol (hereinafter also referred to as“ (d) component ”), and ( e) Water (hereinafter also referred to as “component (e)”).

(A) Salicylic acid ester derivative A salicylic acid ester derivative (component (a)) is a salicylic acid anti-inflammatory agent that locally exerts an analgesic / anti-inflammatory effect upon external application (transdermal administration). Specific examples include glycol salicylate and methyl salicylate. The proportion of the component (a) contained in 100% by weight of the gel-like pharmaceutical composition of the present invention is not limited, but it is possible to make the composition more excellent in stability over time while exhibiting analgesic / anti-inflammatory action. From the point that can be achieved, it can be appropriately adjusted from the range of usually 0.5 to 7.5% by weight, preferably 0.5 to 6% by weight, more preferably 0.5 to 5% by weight, and still more preferably 1. 0.5 to 5% by weight.

(B) Carboxyvinyl polymer The carboxyvinyl polymer (component (b)) is an acrylic acid-based hydrophilic crosslinked polymer. The carboxyvinyl polymer used in the present invention is not particularly limited in viscosity and molecular weight as long as it is used in a preparation for external use (transdermal administration), for example, as a thickener. The viscosity (20 ° C.) of the 2% aqueous solution is 2500 to 29000 mPa · s, preferably 4000 to 29000 mPa · s, and more preferably 12000 to 29000 mPa · s.

  Those having these viscosities are commercially available as Carbopol (980, 981, 2984, 5984, ETD2050, Ultez 10) (Nikko Chemicals Corporation).

  The proportion of the component (b) contained in 100% by weight of the external pharmaceutical composition of the present invention is not particularly limited, but is usually 0 from the viewpoint that the composition can be more excellent in viscosity and stability over time. It can be suitably adjusted from the range of 4 to 2% by weight, preferably 0.5 to 2% by weight, more preferably 0.7 to 2% by weight.

(C) Cellulose-based water -soluble polymer compound By blending the cellulose-based water-soluble polymer compound (component (c)), the stability over time of the shape-retaining property of the gel-like pharmaceutical composition and the water separation inhibition property are further improved. Can be improved.

  Examples of the cellulose water-soluble polymer compound (component (c)) used in the present invention include hydroxypropylcellulose, hydroxyethylmethylcellulose, hydroxypropylmethylcellulose (also known as hypromellose), and hydroxyethylcellulose. From the standpoint of being able to obtain a gel-like composition having better stability over time, hydroxypropylcellulose, hydroxyethylmethylcellulose and hydroxypropylmethylcellulose are preferred, and hydroxypropylcellulose is more preferred.

  Hydroxypropyl cellulose is not particularly limited. For example, the viscosity of a 2% aqueous solution (20 ° C., B-type viscometer) is about 2 to 5000 mPa · s, and a wide range of molecular polymerization is set. These are commercially available as NISSO HPC (L, M, H, SL, SSL) (Nippon Soda Co., Ltd.).

  Hydroxyethyl methylcellulose is not particularly limited. For example, the viscosity of a 2% aqueous solution (20 ° C., Brookfield viscometer) is about 7000 to 10000 mPa · s, and is commercially available as Meserose (Sakai Industrial Co., Ltd.). It is.

  Hydroxypropyl methylcellulose is not particularly limited. For example, 1% aqueous solution has a viscosity (20 ° C., B-type viscometer) of about 2 to 10000 mPa · s, and Metroise 65SH-400, 65SH-1500, 65SH-4000, 90SH. -400, 90SH-4000 (Shin-Etsu Chemical Co., Ltd.) are commercially available.

  Hydroxyethyl cellulose is not particularly limited. For example, the viscosity of a 1% aqueous solution is about 60 to 6000 mPa · s, and commercially available as HEC Daicel (SP200, SP600, SP900, SE550, EP850) (Daicel Chemical Co., Ltd.). It is available.

  The proportion of the component (c) to be blended in 100% by weight of the gel-like pharmaceutical composition of the present invention is not particularly limited as long as it exhibits the above-mentioned action. From the viewpoint of being able to do this, it is preferable to adjust appropriately from the range of usually 0.2 to 5% by weight, more preferably 0.25 to 3% by weight, still more preferably 0.5 to 2% by weight.

  In addition, when the component (c) is converted to a proportion relative to 100 parts by weight of the salicylic acid ester derivative (component (a)) contained in the gel-like pharmaceutical composition, it is preferably adjusted to be usually 2 to 1000 parts by weight. More preferably, the amount is 4 to 600 parts by weight, still more preferably 10 to 400 parts by weight, and still more preferably 10 to 140 parts by weight. Moreover, it is preferable to adjust so that it may become 10-1250 weight part normally, when converted into the ratio with respect to 100 weight part of carboxy vinyl polymer ((b) component) contained in a gel-form pharmaceutical composition, More preferably, 12 -600 parts by weight, more preferably 25-300 parts by weight.

(D) Lower alcohol By adding a lower alcohol (component (d)), the gel-forming ability of the carboxyvinyl polymer is enhanced, and the stability of the shape-keeping property of the gel-like pharmaceutical composition over time and the water separation inhibition are further improved. This can be further improved.

  Examples of the lower alcohol (component (d)) used in the present invention include methyl alcohol; ethyl alcohol; n-propyl alcohol, isopropyl alcohol; butyl alcohol, sec-butyl alcohol, isobutyl alcohol, tert-butyl alcohol; The C1-C7 alcohol of this can be illustrated. Preferably it is a C1-C3 alcohol. More preferred are ethyl alcohol and isopropyl alcohol, which can be blended in an external pharmaceutical composition, and particularly preferred is ethyl alcohol.

  The said (d) component is mix | blended in the ratio of 0.5 weight part or less with respect to 1 weight part of water ((e) component) mix | blended with the gel-like pharmaceutical composition of this invention. The lower limit is not particularly limited as long as the effect of the present invention is exhibited, but usually 0.04 parts by weight or more, more preferably 0.06 parts by weight or more, is exemplified from the shape retention and water separation inhibiting property of the preparation. be able to. (D) As a suitable mixture ratio of component, 0.12-0.5 weight part with respect to 1 weight part of water ((e) component), Preferably 0.2-0.45 weight part, More preferably 0.25-0.45 weight part can be mentioned.

  The ratio of the component (d) to be blended in 100% by weight of the gel-like pharmaceutical composition of the present invention is not particularly limited as long as the above effect is exhibited, but it is preferable to make the composition superior in stability over time. From the viewpoint of being able to do this, it is preferable to adjust appropriately from the range of usually 3 to 30% by weight, more preferably 4 to 28% by weight, still more preferably 5 to 26% by weight.

(E) water in the water present invention ((e) component), the pharmaceutical compositions of the present invention in terms of a gel, is an essential component together with a carboxyvinyl polymer.

  The proportion of the component (e) blended in 100% by weight of the gel-like pharmaceutical composition of the present invention is not particularly limited as long as the above effect is exhibited, but due to the stability over time (shape retention, water separation inhibition). From the point which can be set as the outstanding composition, it can adjust suitably from the range of 50 to 85 weight% normally, Preferably it is 54 to 84 weight%, More preferably, it is 56 to 83 weight%.

(F) pH
The gel-like pharmaceutical composition of the present invention contains the above component (a), component (b), component (c), component (d), and component (e), and the pH is in the range of 4-6. It is characterized by being. If the pH is less than 4, the shape does not retain and tends to be difficult to become a gel-like preparation (see Comparative Examples 12 and 13). On the other hand, if the pH exceeds 6, the shape retainability deteriorates over time, and water separation occurs. Tends to occur (see Comparative Examples 3 to 6). From the point which can be set as the composition which was more excellent by stability over time, suppressing the decomposition | disassembly of a salicylic acid ester derivative and exhibiting an analgesic anti-inflammatory effect, More preferably, it is pH 4.5-6, Especially preferably, pH 4.5- 5.5.

  Such pH adjustment can be performed using a basic substance or an acidic substance. Examples of the basic substance include inorganic bases such as sodium hydroxide and potassium hydroxide; organic amines such as triethanolamine and diisopropanolamine; basic amino acids such as arginine, lysine and ornithine. Examples of acidic substances include inorganic acids and organic acids such as hydrochloric acid, nitric acid, metasulfonic acid, sulfuric acid, p-toluenesulfonic acid, phosphoric acid, citric acid, malic acid, tartaric acid, and succinic acid.

(G) Manufacturing method The gel-form pharmaceutical composition of this invention can be manufactured with the preparation method normally demonstrated below. First, a salicylic acid ester derivative, a carboxyvinyl polymer, a cellulose-based water-soluble polymer compound, a lower alcohol and water are used to increase the viscosity. An agent is added to adjust the pH to be in the range of 4-6.

  More specifically, for example, when a gel is used, the salicylic acid ester derivative as an active ingredient is dissolved in a lower alcohol. Separately, a carboxyvinyl polymer and a cellulosic polymer are added to water and mixed to increase the viscosity, and then the above-mentioned lysate is added and mixed, and adjusted to a pH of 4 to 6 with a pH adjuster.

  The gel-like pharmaceutical composition of the present invention is not particularly limited, but can be usually prepared to have a viscosity of 50,000 to 1,500,000 mPa · s, preferably 70,000 to 130,000 mPa · s. .

  Here, the viscosity is a plastic digital B-type viscometer (for example, a B-type viscometer with a helipath stand (DV-II + manufactured by BrookField), a helipath spindle (TE) and made of plastic having an inner diameter of about 6 cm. It is measured in a state where about 60 g of the gel-like pharmaceutical composition of the present invention is placed in a container (20 ° C., 4.0 rpm, 1 minute).

  Moreover, the gel-like pharmaceutical composition of the present invention can also contain a medicinal aid as another component. Examples of such medicinal aids include: camphor, turpentine oil, peppermint oil, menthol and derivatives thereof, eucalyptus oil, lactic acid menthyl and other local stimulants; nonanoic acid vanillylamide, capsaicin and other local irritants; glycyrrhizic acid and other anti-inflammatory agents; Antihistamines such as diphenylimidazole, diphenhydramine and salts thereof, chlorpheniramine maleate; blood circulation promoters such as tocopherol acetate and benzyl nicotinate; Herbal medicines such as sicon extract, salamander extract, capsicum extract and the like can be mentioned. In addition to the above-mentioned components, the gel-like pharmaceutical composition of the present invention contains additives used for normal skin external preparations such as appropriate active ingredients, preservatives, preservatives, antioxidants and stabilizers. An agent can be used as appropriate.

  The gel pharmaceutical composition of the present invention is prepared as an external preparation having a gel shape as described above, and can be locally administered externally. The dosage of the gel-form external pharmaceutical composition of the present invention depends on the degree of symptoms to be treated, but it is desirable that the application amount per one time is about 500 mg to 3000 mg.

  Specifically, the gel-like pharmaceutical composition of the present invention is an external anti-inflammatory analgesic comprising a salicylic acid ester derivative as an active ingredient, and improves inflammation such as stiff shoulder, muscle pain, joint pain, low back pain, bruise pain, and acne pain ( It can be suitably used for the purpose of (anti-inflammation), and is particularly suitable for improvement of stiff shoulders accompanied by blood flow disturbance and muscle tone.

II. Method for Stabilizing Formulation of Gel Pharmaceutical Composition Containing Salicylic Acid Derivative and Carboxyvinyl Polymer The method of the present invention comprises (a) a salicylic acid ester derivative and (b) a carboxyvinyl polymer as described above in (c) a water-soluble cellulose. It can be carried out by combining the polymer compound, (d) a lower alcohol, and (e) water, and adjusting the pH to be in the range of 4-6.

  As the type and ratio of the component (c) and the component (d) used in combination with the component (a) and the component (b), the stability of the component (a), that is, without adversely affecting the anti-inflammatory analgesic action, This is a range in which the shape retention of the gel composition formed by the component (a) and the component (b) is stabilized over time and water separation suppression is exhibited. Specifically, it is described in (I) Types and ratios can be listed.

  In the method of the present invention, the above-mentioned component (a), component (b), component (c), component (d) and component (e) are blended, and the pH is adjusted to be in the range of 4-6. Features. If the pH is less than 4, the shape does not retain and tends to be difficult to become a gel-like preparation (see Comparative Examples 12 and 13). On the other hand, if the pH exceeds 6, the shape retainability deteriorates with time, and water separation occurs. It tends to occur (see Comparative Examples 3 to 6). Preferably it is pH 4.5-6, More preferably, it is pH 4.5-5.5. Such pH adjustment can be performed using a basic substance or an acidic substance as described in (I).

  According to the method of the present invention, the (a) component, the (b) component, and the (e) component are used in combination with the aforementioned (c) component and (d) component, and the pH is in the range of 4-6. By adjusting in this way, the temporal stability of the gel-like pharmaceutical composition containing the component (a) and the component (b) can be improved. Therefore, the method of the present invention can be effectively used to provide a gel-like pharmaceutical composition excellent in formulation stability, particularly a gel-like external anti-inflammatory analgesic.

  Hereinafter, although an example of an experiment and an example are given and the present invention is explained, the present invention is not limited to these examples.

Experimental Example 1: Evaluation of formulation stability (Part 1)
The components described in Table 1 were mixed and adjusted so that the pH was in the range of 3.4 to 7 to prepare pharmaceutical compositions (Examples 1 to 5 and Comparative Examples 1 to 13). Specifically, according to the description in Table 1, glycol salicylate and ethanol are weighed and mixed by stirring to obtain an organic phase. Separately, water is weighed, carboxyvinyl polymer and hydroxypropyl cellulose are added, and mixed by stirring to obtain an aqueous phase. The organic phase was added to the aqueous phase, and the pH was adjusted with a pH adjuster while stirring and mixing to prepare a pharmaceutical composition.

  Each of the prepared pharmaceutical compositions (Examples 1 to 5 and Comparative Examples 1 to 13) is filled in a plastic jar and stored for 30 days at 50 ° C. and 60% RH or at 4 ° C. and 60% RH. Then, the temporal stability ((1) stability of glycol salicylate, (2) shape retention and water release properties) of the preparation was evaluated according to the following method.

(1) Stability evaluation test of salicylic acid ester derivative HPLC of salicylic acid glycol concentration in the pharmaceutical composition after storage at 50 ° C (stored at 50 ° C) and each pharmaceutical composition before storage (initial product) under the following conditions The residual salicylate glycol after storage at 50 ° C. was calculated from the ratio of the glycol salicylate concentration of the product stored at 50 ° C. to the glycol salicylate concentration of the initial product.

<HPLC conditions>
Using an HPLC column having an inner diameter of 4.6 mm and a length of 15 cm, the test was conducted by applying the internal standard method of liquid chromatography “quantitative” (1) in accordance with the Japanese Pharmacopoeia.

  Based on the residual%, the stability of glycol salicylate in each pharmaceutical composition was evaluated according to the following criteria.

○: Salicylate glycol residual% in a product stored at 50 ° C. 90% or more ×: Residual glycolic acid residual% in a product stored at 50 ° C. Less than 90%.

(2) Evaluation test of mold retention and water separation The evaluation of mold retention and water separation was evaluated by a three-point comparison method. Specifically, two pharmaceutical compositions stored at 4 ° C. and 60% RH for 30 days (stored at 4 ° C.), pharmaceutical compositions stored at 50 ° C. and 60% RH for 30 days (stored at 50 ° C.) Product) One sample was prepared as a specimen, and 10 panelists compared it visually to evaluate the shape retention and water separation.

<Shape retention>
If there are more than 7 out of 10 people who have determined that the product preserved at 50 ° C is “decreased in shape retention” compared to the product stored at 4 ° C, both can be identified It was judged that it was not possible to discriminate (decrease in shape retention of 50 ° C. stored product) if it was 6 or less in 10 people. Samples judged to be indistinguishable were evaluated as “◯” for shape retention.

  Furthermore, for those who judged that both can be discriminated (recognized a decrease in the shape retention of the product stored at 50 ° C.), a five-point evaluation (no problem, not much) No problem, neither, some problem, some problem), and evaluated according to the following criteria.

(Triangle | delta): Although shape retention property falls a little compared with immediately after container filling, there is no problem in use.
(The total number of respondents who answered "no problem" or "no problem" is more than 70% of the total)
X: Although shape retention property falls a little compared with immediately after container filling, it can be used.
(The total number of respondents who answered “no problem” and “no problem” is less than 70% of the total).

<Water separation>
If there are 7 or more people out of 10 who discriminate that the product stored at 50 ° C is “water-removed” compared to the product stored at 4 ° C, both can be discriminated (recognized water from the product stored at 50 ° C can be recognized). Judgment was made, and if it was 6 or less out of 10 persons, it was judged that it was impossible to discriminate (the water separation of the 50 ° C. stored product could not be recognized). About the sample judged to be indistinguishable, the water separation was evaluated as “◯”.

  For those who judge that both can be distinguished (recognized water separation of products stored at 50 ° C), a five-point evaluation (no problem, not a problem, neither is a problem) If there are more than 70% of respondents who answered “no problem” or “not too much problem”, “△”, if less than 70%, "

(3) The test results are shown in Table 1. In Table 1, “-” indicates that measurement was not performed.

  In Table 1, as can be seen from the comparison between Examples 1 to 5 and Comparative Examples 12 and 13, a salicylic acid ester derivative (salicylic acid glycol), a carboxyvinyl polymer, a cellulose water-soluble polymer compound (hydroxypropylcellulose), a lower alcohol (Ethanol) and water are blended, and even if prepared so that the ratio of lower alcohol to 1 part by weight of water is 0.5 parts by weight or less, if the pH is as low as 3.4, it remains liquid and gelled. On the other hand (Comparative Examples 12 and 13), when the pH was adjusted to 4.5 to 6, a gel composition could be prepared, and the salicylic acid ester derivative in the gel composition was also stable. At the same time, it had stable shape retention and water separation was also suppressed (Examples 1 to 5). However, when urea is added, glycolic salicylate tends to become unstable (Comparative Example 13). Therefore, although not necessarily limited, in the gel-like pharmaceutical composition containing the salicylic acid ester derivative of the present invention as an active ingredient, if urea adversely affects the stability of the salicylic acid ester derivative, the urea is added. It is preferable to prepare without.

  From the above, a salicylic acid ester derivative (salicylic acid glycol), a carboxyvinyl polymer, a cellulose-based water-soluble polymer compound (hydroxypropylcellulose), a lower alcohol (ethanol), and water are blended, and the lower alcohol is contained in 1 part by weight of water. By adjusting the ratio to 0.5 parts by weight or less and the pH to 4 to 6, preferably pH 4.5 to 6, more preferably pH 4.5 to 5.5, the salicylic acid ester derivative is stably maintained, In addition, it has been found that the shape retention is good, the occurrence of water separation is suppressed, and a stable shape can be maintained over a long period of time.

  In the examples, when the carboxyvinyl polymer was Carbopol 981, 2984 or 5984, the formulation stability was also excellent.

Experimental Example 2: Evaluation of formulation stability (Part 2)
Based on the formulation of Example 1 that showed the best formulation stability in Experimental Example 1, the type and amount of salicylic acid ester derivative, the type and amount of carboxyvinyl polymer, and the cellulose water-soluble polymer compound In the same manner as in Experimental Example 1, preparation stability (stability of salicylic acid ester derivatives, shape retention and water release of the preparation) was evaluated.

  Tables 2 and 3 show the composition of each pharmaceutical composition and the results of formulation stability evaluation.

  As shown in Tables 2 and 3, the salicylic acid ester derivative, the carboxyvinyl polymer, the carboxyvinyl polymer type and the blending amount, and the cellulose water-soluble polymer compound and the blending amount, regardless of the salicylic acid ester derivative, the carboxy Contains vinyl polymer, cellulose-based water-soluble polymer compound, lower alcohol (ethanol), and water, the ratio of lower alcohol to 1 part by weight of water is 0.5 parts by weight or less, and the pH is in the range of 4-6. All the pharmaceutical compositions showed good formulation stability.

  According to the formulation examples described in Table 4, gel-like pharmaceutical compositions were prepared (formulation examples 1 to 8). In these cases as well as in Examples, good formulation stability (stability of salicylic acid ester derivatives, shape retention and water release properties of the formulation) was exhibited.

Claims (5)

A gel-like pharmaceutical composition comprising a salicylic acid ester derivative, a carboxyvinyl polymer, a cellulose-based water-soluble polymer compound, a lower alcohol and water,
The ratio of lower alcohol to 1 part by weight of water is 0.5 parts by weight or less,
A gel-like pharmaceutical composition having a pH of 4 to 6 (however, the following low-temperature cross-linked gel preparation is excluded from the gel-like pharmaceutical composition:
Below A, B both components were mixed at 30 ° C. or less, pH 4-6 and the low-temperature cross-linked gel base low crosslinked gels made agent which contains the active ingredient in:
A: Ethanol and / or isopropanol, polyacrylic acid and / or salts thereof, and poorly soluble polyvalent metal compound B: hydroxy acid and water. ). The gel-like pharmaceutical composition according to claim 1, wherein the cellulose-based water-soluble polymer compound is hydroxypropyl cellulose. The gel-like pharmaceutical composition according to claim 1 or 2, which is an external anti-inflammatory analgesic. A method for producing a gel-like pharmaceutical composition comprising a salicylic acid ester derivative, a carboxyvinyl polymer, a cellulose-based water-soluble polymer compound, a lower alcohol and water,
(1) a step of dissolving a salicylic acid ester derivative in a lower alcohol;
(2) a step of mixing a carboxyvinyl polymer, a cellulose-based water-soluble polymer compound and water,
(3) The dissolved product and the mixture obtained in (1) and (2) are mixed and adjusted so that the ratio of lower alcohol to 1 part by weight of water is 0.5 parts by weight or less and the pH is 4-6. A method for producing a gel-like pharmaceutical composition having excellent formulation stability. A method for stabilizing a gel-like pharmaceutical composition comprising a salicylic acid ester derivative, a carboxyvinyl polymer, and water, wherein the above components are used in combination with a cellulose-based water-soluble polymer compound and a lower alcohol as other components, and water A method comprising adjusting the ratio of the lower alcohol to 1 part by weight to 0.5 parts by weight or less and the pH to a range of 4-6.
(Except on Kige Le shaped pharmaceutical composition or found the following low-temperature cross-linked gel formulation:
Below A, B both components were mixed at 30 ° C. or less, pH 4-6 and the low-temperature cross-linked gel base low crosslinked gels made agent which contains the active ingredient in:
A: Ethanol and / or isopropanol, polyacrylic acid and / or salts thereof, and poorly soluble polyvalent metal compound B: hydroxy acid and water. ).