JP2002020315A - Homogeneous medical composition - Google Patents

Abstract

PROBLEM TO BE SOLVED: To solve a problem that a homogeneous medicinal composition is hard to obtain, when formulating an acidic drug and a basic drug at the same time to a hydrophobic medicinal base, because of the formation of an aggregate and a paste like product by the reaction of the formulated components. SOLUTION: This homogeneous medicinal composition is obtained by formulating a medium chain triglyceride and a light anhydrous silicic acid to a hydrophobic medicinal base suppressing generation of the aggregate and the paste like product even formulating the acidic drug and the basic drug at the same time.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0001]

TECHNICAL FIELD The present invention relates to a homogeneous pharmaceutical composition, and more particularly to a pharmaceutical composition in which a drug is uniformly dispersed in a hydrophobic ointment containing an acidic drug and a basic drug at the same time. is there.

[0002]

2. Description of the Related Art When an acidic drug and a basic drug are simultaneously incorporated into a hydrophobic pharmaceutical base, aggregates and paste-like substances are generated in the base, and the dispersibility of the drug is remarkably reduced. The uniformity of drug content cannot be guaranteed. Conventionally, to solve this problem, a method of using a water-soluble base or blending a surfactant is used.

[0003]

These water-soluble bases and surfactants have strong irritation and damage to skin and mucous membranes,
Therefore, there has been a strong demand for the development of a safer pharmaceutical composition in which a medicinal ingredient is uniformly dispersed, especially a hydrophobic ointment.

[0004]

Means for Solving the Problems The inventors of the present invention have made intensive studies to solve the above-mentioned problems, and as a result, have found that light silicic anhydride is blended with medium-chain fatty acid triglyceride or a hydrophobic pharmaceutical base containing the same. Thus, it was found that a change in the mixing of the acidic drug and the basic drug was prevented, the generation of aggregates or paste-like substances was prevented, and the drug could be uniformly dispersed. Based on this finding, the present inventors have further studied and completed the present invention. That is, the present invention relates to (1) a homogeneous pharmaceutical composition containing (1) an acidic drug, a basic drug, a medium-chain fatty acid triglyceride or a hydrophobic pharmaceutical base containing the same and light anhydrous silicic acid, and (2) a hydrophobic pharmaceutical base. Is room temperature (25
(C) a semisolid oil or a liquid oil at (C), (3) the pharmaceutical composition according to (1), comprising 1 to 96% by weight of a medium-chain fatty acid triglyceride based on the total amount of the pharmaceutical composition; (4) 0.1% light anhydrous silicic acid to the total amount of the pharmaceutical composition
(5) the pharmaceutical composition according to (1), which further comprises an oily gelling agent;
(5) The pharmaceutical composition according to (5), wherein the oily gelling agent is dextrin fatty acid ester, and (7) the pharmaceutical composition according to (6), containing 1 to 15% by weight of dextrin fatty acid ester based on the total amount of the pharmaceutical composition. .

[0005]

BEST MODE FOR CARRYING OUT THE INVENTION The medium-chain fatty acid triglyceride used in the present invention is mainly composed of a monovalent fatty acid having 4 to 12, preferably 6 to 10 carbon atoms excluding the carbon of the carboxyl group, particularly caprylic acid and capric acid. It is a triglyceride of a fatty acid as a component. As a specific example of the medium-chain fatty acid triglyceride, tri (caprylic / capric acid) glycerin commercially available as Miglyol 812 neutral oil can be used, and it can be preferably used in the present invention. The amount of medium-chain fatty acid triglyceride used is 1 to the pharmaceutical composition.
It is from 96 to 96% by weight, preferably from 2 to 50% by weight, particularly preferably from 5 to 30% by weight. When the amount of the medium-chain fatty acid triglyceride used is small, the compounding of the acidic drug and the basic drug to be compounded causes a change in the compounding, and agglomerates and paste-like substances are formed, resulting in poor dispersibility. Other hydrophobic pharmaceutical bases mixed with medium-chain fatty acid triglycerides include, for example, petrolatum, gelled hydrocarbons and the like at room temperature (25 ° C.).
And semi-solid oils, such as liquid paraffin, animal oils,
Oils that are liquid at room temperature (25 ° C.) such as vegetable oils and fatty acid ester oils can be used. The amount of the semi-solid oil used is usually 10 to 90% by weight, preferably 30 to 90% by weight, based on the pharmaceutical composition.
80% by weight. If the amount of the semi-solid oil used is small, the liquid oil may be separated. The amount of liquid oil used is
Usually 1 to 99% by weight, preferably 2% by weight, based on the pharmaceutical composition
~ 98% by weight. The light anhydrous silicic acid used in the present invention includes those having an average particle diameter of 0.01 to 10 μm, preferably 0.01 to 5 μm. Specific examples include Aerosil 200 (trade name) and Thylsia 3
20 (product name).

The amount of light anhydrous silicic acid is usually 0.1 to 10% by weight, preferably 0.2 to 10% by weight, based on the total amount of the pharmaceutical composition.
~ 5% by weight. If the amount of light anhydrous silicic acid is small,
The acidic drug and the basic drug to be compounded cause a change in the compounding, and aggregates and paste-like substances are formed, resulting in poor dispersibility. Examples of the acidic drug used in the present invention include chlorpheniramine maleate, diphenhydramine hydrochloride, lidocaine hydrochloride, procaine hydrochloride, dibucaine hydrochloride, phenylephrine hydrochloride, naphazoline hydrochloride, tetrahydrozoline hydrochloride, ephedrine hydrochloride, methylephedrine hydrochloride and the like. In addition, as a basic drug,
For example, lidocaine, dibucaine, diphenhydramine, ethyl aminobenzoate, atropine and the like can be mentioned. In addition to the above, the pharmaceutical composition of the present invention may further comprise, if necessary, hydrocortisone acetate, prednisolone acetate, hydrocortisone, steroidal anti-inflammatory agents such as prednisolone, chlorhexidine hydrochloride, benzalkonium chloride, berberine chloride, decanium chloride, cetylpyridinium chloride and the like. Disinfectants, antioxidants, surfactants, solubilizers, solubilizers,
An antifoaming agent or the like can be added in a range that does not impair the effects of the present invention. Examples of the oily gelling agent include dextrin fatty acid esters. The dextrin fatty acid ester is an ester of dextrin with a fatty acid having 12 to 20 carbon atoms such as lauric acid, myristic acid, palmitic acid, stearic acid, arachinic acid, behenic acid, and particularly palmitic acid and stearic acid. The incorporation of the oily gelling agent into the pharmaceutical composition has the effect of preventing the separation of the hydrophobic pharmaceutical base and promoting the absorption of the drug from the skin and mucous membranes. The amount of the oily gelling agent is usually 1 to 15% by weight based on the pharmaceutical composition. The dosage form of the pharmaceutical composition of the present invention is an ointment, a cream, a suppository, a pellet in the mouth and the like, and is particularly suitable for an ointment. The pharmaceutical composition of the present invention is prepared by heating a medium-chain fatty acid triglyceride or a hydrophobic pharmaceutical base containing the same in advance to dissolve the acidic drug and the basic drug, or a drug insoluble in the hydrophobic drug. It is performed by dispersing in a base material, mixing well, making the whole homogeneous, and then cooling to room temperature.

[0007]

The present invention will be specifically described below with reference to Examples, Comparative Examples and Test Examples. Example 1 Lidocaine 3 g Chlorpheniramine maleate 0.2 g Miglyol 812 neutral oil 5 g Aerosil 200 0.3 g Vaseline qs 100 g Aerosol 200 (light silica silicic acid average particle size 0 .012 μm) and uniformly mixed. Lidocaine was dissolved in neutral oil of Miglyol 812 heated to 65 ° C., chlorpheniramine maleate was dispersed, and a uniform liquid was added. It was cooled and filled in an aluminum tube.

Example 2 Prednisolone acetate 0.05 g Lidocaine 3 g Allantoin 1 g Tocopherol acetate 3 g Chlorpheniramine maleate 0.2 g Light liquid paraffin 20 g Miglyol 812 neutral oil 25 g Aerosil 200 0.3 g Dextrin palmitate 6 g Methyl polysiloxane 1 g Vaseline Suitable amount Total amount 100 g Aerosil 200 (light anhydrous silicic acid average particle diameter 0.012 μm) was added to Vaseline preliminarily heated to 65 ° C. and uniformly mixed. Miglyol 8 at room temperature (25 ° C)
12 Neutral oil and light liquid paraffin were mixed, a part of this mixture was heated to dissolve lidocaine and tocopherol acetate, and prednisolone acetate and allantoin were dispersed and added to petrolatum. Chlorpheniramine maleate was dispersed and homogenized in a part of the above mixed solution, added to petrolatum, and uniformly mixed. Add the remaining mixture to room temperature (2
Dextrin palmitate and methylpolysiloxane at 5 ° C.) and uniformly dispersed, and then heated to 90 ° C.
The mixture was added to petrolatum and made uniform, and the temperature was adjusted to 80 ° C. This was further cooled to 60 ° C. and filled in an aluminum tube.

Example 3 Eucalyptus oil 0.05 g Lidocaine 3 g Glycyrrhetinic acid 1.5 g Tocopherol acetate 3 g Chlorpheniramine maleate 0.2 g Liquid paraffin 20 g Miglyol 812 neutral oil 15 g Aerosil 200 0.3 g Dextrin palmitate 5 g Methyl polysiloxane 0.1 g Vaseline Appropriate amount Total amount 100 g Aerosil 200 (light anhydrous silicic acid average particle diameter 0.012 μm) was added to Vaseline preliminarily heated to 65 ° C., and uniformly mixed. Miglyol 8 at room temperature (25 ° C)
12 Mix neutral oil and liquid paraffin, heat part of this mixture to dissolve lidocaine, tocopherol acetate, and eucalyptus oil, further disperse allantoin and glycyrrhetinic acid, add to Vaseline and mix uniformly I combined.
At room temperature (25 ° C.), dextrin palmitate and methylpolysiloxane were added to the remaining mixture at room temperature (25 ° C.), and the mixture was uniformly dispersed. The mixture was heated to 90 ° C., and added to petrolatum to make uniform.
0 ° C. This was further filled in an aluminum tube cooled to 60 ° C.

Example 4 Eucalyptus oil 0.05 g Lidocaine 3 g d-Camphor 1 g Tocopherol acetate 3 g Chlorpheniramine maleate 0.2 g Liquid paraffin 25 g Miglyol 812 neutral oil 15 g Aerosil 200 0.3 g Dextrin palmitate 7 g Methyl polysiloxane 0 0.1 g Vaseline Suitable amount Total amount 100 g Aerosil 200 (light anhydrous silicic acid average particle diameter 0.012 μm) was added to Vaseline heated at 65 ° C. in advance and mixed uniformly. Miglyol 8 at room temperature (25 ° C)
12 Neutral oil and liquid paraffin were mixed, and a part of the mixed solution was heated to dissolve lidocaine, tocopherol acetate, eucalyptus oil and d-camphor, and allantoin was further dispersed and added to petrolatum. Chlorpheniramine maleate was dispersed and homogenized in a part of the above mixture, added to petrolatum, and uniformly mixed. Add the remaining mixture to room temperature (2
(5 ° C.), dextrin palmitate was added, and the mixture was uniformly dispersed. The mixture was heated to 90 ° C., added to petrolatum to make uniform, and the temperature was set to 80 ° C. This was further cooled to 60 ° C. and filled in an aluminum tube.

Comparative Example 1 Lidocaine 3 g Chlorpheniramine maleate 0.2 g White petrolatum qs 100 g Lidocaine and chlorpheniramine maleate were added to white petrolatum heated at 65 ° C. in advance. Comparative Example 2 Lidocaine 3 g Chlorferamine maleate 0.2 g Miglyol 812 neutral oil 5 g Vaseline qs 100 g Prepared by adding lidocaine and chlorpheniramine maleate to neutral oil of vaseline and Miglyol 812 previously heated to 65 ° C. .

Comparative Example 3 Lidocaine 3 g Chlorferamine maleate 0.2 g Light liquid paraffin 20 g Miglyol 812 neutral oil 25 g Dextrin palmitate 6 g Methyl polysiloxane 0.1 g Vaseline qs 100 g Miglyol 812 at room temperature (25 ° C.) The liquid oil and light liquid paraffin were mixed, and a part of the mixture was heated to dissolve lidocaine, and added to petrolatum heated to 65 ° C. Chlorpheniramine maleate was dispersed and homogenized in a part of the above mixture, added to petrolatum, and uniformly mixed. At room temperature (25 ° C.), dextrin palmitate and methylpolysiloxane were added to the remaining mixture at room temperature (25 ° C.), and the mixture was uniformly dispersed. The mixture was heated to 90 ° C., added to petrolatum to make uniform, and heated to 80 ° C. This was further cooled to 60 ° C. and filled in an aluminum tube.

Test Example 1 After the hydrophobic ointment for external use obtained in Examples 1 to 4 and Comparative Examples 1 to 3 was stored at 25 ° C. for 1 day, the presence or absence of agglomerates or pastes in the composition was observed. Were observed and each was evaluated according to the following criteria. No generation of agglomerates or pastes:-Slight generation of agglomerates or pastes: + Significant generation of agglomerates or pastes: ++

[0014]

[Table 1] As is clear from Table 1, when an acidic drug (chlorpheniramine maleate) and a basic drug (lidocaine) were simultaneously added to a hydrophobic ointment base, Miglyol 812 was obtained.
Examples 1-4 in which neutral oil and Aerosil 200 were blended
The hydrophobic ointment did not show any generation of aggregates or pastes after storage for one day. In contrast, in Comparative Example 1 in which an acidic drug and a basic drug were mixed with a hydrophobic ointment base other than the medium-chain fatty acid triglyceride, and in Comparative Examples 2 and 3 in which the medium-chain fatty acid triglyceride was further added, both aggregates or A paste was generated.

Test Example 2 About 1 g of ointment was taken from three places in the aluminum tube of the topical hydrophobic ointment obtained in Examples 1-4 and Comparative Examples 1-3, and chlorphenate maleate in the ointment was obtained in the following manner. The lamin content was measured and the results are shown in [Table 2]. Method for measuring the content of chlorpheniramine maleate Take 1 g of an ointment, accurately add 50 mL of an ethanol / tetrahydrofuran mixed solution (4: 1), dissolve by heating at 70 ° C., and shake immediately. After the solution is sufficiently cooled at -10 ° C or lower, it is centrifuged and left to reach room temperature. 4 mL of this solution is accurately measured, and 4 mL of the internal standard solution is accurately added to prepare a sample solution. Separately, 0.02 g of chlorpheniramine maleate for measurement was precisely weighed, and a mixed solution of ethanol / tetrahydrofuran (4: 1) was added to accurately measure 500 ml.
Let L be a chlorpheniramine maleate standard solution. 4 mL of this solution is accurately measured, and 4 mL of the internal standard solution is accurately added to obtain a standard solution. Sample solution and standard solution 10
For each μL, a test was performed by liquid chromatography under the following conditions, and the ratio Q _T of the peak area of chlorpheniramine maleate to the peak area of the internal standard substance in the sample solution was measured.
And determining the ratio Q _S of the peak area of chlorpheniramine maleate to the peak area of internal standard in the standard solution. Internal standard solution: ethanol / tetrahydrofuran mixed solution (4: 1) of phenyl parahydroxybenzoate (1 → 1
[0000] HPLC condition column: Pro C18 (YMC) 4.6φ × 150mm Guard column: YMC packing material (ODS-AM-120-S5) 4.0φ × 10mm Mobile phase: 0.02 mol / L phosphoric acid with pH 6.9 Potassium buffer / acetonitrile mixture (3: 2) Flow rate: about 1.1 mL / min Injection volume: 10 μL Column temperature: Constant temperature around 40 ° C

[0016]

(Equation 1)

[0017]

[Table 2] As is clear from [Table 2], in Examples 1 to 4, chlorpheniramine maleate is 98% or more with respect to the charged amount, the variation is small, and chlorpheniramine maleate is uniformly present in the ointment preparation. It was proved. On the other hand, in Comparative Examples 1 to 3, the content of chlorpheniramine maleate had a large variation, and non-uniformity occurred in the same preparation.

[0018]

According to the present invention, by blending a medium-chain fatty acid triglyceride and light silicic anhydride with a hydrophobic pharmaceutical base, the formation of aggregates or pastes produced when an acidic drug and a basic drug are simultaneously blended. Thus, it is possible to provide a homogeneous and high-quality medicine.

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Claims (7)

[Claims] 1. A homogeneous pharmaceutical composition comprising an acidic drug, a basic drug, a medium-chain fatty acid triglyceride or a hydrophobic pharmaceutical base containing the same and light anhydrous silicic acid. 2. The pharmaceutical composition according to claim 1, wherein the hydrophobic pharmaceutical base is a semisolid oil or a liquid oil at normal temperature (25 ° C.). 3. The pharmaceutical composition according to claim 1, comprising 1 to 96% by weight of a medium chain fatty acid triglyceride based on the total amount of the pharmaceutical composition. (4) Light anhydrous silicic acid is added to the total amount of the pharmaceutical composition in an amount of 0.
2. The pharmaceutical composition according to claim 1, comprising 1 to 10% by weight. 5. The pharmaceutical composition according to claim 1, further comprising an oily gelling agent. 6. The pharmaceutical composition according to claim 5, wherein the oily gelling agent is a dextrin fatty acid ester. 7. The pharmaceutical composition according to claim 6, comprising 1 to 15% by weight of dextrin fatty acid ester based on the total amount of the pharmaceutical composition.