KR102108153B1 - Pharmaceutical composition containing a retinoid with improved bioavailability and stability - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for preventing or treating skin diseases containing retinoids, which is a poorly soluble drug, and a soft gelatin capsule containing the same, and a pharmaceutical composition for preventing or treating skin diseases according to the present invention and a soft gelatin capsule In addition to the increase in bioavailability due to the improvement of the silver dissolution rate, there is an effect of increasing the formulation uniformity, content stability, and stability of related substances.

Description

Pharmaceutical composition containing a retinoid with improved bioavailability and stability}

The present invention relates to a pharmaceutical composition for preventing or treating skin diseases containing retinoids having improved bioavailability and stability, and a soft gelatin capsule containing the same.

Retinoids are natural or synthetic derivatives of vitamin A. First-generation retinoids are tretinoin, all-trans retinoic acid, isotretinoin, 13-cis-retinoic acid, and alitretinoin, 9-cis-retinoic acid. And second-generation retinoids such as etretinate, acitretin, and third-generation retinoids arotinoid, adapalene, tazarotene, bexarotene, and human body Natural retinoids are retinol, vitamin A (vitamin A), retinaldehyde (retinaldehyde), retinal (retinal), vitamin A aldehyde (vitamin A aldehyde) and retinoic acid (retinoic acid).

Retinoids are activated in the form of retinoic acid in vivo, and are used in the treatment of various skin diseases with various actions. Retinoic acid activated in vivo not only regulates the proliferation and differentiation of keratinocytes, but also suppresses sebaceous glands, modulates immunity, and has anti-inflammatory effects, such as acne, psoriasis, skin cancer, and malignant tumors such as T cell lymphoma. It is widely used.

Retinoic acid activated in vivo exerts its physiological action by binding to a nuclear receptor. Intranuclear receptors of retinoic acid are retinoic acid receptors (RAR) and retinoid X receptors (RXR), and each intranuclear receptor has a subtype of α, β, γ. Tretinoin (all-trans retinoic acid) and isotretinoin (13-cis-retinoic acid) bind only to the retinoic acid receptor to form homo dimers. It is known to exert physiological functions by forming homo and heterodimers in combination with.

In addition, most of the retinoids are poorly water-insoluble materials, and in the case of 9-cis retinoic acid, they correspond to BCS (Biopharmaceutical Classification System) class IV, solubility and permeability are low, and exhibit low bioavailability. Pharmaceuticals containing active ingredients with low bioavailability need to improve bioavailability to exert sufficient medicinal effects when ingested by patients, and for this, it is necessary to design pharmaceuticals with the appropriate formulation and excipient selection and optimal composition ratio. have.

Furthermore, the retinoid has a property that is easily decomposed and deteriorated by light, air or heat. Due to this, decomposition and deterioration of the active ingredient retinoid during storage lowers the content, resulting in insufficient medicinal properties or related substances, which may cause unexpected side effects.

Therefore, there is a need for the development of a pharmaceutical composition that contains retinoids as an active ingredient, increased bioavailability and established stability.

Accordingly, in International Publication No. 2005-048994, a soft gelatin capsule formulation containing 9-cis retinoic acid, which is one of the retinoids, has been studied and disclosed, but it has improved solubility compared to the prior art, but is still very effective in dissolution tests. Due to the low dissolution rate, the bioavailability of retinoids was not significantly improved.

International Publication Patent Publication (WO) 2005/048994

An object of the present invention is to provide a pharmaceutical composition for preventing or treating skin diseases with improved bioavailability of retinoids, improved formulation uniformity, content stability, and related substance stability.

To achieve the above object, the present invention is 100 to 3,000 parts by weight of retinoids, 100 to 3,000 parts by weight of natural plant oil, 1 to 1,000 parts by weight of liquid paraffin, and 1 to 300 parts by weight of wax, preventing or preventing skin diseases. It provides a therapeutic pharmaceutical composition.

The retinoid may be characterized as 9-cis retinoic acid.

The natural plant oil is one or more selected from the group consisting of soybean oil, corn oil, sunflower oil, rapeseed oil, flaxseed oil, sesame oil, olive oil, coconut oil, peanut oil, safflower oil, castor oil and cottonseed oil. It can be characterized as.

The wax may be characterized in that it is platinum.

In addition, the present invention provides a retinoid soft capsule characterized in that the pharmaceutical composition is filled in a capsule film, and the capsule film contains gelatin.

The capsule coating may further include one or more selected from the group consisting of gelatin, concentrated glycerin, amorphous sorbitol solution, iron oxide, and purified water.

 The pharmaceutical composition for preventing or treating skin diseases according to the present invention is a pharmaceutical composition for preventing or treating skin diseases containing retinoids, which are poorly soluble drugs, and increases the bioavailability due to an improvement in dissolution rate, formulation uniformity, content stability and flexibility It has the effect of increasing the material stability.

1 is a graph of results according to <Experimental Example 1> comparing dissolution rates of Comparative Examples and Examples.

Hereinafter, the present invention will be described in detail. Terms or words used in the present specification and claims should not be interpreted as being limited to ordinary or lexical meanings, and the inventor can appropriately define the concept of terms in order to best describe his or her invention. Based on the principle that it should be interpreted as meanings and concepts consistent with the technical spirit of the present invention.

The present invention provides a pharmaceutical composition for preventing or treating skin diseases, which comprises 100 to 3,000 parts by weight of natural plant oil, 1 to 1,000 parts by weight of liquid paraffin, and 1 to 300 parts by weight of wax with respect to 100 parts by weight of retinoid. do.

More specifically, with respect to 100 parts by weight of the retinoid, it may include 100 to 3,000 parts by weight of natural plant oil, 1 to 1,000 parts by weight of liquid paraffin, and 1 to 300 parts by weight of wax, preferably 100 to 2,500 parts by weight of natural plant oil Part, may include 5 to 600 parts by weight of liquid paraffin and 10 to 200 parts by weight of wax, more preferably 100 to 2,000 parts by weight of natural plant oil, 10 to 500 parts by weight of liquid paraffin and 10 to 100 parts by weight of wax You can.

If, on the basis of retinoids, the content of natural plant oil, liquid paraffin, or beeswax falls outside the above-described range, the dissolution rate of the pharmaceutical composition for preventing or treating skin diseases, formulation uniformity, content stability, and stability of related substances are reduced. There is a problem.

The retinoid is an active ingredient that is hardly soluble in water and has a low bioavailability.

As an example, 9-cis retinoic acid exhibits a very low dissolution rate of less than 10% in the dissolution test using the USP dissolution test method (paddle method) in four dissolution test solutions of the Pharmaceutical Equivalence Test Standard (by the Ministry of Food and Drug Safety), and in vivo tests 12 Very low bioavailability at ~ 20%.

Therefore, in order to improve the bioavailability of the poorly soluble substance retinoid, it is necessary to improve the dissolution rate using additional pharmaceutical ingredients, and in addition, it is necessary to secure formulation uniformity, content stability, and stability of the related substance.

The retinoid may use retinol, retinal, retinoic acid, and derivatives thereof.

Specific examples include all-trans retinol, all-trans retinoic acid, 13-cis retinoic acid, and 9-cisretinoic acid. Retinoids can also exist in the form of pharmaceutically acceptable derivatives such as salts, esters or drug precursors.

In the pharmaceutical composition for preventing or treating skin diseases according to the present invention, the retinoid may be characterized as 9-cis retinoic acid.

9-cis retinoic acid is a material having a particularly low bioavailability, and the pharmaceutical composition for preventing or treating skin diseases according to the present invention has an advantage of improving the bioavailability of 9-cis retinoic acid.

The natural plant oil is one or more selected from the group consisting of soybean oil, corn oil, sunflower oil, rapeseed oil, flaxseed oil, sesame oil, olive oil, coconut oil, peanut oil, safflower oil, castor oil and cottonseed oil. It can be characterized as.

Preferably, the natural plant oil may use soybean oil, and soybean oil is a widely used natural plant oil, and has a small side effect.

The liquid paraffin refers to a white liquid oil that is very well purified with paraffinic high-grade hydrocarbons, and is also referred to as liquid paraffin, petrolatum oil, or white oil.

The liquid paraffin is used as a natural plant oil to improve the dissolution rate of retinoids, which are dispersion mediums and poorly soluble retinoids used in dispersing retinoids in pharmaceutical compositions for preventing or treating skin diseases, and improve content stability and stability of related substances There is.

In particular, the liquid paraffin has an effect of significantly improving the dissolution rate, content stability, and related substance stability of retinoids, as compared to pharmaceutical compositions for preventing or treating skin diseases containing partially hydrogenated soybean oil and heavy chain triglycerides.

The beeswax (Beewax) has a platinum and a lead, it is obtained by heat compression filtration and purification of the bees and honeycomb of bees, and the lead is obtained by bleaching the purified wax.

The beeswax prevents sedimentation of natural plant oils and retinoids dispersed by liquid paraffin, thereby improving the uniformity of the formulation by maintaining the internal filling in a uniform state.

In addition, the internal filler, that is, the pharmaceutical composition for preventing or treating skin diseases has an effect of enabling uniform and smooth production during molding of the soft gelatin capsule formulation.

The wax may be characterized in that it is platinum.

When using platinum as the beeswax, there is an effect of improving the formulation uniformity, content stability, and stability of the related substances compared to when using lead.

The pharmaceutical composition for preventing or treating skin diseases may be administered topically or systemically, and for oral use, formulations such as tablets, hard and soft gelatin capsules, and sachets may be used.

In addition, the present invention provides a retinoid soft capsule characterized in that the pharmaceutical composition is filled in a capsule film, and the capsule film contains gelatin.

The soft gelatin capsule not only can shield the odor or flavor of the active ingredient retinoid, but also has an effect of increasing solubility and bioavailability.

The capsule coating may further include one or more selected from the group consisting of gelatin, concentrated glycerin, amorphous sorbitol solution, iron oxide, and purified water.

The skin disease may include acne, psoriasis, skin cancer, and T-cell lymphoma.

The pharmaceutical composition for preventing or treating skin diseases according to the present invention has significantly improved formulation stability without adding DL-α-tocopherol, butylhydroxytoluene or butylhydroxyanisole antioxidant, which is used to prevent oxidation of retinoids. It has a visible effect.

The pharmaceutical composition for preventing or treating skin diseases according to the present invention has a dissolution rate in dissolution test at 100 rpm according to the USP dissolution test method (paddle method) in an eluate with pH 6.8 phosphate buffer 900 ml, Brij 4% surfactant added. It may be characterized by being 60 to 90%.

In addition, the variation in content uniformity according to the uniformity test of the Korean Pharmacopoeia may be characterized as 0.5 to 2.5.

Furthermore, at a temperature of 20 to 100 ° C. and a humidity condition of 30 to 100% RH (Relative humidity), the content may be reduced by 0.3 to 1.3% after 3 months.

In addition, at a temperature of 20 to 100 ° C. and a humidity condition of 30 to 100% RH (Relative humidity), it may be characterized in that 0.1 to 0.5% of a related substance is generated after 3 months.

Furthermore, the present invention comprises the steps of heating the natural plant oil and platinum to 60 to 100 ℃ to obtain a pre-filled material;

Cooling the pre-fill to 30-50 ° C., followed by mixing with retinoids, liquid paraffin and beeswax to obtain an internal fill; And

It provides a method of manufacturing a soft gelatin capsule for preventing or treating skin diseases, including the step of encapsulating the inner filler filled inside the gelatin film.

As an example, the natural plant oil and platinum are melted by heating to 60 to 100 ° C in a preparation tank to obtain a pre-filled material.

Thereafter, the preparation tank containing the pre-filled material is cooled to 30 to 50 ° C, and homogeneously mixed with retinoid, liquid paraffin, and beeswax to obtain an internal filling material.

After the internal filling is sieved, it is defoamed and transferred to a storage tank set to stir intermittently and stored.

Here, the internal filler may be characterized in that it contains 100 to 3,000 parts by weight of natural plant oil, 1 to 1,000 parts by weight of liquid paraffin, and 1 to 300 parts by weight of wax with respect to 100 parts by weight of retinoid.

The gelatin film may be prepared including gelatin, concentrated glycerin, amorphous sorbitol solution, iron oxide, and purified water.

First, purified water, concentrated glycerin and sorbitol solution (amorphous) are homogeneously mixed in a gelatin preparation tank, and gelatin is added thereto to stir and melt.

 Purified water and iron oxide are added to a separate container to stir and homogenize, and then put into a gelatin preparation tank, stirred at about 70 to 80 ° C, and reduced to a vacuum of about 0.80 to 0.90 bar.

After about 30 to 60 minutes, the vacuum is released, transferred to a gelatin storage tank, and stored at about 50 to 60 ° C until molding.

A soft gelatin capsule may be prepared by filling and molding the prepared inner filler inside a gelatin film using a soft capsule molding machine.

When the drug is ingested, the drug should be designed so that the drug concentration in the plasma is sufficiently high to exhibit the drug efficacy, but the concentration of the drug is not excessively high, so that the side effects are not absorbed. Therefore, the industry is evaluating the formulation through the dissolution test in order to design the optimal formulation.

The dissolution test is a method of measuring the amount of active ingredients eluted from a formulation (test sample) within a specified time period. Since the in vivo dynamics of the drug can be predicted, data from dissolution tests are very important in research and development of pharmaceuticals.

In this regard, in the case of 9-cis retinoic acid, the previously known soft gelatin capsule formulation (International Publication WO 2005/048994) has improved solubility compared to the prior art (International Publication WO 99/24024), but dissolution test. In still showing a very low dissolution rate, the bioavailability of the retinoid did not improve significantly.

In addition, content stability must be ensured in order for pharmaceuticals to exhibit proper medicinal effects until the period of use. If the content is lowered within the period of use due to unstable stability, sufficient efficacy cannot be exerted, and this can cause serious problems such as worsening of symptoms by delaying the patient's disease treatment time.

Furthermore, one of the important factors in the evaluation of the formulation is the stability of the related substances.

Related substances are all substances except raw materials contained in pharmaceutical compositions for the prevention or treatment of skin diseases, and impurities that may be generated during synthesis, manufacture, and storage of raw and drug products (starting substances, intermediate substances, parts) Product, decomposition products, etc.). Medicines in which these related substances remain or are produced are severely controlled because they can cause serious side effects even in very small amounts.

In this regard, the stability of the related substance in the soft gelatin capsule formulation of the prior art was also improved, but after analyzing the formulation of the prior art for 3 months storage at 60 ° C and 75% RH conditions, it was confirmed that many related substances are still generated. Content stability was also reduced by about 4% after storage for 3 months at 60 ° C and 75% RH, and the content stability was also confirmed to be unstable.

Thus, in the present invention, a dissolution test, formulation uniformity, content stability, and related substance stability experiments were conducted using a pharmaceutical composition for preventing or treating skin diseases of a new retinoid-containing soft gelatin capsule. In the dissolution test, since the solubility reached the saturation step at a very low dissolution rate, it was difficult to compare the dissolution rate between the formulations, and a dissolution test was conducted using an eluent containing a surfactant.

As a result, the pharmaceutical composition for preventing or treating skin diseases of the present invention showed an improved dissolution rate than the prior art when evaluated by in vitro experiments, and it was confirmed that the bioavailability was improved, and when stored under the same temperature and humidity conditions, It was confirmed that the improved formulation uniformity, content stability and related material stability were exhibited.

Hereinafter, examples and experimental examples will be described in detail to specifically describe the present invention. However, the embodiments according to the present invention may be modified in various other forms, and the scope of the present invention should not be interpreted as being limited to the embodiments described below. The embodiments of the present invention are provided to more fully describe the present invention to those skilled in the art.

<Production Example 1> Preparation of a film of soft gelatin capsules

First, purified water, concentrated glycerin and sorbitol solution (amorphous) were homogeneously mixed in a gelatin preparation tank, and gelatin was added thereto to stir and melt.

Purified water, red iron oxide, and yellow iron oxide were added to a separate container to stir and homogenize, and then added to a gelatin preparation tank, stirred at about 70 to 80 ° C, and decompressed to a vacuum of about 0.80 to 0.90 bar.

After about 30 to 60 minutes, the vacuum was released, transferred to a gelatin storage tank, stored at about 50 to 60 ° C until molding, and used within 2 days after manufacture, and the remaining amount was discarded.

Table 1 shows the coating composition of the soft gelatin capsule used in the preparation.

Raw material name (mg / 1 capsule) gelatin 122.0 Concentrated glycerin 22.0 Sorbitol solution (amorphous) 31.6 Red iron oxide 0.55 Yellow iron oxide 1.13 Purified water ^* 19.72

Here, the purified water ^* describes the calculated amount in the skin after drying.

< Comparative example  1 to 3> 9-cis retinoic acid, soybean oil, partially hydrogenated soybean oil or medium-chain triglycerides, lead, soft gelatin filled with pharmaceutical composition for preventing or treating skin diseases containing DL-α-tocopherol as antioxidant capsule

First, in order to prepare an internal filling, a soybean oil and lead, which are natural plant oils, were added to an inner liquid preparation tank and heated to about 70 ° C to melt.

After cooling the inner liquid preparation tank to about 40 ° C, 9-cis retinoic acid, partially hydrogenated soybean oil, medium chain triglyceride, and DL-α-tocopherol were mixed homogeneously and degassed after degassing the homogeneously mixed internal filler. .

The contents were transferred to a storage tank set to be intermittently stirred and stored, and in order to prevent decomposition or deterioration of light-sensitive retinoids during the manufacturing process, sodium light was turned on when necessary.

A soft gelatin capsule was prepared by molding and filling the soft capsule molding machine using the prepared inner filler and the film prepared in <Production Example 1>, and the composition of the inner filler, that is, a pharmaceutical composition for preventing or treating skin diseases It is shown in 2.

Raw material name (mg / 1 capsule) Comparative Example 1 Comparative Example 2 Comparative Example 3 inside
Filling 9-cis retinoic acid 30.00 30.00 30.00 Soybean oil 212.0 282.40 239.20 Partially hydrogenated soybean oil 70.40 70.40 Closed triglycerides 27.20 27.20 Desolation 10.40 10.40 10.40 DL-α-tocopherol 0.04 0.04 0.04

< Comparative example  4> Commercially available soft capsule containing retinoid

As another comparative example, a commercially available product of Company A was used.

< Example  5 ~ 8> 9- Sheath Retinoic acid , Soybean oil, partially hydrogenated soybean oil, liquid paraffin, Desolation  And a soft gelatin capsule filled with a pharmaceutical composition for preventing or treating skin diseases containing DL-α-tocopherol as an antioxidant

First, in order to prepare an internal filling, soybean oil and lead were put in an inner liquid preparation tank and heated to about 70 ° C to melt.

After cooling the inner liquid preparation tank to about 40 ° C., 9-cis retinoic acid, partially hydrogenated soybean oil, liquid paraffin, DL-α-tocopherol were mixed homogeneously, and the homogeneously mixed internal filler was degassed and sieved.

The contents were transferred to a storage tank set to be intermittently stirred and stored, and in order to prevent decomposition or deterioration of light-sensitive retinoids during the manufacturing process, sodium light was turned on when necessary.

A soft gelatin capsule was prepared by molding and filling the soft capsule molding machine using the prepared inner filler and the film prepared in <Production Example 1>, and the composition of the inner filler, that is, a pharmaceutical composition for preventing or treating skin diseases It is shown in 3.

Raw material name (mg / 1 capsule) Example 5 Example 6 Example 7 Example 8 Internal filling



9-cis retinoic acid 30.00 30.00 30.00 30.00 Soybean oil 250.46 222.46 194.46 138.46 Partially hydrogenated soybean oil 29.00 29.00 29.00 29.00 Floating paraffin 28.00 56.00 84.00 140.00 Desolation 12.50 12.50 12.50 12.50 DL-α-tocopherol 0.04 0.04 0.04 0.04

< Example  9 ~ 12> 9- Sheath Retinoic acid , Soybean oil, liquid paraffin, Platinum  And a soft gelatin capsule filled with a pharmaceutical composition for preventing or treating skin diseases containing DL-α-tocopherol as an antioxidant

First, in order to prepare an internal filling, soybean oil and platinum were added to the preparation tank for the contents and heated to about 70 ° C to melt.

After cooling the inner liquid preparation tank to about 40 ° C, 9-cis retinoic acid, liquid paraffin, DL-α-tocopherol were mixed homogeneously, and the homogeneously mixed internal filling was degassed and sieved.

The contents were transferred to a storage tank set to be intermittently stirred and stored, and in order to prevent decomposition or deterioration of light-sensitive retinoids during the manufacturing process, sodium light was turned on when necessary.

A soft gelatin capsule was prepared by molding and filling the soft capsule molding machine using the prepared inner filler and the film prepared in <Production Example 1>, and the composition of the inner filler, that is, a pharmaceutical composition for preventing or treating skin diseases It is shown in 4.

Raw material name (mg / 1 capsule) Example 9 Example 10 Example 11 Example 12 Internal filling


9-cis retinoic acid 30.00 30.00 30.00 30.00 Soybean oil 281.46 219.46 200.96 158.96 Floating paraffin 35.00 90.00 105.00 140.00 Platinum 3.50 10.50 14.00 21.00 DL-α-tocopherol 0.04 0.04 0.04 0.04

< Example  13 ~ 14> 9- Sheath Retinoic acid , Soybean oil, liquid paraffin, Platinum  And as an antioxidant Butylhydroxytoluene  or Butylhydroxyanisole A soft gelatin capsule filled with a pharmaceutical composition for preventing or treating skin diseases containing the molded and filled soft gelatin capsule

In <Examples 9 to 12>, a soft gelatin capsule was prepared in the same manner, except that butylhydroxytoluene or butylhydroxyanisole was used instead of DL-α-tocopherol as an antioxidant, and the internal filler, that is, Table 5 shows the composition of the pharmaceutical composition for preventing or treating skin diseases.

Raw material name (mg / 1 capsule) Example 13 Example 14 Internal filling



9-cis retinoic acid 30.00 30.00 Soybean oil 219.46 219.46 Floating paraffin 90.00 90.00 Platinum 10.50 10.50 Butylhydroxytoluene 0.04 - Butylhydroxyanisole - 0.04

<Examples 15 to 18> A soft gelatin capsule filled with a pharmaceutical composition for preventing or treating skin diseases containing 9-cis retinoic acid, soybean oil, liquid paraffin, and platinum, and a filled soft gelatin capsule

A soft gelatin capsule was prepared in the same manner, except that the antioxidant components used in <Examples 13 to 14> were not used, and the internal filler, that is, the composition of the pharmaceutical composition for preventing or treating skin diseases It is shown in 6.

Raw material name (mg / 1 capsule) Example 15 Example 16 Example 17 Example 18 Internal filling


9-cis retinoic acid 30.00 30.00 30.00 30.00 Soybean oil 281.46 219.46 200.96 158.96 Floating paraffin 35.00 90.00 105.00 140.00 Platinum 3.50 10.50 14.00 21.00

< Experimental example  1> Dissolution test

(1) Experiment method

In order to infer the dynamics of the drug in the body through an in vitro test, a dissolution test was conducted for the preparations of the comparative examples and examples.

In the in vivo test of 9-cis retinoic acid, the time to reach the highest blood concentration (T _max ) is known to be 3 to 4 hours, so the dissolution rate of the drug in the small intestine pH 6.8 was compared. In addition, it was difficult to compare the dissolution rate of each formulation in the pH 6.8 phosphate buffer solution without the addition of surfactant, so that a dissolution test was performed by adding a surfactant.

 Therefore, Brij 4% as a surfactant was added to 900 mL of the pH 6.8 phosphate buffer, and the elution test was performed at a USP dissolution test method (paddle method) at 100 rpm.

(2) Experiment result

The results of the experiment are shown in Table 7 and FIG. 1.

As shown, in the case of Comparative Examples 1 to 4, the elution rate at the time of elution for 3 hours did not exceed 60%. This can be confirmed that the dissolution rate is very low since 4% of the surfactant is added and the result is performed under 100 rpm.

On the other hand, Examples 5 to 8 showed an improved dissolution tendency compared to Comparative Examples 1 to 4, showing an elution rate of about 65 to 70% when elution for 3 hours, and an elution rate of about 75 to 90% in Examples 9 to 18. It showed a more favorable dissolution tendency.

Sample name 90 minutes 120 minutes 180 minutes Comparative Example 1 30.4 43.9 52.9 Comparative Example 2 31.6 44.6 52.2 Comparative Example 3 25.9 45.0 49.3 Comparative Example 4 31.9 46.1 53.1 Example 5 36.1 51.6 65.1 Example 6 38.2 52.7 68.9 Example 7 40.2 55.1 70.8 Example 8 34.8 54.3 68.3 Example 9 43.3 63.0 76.3 Example 10 44.5 67.3 87.6 Example 11 46.1 68.1 90.3 Example 12 44.3 63.1 82.6 Example 13 43.7 65.3 84.1 Example 14 45.3 64.1 83.0 Example 15 42.8 62.8 77.0 Example 16 45.1 66.5 85.7 Example 17 43.4 67.6 80.8 Example 18 43.7 64.3 81.9

< Experimental example  2> Formulation uniformity test

(1) Experiment method

The formulation uniformity test for the formulations of the comparative examples and examples was carried out according to the content uniformity test in the formulation uniformity test of the Korea Pharmacopoeia.

(2) Experiment result

Table 8 shows the results of the experiment.

As shown, Examples 5 to 18 have better formulation uniformity than the formulations of Comparative Examples 1 to 4, and particularly preferred formulation uniformity was confirmed in Examples 10 to 18.

Sample name One 2 3 4 5 Deviation Comparative Example 1 103.6 97.7 101.1 102.6 96.2 3.2 Comparative Example 2 95.3 102.8 102.1 98.7 101.1 3.1 Comparative Example 3 104.7 99.9 98.7 97.5 101.2 2.8 Comparative Example 4 97.3 96.8 103.2 101.8 99.9 2.8 Example 5 102.9 97.2 96.8 100.4 98.9 2.5 Example 6 99.3 100.8 96.9 102.8 100.3 2.2 Example 7 98.7 100.5 102.9 97.1 98.3 2.3 Example 8 99.3 96.8 102.1 100.9 98.2 2.1 Example 9 102.3 99.2 96.3 102 99.8 2.4 Example 10 100.2 98.6 100.6 99.2 100.9 1.0 Example 11 101.1 100.7 102 99.9 99.8 0.9 Example 12 99.8 102.3 97.2 99.6 100.2 1.8 Example 13 98.7 100.7 99.8 101.1 99.2 1.0 Example 14 101.5 101.2 100.8 103.5 101 1.1 Example 15 100.0 97.8 98.6 97.4 99.7 1.1 Example 16 95.8 98.2 96.8 99.9 98.5 1.6 Example 17 96.1 97.5 95.3 98.5 96.8 1.2 Example 18 99.8 96.4 98.7 97.4 98.8 1.3

< Experimental example  3> Content stability test

(1) Experiment method

The soft gelatine capsules of Comparative Examples and Examples were packaged in PTP and tested for content stability for a formulation stored at 60 ° C and 75% RH for 3 months.

(2) Experiment result

Table 9 shows the results of the experiment. As shown, in Comparative Example 1 to 4, the content of 3.9 to 4.8% was lowered in the content stability confirmed after 3 months at 60 ° C and 75% RH, and the contents of 0.3 to 1.3% in Examples 5 to 18 Only the bay fell.

Therefore, Examples 5 to 18 have less content degradation than Comparative Examples 1 to 4, and thus, after long-term storage, it is possible to expect sufficient efficacy of the active ingredient, and in particular, it was confirmed that Examples 10 to 18 have more preferable content stability.

Sample name content(%) Early 3 months later Deviation Comparative Example 1 100.9 96.5 -4.4 Comparative Example 2 99.8 95.4 -4.4 Comparative Example 3 101.0 96.2 -4.8 Comparative Example 4 101.5 97.6 -3.9 Example 5 100.2 99.2 -1.0 Example 6 100.8 99.7 -1.1 Example 7 99.0 98.0 -1.0 Example 8 100.8 99.5 -1.3 Example 9 100.7 99.7 -1.0 Example 10 100.2 99.8 -0.4 Example 11 101.3 100.8 -0.5 Example 12 101.1 100.8 -0.3 Example 13 100.8 100.1 -0.7 Example 14 100.4 99.7 -0.9 Example 15 99.7 99.1 -0.6 Example 16 99.4 98.9 -0.5 Example 17 98.2 97.9 -0.3 Example 18 98.9 98.2 -0.7

< Experimental example  4> Related substances  Stability test

(1) Experiment method

The soft gelatin capsules of the comparative examples and examples were packaged in PTP, and a stability test for a flexible substance was performed on a formulation stored at 60 ° C and 75% RH for 3 months.

(2) Experiment result

Table 10 shows the results of the experiment. As shown, a lot of related substances were generated in the formulations of Comparative Examples 1 to 4 after 3 months at 60 ° C and 75% RH conditions, and the formulations of Examples 5 to 14 were able to confirm that these related substances were relatively small. , In particular, the formulations of Examples 10 to 18 showed more preferable results.

Sample name Total analogs (%) 3 months later Comparative Example 1 0.71 Comparative Example 2 0.78 Comparative Example 3 0.65 Comparative Example 4 0.71 Example 5 0.49 Example 6 0.35 Example 7 0.37 Example 8 0.51 Example 9 0.41 Example 10 0.18 Example 11 0.11 Example 12 0.10 Example 13 0.15 Example 14 0.14 Example 15 0.42 Example 16 0.20 Example 17 0.14 Example 18 0.13

Claims (6)

A pharmaceutical composition for preventing or treating skin diseases, comprising 100 to 3,000 parts by weight of soybean oil, 300 to 467 parts by weight of liquid paraffin, and 10 to 100 parts by weight of platinum.
According to claim 1,
The retinoid is a pharmaceutical composition for preventing or treating skin diseases, characterized in that 9-cis retinoic acid.
delete delete The pharmaceutical composition of claim 1 is filled inside the capsule coating,
The capsule capsule is a retinoid soft capsule, characterized in that it comprises a gelatin.
The method of claim 5,
The capsule film is a soft retinoid capsule, characterized in that it further comprises at least one selected from the group consisting of gelatin, concentrated glycerin, amorphous sorbitol solution, iron oxide and purified water.

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