KR100517653B1 - Pharmaceutically stable composition for soft capsule - Google Patents

Abstract

The present invention relates to a coating composition of a pharmaceutically stable soft gelatin capsule, and more particularly to a soft capsule containing a hydrophilic or spontaneous filling content and having improved stability. The soft capsule according to the present invention can improve the main component content deterioration problem and the disintegration delay problem generally occurring in soft capsules containing the filling contents of hydrophilic or spontaneous properties by using the sorbitol glycerin blend solution as a plasticizer for the capsule coating. have.

Description

Pharmaceutically stable composition for soft capsule

The present invention relates to a coating composition of a pharmaceutically stable soft gelatin capsule, and more particularly to a coating composition of a soft gelatin capsule containing improved filling contents of hydrophilic or spontaneous properties and having improved stability.

Soft gelatin capsules (hereinafter also referred to as "soft capsules" for convenience) consist of the capsule contents (filling) and the coating (shell), and the capsule contents consist of one or more active ingredients and bases (excipients) that are active, The coating consists of gelatin, an amount of plasticizer and water.

Gelatin, which is a major component of the film, is obtained by hydrolyzing collagen, which constitutes the connective tissue of an animal, and is a polymer in which a polypeptide chain is intricately entangled. Polypeptide chains contain highly reactive active groups (-COOH, -NH ₂ , -SH, -OH) that can bind. The activators between the gelatin molecules form covalent bonds over time, and gradually form large network structures (network molecules). This phenomenon makes gelatin insoluble (insolubilized) in water, which causes the entire capsule of the soft capsule to be insolubilized, causing disintegration to be delayed.

Factors affecting network formation between gelatin molecules include high temperature, high water content of the coating, aldehyde or ketone compounds contained in active ingredients or excipients, tannins, iron or chromium, and aluminum metal ions.

The insolubilization mechanism of the gelatin is mainly carried out by the carbonylamine reaction, which proceeds rapidly when the aldehyde compound is present inside the coating and contains a lot of water. When iron, chromium, or aluminum ions are transferred to water in the film, carboxyl groups in the gelatin molecule are chelated to form a network between the gelatin molecules. Herbal ingredients containing tannins also quickly insolubilize the coating when transferred to the coating.

Soft capsules should be stored under low temperature and dry conditions in order to suppress the insolubilization of gelatin as described above, and the moisture content of the film is minimized to reduce the transfer of the filling contents containing aldehydes or ketones, tannins and metal ions into the film. Should be.

The filling content of the soft capsule has the advantage of easily filling the liquid or paste form, so that the main ingredient is suspended or dissolved in oil or hydrophilic base to be used as the filling content. When the oil base is used as the filling content, the physical stability is better than the soft capsules using the hydrophilic base, but the bioavailability and fastness are inferior in terms of formulation.

Pharmacologically active ingredients are generally hydrophilic, lipophilic or poorly soluble. When the active ingredient is hydrophilic, it is rapidly dissolved in the water or the plasticizer of the film to decrease the content. When the active ingredient is lipophilic or insoluble, in general, the dissolution rate or bioavailability is low. Thus, in order to improve this, the active ingredient is dissolved in a mixture of a surfactant, a dissolution aid, and a lipid material to form a filler having the characteristics of spontaneous emulsification. Manufacture. This content has the property of being easily dispersed in water, so that it is dispersed and carried into the water in the film.

Attempts to improve the performance of gelatin coatings by using plasticizers in soft capsule coatings include Korean Patent Application No. 1984-1066 (1984.3.2). However, in this technique, the active ingredient must be soluble in the polyethylene glycol as an excipient, and the composition of the film must be varied according to the amount of the excipient used, so the selection of the composition ratio of each component is very complicated, and the specific active ingredient, Not only is it very difficult to find the optimal combination of excipients and coating compositions, but even if the embrittlement of the gelatine capsules is solved by such combinations, all the problems associated with the gelatine capsules, such as lowering of the main ingredient content in the capsules, gelatin insolubility (disintegration problem) Has not been considered for

The present inventors have studied diligently to increase the dissolution or bioavailability of the pharmacologically active ingredients contained in the soft capsule, and as a result, the soft capsule containing the filling contents of hydrophilic or spontaneous properties by using sorbitol glycerin blend as a plasticizer for the capsule coating It was confirmed that the problem of lowering the content of the active ingredient tends to occur, the film insolubilization (disintegration delay) problem, and came to complete the present invention.

Accordingly, an object of the present invention is to significantly reduce the problem of the prior art, namely, the transition of the active ingredient to the coating due to the moisture of the soft capsule coating, by using sorbitol glycerin blend having excellent stability as a plasticizer of the soft capsule coating, the content of the main component It is an object of the present invention to provide a pharmaceutically stable soft capsule having improved degradation, encapsulation problem and encapsulation of the film.

In one aspect, the present invention includes a sorbitol glycerin blend as a plasticizer, wherein the sorbitol glycerin blend is 40 to 55 wt% of glycerin (Glycerin 98.5%), 7.5 to 15 wt% of anhydrous sorbitol (Sorbitol anhydrides), 20 to 27.5 sorbitol It provides a coating composition of a pharmaceutically stable soft capsule, characterized in that it contains 13% by weight, water and 13 to 18% by weight of polyols (eg mannitol).

In a further aspect, the present invention provides a pharmaceutically stable soft capsule comprising a filling content of hydrophilic or spontaneous characterization and comprising the sorbitol glycerin blend as a plasticizer.

Soft capsules are characterized by the properties of the base (or excipient) used to dissolve or suspend the pharmacologically active ingredient, and the physicochemical properties of the filling contents thereof are determined in the present invention. Various additives such as sugars, syrups, low molecular polyols, and starches are used to prevent various problems that occur in soft capsules containing the contents of the capsule, that is, content degradation problems and film insolubilization problems and to reduce moisture content. As a result, by using sorbitol glycerin blend in which sorbitol, sorbitol anhydrides, and glycerin are properly combined as described above, the above problems are likely to occur in conventional glycerin plasticizers. Can improve the water content of the film Yihaengryul of the film was confirmed that reducing.

In addition, in the present invention, by adding various types of polyol as a plasticizer component, the water content of the soft capsule film is maintained more appropriately than the conventional plasticizer of glycerin alone, which significantly reduces the transition of the filler into the film, and at the same time, the content decreases and the film disintegrates. It was also confirmed that the delay can be further prevented. The polyol may be one known in the art, and examples thereof include mannitol, but are not limited thereto.

When sorbitol solution (D-Sorbitol 70%) is used as a plasticizer alone according to the prior art, the water content of the film can be kept low, but white blooming (Sloobitol crystal is precipitated into the film depending on the distribution conditions) There is a problem that appears.

Even in the case of conventional glycerin plasticizers, the loss on dry (capsule on dry: 120 hours for 1 hour) of the soft capsule film during distribution is 10 to 14% by weight, while the soft capsule using sorbitol glycerin blend as a plasticizer is 6.5 to 10% by weight. The water content is small and kept constant. Due to this feature, it is possible to improve the transition of the active ingredient into the coating.

The sorbitol glycerin blend is preferably contained 15 to 40% based on the weight of the dry film with respect to the soft capsule film.

In a further aspect of the invention, 15 to 40% by weight of sorbitol glycerin blend, 30 to 60% by weight of gelatin (more preferably acid or alkali or succinic acid) and polyhydric alcohol or polyol Provided is a film composition of a soft capsule for reducing the main ingredient content and preventing film insolubilization, characterized by containing 0 to 25% by weight.

The coating composition which concerns on this invention can add a well-known coloring agent, fragrance | flavor, flavoring agent, opacifier, preservative, light-shielding agent, and enteric coating agent as needed.

The soft capsule according to the present invention is prepared by dissolving or suspending one or more pharmacologically active ingredients in one or more liquid or semi-solid pharmaceutical excipients, thereby filling the gelatinous coating composition containing a plasticizer with the filling contents of the liquid or paste form. Are manufactured.

In the soft capsule according to the present invention, the active ingredient may be used at least one of hydrophilic or spontaneous properties when dissolved or suspended in a pharmaceutical excipient, the content of which is 0.001 based on the total weight of the coating composition of the soft capsule. It is preferable to contain in the quantity of-65 weight%.

In the case of an active ingredient having hydrophilic or spontaneous properties that can be included in the capsule composition according to the present invention, it is preferable to include the following excipients.

Category A (if active ingredient is hydrophilic):

50-99% by weight of polyethylene glycol having an average molecular weight of 200 to 600 is used, and 0 to 30% by weight of polyethylene glycol having an average molecular weight of 800 to 10000, 0 to 15% by weight of glycerin, and 0 to 15% by weight of propylene glycol as necessary. %, 0-15% by weight of propyl carbonate, 0-10% by weight of polyvinylpyrrolidone (povidone), 0-13% by weight of purified water, 0-20% by weight of nonionic surfactant, 0-20% by weight of water-soluble polyols, Charge contents are prepared by dissolving or suspending one or more pharmacologically active ingredients alone or in combination of sugar alcohols 0 to 10% by weight, pH adjusting agent 0 to 10% by weight, and antioxidants 0 to 5% by weight.

Category B (if the filling contents have the characteristics of spontaneous emulsification):

Spontaneous emulsifiable contents are those in which one or more pharmacologically active ingredients (approximately 0.25 µg to 500 mg) are dissolved in one of a lipid component, a surfactant and a dissolution aid, followed by blending, or the contents dissolved or suspended after blending with water. When used, it refers to the contents that form an emulsion or microemulsion. The contents having the property of spontaneous emulsification are characterized by comprising 0.1 to 90% by weight of lipid component, 0.05 to 99% by weight of surfactant, 0.05 to 50% by weight of dissolution aid or other pharmaceutical excipients.

Examples of lipid components in category B include saturated or unsaturated natural fats and partially or wholly hydrogenated vegetable oils (e.g., Lobritab ^™ , hydrogenated palm oil (Dynasan ^™ ), hydrogenated soymilk (Sterotex ^™ HM)), ( Semi-synthetic and synthetic mono-, di-, triglycerides containing saturated and / or unsaturated fatty acids with C ₁₀ -C ₂₂ aliphatic chains (Imwitor ^TM , Softigen ^TM 701, Capmul ^TM , Maisine ^TM , Peceol ^TM , Mycerol ^TM ) And their polyhydroxyethylated derivatives (e.g., tristearin, capriccocapryl, triglycerides (Myglyol ^™ , Captex ^™ , Labrafac ^™ LIPO), Compritol ^™ , Mirpyl ^™ , Neobee ^™ M-20, Glyceryl Mono Monoglycerides such as stearate (Myvaplex ^™ 600), Lauroglycol ^™ , or glyceryl palmitostearate (Precirol ^™ ) and saturated or unsaturated polyhydroxy triglycerides (Labrafil ^™ , Labrafac ^™ Hydro, Gelucir ^eTM series)), liquid waxes (e.g. isopropyl myristate, isopropyl-caprinate, -caprylate, -laurate, -palmitate, -stearate and ethyl oleate and oleyl oleate, etc. Fatty acid esters), solid waxes (e.g. carnauba wax, beeswax), aliphatic alcohols (e.g. cetyl alcohol, stearyl alcohol, lauryl alcohol, cetylstearyl alcohol and polyhydroxyethylation thereof Derivatives), preferably aliphatic carboxylic acids having medium and long chains (C _{10 to} C ₂₂ ), saturated (decanoic acid, lauric acid, palmitic acid, stearic acid, docoic acid, etc.), unsaturated (oleic acid, Linolenic acid) and polyhydroxyethylated derivatives thereof. Lipids with hydrophilic moieties are also included in this category. Phospholipids (phosphatidylcholine and phosphatidylglycerol), decyl esters of oleic acid (Cetiol ^™ V), medium chain fatty acids (capric acid, capronic acid and lauric acid) and polymer types can be used. Polymers include polyethylene glycol (average molecular weight 200-20000), poloxamer (Lutrol ^TM 188, Lutrol ^TM 407), polyvinyl alcohol, polyacrylates (Carbopol ^TM , Pemulen ^TM , Noveon ^TM ), chitosan, hyaluronic acid and derivatives thereof Xanthan, screroglucan, gellan, guar gum, locust bean gum, alginate, dextran can be used.

Surfactants in category B are divided into conventional lipophilic and hydrophilic surfactants, most of which are nonionic surfactants. Lipophilic surfactants include fatty acids (oleic acid, linoleic acid, linolenic acid, stearic acid, myristic acid, lauric acid, palmitic acid, capric acid, caprylic acid), mono-, di-glycerides of fatty acids, Mono- and di-glycerides of acetic acid, succinic acid, citric acid, tartaric acid esters, poly ethylene glycol mono-, di-esters of fatty acids, polyglycerol esters of fatty acids (polyglyceryl oleate), ethoxylate castor oil , Fatty acid esters of polyoxyethylene, sorbitan esters of fatty acids, and the like, and commercially available products under the following trade names can be used. ^TM 20-80 Span, Crill ^TM 1, Crill 4 ^{TM, TM} Imvitor 988, Imvitor 742 ^{TM, TM} Imvitor 308, Imvitor 191 ^{TM, TM} Softigen 701, Capmul ^TM MCM, Capmul GMO ^{TM, TM} Capmul GDL, ^TM Maisine, Peceol ^TM , Myverol ^TM 18-92, Myverol ^TM 18-06, Myvacet ^TM 9-45, Miglyol ^TM 829, Myverol ^TM SGM, Imwitor ^TM 370, Imwitor ^TM 375, Crodatem ^TM T22, Lauroglycol ^TM , Mirpyl ^TM , Captex ^TM 200, ^{Miglyol TM 840, Neobee TM M-} 20, Caprol TM ET, Capryol TM PGMC, Drewpol TM, Etocas TM 5, Sandoxylate TM 5, Crodet TM 04, Cithrol TM 2MS, Marlosol TM 183, Marlowet TM G12DO, Labrafil TM M1944CS, Labrafil M2125CS ^{TM, TM} Glucire 37/06, N3 ^TM Volpo, Brij 93 ^{TM, TM} Marlowet LA4, ^TM Synperonic PE L42, Synperonic PE L61 ^TM.

Hydrophilic surfactants include lecithin, polyoxyethylene sorbitan fatty acid derivatives, ethoxylated castor oil or hydrogenated castor oil, ethoxylated fatty acids, ethoxylated alcohols, polyethylene glycol-polyoxypropylene copolymers and block co The polymer may be mentioned, and cationic surfactants may be classified into sodium lauryl sulfate, sodium oleate, and alkylphenols, and commercially available products under the following trade names may be used. ^{Tween TM 20, Tween TM 80,} Crillet TM 4, Montanox TM 40, Cremophor TM EL, Cremophor TM RH40, Etocas TM 40, Nikkol TM HCO-60, Myrj TM 45, Tagat TM L, Marlosol TM 1820, Marlosol TM OL15, ^TM 96 Brij, Volpo ^TM 015, ^TM Marlowet OA30, Marlowet LMA20 ^{TM, TM} Syperonic PE L44, Syperonic F127 ^{TM, TM} Labrasol, Softigen 767 ^TM.

Dissolution aids in category B are short-chain alcohols such as ethanol, 2-propanol, n-butanol, isopropanol, short or medium chain fatty acids (butyric acid, valeric acid, capronic acid), aromatic alcohols (benzyl alcohol), decanoic acid, lauric acid, Medium chain alcohols such as caprinyl alcohol and lauryl alcohol, fatty acids, and the like.

Soft capsules containing the contents of the category A and B, and using glycerin alone as a plasticizer, have at least 20 pharmacologically active ingredients dissolved or suspended in the contents and dissolved in a large amount of water contained in the coating. If aldehydes, ketones, metal ions, tannins, etc. are present in the components transferred to the film, the formation of the network between the gelatin molecules is accelerated, and the entire film becomes insoluble (disintegration delay). This phenomenon occurs quickly when the storage conditions are high temperature and high humidity, and serious problems that the product must be collected and disposed of when the content decreases and disintegration inconvenient within the shelf life.

Hereinafter, the formulation will be described in more detail with respect to the pharmaceutical stable soft capsule developed by the present invention. However, these examples are intended to illustrate the invention and are not intended to limit the scope of the invention in any way.

Example 1

Using the plasticizer coating formulation according to the present invention and the prior art [Table 1] to prepare the capsule contents to be applied to category A to produce a soft capsule. That is, after preparing the coating according to the composition shown in [Table 1], the contents of the filling were prepared in each composition from I to IV, and each of the soft capsules was molded and filled in a predetermined amount using a soft capsule molding machine and dried for 10 days to prepare a total of 8 batches of soft capsules. .

ingredient The present invention Comparative example gelatin  42.5%  42.5% Sorbitol Glycerin Blend  30.0% glycerin  30.0% Purified water  Quantity  Quantity

The sorbitol glycerin blend includes 50% by weight glycerin (Glycerin 98.5%), 10% by weight sorbitol anhydrous (Sorbitol Anhydrides), 25% by weight sorbitol, water and 15% by weight mannitol.

Filling Content Composition I

Guapefenin 78.75 mg

Trimethoquinol hydrochloride 2.16 mg

Noscarpine hydrochloride 21 mg

Chlorpheniramine Maleic Acid 2.16 mg

21 mg of dextromethorphan bromide

Polyethylene glycol 600 210 mg

Polyethylene Glycol 400 140 mg

Concentrated glycerin 24 mg

Filling Content Composition II

Acetaminophen 250 mg

Hydrobromide dextromethorphan 10 mg

Pseudohydrophedrine hydrochloride 30 mg

Succidoxylamine 6.25 mg

Polyethylene glycol400 458 mg

Propylene Glycol 46 mg

Povidone 46 mg

Purified water

Filling Content Composition III

Mugwort soft extract (ethanol extract) 40 mg

Polyethylene Glycol 400 230 mg

Concentrated glycerin 20 mg

Povidone 5 mg

Filling Content Composition IV

Pear Nongsan Tang Hot Salt Extract 310 mg

Polyethylene Glycol 4000 8 mg

Concentrated glycerin 20 mg

Polyethylene Glycol 400 300 mg

Test Example 1

For each of the filling contents composition prepared according to Example 1 above, the decrease in content (transformation), disintegration state, and change in properties at the time of coating formulation were compared according to the method shown below.

Test Example 1-I

The stability of the capsules according to the invention and comparative examples for the filling content composition I was carried out by the following procedure and the results are shown in Table 2 and FIGS. 1 and 2.

Capsule storage condition: accelerated test condition 40 ℃, 75% RH

Content test method: reference 90-110%

Test procedure:

20 Accurately weigh the capsules into a 1L flask and fill it with water until the mark, then shake for 10 minutes, shake 50ml, put into a 100ml beaker, add 30ml of mobile phase, shake for 10 minutes, transfer to a 100ml flask and wash the beaker with 10ml of mobile phase. After filling with mobile phase to make 100ml and filtered to the sample solution.

HPLC conditions are as follows.

Column: Shimpak ODS-C18 (4.6mm x 15cm)

Mobile phase: 2 g of potassium dihydrogen phosphate and 2 g of sodium heptane sulfonate are precisely weighed into a 1 L flask and dissolved in water to 1 L. The pH is adjusted to 3.0 with phosphoric acid, and the solution and acetonitrile are mixed at 7: 3. do.

Chlorpheniramine maleate, noscarpine hydrochloride, dextromethorphan hydrobromide

Wavelength: 230 nm, Flow rate 2.0 ml / min, Temperature: 40 ° C., Sensitivity 0.03 x 5, Injection volume: 20 μl

Noscapin hydrochloride, trimethoquinol hydrochloride

Wavelength: 295 nm, Flow rate 2.0 ml / min, Temperature: 40 degrees, Sensitivity 0.04 x 2, Injection volume: 20 μl

Disintegration test Pharmacopoeia (within 20 minutes)

Early 1 month 3 months Invention Main ingredient content Guapenesine 95.2% 96.0% 95.1% Trimethoquinol Hydrochloride 95.1% 92.0% 91.7 Noscarpine Hydrochloride 96.3 95.5 95.3 Chlorpheniramine for maleic acid 94.0 94.9 94.5 Dextromethorphan HBr 96.7 93.9 93.8 Constellation Good Good Crystallization Disintegrate 7 minute, 10 seconds 8 minute, 54 seconds 8 minute, 06 seconds Comparative example Main ingredient content Guapenesine 94.3 94.2 93.0 Trimethoquinol Hydrochloride 95.0 90.1 87.8 Noscarpine Hydrochloride 96.8 96.0 94.6 Chlorpheniramine for maleic acid 94.1 94.2 92.3 Dextromethorphan HBr 94.0 93.8 92.6 Constellation Good Crystallization Crystallization Disintegrate 7 minute 00 seconds 8 minute, 20 seconds 13 minute, 10 seconds

From the results of Table 2 and Figs. 1 and 2, in the comparative example using the conventional glycerin plasticizer, crystals were precipitated from 1 month of the accelerated test, whereas crystals were observed in 3 months when the plasticizer of the present invention was used. It can be seen that the use of the plasticizer of the present invention was also considerably improved in content and disintegration. In particular, it can be seen that the content of trimethoquinol hydrochloride is significantly reduced in the comparative example.

Test Example 1-II

The stability of the capsules according to the invention and comparative examples for the contents of the filling contents II was compared by the following procedure and the results are shown in Table 3 and FIGS. 3 and 4.

Capsule storage condition: Store at room temperature

Content test method: acetaminophen, dextromethorphan hydrobromide, pseudoephedrine hydrochloride: According to KFDA acetic aminophene, clofeniramine maleate, hydrobromide dextromethorater determination method. (Standard 90%-110%)

Succidoxylamine: Complies with USP Succitoxylamine tablet test (92% to 108%)

lapse Early 2 years Invention Main ingredient content Acetaminophen 96.6 92.1 Dextromethorphan HBr 96.3 93.2 Hydrochloric acid 95.6 90.1 Succidoxylamine 96.8 92.8 Comparative example Main ingredient content Acetaminophen 96.2 89.1 Dextromethorphan HBr 94.6 90.8 Hydrochloric acid 93.2 82.7 Succidoxylamine 98.2 88.9

As can be seen from the results of Table 3 and the results of FIGS. 3 and 4, the use of the plasticizer of the present invention in the main component content is considerably improved compared to that of the comparative example, whereas in the comparative example, the content of trimethoquinol hydrochloride is remarkably improved. It can be seen that the formulation is not satisfactory.

Test Example 1-III

The disintegration state (degree of insolubilization of the film) of the present invention and the comparative example for the packed content composition III were compared by the following procedure, and the results are shown in Table 4 and FIG. 5.

Capsule storage condition: Accelerated test condition 40 ℃ 75% RH

Disintegration test Pharmacopoeia (within 20 minutes)

Early 2 weeks 4 Weeks 6 Weeks 8 Weeks Invention Disintegration time 7 minute, 10 seconds 8 minute, 25 seconds 9 minute, 20 seconds 12 minute, 30 seconds 18 minutes Comparative example 7 minute, 10 seconds 8 minutes 37 18 minute, 10 seconds 24 minutes 36 minutes

From the results of Table 4 and Figure 5, it can be seen that the capsules using the plasticizer of the present invention has a remarkably improved effect on the film insolubilization (disintegration delay).

Test Example 1-IV

The present invention for the filling content composition IV was compared with the disintegration state (degree of insolubilization of the film) of the comparative example by the following procedure, and the results are shown in Table 5 below.

Capsule storage condition: Accelerated test condition 40 ℃ 75% RH

Disintegration test Pharmacopoeia (within 20 minutes)

Early 2 weeks 4 Weeks 6 Weeks Invention Disintegration time 9 minute, 12 seconds 10 minute, 20 seconds 13 minute, 50 seconds 18 minute, 10 seconds Comparative example 10 minute, 24 seconds 11 minute, 40 15 minute, 50 seconds 20 minutes or more

According to the test results of Test Examples 1-I to 1-IV described above, the soft capsule according to the embodiment of the present invention using sorbitol glycerin blend as a plasticizer in terms of the overall capsule compared to the soft capsule prepared with the conventional glycerin plasticizer film It can be seen that the problems associated with the coating have been improved, in particular the transition of the content of the main component is significantly lower, and the disintegration state is good.

Example 2

Using the plasticizer film formulation according to the present invention and the prior art [Table 1] to prepare the capsule contents to be applied to the category B to produce a soft capsule. That is, after preparing the coating film in the composition shown in [Table 1], the filling contents were prepared in the V composition below, and the capsules were dried for 8 days after molding and filling by a predetermined amount by using a soft capsule molding machine to prepare a total of 2 batches of soft capsules.

Filling Content Composition V

Naproxen 250mg

Labrasol ^TM 500mg

Transcutol ^TM P 625mg

Lauroglycol ^TM 90 238 mg

Capryol ^TM PGMC appropriate amount

Propylene Glycol

Ethanol

Test Example 2

For each of the filling contents composition prepared according to Example 2, the decrease in content (transformation), disintegration state, and change in properties at the time of coating were compared according to the method shown below.

Test Example 2-I

The disintegration state (degree of insolubilization of the film) of the capsule according to the present invention and the comparative example for the filling content composition V was carried out by the following procedure and the results are shown in Table 6 and FIG. 6.

Capsule storage condition: accelerated test condition 40 ℃, 75% RH

Content test method: According to the Korean Pharmacopoeia naproxen test method (standard 90% ~ 110%)

Disintegration test method: Korean Pharmacopoeia (within 20 minutes)

lapse Early 2 months 4 months 6 months Invention Naproxen 93.8 93.0 91.6 90.6 Disintegrate 8 minutes 30 seconds 9 minutes 12 minute, 10 seconds 18 minute, 50 seconds Comparative example Naproxen 93.4 92.2 90.1 88.3 Disintegrate 8 minutes 30 seconds 10 minute, 20 seconds 16 minute, 25 seconds 21 minute, 30 seconds

As can be seen from the results of Table 6 and FIG. 6, the plasticizer formulation of the present invention in the soft capsules of the present invention and the comparative example containing the filling content V belonging to the category B category was compared to that of the comparative example. It can be seen that (lowering) is significantly low, and the disintegration state is also very good. It can be seen that the transition of the main component to the film is reduced, thereby preventing the film insolubilization phenomenon.

As can be seen from the above examples and experimental examples, by using the plasticizer according to the present invention, it is possible to improve the problem of lowering of the main component content, disintegration, depression and crystallization of the main component, which generally occur in soft capsules. Soft capsules containing such plasticizers are pharmaceutically stable.

1 is a graph showing the content of the composition over time of the filling content composition I of the capsule according to the present invention.

Figure 2 is a graph showing the content of the composition over time of the filling content composition I of the capsule according to the comparative example.

Figure 3 is a graph showing the content change over time of the filling content composition II of the capsule according to the present invention.

Figure 4 is a graph showing the content change over time of the filling content composition II of the capsule according to the comparative example.

5 is a graph showing the disintegration difference between the present invention and the comparative example for the contents of the composition III.

Figure 6 is a graph showing the disintegration difference and the content of the present invention and comparative example for the filling content composition V.

Claims (7)

When the active ingredient is dissolved or suspended in a pharmaceutical excipient, it is applied to a filling content exhibiting the characteristics of hydrophilicity or spontaneous emulsification, and 15 to 40% by weight of sorbitol glycerin blend and 30 to 60% by weight of gelatin as a plasticizer based on the weight of the dry film. , Polyhydric alcohols or polyols 0 to 25% by weight, the sorbitol glycerin blend is 40 to 55% by weight glycerin, 7.5 to 15% by weight sorbitol anhydrous, 20 to 27.5% by weight sorbitol, 13 to 18% by weight water and polyols A coating composition of a pharmaceutical stable soft capsule, characterized in that it contains%. delete delete The coating composition of claim 1, further comprising colorants, fragrances, flavoring agents, opacifying agents, preservatives, shading agents, or enteric coating agents. A pharmaceutical stable soft capsule comprising a coating composition according to claim 1 and a filling content which exhibits the properties of hydrophilicity or spontaneization when the active ingredient is dissolved or suspended in a pharmaceutical excipient. The soft capsule of claim 5, wherein the active ingredient is contained in an amount of 0.001 to 65% by weight based on the total weight of the composition. The pharmaceutical excipient according to claim 5, wherein the pharmaceutical excipient is 50-99% by weight of polyethylene glycol having an average molecular weight of 200 to 600, 0-30% by weight of polyethylene glycol having an average molecular weight of 800-10000, and glycerin, based on the hydrophilic active ingredient. 0-15% by weight, propylene glycol 0-15%, propyl carbonate 0-15%, polyvinylpyrrolidone (povidone) 0-10% by weight, purified water 0-13% by weight, nonionic surfactant 0-20 A soft capsule comprising, by weight or by weight, 0 to 20% by weight of water-soluble polyols, 0 to 10% by weight of sugar alcohols, 0 to 10% by weight of pH adjuster, and 0 to 5% by weight of antioxidant.