KR102266704B1 - Soft Capsule Preparations for Delivering Poorly Water-soluble Drugs - Google Patents

Abstract

The present invention provides a soft capsule formulation for delivery of poorly soluble acidic drugs. The soft capsule formulation of the present invention has excellent dissolution rate of poorly soluble acidic drugs, so it is suitable as a carrier of poorly soluble acidic drugs. In addition, the soft capsule of the present invention has excellent physical and chemical stability due to improved physical properties of the formulation, and there is no change over time in the formulation. In addition, the soft capsule of the present invention can minimize the size of the capsule, thereby improving the medication compliance.

Description

Soft Capsule Preparations for Delivering Poorly Water-soluble Drugs

The present invention relates to a soft capsule for poorly soluble drug delivery. Specifically, the present invention relates to a soft capsule for delivering a drug that is particularly acidic among poorly soluble drugs.

Soft capsule refers to a formulation made by molding into a certain shape by encapsulating the contents containing active ingredients and excipients exhibiting pharmacological activity with a capsule coating base such as gelatin.

However, for soft capsules, an excipient must be selected in consideration of the physicochemical properties of the active ingredient, and the selected excipient can concentrate the drug in a high content without reducing the fast-acting and bioavailability of the active ingredient, and at the same time, it is possible to concentrate the drug for a long period of time. Physicochemical and biological stability according to time-dependent change that does not generate Also, it is desirable to minimize the size of the capsule.

Therefore, it is not easy to prepare a soft capsule that satisfies all of the above desirable properties with a specific drug formulation. In particular, the development of soft capsules for delivery of poorly soluble drugs, which is not easy to solubilize, is more difficult.

US Registered Patent Publication No. 3,557,280 US Registered Patent Publication No. 4,002,718 US Registered Patent Publication No. 5,071,643 Republic of Korea Patent Publication No. 10-0612070

Another object of the present invention is to provide a soft capsule for delivery of a poorly soluble acidic drug, which has excellent dissolution rate of poorly soluble acidic drug and has excellent physicochemical stability without temporal change.

Another object of the present invention is to provide a soft capsule for poorly soluble acidic drug delivery with excellent drug compliance by minimizing the size of the capsule while having the same or superior dissolution rate compared to conventional soft capsules.

This will be described in detail as follows. Meanwhile, each description and embodiment disclosed in the present invention may be applied to each other description and embodiment. That is, all combinations of the various elements disclosed herein fall within the scope of the present invention. In addition, it cannot be considered that the scope of the present invention is limited by the specific descriptions described below.

The present invention provides a soft capsule for poorly soluble acidic drug delivery. Specifically, the soft capsule for poorly soluble acidic drug delivery of the present invention may contain a solvent system having the following composition:

10 to 90% by weight of polyethylene glycol;

1 to 30% by weight of water;

0.1 to 20% by weight of a surfactant;

0.1 to 10% by weight of at least one solubilizing agent selected from the group consisting of povidone, glycerin and cyclodextrin;

0.1 to 40 wt% of diethylene glycol monoethyl ether; and

Cation acceptance 1 to 30% by weight.

Here, the content of the above components is based on the total weight of the solvent system excluding the content of the poorly soluble acidic drug.

According to an embodiment of the present invention, the soft capsule for poorly soluble acidic drug delivery of the present invention may contain a solvent system of the following composition:

30 to 80% by weight of polyethylene glycol;

3 to 20% by weight of water;

0.2 to 15% by weight of surfactant;

0.5 to 5% by weight of at least one solubilizing agent selected from the group consisting of povidone, glycerin and cyclodextrin;

0.2 to 25% by weight of diethylene glycol monoethyl ether; and

Cation Acceptance 3 to 20% by weight.

In addition, the soft capsule for poorly soluble acidic drug delivery of the present invention may contain a solvent system of the following composition:

Polyethylene glycol 45 to 75% by weight;

6 to 18% by weight of water;

1 to 12% by weight of surfactant;

1 to 3% by weight of at least one solubilizing agent selected from the group consisting of povidone, glycerin and cyclodextrin;

0.4 to 20 wt% of diethylene glycol monoethyl ether; and

6 to 18% by weight of cation acceptance.

According to an embodiment of the present invention, the weight ratio of the solubilizing agent and diethylene glycol monoethyl ether may be 1:0.5 or more. The dissolution aid increases the viscosity upon dissolution according to the type and ratio of the solute, which interferes with the adhesion site during encapsulation (encapsulation) with a capsule base, so that the drug in the internal solution leaks out during the change over time. It may make the formulation impossible or reduce the stability of the formulation and formulation. When the weight ratio of the dissolution aid and diethylene glycol monoethyl ether is 1:0.5 or more, the above problems can be solved.

According to an embodiment of the present invention, the polyethylene glycol may have an average molecular weight of 200 to 800.

According to an embodiment of the present invention, the surfactant serves as a eutectic solvent or a dissolution aid that promotes dissolution, and a material having the characteristics of a hydrophilic base and a hydrophobic base may be used. Among these bases, a surfactant having a hydrophilic lipophilic balance (HLB) value of 3 to 40 is used, and preferably a surfactant having a value of 5 to 30 may be used alone or in a mixture of two or more. can Specifically, the surfactant is a reaction product of natural or hydrogenated vegetable oil and ethylene glycol, polyoxyethylene sorbitan fatty acid esters, ester group transfer reaction products of natural vegetable oil triglyceride and polyalkylene polyol, poly Oxyethylene fatty acid esters, sorbitan fatty acid esters, propylene glycol mono- and di-fatty acid esters or tetrahydrofurfuryl di- or partial-ethers, polyoxyethylene fatty acid ethers, polyoxyethylene-polyoxypropylene copolymers It may be one or more selected from the group consisting of. For example, the surfactant is Cremophor RH40 (polyoxyl 40 hydrogenated castor oil), Cremophor EL (polyoxyl 35 castor oil), Labrasol (polyethylene glycol caprylate/caprylate), Tween (poly Sorbate 20, 21, 40, 61, 65, 80, 81, 85, 120), Poloxamer (124, 188, 237, 338, 407) (Polyoxyethylene-Polyoxypropylene), Nicole HCO-40 (Poly Oxyethylene glycolated natural or hydrogenated castor oil), Myrj 45 (polyoxyethylene (8) stearate), Tagat L (polyoxyethylene (30) monolaurate), Marrosol ( Marlosol) 1820 (polyoxyethylene (20) stearate), Marlosol OL 15 (polyoxyethylene (15) oleate), Breeze (Brjj) 96 (polyoxyethylene (10) oleyl ether), Volpo 015 (polyoxyethylene (15) oleyl ether), Marlowet OA30 (polyoxyethylene (30) olein ether), Marlowet LMA 20 (polyoxyethylene (20) oleyl ether) Inether), Syperonic PE L44 (polyoxyethylene-polyoxypropylene copolymer), Syperonic F127 (polyoxyethylene-polyoxypropylene copolymer, Labrafil M 2125 CS (Lino) Leolmacrogolglyceride), Labrapec PG (Propylene Glycol Dicaprylic Ocaprate), Imvitor (Caprylic/Capric Acid Mono- and Di-glycerides), Sorbitan Mono-Stearate, Sorbitan Tri-Stearate Late, sorbitan mono-oleate, polyethylene glycol monooleate, MIGLYOL 840 (propylene glycol dicaprylate), gelucir 44/14 (lauroyl polyoxyl-32 glyceride) and their It may be selected from the group consisting of mixtures.

In the solvent system contained in the soft capsule of the present invention, diethylene glycol monoethyl ether may be synthesized or commercially available products may be used. Here, a commercially available product may use Transcutol. By containing diethylene glycol monoethyl ether in the solvent system of the present invention, it was confirmed that the physical properties of the formulation were remarkably improved, such as a decrease in leakage during soft encapsulation (molding) compared to the conventional soft capsule formulation, and through this, the stability of the formulation was ensured. can do.

According to an embodiment of the present invention, the cation acceptance is a pharmaceutically usable basic compound, a metal salt of a weak acid, an amine, and a mixture thereof having a property of dissociating into a cation and an anion or taking a hydrogen ion. It may be selected from the group consisting of. For example, the cation acceptance is potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate, potassium acetate, potassium citrate, sodium citrate, prolamin, diethanolamine, monoethanolamine, triethanolamine, It may be selected from the group consisting of lysine, methylglucamine, and mixtures thereof. Such cationic acceptance can easily take up the hydrogen ion of the carboxyl group of the acidic drug to increase solubility.

According to an embodiment of the present invention, it may further include an antioxidant. The antioxidant may be at least one selected from the group consisting of butylhydroxytoluene (BHT), butylhydroxyanisole (BHA), butylhydroquinone, butyl-para-hydroxybenzoic acid, dihydroxyphenol and tocopherol. In this case, the antioxidant may be included in an amount of 0.01 to 1% by weight in the solvent system.

According to an embodiment of the present invention, the pH of the solvent system may be maintained at 2.0 to 8.0.

According to an embodiment of the present invention, the poorly soluble acidic drug is naproxen (Naproxen), ibuprofen (R,S-Ibuprofen), dexibuprofen (S-Ibuprofen), indomethacin (Indomethacin), acetaminophen (Acetaminophen), Mefenamic acid, Chlorocinnazine, Loxoprofen, Fenoprofen, Ketoprofen, Pranoprofen, Meclo Meclofenamic acid, Sulindac, Piroxicam, Meloxicam, Tenoxicam, Diclofenac, Aceclofenac, Rebamipide , enalapril, captopril, ramipril, fosinopril, benazepril, quinapril, temocapril, silazapril ( Cilazapril), Lisinopril, Valsartan, Losartan, Irbesartan, Cetirizine, Diphenhydramine, Pseudoephedrine, Pseudoephedrine , Methylephedrine, Dextromethorphan, Guaifenesin, Noscapine, Trimetoquinol, Doxylamine, Ambroxol, A drug selected from the group consisting of Letosteine, Sobrerol, Bromhexine and Chlorpheniramine, or a pharmaceutically acceptable salt thereof can

In general, poorly soluble drugs have different solubility due to the characteristics of each compound, so it is very difficult to provide a compatible solvent system regardless of the kind of poorly soluble drugs. However, when a soft capsule is prepared by adding the poorly soluble acidic drug to the solvent system of the present invention as mentioned above, the dissolution rate of the poorly soluble acidic drug is excellent and there is no change over time, so that the poorly soluble acidic drug is delivered with excellent physicochemical stability It is possible to provide a soft capsule for use. This effect is achieved even with naproxen, which is widely known to have the lowest dissolution rate, and is an effect that can be achieved by the soft capsule of the present invention regardless of the kind of poorly soluble acidic drug.

In addition, the soft capsule of the present invention can significantly reduce the total content contained in the capsule as compared to a conventional soft capsule of a poorly soluble acidic drug or a commercially available soft capsule, thereby minimizing the size of the capsule. For example, a soft capsule containing 300 mg of dexibuprofen can be made into small capsules with a total of 565 mg, and a soft capsule containing 250 mg of naproxen can be made into small capsules with a total of 650 mg. Through this, the patient's medication compliance can be greatly improved, and this effect can also be achieved by the soft capsule of the present invention regardless of the type of poorly soluble acidic drug.

The soft capsule of the present invention is suitable as a carrier of a poorly soluble acidic drug because of its excellent dissolution rate of the sparingly soluble acidic drug.

In addition, the soft capsule of the present invention has excellent physical and chemical stability due to improved physical properties of the formulation, and there is no change over time in the formulation.

In addition, the soft capsule of the present invention can minimize the size of the capsule while having the same or superior dissolution rate as compared to the conventional soft capsule, thereby improving the medication compliance.

1 is a graph comparing the dissolution results of dexibuprofen in Experimental Example 1.
2 is a graph comparing the dissolution results of naproxen in Experimental Example 2.

Hereinafter, the present invention will be described in more detail through Examples and Experimental Examples. However, these Examples and Experimental Examples are for illustrative purposes of the present invention, and the scope of the present invention is not limited to these Examples and Experimental Examples.

Example 1. Preparation of soft capsules containing dexibuprofen

The components and contents of the composition in the film of the soft capsule containing dexibuprofen among the poorly soluble acidic drug are as summarized in Table 1 below (the following weight % is a value calculated based on the total content of the solvent system) .

[Table 1]

A soft capsule was prepared by forming a soft capsule film on the composition in the gastric film by a conventional manufacturing method (mixing gelatin, partially dehydrated liquid sorbitol, amorphous sorbitol solution, glycerin and water).

Example 2. Preparation of Soft Capsules Containing Naproxen

The components and contents of the composition in the film of the soft capsule containing naproxen among the poorly soluble acidic drugs are as summarized in Table 2 below (the following weight % is a value calculated based on the total content of the solvent system).

[Table 2]

A soft capsule was prepared in the same manner as in Example 1 for the composition in the gastric film.

Comparative Example 1. Commercially available soft capsules containing dexibuprofen

A commercially available product of Sville (RPBio) was used as Comparative Example 1 (diethylene glycol monoethyl ether not included).

Comparative Example 2. Commercially available soft capsules containing dexibuprofen

As a commercially available soft capsule containing dexibuprofen, EZN 6 Pro (Daewoong Pharmaceutical) was used as Comparative Example 2 (diethylene glycol monoethyl ether was not included).

Comparative Example 3. Commercially available naproxen-containing soft capsules

A commercially available product of Ace Pen (RPBio) was used as Comparative Example 3 (diethylene glycol monoethyl ether not included).

Comparative Example 4. Conventional naproxen-containing soft capsules

The soft capsules of Examples 4-11 disclosed in Korean Patent Publication No. 10-0612070 were used as Comparative Example 4.

[Table 3]

Experimental Example 1. Comparative dissolution test of dexibuprofen

The dissolution results (dissolution rate/standard deviation) of the soft capsules containing dexibuprofen prepared in Example 1, Comparative Example 1 and Comparative Example 2 are summarized in Tables 4, 5 and 1 below. .

[Table 4]

[Table 5]

As can be seen in Table 4 and Figure 1 (left graph) above, Comparative Example 2 under the pH 6.8 condition did not have good initial release and thus did not have excellent fast-acting, whereas Example 1 and Comparative Example 1 were compared with Comparative Example 2 It was confirmed that the fast-acting properties were improved.

In addition, as confirmed in Table 5 and FIG. 1 (right graph) above, Example 1 in water released about 80% at 45 minutes, whereas Comparative Example 1 released about 75% at 45 minutes. It can be seen that the elution result of 1 is more excellent.

In addition, Example 1 reduced the composition in the coating film by about 35% from about 760 mg to 565 mg compared to Comparative Example 1, and compared to Comparative Example 1, it was possible to minimize the size of the capsule while maintaining the same or more dissolution pattern. possible effects were achieved simultaneously.

Experimental Example 2. Comparative dissolution test of naproxen

The dissolution results (dissolution rate/standard deviation) of the soft capsules containing naproxen prepared in Example 2, Comparative Example 3, and Comparative Example 4 are summarized in Tables 6, 7 and 2 below.

[Table 6]

(* Comparative Example 4 is the estimated dissolution result for FIG. 7 of Korean Patent Publication No. 10-0612070)

[Table 7]

(* Comparative Example 4 is the estimated dissolution result for FIG. 2 of Korean Patent Publication No. 10-0612070)

As can be seen in Tables 6, 7 and 2 above, Comparative Example 4 under pH 6.8 conditions and water did not have good initial release and thus did not have excellent fast-acting, whereas Examples 2 and 3 were compared with Comparative Example 4 Thus, it is confirmed that the fast-acting properties are significantly improved.

In addition, as confirmed in Table 7 and Figure 2 (right graph) above, Example 2 released about 46% at 45 minutes, whereas Comparative Example 3 released about 36% at 45 minutes, resulting in excellent dissolution results. can be known

In addition, in Example 2, compared with Comparative Examples 3 and 4, the composition in the coating film was reduced by about 23% from about 800 mg to about 650 mg, and compared to Comparative Examples 3 and 4, while maintaining the same or more dissolution pattern of the capsule. At the same time, the effect of minimizing the size was achieved.

Dissolution test method

The dissolution test method used in Experimental Example 1 and Experimental Example 2 above is as follows.

- Apparatus: Korean Pharmacopoeia dissolution test method 2 (paddle method), 50 rpm

- Amount of test solution: 900 mL

- Temperature of test solution: 37±0.5 ℃

- pH 6.8: 2nd solution of disintegration test method

From the above description, those skilled in the art to which the present invention pertains will understand that the present invention may be embodied in other specific forms without changing the technical spirit or essential characteristics thereof. In this regard, it should be understood that the embodiments described above are illustrative in all respects and not restrictive. The scope of the present invention should be construed as being included in the scope of the present invention, rather than the above detailed description, all changes or modifications derived from the meaning and scope of the claims described below and their equivalents.

Claims (13)

10 to 90% by weight of polyethylene glycol;
1 to 30% by weight of water;
0.1 to 20% by weight of a surfactant;
0.1 to 10% by weight of at least one solubilizing agent selected from the group consisting of povidone, glycerin and cyclodextrin;
0.1 to 40 wt% of diethylene glycol monoethyl ether; and
containing a solvent system comprising 1 to 30% by weight of cationic acceptance,
The surfactant is a reaction product of natural or hydrogenated vegetable oil and ethylene glycol, polyoxyethylene sorbitan fatty acid esters, ester group transfer reaction products of natural vegetable oil triglyceride and polyalkylene polyol, polyoxyethylene fatty acid At least one selected from the group consisting of esters, sorbitan fatty acid esters, propylene glycol mono- and di-fatty acid esters, polyoxyethylene fatty acid ethers, and polyoxyethylene-polyoxypropylene copolymers;
Soft capsules for poorly soluble acidic drug delivery. [Claim 2] The soft capsule for poorly soluble acidic drug delivery according to claim 1, wherein the solvent system comprises the following components:
30 to 80% by weight of polyethylene glycol;
3 to 20% by weight of water;
0.2 to 15% by weight of surfactant;
0.5 to 5% by weight of at least one solubilizing agent selected from the group consisting of povidone, glycerin and cyclodextrin;
0.2 to 25% by weight of diethylene glycol monoethyl ether; and
Cation Acceptance 3 to 20% by weight. [Claim 3] The soft capsule for poorly soluble acidic drug delivery according to claim 2, wherein the solvent system comprises the following components:
Polyethylene glycol 45 to 75% by weight;
6 to 18% by weight of water;
1 to 12% by weight of surfactant;
1 to 3% by weight of at least one solubilizing agent selected from the group consisting of povidone, glycerin and cyclodextrin;
0.4 to 20 wt% of diethylene glycol monoethyl ether; and
6 to 18% by weight of cation acceptance. The method of claim 1,
The weight ratio of the dissolution aid and diethylene glycol monoethyl ether is 1:0.5 or more, a soft capsule for poorly soluble acidic drug delivery. The method of claim 1,
The polyethylene glycol has an average molecular weight of 200 to 800, a soft capsule for poorly soluble acidic drug delivery. delete The method of claim 1,
The surfactant is polyoxyl 40 hydrogenated castor oil; polyoxyl 35 castor oil; polyethylene glycol caprylate/caprylate; polysorbate 20, 21, 40, 61, 65, 80, 81, 85, 120; polyoxyethylene-polyoxypropylene; polyoxyethylene glycolated natural or hydrogenated castor oil; polyoxyethylene (8) stearate; polyoxyethylene (30) monolaurate; polyoxyethylene (20) stearate; polyoxyethylene (15) oleate; polyoxyethylene (10) oleyl ether; polyoxyethylene (15) oleyl ether; polyoxyethylene (30) olein ether; polyoxyethylene (20) olein ether; polyoxyethylene-polyoxypropylene copolymers; polyoxyethylene-polyoxypropylene copolymers; linoleol macrogol glyceride; propylene glycol dicaprylocaprate; caprylic/capric acid mono- and di-glycerides; sorbitan mono-stearate; sorbitan tri-stearate; sorbitan mono-oleate; polyethylene glycol monooleate; propylene glycol dicaprylate; lauroyl polyoxyl-32 glyceride; And one selected from the group consisting of mixtures thereof, a soft capsule for poorly soluble acidic drug delivery. The method of claim 1,
The cation acceptance is selected from the group consisting of pharmaceutically usable base compounds, metal salts of weak acids, amines, and mixtures thereof having the property of dissociating into cations and anions or taking hydrogen ions. Soft capsules for the delivery of soluble acidic drugs. 9. The method of claim 8,
The cation acceptance is potassium hydroxide (KOH), sodium hydroxide (NaOH), sodium acetate, potassium acetate, potassium citrate, sodium citrate, prolamin, diethanolamine, monoethanolamine, triethanolamine, lysine, methyl glue A soft capsule for poorly soluble acidic drug delivery, which is selected from the group consisting of carmine and mixtures thereof. 10. The method according to any one of claims 1 to 5 or 7 to 9,
A soft capsule for poorly soluble acidic drug delivery, further comprising an antioxidant. 11. The method of claim 10,
The antioxidant is contained in 0.01 to 1% by weight, a soft capsule for poorly soluble acidic drug delivery. The method of claim 1,
The pH of the solvent system is to maintain 2.0 to 8.0, a soft capsule for poorly soluble acidic drug delivery. The method of claim 1,
The poorly soluble acidic drug is naproxen, ibuprofen (R,S-Ibuprofen), dexibuprofen (S-Ibuprofen), indomethacin, acetaminophen, mefenamic acid acid), Chlorocinnazine, Loxoprofen, Fenoprofen, Ketoprofen, Pranoprofen, Meclofenamic acid, Sulfur lindac, piroxicam, meloxicam, tenoxicam, diclofenac, aceclofenac, rebamipide, enalapril, Captopril, Ramipril, Fosinopril, Benazepril, Quinapril, Temocapril, Cilazapril, Lisinopril ), Valsartan, Losartan, Irbesartan, Cetirizine, Diphenhydramine, Fexofenadine, Pseudoephedrine, Pseudoephedrine, Methylephedrine Dextromethorphan, Guaifenesin, Noscapine, Trimetoquinol, Doxylamine, Ambroxol, Letosteine, Sobre A drug selected from the group consisting of Sobrerol, Bromhexine, and Chlorpheniramine, or a pharmaceutically acceptable salt thereof, which is a sparingly soluble acid drug for delivery vaginal capsules.

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