KR100569595B1 - Formulation and manufacturing process solubilized simvastatin soft capsules - Google Patents

Abstract

The present invention relates to a pharmaceutical composition for treating hyperlipidemia solubilizing simvastatin, which is poorly soluble, and a method for preparing the same. Specifically, a hydrophobic, poorly soluble simvastatin is dissolved in a mixture of a solubilizer, a pH adjuster, a surfactant, an oil, and an antioxidant to a nanoemulsion. As a self-emulsifying drug delivery system that prepares a concentrated solution and forms a nanoemulsion by digestive fluid when taken, greatly improving bioabsorption, a simvastatin-containing composition characterized by solubilization and stability and a soft capsule containing the same as an active ingredient To a formulation.

According to the present invention, the solubilization and stabilization method which can greatly improve the dissolution rate by increasing the solubilization by completely solubilizing simvastatin, and the invention about the soft capsule formulation containing the composition and the solubilizing composition have not been solved. New formulations can be developed that improve the dissolution rate and improve the absorption of the poorly soluble drugs.

Simvastatin, solubilization, pH adjusters, antioxidants, surfactants, nanoemulsions, compositions, self-emulsifying, drug delivery systems, soft capsules

Description

Soft capsule composition of soluble simvastatin and a method for preparing the same {Formulation and manufacturing process solubilized simvastatin soft capsules}

       Simvastatin (2,2-Dimethylbutyric acid, 8-ester with (4R, 6R) -6- [2-[(1S, 2S, 6R, 8S, 8alphaR) -1,2,6,7, 8,8a-hexahydro-8-hydroxy-2,6-dimethyl-1-naphthyl] ethyl] tetrahydro-4-hydroxy-2H-pyran-2-one) is a known compound that strongly inhibits the biosynthesis of cholesterol. Known as a substance.

Simvastatin inhibits cholesterol synthesis by inhibiting HMG-CoA reductase in the stage of HMG-CoA reduction, which is the most important rate-limiting step in cholesterol synthesis, to mevalonate. Prevents accumulation Therefore, the cholesterol lowering effect than the conventional HMG-CoA reductase inhibitors, such as lovastatin, pravastatin, and the like-PDR data shows that the dose is lowered by about 1.5 times or more. Expression is also low.

       Simvastatin is mainly absorbed by the intestine approximately 85%, distributed in the liver, kidneys, lungs, etc., actually high in the liver, the time to reach the peak blood concentration is 1.3 to 2.4 hours, the action time is about 2.5 after administration Appears from time and lasts 12 to 16 hours. The half-life is known as about 4 hours and is excreted 60% in 13% feces with urine.

      Acute toxicity of simvastatin is expressed when LD50 is above 5000mg / kg, and chronic toxicity is weak and transient increase in serum ALT and alkaline phosphatase activity in high dose group in the case of 2mg administration in dogs for 2 years. In the case of continue with the drug return to the control value. There were no changes in electrocardiogram and no gross or histological changes associated with drug administration.

      The clinical benefits of simvastatin include: 1) The world's first FDA to be approved as the only HMG-CoA RI with a second prevention effect that significantly lowers mortality from CHD. It was found that the overall mortality rate was reduced by 30% compared to the placebo and the mortality rate due to the Coronary Event was reduced by 42%. 2) After oral administration, liver selectivity resulted in effective distribution of the target organs and peripheral organs, especially brain and aqueous water. humor), cerebrospinal fluid is rarely distributed, it has been found to have excellent tolerability and minimal side effects, 3) inhibits the progression of coronary atherosclerosis, and 4) different HMG-CoA RI per unit content. It is known to be an excellent agent compared to these.

      In general, in order for a drug to be absorbed into the human body and exhibit high pharmacological activity in vivo, it must first be eluted rapidly. The dissolution rate of the drug determines the rate of absorption in the body and is a significant indicator of drug concentration in the blood. It depends on the solubility. However, since the solubility of the drug is poorly soluble in water, various methods have been studied to improve the solubility.

Representative examples include the use of cosolvents, the addition of counterions to poorly soluble materials to form salts of acids or bases, and the combination of polymer compounds or ligands to form soluble complexes. In addition, there is a method of increasing the solubility by using a surfactant and a cosolvent as a soft capsule as a solubilized liquid solubilizing drugs.

Korean Patent Laid-Open Publication No. 2002-0042218 discloses a pharmaceutical composition for treating autophagy hyperlipidemia by solubilizing simvastatin using a dissolving agent, a surfactant, and a co-surfactant, but this has a problem in that stability is lowered during long-term storage. Therefore, the method of increasing the stability of the drug by adding an antioxidant and a pH adjuster as a stabilizer will be a method of producing a more effective soft capsule.

Simvastatin is currently developed as a tablet containing most of the formulation 20mg, soft capsules are not yet developed or commercially available. Simvastatin tablets should be administered at 20 mg once daily in the initial starting dose for adults and from 10 mg to 5 to 80 mg once daily for the purpose of moderate reduction of LDL-cholesterol. Can be. In the case of tablets, simvastatin is poorly soluble, so the dissolution rate and dissolution rate are not excellent, and thus the bioavailability and bioavailability are low, and thus the expression of drugs cannot be properly expressed. Therefore, the technical problem to be achieved by the present invention is to improve the dissolution rate of the tablets as described above to increase the bioabsorption amount, to develop a formulation that shows the drug expression of the maximum effect to patients, and for this specific component that can solubilize the drug The purpose of the present invention is to prepare a nanoemulsion concentrate containing a surfactant, a dissolving agent for improving the absorption rate, a co-surfactant and an antioxidant, and a pH adjusting agent to develop a formulation as a stable soft capsule having high human absorption rate and bioabsorption rate.

The present invention relates to a pharmaceutical composition comprising an active ingredient simvastatin, a therapeutic agent for hyperlipidemia, comprising 1 to 10% by weight of active ingredient, 10 to 70% by weight of surfactant, 10 to 70% by weight of surfactant, 1 to 20% by weight of oil, and antioxidant A self-emulsifying drug delivery system configured to contain 0.1 to 20% by weight and 0.1 to 5% of a pH adjuster.

 Specifically, simvastatin, which is poorly soluble in water, is dissolved in polyethylene glycol, propylene glycol, diethylene glycol monoethyl ether, triacetin, and the like, and polyoxyl 35 castor oil, polyoxyl 40 hydrogenated castor oil, polysorbate, polyethylene glycol -8 Fatty acids, monohydric alkanols and ester compounds, intermediate fatty acid triglycerides and fatty acid monoglycerides as oil components to form surfactants such as glyceryl caprylate, dimethylisosorbide, poloxamer and self-emulsifying drug delivery system As an antioxidant to ensure the stability of nanoemulsion concentrates, lipophilic tocopherol, dibutylhydroxytoluene, butylhydroxyanisole, etc., hydrophilic ascorbic acid, sodium sulfite, sodium pyrosulfite, sodium hydrogen sulfite and nanoemulsion 6.2, the pH at which the stability of the concentrate is ensured A stable simvastatin-containing composition and a soft capsule formulation containing the same as an active ingredient, characterized in that it is solubilized by adding a pH adjuster to adjust 6.8, in particular an acidifying agent citric acid, succinic acid, tartaric acid, formic acid, malic acid and the like. .

Hereinafter, the present invention will be described in detail.

The present invention is a pharmaceutical composition that can increase the absorption rate by minimizing the particles of the drug by self-emulsifying in the body fluids by taking a mixture of solubilizer, surfactant and oil to solve the poorly soluble in water of simvastatin, a hyperlipidemia treatment agent It is about.

The present invention relates to a novel simvastatin solubilizing agent using a self-microemulsifying drug delivery system (SMEDDS), comprising the following components (1) to (6):

(1) As a solvent, polyethylene glycol, triacetin, propylene glycol, diethylene glycol monoethyl ether, glycerol,

(2) The surfactant serves to stably emulsify the oil component and the co-surfactant in water to form a stable emulsion, and includes various pharmaceutically acceptable anionic, cationic, nonionic or amphoteric surfactants. Surfactants may be used.

Specifically, for example, (a) reaction products of natural or hydrogenated vegetable oils with ethylene glycol, ie polyoxyethylene glycolated natural or hydrogenated vegetable oils, such as polyoxyethylene glycolated natural or hydrogenated castor oil (Trade name: Cremophor or HCO, manufacturer BASF),

(b) polyoxyethylene-sorbitan-fatty acid esters, for example esters of mono or trilauryl, palmityl, stearyl or oleyl (trade name: Tween, manufacturer: ICI),

(c) polyoxyethylene fatty acid esters such as polyoxyethylene stearic acid ester (trade name: Myrj, manufacturer: ICI),

(d) polyoxyethylene-polyoxypropylene copolymer (trade name: Pluronic, manufactured by BASF),

(e) polyoxyethylene-polyoxypropylene block copolymer (trade name: Poloxamer, manufactured by BASF),

(f) Sodium Dioctylsulfosuccinate or Sodium Lauryl Sulfoate

(g) phospholipids

(h) propylene glycol mono- or di-fatty acid esters, such as propylene glycol dicaprylate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol ricinoleate or trade name Miglyol Propylene Glycol Caprylic-Capric Acid Diester, marketed as 840 (Miglyol 840, manufactured by Huls),

(i) the trans-esterification products of natural vegetable oil triglycerides with polyalkylene polyols (trade name: Labrafil M, manufactured by Gattefosse),

(j) mono-, di- or mono / di-glycerides, for example capryl / capric acid mono- or di-glycerides (trade name: Imwitor, manufacturer: Huls),

(k) sorbitan fatty acid esters such as sorbitan monolauryl, sorbitan monopalmityl or sorbitan monostearyl, sold under the trade name Span,

(l) sterols or derivatives thereof, such as cholesterol, phytosterol or cytosterol.

These may each be used alone or as a mixture of two or more, and may be appropriately selected depending on the type of oil component. Among them, trade name cremophor or trade name HCO, which is a reaction product of natural or hydrogenated vegetable oil, and ethylene glycol, or trade name Tween, which is polyoxyethylene-sorbitan-fatty acid ester, can be used.

(3) In the present invention, it is preferable that the co-surfactant is a solvent having both hydrophilicity and lipophilic property, which can easily disperse the emulsion and dissolve the active ingredient and various additives. Co-surfactants not only provide the solubility suitable for formulation to the active ingredient, but also have both hydrophilicity and lipophilic properties in terms of physical properties, and thus aid in emulsification of the formulation so that the emulsion or microemulsion can be uniformly dispersed. In addition, even during the preservation of the formulation, there is no change over time of the active ingredient and provides the advantage of ensuring uniformity of the composition.

In particular, the co-surfactant serving this purpose is ethanol, propylene glycol (1,2-dihydroxypropane), polyethylene glycol (molecular weight 200 to 600), propylene carbonate (4-methyl-2-oxo-1, 3-dioxolane), transcutol (diethylene glycol monoethyl ether), glycofurol (tetrahydrofurfuryl alcohol polyethylene glycol ether) and dimethyl isosorbide (1,4: 3,6- dianhydro- 2,5-dimethyl-D-glucinol).

(4) The oils used in the present invention are well mixed with co-surfactants and surfactants and emulsified in water to form stable microemulsions, and are capable of dissolving drugs and compounds of formula (1). Various oils can be used.

Specifically, for example,

(a) fatty acid triglycerides, preferably intermediate fatty acid triglycerides, for example fractionated coconut oil (trade name: Miglyol 812N, manufactured by Huls),

(b) mono-, di- or mono / di-glycerides, preferably mono- or di-glycerides of oleic acid,

(c) ester compounds of fatty acids and monohydric alkanols, in particular ester compounds of fatty acids having 8 to 20 carbon atoms and monovalent alkanols having 2 to 3 carbon atoms, for example isopropyl myristate, isopropyl palmitate, ethyl linoleate or Ethyl oleate,

(d) natural vegetable or animal oils, such as corn oil, olive oil, soybean oil or fish oil,

(e) hydrocarbons, for example squalene or squalane,

(f) free fatty acids, preferably liquid oleic acid or linoleic acid.

(g) tocopherols, for example dl-α-tocopheryl acetate

(5) As antioxidants, lipophilic tocopherol, dibutylhydroxytoluene, butyl hydroxy cyanisole and the like and hydrophilic ascorbic acid, sodium sulfite, sodium pyrosulfite, sodium hydrogen sulfite may be contained alone. Or as a mixture of two or more thereof. In addition, the above-mentioned oil components may be mixed and used.

(6) pH adjuster is added to adjust the pH of 6.0-7.5 to ensure the stability of the nanoemulsion concentrate, especially acidifying agents citric acid, succinic acid, tartaric acid, formic acid, malic acid, etc. may be contained, each of these alone or two It can be used as a mixture of two or more.

The composition of the present invention may further include various pharmaceutically acceptable additives such as fragrances and preservatives for oral administration within the scope of not impairing the effects of the present invention.

In the present invention, the solubilization method of simvastatin is solubilized simvastatin in solubilizers, surfactants, cosurfactants, and oils, and antioxidants and pH adjusters are added to further enhance the solubility and stability of the drug to obtain a liquid content and general softness. The capsule preparation method allows simvastatin soft capsules to be easily administered orally and to increase absorption.

The composition of the present invention is preferably prepared so as not to exceed 20% of the total weight of the active ingredient. This is because when the amount of the active ingredient increases, the solubility decreases rapidly, resulting in poor stability such as sedimentation or decrease in content during storage, and when the active ingredient is added below 1% of the total weight, solubility and stability increase. However, there is a disadvantage that the dosage can be increased. In addition, the surfactant is suitable about 10 to 70% by weight of the total weight, when less than 10% is used, the self-emulsifying ability to meet the object of the present invention is poor, when more than 70% is added to form a soft capsule In this case, it may affect the adhesive ability of the gelatin, so that the adhesive surface may open or burst during storage. That is, if this phenomenon occurs, it is not preferable because the expense of new equipment investment, such as additional equipment to the soft capsule molding equipment is generated.

Hereinafter, the present invention will be described in more detail with reference to the following examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited thereto.

Example 1

Mix 120 grams of polyethylene glycol, 100 grams of Cremophor RH40, and 100 grams of Cremophor EL. Mix well while maintaining 50 ° C. Add 10 grams of Migliool 812N and 10 grams of tocopherol and stir well. After confirming that the solution was completely transparent, add 20 grams of simvastatin, and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-polyethylene glycol solution (w / v).

Example 2

Mix 120 grams of polyethylene glycol, 100 grams of HCO50 and 100 grams of Cremophor RH40 and mix well while maintaining 50 ° C. Add 10 grams of migliol812N and 10 grams of tocopherol and stir well. After confirming that the solution was completely transparent, add 20 grams of simvastatin, and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-polyethylene glycol solution (w / v).

Example 3

After mixing 120 grams of polyethylene glycol and 150 grams of T20, 50 grams of Cremophor RH40, mix well while maintaining 50 ° C, add 10 grams of migliol 812N and 10 grams of tocopherol and stir well. After confirming that the solution was completely transparent, add 20 grams of simvastatin, and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-polyethylene glycol solution (w / v).

Example 4

Mix 120 grams of polyethylene glycol, 50 grams of poloxamer 124, and 150 grams of cremophor EL. Mix well while maintaining 50 ° C. Add 10 grams of Miglyol 812N and 10 grams of tocopherol and stir well. After confirming that the solution was completely transparent, add 20 grams of simvastatin, and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-polyethylene glycol solution (w / v).

Example 5

Mix 120 grams of propylene glycol, 100 grams of Cremophor RH40, and 100 grams of Cremophor EL. Mix well while maintaining 50 ° C. Add 10 grams of Migliool 812N and 10 grams of tocopherol and stir well. After confirming that the solution was completely transparent, add 20 grams of simvastatin, and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-polyethylene glycol solution (w / v).

Example 6

Mix 80 grams of triacetin, 140 grams of Cremophore RH40, and 100 grams of Cremophore EL and mix well while maintaining 50 ° C. Add 10 grams of Migliool 812N and 10 grams of tocopherol and stir well. After confirming that the solution was completely transparent, add 20 grams of simvastatin, and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-polyethylene glycol solution (w / v).

<Production of Film>

Soft capsule film of the present invention is a general soft capsule containing a known gelatin, a plasticizer, as a prescription for producing a general soft capsule, gelatin 118 mg per 1 capsule (166 mg), glycerin 46.9 mg, ethyl vanillin 0.7 mg, paraoxybenzoic acid methyl 0.35 mg, para It is prepared by a conventional preparation method containing 0.05 mg of oxyoxybenzoic acid propyl.

Soft capsule production of simvastatin solubilizing agent of the present invention is molded into Oval # 6 by a conventional filling method using a rotary automatic filling machine, which is generally used, and then subjected to drying and sorting to produce a prototype.

Comparative Example 1

Add 27 grams of pregelatinized starch to 35 grams of purified water, add 20 g of simvastatin, 10 grams of microcrystalline cellulose, and 129 grams of lactose using the luxurious solution as a binding solution. The lubricant is compressed into tablets and used as a comparative example.

Comparative Example 2

Manufactured in the same manner as in Preparation Example 1, except for tocopherol, which was prepared and molded to be a comparative example.

Comparative Example 3

Prepare in the same manner as in Preparation Example 1, but adjust the pH to 5.7 and then molded to be a comparative example.

[Comparative Example 4]

Prepare in the same manner as in Preparation Example 1, but adjust the pH to 8.0 to form a comparative example.

Experimental Example 1 Dissolution Rate Test and Comparative Evaluation

The comparative evaluation of the dissolution rate was conducted using a soft capsule solubilized simvastatin and a commercially available tablet. The test results are shown in Table 1.

Simvastatin soft capsule in the present invention was tested using Simvastatin dissolution test method and purified water described in the US Pharmacopoeia.

 ▶ Temperature: 37 ℃

 Dissolution method: Paddle method

 Eluate: Use water alone or add 0.5% sodium lauryl sulfate to 900 milliliters of 0.01 M sodium phosphate buffer (pH 7.0).

 Stirring Speed: 50 rpm

 ▶ Analysis method: Eluate was collected at 5, 10, 15, 30, 45, and 60 minutes after the start of the dissolution test. The solution was filtered using a 0.45 ㎛ membrane filter as a sample solution. And at a wavelength of 257 nm.

TABLE 1 Dissolution test results in phosphate buffer (sodium lauryl sulfate 0.5%)

Elution time (minutes) Dissolution rate (%) Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 2 Comparative Example 3 Comparative Example 4 5 37.8 81.2 78.3 75.2 84.1 81.6 87.8 82.2 79.2 80.2 10 70.8 98.2 95.3 90.8 98.7 98.2 98.3 96.2 97.2 99.2 15 81.3 99.1 100.1 98.7 99.8 97.9 99.2 98.1 98.1 99.1 30 87.5 100.2 100.2 99.2 99.8 100.2 99.9 98.2 99.2 100.1 45 88.7 100.2 100.2 100.3 99.2 100.7 100.3 100.2 100.2 100.2 60 89.8 100.3 100.3 100.8 100.8 100.5 100.7 100.3 100.3 100.3

TABLE 2 Dissolution Test Results in Water

Elution time (minutes) Dissolution rate (%) Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 2 Comparative Example 3 Comparative Example 4 5 2.4 77.5 74.5 70.5 80.5 78.5 87.5 76.5 78.5 74.5 10 4.5 93.4 90.4 90.7 95.4 91.4 89.4 92.4 90.4 91.4 15 5.3 99.7 98.7 99.7 99.7 98.7 97.7 97.7 98.7 97.3 30 7.1 98.3 99.3 99.3 100.3 99.3 98.3 98.3 99.3 99.3 45 9.8 100.7 100.1 98.8 99.9 100.1 99.9 99.7 100.5 100.1 60 10.3 100.4 100.0 100.4 100.4 100.8 100.4 100.9 100.4 100.1

Experimental Example 2 Comparative Evaluation of Stability with Time

Table 3 Results of stability test of simvastatin formulations (content test, acceleration condition)

Elapsed time (months) content(%) Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 2 Comparative Example 3 Comparative Example 4 0 100.6 100.4 100.5 100.1 100.2 100.1 100.1 100.6 100.6 100.6 One 99.2 98.9 98.5 98.1 97.3 98.7 98.7 92.2 94.2 95.2 2 98.2 98.8 98.4 97.6 98.2 98.5 98.5 85.2 87.2 89.2 4 98.1 97.2 98.2 98.2 97.3 98.5 97.5 80.2 82.2 85.2 6 98.5 97.8 97.7 98.1 97.5 98.3 98.1 78.1 79.1 82.1

As shown in Table 3, the soft capsules prepared by the method of adjusting the antioxidant and pH as in the present invention did not cause a decrease in content, but the comparative example did not have a decrease in content.

Table 4 Results of Stability of Simvastatin-Containing Formulations

division 6 months accelerated condition Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Example 6 Comparative Example 2 Comparative Example 3 Comparative Example 4 Change of appearance - - - - - - - - - - Precipitation - - - - - - - - - -

[Precipitation (Appearance): Very much ++++ Many +++ Normal ++ A little + None-]

As shown in Table 4, the soft capsule prepared in the same manner as in the present invention did not cause browning or precipitation.

The present invention relates to the solubilization of a drug that is very poorly soluble in water, and more particularly, to the solubilization and stable formulation of simvastatin, a drug for treating hyperlipidemia. It is true that it is very poor. However, by achieving the solubilization of the drug as in the present invention, the absorption rate can be increased to enhance the bioavailability. In addition, by overcoming instability in the liquid phase of simvastatin it can ensure the stability of long-term preservation during formulation. In addition, it is possible to develop a formulation that maximizes the therapeutic effect compared to existing drugs by applying the completed technology in the present invention for drugs that have poor absorption because it exhibits poorly soluble properties.

Claims (9)

A soft capsule containing a self-emulsifying emulsion comprising 5 to 6% by weight simvastatin, 30 to 40% by weight solubilizer, 55 to 60% by weight surfactant and 2 to 3% by weight oil, based on the total weight of the self-emulsifying emulsion, The self-emulsifying emulsion comprises 2-3 wt% of an antioxidant and a pH adjuster, wherein the pH adjuster is added to the pH of the concentrated self-emulsifying emulsion is a soft capsule containing a self-emulsifying emulsion.  The soft capsule of claim 1, wherein the antioxidant is tocopherol. The soft capsule of claim 1, wherein the pH adjuster is 20% citric acid-polyethylene glycol solution (w / v). delete delete delete delete delete delete