KR100570450B1 - Formulation and manufacturing process solubilized lovastatin soft capsules - Google Patents

Abstract

The present invention is a poorly soluble hyperlipidemia treatment, lovastatin as an active ingredient, solubilized using a self-emulsifying emulsion system consisting of a hydrophilic solvent, pH adjuster, surfactant, oil, antioxidants, etc. It is related with the manufacturing method of the lovastatin containing soft capsule which greatly improved and secured stability.

The lovastatin-containing soft capsule according to the present invention ensures stability, maximizes the absorption rate of the drug, greatly improves bioavailability and ensures stability.

Hyperlipidemia treatment, lovastatin, pH adjuster, surfactant, antioxidant, self-emulsifying emulsion system, soft capsule

Description

Soft capsule composition of soluble lovastatin and its manufacturing method {Formulation and manufacturing process solubilized lovastatin soft capsules}

Lovastatin is commonly known as mebinolic acid and is a derivative of mevinic acid. Chemical name is (1 ', 2', 6 ', 7', 8 ', 8a'-hexahydro-3,5-dihydroxy-2', 6'-dimethyl-8 '-(2-methyl-1- Oxobutyl) -1-naphthaleneheptanoic acid 5-lactone), a lactone ring-containing compound having a molecular weight of 404 and a chemical formula of C ₂₄ H ₃₆ O ₆ , obtained from a metabolite of the fungus Aspergillus spp. It is known to exhibit pharmacological action upon oxidation.

Lovastatin is a non-hygroscopic crystalline powder of white water is not green, ethanol, as a material that exhibits a slightly melting the relatively non-polar in methanol and acetonitrile, are separated from the culture broth of Aspergillus across switch terephthalate mouse (Aspergillus terreus) producing strain of lovastatin It is known that it is useful for hypercholesterolemia and hyperlipidemia due to its excellent property of inhibiting cholesterol biosynthesis, and also has antibacterial activity.

Hypercholestemia caused by excessive cholesterol is a disease caused by the genetic and environmental factors in the blood vessels by Lipoprotein, especially LDL-cholesterol, and HMG-CoA reductase, an important enzyme involved in cholesterol biosynthesis (3- Hydroxy-3-methyl glutaryl-coenzyme A reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the rate-limiting steps for cholesterol biosynthesis. The lovastatin to be prepared in the present invention is a hyperlipidemia therapeutic agent in which the inactive lactone type is metabolized in the liver in the corresponding β-oxy acid form after oral administration to have a competitive antagonistic action against HMG-CoA.

However, since lovastatin has a very poorly soluble property with water solubility of about 400 ng / ml, it shows an absorption rate of about 30% upon oral administration, and its half-life in blood is about 1.1 to 1.7 hours, thereby achieving a therapeutic effect. To do this, it is recommended to take 3 to 4 times of 20 mg daily. This is because it is difficult to achieve a therapeutic effect because of poor patient compliance as well as economic burden.

Korean Patent Laid-Open Publication No. 2002-0042218 discloses a pharmaceutical composition for treating auto-microemulsified hyperlipidemia by solubilizing lovastatin 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 solubilizing the drug by adding a stabilizer can be produced more effectively soft capsule.

The present invention has been made to solve the above problems, and because of the very poorly soluble properties, solubilization of low-absorbance lovastatin using a suitable dissolving agent and surfactant, and stabilizer to increase storage stability and pH adjuster and The purpose of the present invention is to provide a pharmaceutical composition in which an antimicrobial agent is added to the body to be micronized to maximize absorption of the drug and to improve bioavailability.

The present invention relates to a pharmaceutical composition comprising lovastatin, a therapeutic agent for hyperlipidemia, as an active ingredient, 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 It relates to a self-emulsifying drug delivery system consisting of 0.1 to 20% by weight, pH adjuster of 0.1 to 5%.

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 fluid when taking a combination of solubilizer, surfactant and oil to solve the poorly soluble in water of lovastatin, a hyperlipidemia treatment agent It relates to a composition.

The present invention relates to a novel lovastatin solubilizing agent using a self-microemulsifying drug delivery system (SMEDDS), comprising a pharmaceutical composition comprising the following components. , Triacetin, propylene glycol, diethylene glycol monoethyl ether, glycerol can be used.

In addition, the surfactant used in the present invention serves to stably emulsify the oil component and the co-surfactant in water to form a stable emulsion, a pharmaceutically acceptable anionic, cationic, nonionic or amphoteric surfactant Various surfactants can be used, including.

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 ( Cremophor) or HCO from BASF)

(b) polyoxyethylene-sorbitan-fatty acid esters, such as mono or trilauryl, palmityl, stear0000yl or oleyl esters (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 Corporation),

(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, for example 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.

As the co-surfactant of the present invention, a solvent having both hydrophilicity or lipophilic property is preferably one 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 lipophilicity in terms of physical properties, which helps emulsification of the formulation so that emulsions or microemulsions can be uniformly dispersed. In addition, the present invention provides the advantage of ensuring the uniformity of the composition without changing the active ingredient over time even during the preservation of the formulation.

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).

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

Antioxidants of the present invention may contain tocopherol, dibutylhydroxytoluene, butyl hydroxy cyanisole, ascorbic acid, sodium sulfite, sodium pyrosulfite, sodium hydrogen sulfite, each alone or as a mixture of two or more thereof. Can be used. In addition, the above-mentioned oil components may be mixed and used.

In addition, a pH adjusting agent is added to adjust the pH of 6.0-7.5, which is a stability of the nanoemulsion concentrate, and may include, in particular, an acidifying agent, citric acid, succinic acid, tartaric acid, formic acid, malic acid, etc., each alone or two. It can be used as a mixture of the above.

To the composition of the present invention, various additives pharmaceutically acceptable for oral administration, for example, fragrances and preservatives, may be further added to the composition of the present invention without departing from the effect of the present invention.

In the present invention, the solubilizing method of lovastatin is solubilizing lovastatin in a dissolving agent, a surfactant, a cosurfactant, and an oil, and adding an antioxidant and a pH adjuster to further enhance the solubility and stability of the drug to obtain a liquid content and a general softness. A capsule preparation method provides a lovastatin soft capsule having an easy oral administration and an increased absorption rate.

The composition of the present invention is preferably prepared so as not to exceed 20% of the total weight of the active ingredient. If the amount of the active ingredient is greater than this, the solubility is drastically lowered, resulting in poor stability such as sedimentation or decrease in content during storage, whereas when the active ingredient is added below 1% of the total weight, the solubility and This is because there is a disadvantage that the stability may be increased but the dosage may be increased. In addition, the surfactant is about 10 to 70% of the total weight is suitable that when 10% or less is used, the self-emulsification capacity is poor in accordance with the object of the present invention, when 70% or more is added to form a soft capsule This 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

After mixing 50 grams of propylene glycol, 300 grams of dimethyl isosorbide and 400 grams of HCO50, mix well while maintaining 80 ° C. Add 10 g of Migliool 812N and 10 grams of tocopherol and stir well. After confirming that the solution is completely transparent, add 20 grams of lovastatin and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-propylene glycol solution (w / v).

Example 2

Mix 100 grams of propylene glycol, 250 grams of dimethylisosorbide, 200 grams of HCO50, 200 grams of Cremophor RH40, mix well while maintaining 80 ℃, add 10 grams of migliol812N and 10 grams of tocopherol, and then stir. Mix well. After confirming that the solution was completely transparent, add 20 grams of lovastatin and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-propylene glycol solution (w / v).

Example 3

Mix 100 grams of propylene glycol, 150 grams of dimethylisosorbide, 300 grams of poloxamer 124 200 grams HCO50, mix well while maintaining 80 ℃, add 10 grams of migliol812N and 10 grams of tocopherol, and stir well give. After confirming that the solution is completely transparent, add 20 grams of lovastatin and confirm that the solution is completely transparent in the same way. Then, add 20 grams of lovastatin, and dissolve completely and completely in the same way. 20% citric acid-propylene glycol solution (w / v) Add pH to 6.7.

Example 4

Mix 50 grams of triacetin, 200 grams of dimethylisosorbide, 300 grams of HCO40, and 200 grams of HCO50, mix well while maintaining 80 ℃, add 10 grams of Miglyol 812N and 10 grams of tocopherol, and stir well. . After confirming that the solution is completely transparent, add 20 grams of lovastatin, and confirm that the solution is completely transparent in the same way. Then, add 20 grams of lovastatin, and completely dissolve in the same way. 20% citric acid-triacetin solution (w / v) Add pH to 6.7.

Example 5

Mix 50 grams of propylene glycol, 50 grams of triacetin, 300 grams of dimethylisosorbide, 350 grams of Cremophor RH40, mix well while maintaining 80 ℃, add 10 grams of migliol812N and 10 grams of tocopherol, and then stir. Mix well. After confirming that the solution is completely transparent, add 20 grams of lovastatin and completely dissolve in the same manner, and adjust the pH to 6.7 by adding 20% citric acid-propylene glycol solution (w / v).

<Production of Film>

Soft capsule film in the present invention is a general soft capsule containing a known gelatin, plasticizer, prescribing gelatin 234mg, glycerin 95.8mg, glycerol 1.4mg, paraoxybenzoate methyl 0.7mg, para It is prepared by a conventional preparation method containing 0.1 mg of propyl oxycyanate.

The soft capsule production of the lovastatin solubilizing agent of the present invention is molded into Oblong # 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

27 grams of pregelatinized starch is added to 35 grams of purified water, and the luxurious solution is combined with 20 grams of lovastatin, 10 grams of microcrystalline cellulose, and 129 grams of lactose, wet granulated. 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

Comparative evaluation of the dissolution rate was conducted using a soft capsule solubilized with lovastatin and a commercially available tablet. The test results are shown in Tables 1 and 2.

The lovastatin soft capsule in the present invention was tested using the eluate of simvastatin tablets described in the US Pharmacopoeia. The eluate of lovastatin tablets described in the US Pharmacopoeia was tested using a more relaxed eluate and water of simvastatin tablets because the solubility was difficult to assess because of the excessive amount of sodium lauryl sulfate.

 Temperature: 37 ℃

 Dissolution Method: Paddle Method

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

 Stirring Speed: 50 rpm

 Analysis method: Eluate was taken at 5, 10, 15, 30, 45, and 60 minutes after the start of the dissolution test. The solution was filtered using a 0.45 μm membrane filter as a sample solution and measured at 230 nm using HPLC. .

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 Comparative Example 2 Comparative Example 3 Comparative Example 4 5 3.1 84.2 78.8 77.2 81.1 83.6 82.2 79.3 87.2 10 8.7 98.2 87.7 89.8 92.7 94.2 94.2 95.2 96.2 15 12.8 99.1 98.4 96.7 97.8 98.6 98.1 97.1 97.1 30 18.6 98.1 98.3 98.2 98.8 99.2 99.1 98.1 99.7 45 25.4 100.4 97.7 99.1 97.2 98.7 100.1 98.4 98.4 60 34.3 100.3 99.5 98.8 98.8 99.5 100.3 99.3 100.1

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 Comparative Example 2 Comparative Example 3 Comparative Example 4 5 2.1 50.7 48.8 54.2 53.2 47.6 51.7 52.3 46.2 10 2.3 74.8 70.7 65.8 71.7 68.2 69.5 65.2 70.2 15 3.2 94.2 91.4 87.7 96.8 95.6 90.2 98.1 95.1 30 5.2 98.7 97.5 94.2 97.8 98.2 97.2 98.7 97.1 45 6.4 98.7 97.9 95.1 97.9 98.7 97.5 98.9 98.9 60 7.3 98.8 98.5 96.8 98.3 99.5 98.2 99.3 97.4

Experimental Example 2 Comparative Evaluation of Stability with Time

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

Elapsed time (months) content(%) Comparative Example 1 Example 1 Example 2 Example 3 Example 4 Example 5 Comparative Example 2 Comparative Example 3 Comparative Example 4 0 100.3 100.4 99.8 100.1 100.3 100.4 100.4 100.6 100.6 One 99.1 98.1 98.5 97.1 97.8 98.9 91.8 93.1 94.2 2 98.2 98.5 98.1 97.6 98.5 97.8 87.2 85.2 87.2 4 98.4 97.1 97.2 98.1 97.3 97.2 79.2 80.2 83.2 6 98.2 97.2 97.7 97.5 97.0 97.5 77.1 76.1 80.1

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

Table 4 Results of Stability Test of Lovastatin-Containing Formulations

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

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

In addition, the soft capsule prepared in the present invention as shown in Table 4 did not occur browning or precipitation.

The present invention relates to the solubilization of drugs that are very poorly soluble in water and in particular to the solubilization and formulation of lovastatin, a therapeutic agent for hyperlipidemia. Lovastatin is absorbed at oral doses of less than 30%, and therefore bioavailability is known to be only about 5%, resulting in poor patient compliance and therapeutic effects. However, by achieving the solubilization of the drug as in the present invention, it is possible to reduce the single dose by increasing the absorption rate, and also to overcome the instability in the liquid phase of lovastatin to ensure stability of long-term preservation during formulation. In addition, it is possible to develop a formulation that maximizes the therapeutic effect compared to the existing drugs by applying the completed technology in the present invention for the drug that was poor absorption because it exhibits poorly soluble properties.

Claims (8)

A soft capsule containing a self-emulsifying emulsion comprising 2.5% by weight lovastatin, 13% by weight solubilizer, 40 to 65% by weight surfactant, 20 to 40% by weight cosurfactant and 1.2 to 1.4% by weight oil, A soft capsule containing a self-emulsifying emulsion, characterized in that it further comprises 1.2 to 1.3% by weight of an antioxidant relative to the weight of the self-emulsifying emulsion, and a pH adjuster is added so that the pH of the self-emulsifying emulsion is 6.7. 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-propylene glycol solution (w / v) or 20% citric acid-triacetin solution (w / v). delete delete delete delete delete