KR20090031011A - Pharmaceutical composition of artemisia extract using gastro-retentive drug delivery system and its oral sustained release formulation - Google Patents

Abstract

A pharmaceutical composition with an artemisia extract is provided to maintain a floating state of a slow-release oral medicine by a digestive fluid or body fluid in order to improve an absorption rate for gastrointestinal tracts. A pharmaceutical composition with an artemisia extract uses a drug delivery system including a swelling polymer, foam generator, slow-release adjustment polymer, and a dissolution assisting agent. The swelling polymer is selected from the group consisting of hydroxy propyl methyl cellulose, hydroxypropyl cellulose, sodium carboxymethylcellulose, calcium carboxymethyl cellulose, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose tri mellidate, and hydroxy propyl methyl cellulose maleate.

Description

Pharmaceutical composition of Artemisia extract using gastro-retentive drug delivery system and its oral sustained release formulation}

The present invention relates to a pharmaceutical composition containing a leaf extract using a gastro-retentive drug delivery system (GRDDS) and a sustained release oral preparation using the same.

Larvae is a perennial herbaceous plant belonging to the compositae , and its extract is known to have an effect of prolonging blood coagulation time (Journal of Pharmaceutical Sciences 28 (2): 69-77, 1984), flavones are known to have anticancer activity ( Chem. Pharm. Bull. 32 (2): 723; 1984), platelet aggregation inhibitory activity ( Zhongguo Zhongyao Zazhi , 17 (6): 353, 1992), antifungal activity ( J. of Chemical Ecology , 19 (11), 1993), and anti-complementation to help the host's defense system to treat allergies and inflammation ( Chem. Pharm. Bull. 33 (5): 2028-2034, 1985), lowering blood pressure Action and sedation ( Indian J. Med . Res. 60, 1972). In addition, eupatilin extracted from the leaf lobe is known as anti-tumor (WO 8803805), psoriasis treatment (WO 8803800), allergy treatment (JP 84155314) and aphthous ulcer treatment (CA 2065496 AA) It is.

Korean Patent Application No. 94-00147 discloses a medicinal use for the treatment of gastrointestinal diseases of eupatillin extracted from a leaf lobe, and Korean Patent Application No. 94-39337 discloses a stomach of jaceosidin isolated from a leaf lobe. The use as a therapeutic agent for diseases is described, and Korean Patent Application No. 96-28230 discloses that the foliar extract containing eupatillin and postiosidine is effective in inflammatory bowel disease.

In addition, Korean Patent Application No. 2003-41628 discloses that the active ingredient of the leaf extract is selectively removed while only the harmful component is removed, thereby preventing or treating gastrointestinal diseases or inflammatory bowel disease. There are known methods for extracting superior leaflets.

The leaf extract preparation is known as a poorly soluble drug, and therefore, a fast-acting preparation that is used in combination with sustained-release preparations for the prevention or treatment of gastrointestinal diseases or inflammatory bowel disease is required, and Korean Patent Application No. 2004-23663 is a water-soluble extract as a leaf extract and carrier. A fast-acting oral preparation of a leaf extract containing a solid dispersion prepared by containing a polymer is disclosed. Korean Patent Application No. 2004-23664 discloses a leaf extract, oil, surfactant and cosolvent using a self-emulsifying drug delivery system. The fast-acting emulsion concentrate composition of the leaf extract which consists of 1: 0.5-50: 0.1-50: 0.1-50 weight ratio is known.

In addition, the herbal extracts including the leaf extract of the prior art were developed as preparations for oral administration, but even if the herbal preparations were powdered, the herbal extracts themselves had strong hygroscopicity, and due to the characteristics of density, fluidity, adhesion cohesion, etc. There is a problem that has been produced in the form of fine granules have been used in capsule formulation by filling in capsules or using excess lubricant.

However, there are inconveniences in the process of repeatedly filling several times without filling at one time. Due to the nature of the herbal medicines, there are many inconveniences in patients who take the medicine because the smell of the herbal products is unique. Pharmacological activity is due to a variety of factors, including the types of auxiliaries included in the formulation, the environmental factors required for the formulation process (e.g. wet granulation, etc.) or the storage environmental factors (e.g. moisture, temperature, etc.) and the mechanical stress of the manufacturing process. The problem is that the substance is easily degraded in pharmaceutical dosage forms.

The present inventors can reduce the mass deviation in herbal preparations, especially oral administration formulations containing leaf extracts and block the odor peculiar to herbal medicines, thereby solving problems of formulation due to hygroscopicity, density of raw materials, fluidity, adhesion cohesion, etc. Developed a tablet formulation and patented it as Republic of Korea Patent Application No. 2005-49830.

Oral preparations containing leaf extracts are intended to be taken once daily, three times a day, with 60 mg of young leaf 95% ethanol soft extract. In general, patients' compliance with medication is reported to improve as the number of doses decreases. In particular, when going out or working at work, it is true that there is a hassle to take a separate medicine taken after lunch, and therefore, it is thought that there are many cases of taking twice a day as a result as a result of skipping the lunch. In addition, a number of unwanted side effects have been reported in the case of drugs and efficacy. Pharmaceutical companies are working hard to reduce these side effects. As part of this, most pharmaceutical companies are developing slow-release drugs that can reduce side effects by reducing drug peak blood concentrations while slowing the release of drugs. It is released.

The leaf extract has both effects through systemic absorption and local release. Therefore, when developed as a sustained-release preparation using a gastric retention system that can stay in the stomach for a long time, the absorption of the drug can be increased as well as maximize the local effect of the leaf.

Gastric drug delivery systems are known in three technologies: floating system, expansion system, and bioadhesive system. Suspension system is a system that keeps drug in gastrointestinal tract for a long time by using the property that the agent is suspended in gastric fluid due to the decrease in density caused by bubbles generated by using bubble generator, and the expansion system swells the agent by using swellable polymer. It is a system that keeps the drug inside the stomach for a long time by preventing passage of the stomach pylorus. Adsorption system is a system that adsorbs drug on gastric wall using sticky polymer and keeps drug in gastrointestinal tract for a long time. However, in the case of the adsorption system, due to the difference in the amount of mucus, consistency and metabolic rotation between humans, it is difficult to achieve consistency, and the drug attached to the gastric mucosa may cause a problem of unexpected dropping due to secretion of gastric juice. Therefore, it is appropriate that gastric drug delivery system for slow release control of leaf extracts is selected from floating system and expansion system.

However, the gastric floating drug delivery system using the floating system or the expansion system is a system in which the drug dissolves with water introduced through the pores generated on the surface of the preparation while the form of the preparation is steadily dissolved and escapes through the pore. However, the foliar extract with strong adhesiveness has a disadvantage in that it is not easy to dissolve the drug from the formulation when the gastric drug delivery system using the general floating system and the expansion system is applied. The above system is a system that can exert its effect when applied to a water-soluble substance that is not tacky, and the lobe is a material that is difficult to apply as a simple gastric drug delivery system.

Therefore, there has been a need for oral sustained-release preparations containing leaflet extracts which can solve the problem of sustained release of poorly soluble and sticky leaflet extracts.

The inventors of the present invention have found that by inventing a new drug release system that is modified from a general suspension system and an expansion system and applied to the present invention, it is possible to enhance local action and increase absorption rate in pharmaceutical compositions containing leaf extracts and sustained-release preparations using the same. This invention was completed.

The present invention is to provide a pharmaceutical composition and a sustained-release oral formulation using the same, which can increase the gastric retention time of the drug containing the leaf extract to enhance the local action and increase the absorption rate.

In order to achieve the above object, the present invention provides a pharmaceutical composition and the sustained-release oral preparation using the leaf extract and swellable polymer, foaming agent, sustained release control polymer, soybean extract containing a dissolution aid.

Sustained release oral preparations according to the present invention is a gastric suspension delivery system that is modified from a general suspension system and an inflation system, while the swelling and suspension state is maintained for more than 12 hours while some fragments steadily fall off the outer layer of the drug from the fragment. It has a release system of new drugs being released.

Hereinafter, the present invention will be described in detail.

The present invention contains the extract of Artermisia asiatica Nakai, a perennial herbaceous plant belonging to the compositae , as an active substance. The leaf extract is preferably contained 0.8 ~ 2.40% by weight of eu Patillin (C ₁₈ H ₁₆ O ₇ : molecular weight 344.31) per 1 g of leaf extract. As the extraction solvent, lower alcohol, in particular, ethanol is used, and 95% ethanol is preferably used. The leaf extracts were prepared by stirring extract, cold immersing, and filtering the leaflets with 95% ethanol as an extraction solvent, and then concentrated under reduced pressure at 78 ° C. or lower.

The leaf extract is known to have an excellent effect in the treatment of gastrointestinal diseases, gastritis and gastric ulcer, the effective dose is 60mg once, 180mg per day.

The new drug release system according to the present invention is achieved by a pharmaceutical composition comprising a leaf extract and a swellable polymer, a foaming agent, a sustained release polymer and a dissolution aid.

Swellable polymers according to the invention are hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, cellulose acetate phthalate, hydroxypropyl-methyl Cellulose phthalate, hydroxypropylmethylcellulose trimellidate, hydroxypropyl methylcellulose maleate, xanthan gum, xanthan gum and the like, but are not limited thereto, and preferably hydroxypropylmethylcellulose, hydroxypropylcellulose, carbo Mercant, xanthan gum, xanthan gum and the like can be selected.

The swellable polymer swells rapidly upon contact with an aqueous medium such as gastric juice, thereby lowering the density of the formulation and controlling initial rapid release of the drug.

In the present invention, the bubble generator may be selected from alkaline materials such as potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, and the like, but is not limited thereto. Preferably, sodium carbonate, sodium bicarbonate, etc. may be used, and acid-alkali neutralization reaction may be performed. You can also add an alkalizing agent to facilitate

The foaming agent rapidly forms bubbles upon contact with an aqueous medium such as gastric fluid, and retains or discharges them inside, thereby maintaining the floating property of the formulation and releasing the drug through pores formed by the removed bubbles. It plays a role of controlling.

The present invention includes, but is not limited to, Eudragit, methacrylic acid copolymer, methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, etc. Preferably, Eudragit, methacrylic acid-acrylic acid ethyl ester copolymer, and the like can be selected.

The sustained release control polymer is poorly soluble and sticky, and serves to remove the fragments from the outer layer of the preparation to facilitate the dissolution of the leaf extract, and at the same time, to control the rapid release of the drug.

In addition, the dissolution aid in the present invention may be used a variety of surfactants, including pharmaceutically acceptable anionic, cationic, nonionic or amphoteric surfactant. Specifically, polyoxyethylene sorbitan fatty acid ester, sorbitan fatty acid ester, polyoxyethylene fatty acid ester, polyoxyethylene polyoxypropylene block copolymer (polyoxyethylene polyoxypropylene block copolymer), polyoxyethylene polyoxypropylene copolymer, reactant of natural or hydrogenated vegetable oil and ethylene glycol, sodium dioctyl sulfosuccinate (dioctylsulfosuccinic acid sodium salt), lauryl sulfonic acid sodium salt, phospholipids, propylene glycol mono or di fatty acid esters, natural vegetable oils of triglycerides and polyalkylene polyols Trans Esterification products, mono-, di- or mono / di glycerides, of propylene glycol mono or di fatty acid esters with mono-, di- or mono / diglycerides One or more selected from the group consisting of mixtures and derivatives thereof can be used. Preferably the surfactant is a polyoxyethylene polyoxypropylene block copolymer, a reaction product of natural or hydrogenated vegetable oils with ethylene glycol, polyoxyethylene sorbitan fatty acid esters and propylene glycol mono or di fatty acid esters with mono-, di- Or a mixture of mono / diglycerides.

The pharmaceutical composition provided by the present invention is a leaf extract, swellable polymer, foaming agent, sustained release control polymer and dissolution aid in a ratio of 1: 0.1-20: 0.1-20: 0.1-20: 0.1-20, preferably Is 1: 0.2-5: 0.2-5: 0.2-5: 0.2-5 is prepared by mixing in a weight ratio.

Sustained release oral preparations in the present invention are tablets, granules, hard capsules. In particular, the present invention provides a film-coated tablet formulation using an odor blocking polymer to block unpleasant odors of the herbal medicine during tableting as a tablet formulation containing a leaf extract.

Odor blocking polymers used above include hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, eudragit, methacrylic acid- Acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, cellulose acetate phthalate, hydroxypropyl-methylcellulose phthalate, hydroxypropylmethylcellulose trimellidate, hydroxypropyl methylcellulose maleate, etc. And, but not limited to, Eudragit, methacrylic acid copolymer, methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, hydroxypropylmethylcellulose Etc will be selected There.

The coating agent used in the present invention produces a film coated tablet with the composition described below.

In the present invention, coating agent A, coating agent B is defined the following composition.

Coating agent A is a composition which mixed 83.38 weight% of methacrylic acid copolymer, 6.65 weight% of sodium lauryl sulfate, and 9.97 weight% of stearic acid.

Coating agent B is talc 51.72% by weight, titanium oxide 26.69% by weight, magnesium stearate 15.96% by weight, blue No.2 aluminate (1.15% by weight of the approved tar pigment of the Korea Food and Drug Administration), yellow No.203 aluminum lake (Korea Food and Drug Administration approved tar Dye) 4.48% by weight of the composition.

The present invention is coated by a conventional film coating method using an appropriate amount of the coating agents A and B, respectively.

The present invention can block the odor peculiar to the herbal medicine as a film-coated tablet formulation can eliminate the discomfort of the patient taking.

In the present invention, the following steps are generally used in the tablet manufacturing method.

조 To prepare the herbal extracts by preparing the herbal medicine by stirring, extracting, cooling and soaking in an extraction solvent for an appropriate period.

연 Prepare the soft wax in the same way as in ⑴ and mix with the soft extract in ⑴.

The soft-axe and poloxamer mixed in IX and IX were mixed and dissolved in the solvent ethanol to prepare a juvenile ethanol solution.

혼합 Calcium silicate, lactose, sodium bicarbonate, citric anhydride and microcrystalline cellulose are mixed and prepared. At this time, an excipient and a disintegrant may be included.

The ethanol solution prepared in Section and the mixture prepared in Section 연합 are combined, dried and formulated.

과립 The granules prepared in item ⑹ are mixed with a swellable polymer, a sustained release controlling polymer and a lubricant.

적 Take an appropriate amount of each coating agent and mix with ethanol and water to prepare a coating solution.

나 Film coated tablets are prepared by coating the uncoated tablet prepared in ⑻ with the coating solution prepared in ⑺.

The leaf extract generally contains one or more pharmaceutically acceptable excipients, carriers or diluents. The particular carrier, diluent or excipient used will depend upon the means and purposes to which the active leaf extract is applied. Tablets containing herbal extracts generally include substances such as diluents, lubricant disintegrants, and mixtures thereof.

The present invention may contain excipients, disintegrants, glidants, and the like, which are conventionally used in the preparation of tablet formulations in the pharmaceutical field, and the excipients include lactose, starch, lactose, mannitol, kaolin inorganic salts (eg : Sodium chloride), powdered sugars and powdered cellulose derivatives, which increase the solubility and absorption in the gastrointestinal tract of substances commonly used in pharmaceuticals, for example, leaf extracts, within a range that does not adversely affect drug efficacy. Dispersing and emulsifying with water during oral administration, additives such as fatty acids or fatty alcohols, which can be widely used to increase elution and improve bioavailability, sugars such as white sugar, macion syrup, white sugar, gelatin, sugar and starch syrup, stearic acid Lubricants such as magnesium, talc, colloidal silicon dioxide, microcrystalline cellulose, calcium dihydrogen phosphate, starch, Excipients such as mannitol, polyvinylpyrrolidone, sodium starch glycolate, crospovidone, low-substituted hydroxypropyl cellulose, disintegrants such as calcium carboxymethylcellulose, antioxidants that prevent the agent from oxidizing, Flavoring agents, preservatives, fragrances, sweeteners, pigments, pH adjusting agents and viscosity adjusting agents may be further included, and these are preferably added in the usual amount of use usually used for the leaf extract.

The pharmaceutical composition comprising the leaf extract according to the present invention and the sustained release oral preparation using the same can increase the dissolution rate of the leaf extract, which is a poorly soluble drug, by using a gastric drug delivery system, the present invention controls the release of the drug. By slowly releasing the drug in vivo and controlling the absorption of the drug in vivo, the slow release system of leaf extracts was established. Multiple doses may show more than equivalent efficacy.

The present invention will be described in detail by way of examples. However, the following examples are only for illustrating the present invention, and the scope of the present invention is not limited by the examples.

< Example  1> Love  Oral preparations containing extracts 1

90 mg of leaf extracts and 70 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 45 mg of calcium silicate, 32 mg of lactose, 36 mg of microcrystalline cellulose, 80 mg of sodium bicarbonate, 30 mg of anhydrous citric acid, and 45 mg of crospovidone. Granules are prepared by injection into a mounted oscillator. To the granules prepared above, 30 mg of Carbomer 934, 30 mg of hydroxypropylmethylcellulose 2910, 60 mg of hydroxypropylmethylcellulose 2208, 80 mg of methacrylic acid copolymer, and 2 mg of hard silicic anhydride were mixed homogeneously and tableted. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 2 Oral Formulation 2 Containing Petal Extract

90 mg of leaf extracts and 70 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 45 mg of calcium silicate, 100 mg of microcrystalline cellulose, 40 mg of sodium bicarbonate, 15 mg of anhydrous citric acid, and 30 mg of crospovidone. To granules. 40 mg of hydroxypropyl methyl cellulose 2910, 80 mg of hydroxypropyl methyl cellulose 2208, 50 mg of methacrylic acid copolymer, 50 mg of xanthan gum and 2 mg of hard silicic anhydride are added to the granules, and the tablets are uniformly mixed. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 3 Oral Formulation 3 Containing Petal Extract

90 mg of leaf extracts and 20 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 45 mg calcium silicate, 80 mg lactose, 120 mg sodium bicarbonate, 50 mg anhydrous citric acid, and 80 mg crospovidone, gradually add the above-mentioned larvae of ethanol, and dry it at 40 ° C to an oscillator equipped with an 18 mesh sieve. Inject to produce granules. To the granules prepared above, 50 mg of Carbomer 934, 100 mg of hydroxypropylmethylcellulose 2208, 50 mg of methacrylic acid copolymer, 50 mg of hydroxypropyl cellulose, and 2 mg of hard silicic anhydride were added to the homogeneous mixture, and the tablets were compressed. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 4 Oral Formulation 4 Containing Petal Extract

90 mg of leaf extracts and 80 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 80 mg of calcium silicate, 100 mg of sodium bicarbonate, 50 mg of anhydrous citric acid, and 60 mg of crospovidone, gradually add the above-mentioned ethanol solution to the above-mentioned larvae, dry it at 40 degrees, and inject it into an oscillator equipped with an 18 mesh sieve. To prepare. To the granules prepared above, 50 mg of Carbomer 934, 50 mg of methacrylic acid copolymer, 50 mg of hydroxypropyl cellulose, 50 mg of ethyl cellulose, and 2 mg of hard silicic anhydride were added, mixed homogeneously, and tableted. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 5 Oral Formulation 5 Containing Petal Extract

90 mg of leaf extracts and 70 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 50 mg of calcium silicate, 30 mg of lactose, 40 mg of microcrystalline cellulose, 80 mg of sodium bicarbonate, 30 mg of anhydrous citric acid, and 45 mg of crospovidone. Granules are prepared by injection into a mounted oscillator. 50 mg of Carbomer 971 paper, 25 mg of hydroxypropyl methyl cellulose 2910, 65 mg of hydroxypropyl methyl cellulose 2208, 80 mg of methacrylic acid copolymer and 80 mg of hard silicic anhydride were added to the granules, and the tablets were tableted. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 6 Oral Formulation 6 Containing Petal Extract

90 mg of leaf extract and 50 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 40 mg of calcium silicate, 30 mg of lactose, 30 mg of microcrystalline cellulose, 50 mg of sodium bicarbonate, 15 mg of anhydrous citric acid, and 35 mg of crospovidone. Granules are prepared by injection into a mounted oscillator. 20 mg of Carbomer 971 paper, 70 mg of hydroxypropylmethylcellulose 2208, 50 mg of methacrylic acid copolymer and 2 mg of hard silicic anhydride were added to the granules prepared above, and the mixture was homogeneously mixed and tableted. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 7 Oral Formulation 7 Containing Petal Extract

90 mg of leaf extracts and 30 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 30 mg of light silicic anhydride, 100 mg of lactose, 40 mg of sodium bicarbonate, 10 mg of anhydrous citric acid, and 50 mg of crospovidone. To granules. Carbomer 934 10 mg, hydroxypropyl methyl cellulose 2910 10 mg, hydroxypropyl methyl cellulose 2208 20 mg, 20 mg methacrylic acid copolymer and 1 mg of hard silicic anhydride were added to the granules prepared above, and the mixture was uniformly mixed and tableted. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 8 Oral Formulation 8 Containing Petal Extract

90 mg of leaf extract and 10 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 30 mg of hard silicic anhydride, 50 mg of microcrystalline cellulose, 30 mg of sodium bicarbonate, 10 mg of anhydrous citric acid, and 20 mg of crospovidone. Granules are prepared by injection into an oscillator. 50 mg of Carbomer 971 paper, 100 mg of methacrylic acid copolymer, 50 mg of xanthan gum, and 3 mg of hard silicic anhydride were added to the granules thus prepared, mixed homogeneously and tableted. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

< Example  9> Love  Oral preparations with extracts 9

90 mg of leaf extracts and 70 mg of polyoxyethylene polyoxypropylene block copolymers were dissolved in ethanol using a stirrer and dried in a vacuum to obtain leaf powders. Separately calcium silicate 40 mg, lactose 30 mg, microcrystalline cellulose 30 mg, sodium bicarbonate 50 mg, citric anhydride 10 mg, crospovidone 30 mg, carbomer 934 20 mg, hydroxypropyl methyl cellulose 2910 10 mg, hydroxypropyl methyl cellulose 2208 20 mg, methacrylic acid copolymer 10 mg, xanthan gum 10 mg, and 2 mg of hard silicic anhydride are added and mixed homogeneously. After homogeneously mixing the leaf powder, tablets are tableted immediately. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 10 Oral Formulation 10 Containing Petal Extract

90 mg of leaf extract and 50 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately calcium silicate 35 mg, lactose 38 mg, microcrystalline cellulose 25 mg, sodium bicarbonate 50 mg, citric anhydride 10 mg, crospovidone 40 mg, carbomer 971 g 15 mg, hydroxypropyl methyl cellulose 2910 50 mg, hydroxypropyl methyl cellulose 2208 10 mg, methacrylic acid copolymer After homogeneously mixing 20 mg and 1 mg of hard silicic anhydride, pellets are prepared by incorporating the above-mentioned leaflet ethanol solution slowly and injecting it into a pelletizer equipped with 18 mesh bodies. Separately, coating A and coating B are prepared and mixed in appropriate amounts, respectively, and the tablets tableted above are coated by conventional film coating methods.

Example 11 Oral Formulation 11 Containing Petal Extract

90 mg of leaf extracts and 40 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately calcium silicate 35 mg, lactose 35 mg, microcrystalline cellulose 35 mg, sodium bicarbonate 20 mg, citric anhydride 5 mg, crospovidone 20 mg, carbomer 971 g 10 mg, hydroxypropyl methyl cellulose 2910 10 mg, hydroxypropyl methyl cellulose 2208 20 mg, methacrylic acid copolymer After homogeneously mixing 15 mg and 2 mg of hard silicic anhydride, pellets are prepared by incorporating the above-mentioned leaflet ethanol solution slowly and injecting it into a pelletizer equipped with 18 mesh bodies. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Example 12 Oral Formulation 12 Containing Petal Extract

90 mg of leaf extracts and 70 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 45 mg calcium silicate, 32 mg lactose, 36 mg microcrystalline cellulose, 80 mg sodium bicarbonate, 30 mg anhydrous citric acid, and 45 mg crospovidone. It is injected into a mounted roller compactor to produce granules of 80 mesh or more. To the granules prepared above, 30 mg of Carbomer 934, 30 mg of hydroxypropylmethylcellulose 2910, 60 mg of hydroxypropylmethylcellulose 2208, 80 mg of methacrylic acid copolymer, and 2 mg of hard silicic anhydride were mixed homogeneously and tableted. Separately, coating A and coating B are prepared and mixed in an appropriate amount to coat the tablets tableted above by a conventional film coating method.

Comparative Example 1

8 kg of lactose and 4 kg of corn starch were mixed in a high speed mixer. The mixture was mixed with 3 Kg of leaf extracts prepared in the same manner as in Example 1, combined in a coalescer, and then assembled into No. 20 sieves. After hot-air drying at 60 degreeC, it granulated by the No. 20 sieve and obtained granules. The prepared granules were filled in an automatic capsule filling machine to prepare capsule formulations corresponding to 90 mg of leaf extracts.

Comparative Example 2

60 mg of leaf extracts and 5 mg of polyoxyethylene polyoxypropylene block copolymer were dissolved in ethanol using a stirrer. Separately, homogeneously mix 20 mg of calcium silicate, 100 mg of microcrystalline cellulose, 133 mg of lactose, and 5 mg of croscarmellose sodium, gradually combine the above-mentioned larvae of ethanol, and dry it at 40 ° C. To granules. A proper amount of magnesium stearate and talc are added to the granules thus prepared, mixed homogeneously, and tableted. Separately, coatings A, B and C are prepared. Coating agent A is a composition in which 54.85% by weight of hydroxypropyl methylcellulose, 22.86% by weight of titanium oxide, 13.72% of ethylcellulose and 8.57% by weight of dimethylphthalate are mixed. Coating agent B is 45.52% by weight of polyvinyl alcohol, 22.30% by weight of titanium oxide, 20.00% by weight of talc, 5.00% by weight of tarrazine aluminate (Targinine Alumina Certified by Korea Food and Drug Administration), Brilliant Blue FCF Aluminum Lake Pigment) 3.00% by weight, lecithin 2.00% by weight, indigocarmine aluminum lake (1.70% by weight of certified tar pigments of the Korea Food and Drug Administration) and 0.48% by weight of xanthan gum. Coating agent C is a composition comprising 54.16% by weight of sodium carboxymethylcellulose, 20.79% by weight of maltodextrin, 16.95% by weight of glucose, 6.10% by weight of lecithin and 0.48% by weight of sodium citrate. The tablets prepared with the coating agents A, B and C are coated in the appropriate order by the usual film coating method, respectively.

Experimental Example 1 Dissolution Rate Comparison Experiment

The dissolution rate of the oral preparations comprising the leaf extracts by the gastric drug delivery system of the present invention and the oral preparations containing the leaf extracts without this system were measured and compared.

The experimental method is as follows.

An amount corresponding to 90 mg of leaf leaf extract in the oral preparation containing leaf leaf extract prepared in Example 1 and Comparative Example 1 was taken, and the dissolution rate (Korean Pharma paddle method, 50 rpm) was compared under a pH = 1.2 buffer solution. Samples were taken at stirring times 15, 30 minutes, 60 minutes, 90 minutes, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, 10 hours and 12 hours to determine the content of the leaf extracts extracted therefrom. The dissolution rate was 100% of the leaf extract in the oral preparation and measured in% using the leaf extract measured from the sample. The dissolution rate measured at pH = 1.2 is shown in FIG.

As shown in Figure 1, the oral preparation prepared in Example 1 of the present invention (test formulation) showed a dissolution rate of 20% or more in 1 hour, the dissolution rate of 35% in 4 hours to 80% until 12 hours thereafter Showed dissolution rate. On the other hand, the oral preparation prepared in Comparative Example 1 (comparative) compared to the oral preparation prepared in Example 1, the initial dissolution rate was very high, and the dissolution rate was not higher than 30% at 1 hour. .

Therefore, it can be seen that the oral preparation according to the present invention has a sustained release system in which the drug is slowly released in a pH = 1.2 buffer solution. In addition, the oral preparation according to the present invention is suspended in the upper part of the eluator within 5 minutes after stirring, while maintaining a floating state for up to 12 hours, while the comparative agent loses all the form of the preparation within 5 minutes and shows a disintegration state have.

Therefore, the pharmaceutical composition and the sustained release oral preparation using the same according to the present invention can be seen that the formulation is suitable for gastric drug delivery system as a result of maintaining suspension for 5 minutes to 12 hours through the floating phase at pH = 1.2. have.

Experimental Example 2 Blood Concentration Comparison Experiment

When the oral preparation of Example 1 according to the present invention and the oral preparation prepared from Comparative Example 1 were administered to dogs, blood concentrations were measured and compared.

The experimental method is as follows.

Ten male dogs of 15 ± 5 kg were purchased and used for experiments after adapting for about 1-2 weeks. 24 hours before the start of the experiment was fasted so as not to eat any food other than water, oral oral preparations containing the pharmaceutical composition of the leaf extracts prepared in Example 1 and Comparative Example 1 oral by taking an amount corresponding to 90 mg leaf extract About 3 ml of venous blood was drawn from the forelimb vein at 5, 10, 20, 30 minutes, 1, 2, 4, 6, 8, 10, 12 hours after administration. The collected blood was stored at -20 ° C until analysis.

The content of eupatillin in the blood was quantified using HPLC. First, 100 μl of blood is added to a microtube, 100 μl of acetate buffer and 20 μl of beta-glucuronidase are added, followed by reaction at 37 ° C. for 2 hours. 100 μl of biochainin A and 1.5 ml of ether were added and then vortexed for 2 minutes. After centrifugation at 12,000 rpm for 2 minutes, the supernatant is separated and evaporated under nitrogen gas. 130 μl of the mobile phase was added and vortexed for 1 minute, and 100 μl of which was injected into HPLC. Analytical conditions are the column is a mixture of Hichrom RPB (250 * 4.6mm, particle size: 5㎛), analysis wavelength 350nm, mobile phase 0.5% acetic acid buffer and acetonitrile in a volume ratio of 50:50. The flow rate of the mobile phase was 1 ml / min, and the sample injection amount was 100 µl. Eupatillin was quantified as area ratio with internal standard.

The results are shown in FIG.

As shown in FIG. 2, the Cmax when the formulation (test formulation) of the present invention prepared from Example 1 was administered to a dog was higher than the blood concentration when the formulation (comparative formulation) prepared from Comparative Example 1 was administered. It can be seen that low. In addition, it can be seen that the formulation according to the present invention has an area of lower concentration curve (AUC) of 10 times or more than the formulation prepared from Comparative Example 1. In addition, the formulation prepared from Comparative Example 1 was zero in blood after 4 hours of administration to the dog, but the formulation according to the present invention was almost zero after 12 hours in the pharmaceutical composition according to the present invention. And it can be seen that the sustained release oral preparation using the same for a longer time in the blood.

Therefore, the present invention shows that the gastric drug delivery system has been successfully applied, and because of the low toxicity due to the gastric drug delivery system, the bioavailability is higher and can be used as an agent that exhibits a sustained release pattern.

< Experimental Example  3> efficacy test

By experimentally administering the oral preparation of Example 1 according to the present invention, the oral preparation prepared from Comparative Example 2, and a placebo according to the present invention, and then evaluating its therapeutic effect through endoscopy, The efficacy of the oral formulations of the present invention on induced gastric ulcers was evaluated.

The experimental method is as follows.

Nine clinically recognized 9 female beagle dogs weighing 7-8 kg were used in this study. All test dogs were stocked one month before the test, and were adapted to the breeding environment. Blood tests, serum chemistry, abdominal and chest radiographs were performed to confirm that they were in a healthy condition.

Beagle dogs fasted for 12 hours were used in combination with meditomidine and midazolam, and the gastric wall was examined by an endoscope to confirm that the gastric wall was normal, and biopsy forceps for endoscopy were examined. Using the same size of 3mm in diameter and 3mm in depth, damage to the gastric wall caused gastric ulcers. Injury sites were selected for 3 individuals at the base of the gastric endoscopic examination.

The test group was divided into Example 1, Comparative Example 2, placebo administration group of the present invention and three beagle dogs were used in each group. Example 1 was administered orally twice a day in an amount corresponding to 90 mg as a leaf extract, Comparative Example 2 was orally administered three times a day as an amount corresponding to 60 mg as a leaf extract, It was orally administered three times a day as it did not contain.

Endoscopy with a diameter of 10 mm was used to evaluate gastric ulcer healing effect, and Olympus CLV-E was used as an endoscope light source. Endoscopy was performed before, 3, 6, 9, 12, and 15 days after the induction of gastric ulcer, and the animals were fasted for 12 hours for endoscopy.

Gastric ulcer sites induced in three locations on each individual were evaluated by adding grades from 0 to 5. The evaluation criteria are as follows.

Endoscopy results of Example 1 and Comparative Example 2 gastroscope of each group, two sites (site 1, site 2) observed by endoscopy before, immediately after, and 3, 6, 9, 12, and 15 days after induction of gastric ulcer Examination grades are shown in Table 1 and gastroscopy images are shown in FIGS. 3A to 6.

As shown in Table 1 and FIGS. 3A to 5F, gastric endoscopy showed that in the placebo-administered group, the ulcer state continued until 12 days after gastric ulcer induction at each site, and on the 15th day, ulcers tended to heal, but in the form of bleeding plaques. Some were observed. In Example 1 and Comparative Example 2 administration group, the ulcer site tended to heal in the form of erosion from day 6 after gastric ulcer induction, and the size of erosion was reduced on day 9 after induction. After 12 days of administration, the size of the erosion was markedly reduced, and at day 15 after the administration, most of the ulcers showed a tendency to heal into scars. In particular, in the administration group of Example 1, it was observed that the scar size was significantly reduced in comparison with the comparison administration group on the 12th and 15th days after the ulcer induction.

As a specific matter during the endoscopy, it was observed that a large amount of white powder, which is regarded as a drug, was evenly spread on the stomach wall in comparison with placebo and Comparative Example 2 administration group, as shown in FIG. 6. .

As a result, Example 1 can confirm that the healing effect against gastric ulcer is superior to placebo-administered group as in Comparative Example 2, in particular, the dosage of the active ingredient of Example 1 is the same as Comparative Example 2 (180 mg / dog / day) while reducing the number of administration twice a day, the healing effect on the gastric ulcer was equal or more compared with Comparative Example 2 and the size of the scar produced by the healing was smaller. These results indicate that the formulation of Example 1 has the same daily dose as compared to Comparative Example 2, but shows a higher therapeutic effect through local effect at the wound site by reducing the number of administrations and maintaining the stomach. .

Through such experiments, oral preparations according to the present invention exhibited sustained release due to gastric drug delivery system. Thus, administration of the oral preparation compared to Comparative Example 2, which is the same as the commercially available product of the immediate release formulation, was performed three times a day. It is reduced to 2 times, but has an excellent gastric ulcer healing effect.

1 is a comparison of the dissolution rate of the preparations according to the present invention and Comparative Example 1 containing 90 mg of leaf extract in the pH = 1.2 buffer solution of Experimental Example 1,

Figure 2 is a comparison of blood concentrations over time after oral administration of the formulation of the present invention and Comparative Example 1 containing 90mg of eupatillin of Experimental Example 1 to dogs.

3A to 3F are endoscope images of placebo-administered placebo after placebo-induced gastric ulcer,

3A is an endoscope photograph of the site 1, 2 immediately after the induction of gastric ulcer,

3B is an endoscopic picture of site 1, 2 at day 3 of placebo dosing,

3C is an endoscopic picture of site 1 and 2 at day 6 of placebo administration,

3D is an endoscopic picture of site 1, 2 on day 9 of placebo administration,

3E is an endoscopic picture of site 1, 2 on day 12 of placebo administration,

3F is an endoscopic picture of site 1, 2 on day 15 of placebo dosing.

4A to 4F are endoscope images of Comparative Example 2 administered groups after administration of the formulation of Comparative Example 2 after gastric ulcer induction,

4A is an endoscope photograph immediately after gastric ulcer induction,

Figure 4b is an endoscopic picture of the site 1, 2 of the third day of the formulation administration of Comparative Example 2,

4C is an endoscopic photograph of site 1, 2 on day 6 of Formulation 2 of Comparative Example 2,

4D is an endoscope photograph of site 1, 2 on day 9 of Formulation 2 of Comparative Example 2,

FIG. 4E is an endoscope photograph of site 1,2 at 12 days of dosing of Comparative Example 2 formulation,

4F is an endoscopic picture of site 1, 2 on day 15 of the formulation administration of Comparative Example 2. FIG.

Figures 5a to 5f is an endoscope photograph of the Example 1 administration group after administering the formulation of Example 1 of the present invention after gastric ulcer induction,

Figure 5a is an endoscope photograph of the area 1,2 immediately after induction of gastric ulcer,

5B is an endoscopic picture of site 1, 2 at day 3 of the formulation administration of Example 1,

5C is an endoscopic picture of site 1, 2 at day 6 of the formulation administration of Example 1,

5D is an endoscopic picture of site 1, 2 on day 9 of Example 1 formulation dosing,

5E is an endoscopic picture of site 1, 2 at day 12 of the formulation administration of Example 1,

FIG. 5F is an endoscopic image of site 1, 2 on day 15 of formulation administration of Example 1. FIG.

Figure 6 is an endoscope photograph of the distribution of the drug in the lesion site for the four different sites during the administration of Example 1 of the present invention.

Claims (12)

A pharmaceutical composition of a leaf extract using a gastrointestinal drug delivery system comprising a leaf extract comprising a swellable polymer, a bubble generator, a sustained release control polymer and a dissolution aid. The swellable polymer of claim 1, wherein the swellable polymer is hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, carboxymethylcellulose calcium, propylene glycol alginate, polyvinyl alcohol, povidone, carbomer, cellulose acetate phthalate, hydroxy A pharmaceutical composition of a leaf extract, characterized in that it is selected from the group consisting of propyl-methylcellulose phthalate, hydroxypropylmethylcellulose trimellidate, hydroxypropyl methylcellulose maleate, xanthan gum, xanthan gum and the like. The pharmaceutical composition of the leaf extract according to claim 1, wherein the bubble generator is selected from the group consisting of potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate and the like. The method of claim 1, wherein the controlled release polymer is selected from the group consisting of Eudragit, methacrylic acid copolymer, methacrylic acid-acrylic acid ethyl ester copolymer, dimethylaminoethyl methacrylate-methacrylic acid ester copolymer, and the like. Pharmaceutical composition of leaf extract, characterized in that selected. According to claim 1, wherein the dissolution aid is polyoxyethylene sorbitan fatty acid ester (polyoxyethylene sorbitan fatty acid ester), sorbitan fatty acid ester (sorbitan fatty acid ester), polyoxyethylene fatty acid ester (polyoxyethylene fatty acid ester), polyoxy Ethylene polyoxypropylene block copolymer, polyoxyethylene polyoxypropylene copolymer, reactant of natural or hydrogenated vegetable oil and ethylene glycol ), Dioctylsulfosuccinic acid sodium salt, lauryl sulfonic acid sodium salt, phospholipids, propylene glycol mono or di fatty acid esters, natural vegetable oil triglycol Ceride and polyal Trans-esterification reaction products of styrene polyols, mono-, di- or mono / di glycerides, propylene glycol mono or di fatty acid esters with mono-, di- or mono / A pharmaceutical composition of a leaf extract, characterized in that selected from the group consisting of a mixture of diglycerides and derivatives thereof. The method according to claim 1, wherein the swellable polymer, the bubble generator, the sustained release control polymer, and the dissolution aid are prepared in a weight ratio of 1: 0.1 to 20: 0.1 to 20: 0.1 to 20: 0.1 to 20 with respect to 1 part by weight of the leaf extract. Pharmaceutical composition of a leaf extract. The method according to claim 6, wherein the swellable polymer, the bubble generator, the sustained release control polymer, and the dissolution aid are mixed in a weight ratio of 1: 0.2-5: 0.2-5: 0.2-5: 0.2-5 with respect to 1 part by weight of the leaf extract. Pharmaceutical composition of a leaf extract, characterized in that it is prepared. Sustained release oral formulation of leafy leaf extract using gastric drug delivery system comprising swellable polymer, foaming agent, sustained release control polymer and dissolution aid. 10. The sustained-release oral preparation of larvae extract according to claim 8, wherein the oral preparation is selected from the group consisting of tablets, granules, and hard capsules. Preparing the leaf ethanol solution by dissolving the leaf extract and poloxamer in 95% ethanol; Preparing granules by mixing the bile ethanol solution with calcium silicate, microcrystalline cellulose, sodium bicarbonate, citric anhydride, and a pharmaceutically acceptable excipient; Mixing and swelling the swellable polymer and the sustained release controlling polymer lubricant into the granules; Method of producing a film coating tablet containing leaf extract, characterized in that the film coating the tableted uncoated tablet. 11. The method of claim 10, wherein the leaf extract is a method for producing a leaf extract containing film coating tablet, characterized in that the soft extract extracted with 95% ethanol. The method according to claim 10, wherein the leaf extract is a method for producing a leaf extract containing film coating tablets, characterized in that it contains 0.8 ~ 2.40% by weight of eu Patillin (C ₁₈ H ₁₆ O ₇ : molecular weight 344.31) per 1 g of leaf extract.

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