KR20190103753A - Oral sustained-release formulation containing ivy leaf extract and manufacturing process thereof - Google Patents

Abstract

The present invention relates to a sustained-release formulation for oral administration of an ivy leaf extract and a method for manufacturing the same. The sustained-release formulation of the present invention can constantly release an active component irrespective of changes in a state of long-term exercise and pH of a gastrointestinal tract. In addition, the sustained-release formulation can release the active component at a uniform speed in the body over 24 hours, thereby being able to deliver a drug by once a day administration and improve medication compliance.

Description

Oral sustained-release preparation containing ivy leaf extract and preparation method thereof {Oral sustained-release formulation containing ivy leaf extract and manufacturing process etc}

The present invention relates to an oral sustained release preparation containing an ivy leaf extract and a preparation method thereof.

Infectious diseases such as bronchitis, sinusitis, tonsillitis and sore throat and chronic obstructive pulmonary diseases such as asthma and bronchitis are typical respiratory diseases. The etiology of these diseases is known to be due to inflammation, which affects a lot of daily life and, if chronic, reduces the quality of life. Among the drugs used to treat respiratory diseases, bronchodilators relieve only simple cough symptoms rather than relieve inflammation, making it difficult to treat the underlying inflammation even for long-term use. Steroids, which are widely used in other therapies, have excellent efficacy in relieving inflammation, but they can cause side effects such as Cushing's syndrome when used for long periods of time. Bronchodilators and steroids are often administered in combination for short-term treatment, but the form of the formulation is developed as an inhalant, resulting in a poor compliance with medication. Therefore, Ivy leaf extract can be used as a drug to alleviate inflammation, have an antitussive expectorant effect, and have fewer side effects.

Ivy leaves are named after Hedera Helix, and the leaves are extracted with 70% ethanol to treat bronchial diseases. The extract of the ivy leaf shows mucolytic effect, spasm suppression effect and antitussive effect, which can be used for the treatment of bronchitis (Korean Patent Publication No. 2004-0106201). Among them, mucolytic action is caused by saponin called hederacoside, and the anticonvulsive effect is believed to be due to the parasympathetic effect of some glycosides (Demirci et al., Pharmazie 59, 770-774). , 2004; Korean Patent Publication No. 2006-0008310). In addition, antibacterial, anti-fungal, anti-lesmanian, and digestive effects of Hederacoside C in ivy leaf extract have been reported in addition to mucolytic and anticonvulsant effects (Korean Patent Publication No. 2016-0081359). No. Majester-Savornin et al., Planta Med. 57, 260-262, 1991; Exp. Parasitol.116, 340-345, 2007; Mendel et al., J. Ethnopharmacol. 134, 796-802, 2011). Therefore, the indicator material of the ivy leaf is evaluated as hederacoside C, and the extracts are produced by indicating the content including the same.

Currently, herbal extract formulations including ivy leaf extract have been developed for oral administration, but are supposed to take 25mg 3 times a day or 50mg twice a day. However, it is cumbersome to take it frequently, so if you miss your lunch and dinner after meals, it is difficult to show the efficacy benefits from many clinical trials and it is very likely that your treatment will be delayed in patients who need ongoing treatment. Many inventors intend to develop a product that can improve drug compliance by developing a sustained release formulation that can control the release of the drug and reduce the number of doses of the drug while maintaining the same therapeutic effect. Due to difficulty in controlling, there has been no description of a sustained release preparation that can be taken once daily. In addition, it was difficult to develop the sustained-release tablet containing the herbal extracts because the analysis of the index component is difficult and the exact dissolution criteria and test methods for the herbal medicines are not determined.

In the prior art, Korean Registered Patent No. 1647506 is a composition for treating respiratory diseases containing herbal extracts such as rhododendron extract and ivy leaf extract. It is not easy to adjust the dissolution rate of this, there is a problem in taking compliance with frequent taking.

Therefore, the present inventors have studied the dissolution properties of Hederacoside C, a representative indicator component for evaluating the formulation of the ivy leaf extract, including the hydrophilic sustained-release polymer and exhibiting dissolution properties not affected by gastrointestinal motility and pH in the gastrointestinal tract. An oral sustained release formulation of the ivy leaf extract was completed.

Korean Laid-Open Patent No. 2004-0106201 (Method for preparing Hedera helisis leaf extract for inhibiting asthma, published on Dec. 17, 2004) Korean Laid-Open Patent No. 2006-0008310 (Method for preparing extract of ivy leaf, published Jan. 26, 2006) Korean Laid-Open Patent No. 2016-0081359 (pharmaceutical composition for preventing or treating respiratory diseases comprising a composite herbal extract, published on July 8., 2016) Korean Registered Patent No. 1647506 (Method for reducing toxicity of rhubarb extract, herbal extract prepared with reduced toxicity, and composition for preventing or treating respiratory diseases containing the herbal extract, registered on August 8, 2016)

Demirci et al., Pharmazie 59, 770-774, 2004 Majester-Savornin et al., Planta Med. 57, 260-262, 1991 Exp. Parasitol. 116, 340-345, 2007 Mendel et al., J. Ethnopharmacol. 134, 796-802, 2011

It is an object of the present invention to provide an oral sustained release formulation containing an ivy leaf extract capable of releasing a constant active ingredient for a long time regardless of the state of long-term exercise and the change of pH in the gastrointestinal tract.

It is another object of the present invention to provide an ivy leaf extract-containing sustained release preparation capable of releasing the active ingredient at a uniform rate in the body over a period of 24 hours, thereby allowing administration once daily.

Still another object of the present invention is to provide a method for preparing an oral sustained release preparation containing an ivy leaf extract.

The present invention relates to oral sustained-release preparations for once-daily administration, comprising oral sustained release formulations containing an ivy leaf extract, including a hydrophilic sustained-release polymer, a diluent, a lubricant, a hygroscopic agent and a binder.

The ivy leaf extract may include more than 10% by weight of hederacoside C based on the weight of the ivy leaf extract.

The hydrophilic sustained-release polymer is selected from the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, polyacrylic acid, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide It may be one or more, preferably one or more of hydroxypropyl methyl cellulose and polyethylene oxide.

The hydrophilic sustained-release polymer is hydroxypropyl methyl cellulose, the hydroxypropyl methyl cellulose is included in 10 to 50% by weight of the total formulation weight, it may have a viscosity of 3,000cps to 120,000cps.

The hydrophilic sustained-release polymer is polyethylene oxide, the polyethylene oxide is contained in 10 to 50% by weight of the total formulation weight, and may have a molecular weight of 3,000,000 to 8,000,000.

The diluent may be one or more of microcrystalline cellulose and lactose.

The moisture absorbent may be hard silicic anhydride.

The binder may be polyvinylpyrrolidone.

The oral sustained release preparation may include 50 to 200 mg of ivy leaf extract.

The oral sustained-release preparation, according to the dissolution test method 2 of the Korean Pharmacopoeia, Hederacoside C when dissolution test at 37 ± 0.5 ℃, 500 mL of purified water, pH 4.0 and pH 6.8 eluent at 50 rpm Elution rate of 20 to 50% in 6 hours, may be 80 to 100% in 24 hours.

The oral sustained release formulation, In the dissolution test in 37 ± 0.5 ° C, 500 mL of purified water, pH 4.0 and pH6.8 eluate according to the dissolution test method of the Korea Pharmacopoeia, the difference between the dissolution rate at the paddle speed 50 rpm and the paddle speed 100 rpm was 20 Can be less than or equal to

According to another aspect of the present invention, as a method for preparing oral sustained release formulation containing ivy leaf extract,

(a) mixing the ivy leaf extract, a hydrophilic sustained release polymer, a diluent, and a hygroscopic agent to prepare a mixture;

(b) mixing the mixture of step (a) with a binder to form a powder or granules, and then sizing them to produce a sieved material; And

(c) preparing a tablet by mixing the tablets of the step (b) with the lubricant and preparing a tablet.

The manufacturing method may further include (d) coating the tableting material of step (c).

Hereinafter, the present invention will be described in more detail.

The present invention is an oral sustained release preparation containing an extract extracted from the ivy leaf as an active substance, and includes a hydrophilic sustained release polymer, a diluent, a lubricant, a hygroscopic agent, and a binder. The ivy leaf extract may include at least 10% by weight of heteracoside C, which is an indicator, based on the weight of the ivy leaf extract, and may include 10 to 70% by weight. Preferably Hederacoside C is included in the range of 10 to 20% by weight based on the weight of the ivy leaf extract.

Ivy leaf extract has an expectorant action has been used for the treatment of bronchitis, in addition to the antibacterial, antifungal, anti-leishmania action, oral sustained-release preparation of the present invention can be used for the treatment of these various diseases.

The sustained release oral preparation of the present invention may contain 50 to 200 mg of the ivy leaf extract as a daily dose, preferably 50 to 150 mg, more preferably 75 to 100 mg. In addition, the formulation may contain the ivy leaf extract in the range of 30 to 50% by weight of the total formulation weight.

Sustained release oral preparations according to the present invention are hydrophilic sustained release polymers that maintain a constant water absorption system for at least 3 to 24 hours, and the formulation is wetted by an external solution to gel and release the drug constantly. . When the hydrophilic sustained-release polymer is mixed with 10 to 50% by weight of the total formulation, it not only delays the release of the ivy leaf extract but also has the effect of enabling continuous release regardless of gastrointestinal motility and gastrointestinal pH. . In addition, the dissolution rate may be adjusted to elute at a target time. If the hydrophilic sustained-release polymer is used in less than 10% by weight, it may be difficult to show sustained release due to the rapid dissolution of the active ingredient, and when used in excess of 50% by weight, the dissolution of the active ingredient may be delayed too much to maintain an appropriate therapeutic concentration. There is.

In the present invention, as the hydrophilic sustained-release polymer, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, polyacrylic acid, polyvinylpyrrolidone, polyethylene glycol, polyethylene oxide It may be one or more selected from the group consisting of. In addition, two or more hydrophilic sustained-release polymers selected from the group may be mixed. Preferably, at least one of hydroxypropylmethylcellulose and polyethylene oxide is used as the hydrophilic sustained-release polymer.

When hydroxypropylmethylcellulose is used as the hydrophilic sustained-release polymer, those having a viscosity of 3,000 to 120,000 cps may be used at 10 to 50% by weight of the total formulation weight. Preferably, 30 to 50% by weight of the total formulation weight is used, or 20 to 40% by weight of hydroxypropylmethylcellulose having a viscosity of more than 5,000 to 20,000 cps, having a viscosity of 3,000 to 5,000 cps. Hydroxypropylmethylcellulose having a viscosity of more than 20,000 to 120,000 cps, or 10 to 30% by weight of the total formulation weight, more preferably hydroxypropylmethyl having a viscosity of 10,000 to 20,000 cps. Cellulose is used at 20-40% by weight of the total formulation weight.

When polyethylene oxide is used as the hydrophilic sustained-release polymer, a molecular weight of 3,000,000 to 8,000,000 may be used, and may include 10 to 50% by weight of the total formulation weight. Preferably, a molecular weight of 3,000,000 to 5,500,000 is used as 20 to 50% by weight of the total formulation weight, or polyethylene oxide having a molecular weight of more than 5,500,000 to 8,000,000 is used as 10 to 40% by weight of the total formulation weight, more preferably 20 to 40% by weight of polyethylene oxide having a molecular weight of 6,000,000 to 8,000,000.

The hydrophilic sustained-release polymer may be gelated due to a wet nature when contacted with gastric and intestinal fluids, thereby exhibiting sustained release of the drug.

In the present invention, a diluent may use a pharmaceutically conventional substance within the range that does not affect the drug efficacy, and may be selected from the group consisting of lactose, starch, mannitol, microcrystalline cellulose, and calcium dihydrogen phosphate. , Two or more diluents selected from the group may be mixed. The diluent may be mixed with the sustained release agent to control the release of the drug, and may adjust the type and ratio according to the characteristics of the active material. In addition, it affects the hardness and wear and tear of the tablet and can be adjusted according to the properties of the tablet. In a preferred embodiment, at least one of lactose and microcrystalline cellulose may be used in the present invention, and more preferably, a 1: 1 mixture of lactose and microcrystalline cellulose may be used. In an embodiment, the 1: 1 mixture of lactose and microcrystalline cellulose may comprise 5-50% by weight of the total formulation weight.

In the present invention, the binder is added to prevent and improve sticking, laminating, and capping, such as obstacles that may occur during tableting. Specific examples thereof include hydroxypropyl cellulose, polyvinylpyrrolidone, and carboxymethyl. Sodium cellulose, povidone, pregelatinized starch and the like can be used. Preferably in the present invention, polyvinylpyrrolidone may be dissolved in ethanol and used within the range of 1 to 5% by weight of the total formulation weight.

In the present invention, the hygroscopic agent may be added to improve the stickiness, change of state, and the like due to the water absorption, which is a chronic problem of the herbal medicine. Specific examples may include calcium silicate, light silicic anhydride, magnesium aluminate silicate, and the like. Preferably, in the present invention, hard silicic anhydride may use 0.5 to 3% by weight of the total formulation weight.

In the present invention, the lubricant may prevent the problem that the surface of the tablet adheres to the tableting punch during tableting, and may increase the fluidity of the granules. Specific examples include magnesium stearate, sodium stearyl fumarate, talc, and the like. The amount of the additive used in the present invention is not determined and may be adjusted based on pharmaceutical knowledge. Preferably, the present invention may include 0.5 to 3% by weight of the total weight of magnesium stearate.

The present invention is a sustained-release preparation containing an ivy leaf extract and a hydrophilic sustained-release polymer, and may further contain a yellow lotus extract as an additional pharmacologically active substance capable of synergistically or complementarily acting on the pharmacological activity of the ivy leaf extract.

Formulations in the present invention can be prepared comprising the following steps:

(a) mixing the ivy leaf extract, a hydrophilic sustained release polymer, a diluent, and a hygroscopic agent to prepare a mixture;

(b) mixing the mixture of step (a) with a binder to form a powder or granules, and then sizing them to produce a sieved material; And

(c) mixing and tableting the formulation and the lubricant of step (b);

It may include.

The manufacturing method of the present invention may further include the step of (d) coating by adding a coating agent to the tablet of step (c).

Oral sustained-release preparations in the present invention are tablets, granules, hard capsules of uncoated or coated tablets. Preferably, the present invention provides a moisture-proof film-coated tablet to improve the hygroscopicity of the herbal preparations with tablets containing ivy leaf extract.

The coating step of step (d) may be coated with a film coating agent commonly used. The film coating agent includes at least one polymer substrate selected from the group consisting of hydroxypropylmethyl cellulose, hydroxypropyl cellulose, polyvinyl alcohol, polyvinylpyrrolidone, methacrylic acid copolymer and polyethylene oxide, polyethylene glycol, glyceryl mono It can be composed of plasticizers, stabilizers and pigments such as stearate, sodium lauryl sulfate, maltodextrin, dextrose, sodium citrate, lecithin, talc, sodium bicarbonate, triethyl citrate, titanium oxide, stearic acid, According to the present invention can be prepared by coating the coating liquid using a solvent in the form of oil, water or semi-aqueous. In addition, the film coating agent may be a trade name Opadry (Opadry, Colorcon), specifically, Opadry II, Opadry fx, Opadry AMB and the like.

With respect to 100 parts by weight of the formulation consisting of the ivy leaf extract, hydrophilic sustained-release polymer, a diluent, a lubricant, a moisture absorbent and a binder, the film coating may be film coated with 0.5 to 5 parts by weight, more preferably 2 to 5 parts by weight.

Oral sustained-release preparation containing the ivy leaf extract of the present invention is 50rpm in the eluate of 37.0 ± 0.5 ℃, 500mL purified water, pH4.0, pH6.8 according to the second method (paddle method) of the Korean Pharmacopoeia Dissolution Test method As dissolution test, the dissolution rate of Hederacoside C in the ivy leaf extract is 20 to 50% in 6 hours, 80 to 100% in 24 hours, specifically, 20 to 40% in 6 hours, 10 hours At 40 to 80%, at 24 to 80%. In particular, the formulation of the present invention is an oral sustained release formulation for once-daily administration, characterized in that it exhibits a linear dissolution pattern in the dissolution test and has a similar dissolution pattern regardless of the pH of the eluate and the speed of the dissolution paddle. .

The oral preparation of the present invention is a disease type of the patient, the severity of the disease, the type of formulation, the age, sex, weight, health status, diet, the administration time and method of administration of the pharmaceutical treatment composition, route of administration, rate of excretion And various factors such as response sensitivity. Preferably, the dosage of the formulation of the present invention is 0.001 to 100 mg / kg per day, more preferably 0.01 to 80 mg / kg body weight, most preferably 0.1 to 60 mg / kg body weight per adult. to be. In addition, depending on the judgment of the doctor or pharmacist can be administered once a day or divided twice a day at a predetermined time interval, preferably once a day can be administered to improve the patient's medication compliance.

Oral sustained release formulations comprising the ivy leaf extract of the present invention is a uniform sustained release formulation using a sustained release agent, the drug can be continuously maintained by making the absorption of the active ingredient continuously in vivo. Through the present invention, even once-daily administration can have a therapeutic effect equivalent to that of the administration twice or three times a day, thereby greatly improving patient compliance.

In addition, the formulation of the present invention has the effect of improving the problem caused by the hygroscopicity of the herbal formulations, even if long-term storage does not reduce the stability.

1 is a result of the elution of the tablets prepared in Examples 1 to 6 and Comparative Examples 1 to 5 of the present invention, a graph evaluating the elution of the ivy leaf extract sustained release tablet according to the sustained release.
Figure 2 is the elution results of the tablets prepared in Examples 1, 7 and 8 of the present invention, hydroxypropyl methyl cellulose to evaluate the elution of the ivy leaf extract sustained release tablet prepared by varying the ratio of 4,000 cps viscosity It is a graph.
Figure 3 is the elution results of the tablets prepared in Examples 2, 9 and 10 of the present invention, hydroxypropyl methyl cellulose to evaluate the elution of the ivy leaf extract sustained release tablet prepared by varying the ratio of 15,000 cps viscosity It is a graph.
Figure 4 is the elution results of the tablets prepared in Examples 3 and 11 to 13 of the present invention, hydroxypropyl methyl cellulose to evaluate the elution of the ivy leaf extract sustained release tablet prepared by varying the ratio of the viscosity of 100,000 cps It is a graph.
Figure 5 is a result of the elution of the tablets prepared in Examples 5, 14 and 15 of the present invention, a graph evaluating the elution of the ivy leaf extract sustained release tablet prepared by varying the ratio of polyethylene oxide molecular weight 4,000,000.
Figure 6 is a result of the elution of the tablets prepared in Examples 6, 16 and 17 of the present invention, a graph evaluating the elution of the ivy leaf extract sustained release tablet prepared by varying the ratio of polyethylene oxide molecular weight 7,000,000.
7 is a graph evaluating elution of Examples 2 and 6 of the present invention at a paddle speed of 50 rpm and 100 rpm.
8 is a graph evaluating elution of the sustained-release tablet of Example 2 of the present invention in pH 1.2, 4.0, 6.8, and purified water.
9 is an elution result of the tablets prepared in Examples 2 and 18 of the present invention.

Hereinafter, a preferred embodiment of the present invention will be described in detail. However, the present invention is not limited to the embodiments described herein and may be embodied in other forms. Rather, the information provided herein is to be thorough and complete, and to fully convey the spirit of the present invention to those skilled in the art.

< Example  1-6 and Comparative example  1-5. In the West  According Ivy leaf  Preparation of Oral Sustained-Release Tablet Containing Extracts>

A tablet containing an ivy leaf extract was prepared according to the composition described in Table 1 below. That is, in Examples 1 to 6 and Comparative Examples 1 to 4, first, the ivy leaf extract, microcrystalline cellulose, lactose hydrate, sustained-release agent, and hard anhydrous silicic acid are precisely weighed and mixed. Then, the combined solution of polyvinylpyrrolidone and ethanol is mixed with the mixture to prepare wet granules, and then drying is performed. After drying the granules prepared, the granulation is carried out and the magnesium stearate is post-mixed to complete the granules. Tableting is carried out using a tableting machine. Tablets are tableted at a hardness of about 7 kp.

On the other hand, Comparative Example 5 was prepared in the same manner as in Example 1 except for the sustained-release base, the general rapid release tablet of the ivy leaf extract.

ingredient Example Comparative example One 2 3 4 5 6 One 2 3 4 5 Content (mg) Ivy Leaf Extract 100 100 100 100 100 100 100 100 100 100 100 Microcrystalline cellulose 32.5 32.5 32.5 32.5 32.5 32.5 32.5 32.5 32.5 32.5 70 Lactose Carb 32.5 32.5 32.5 32.5 32.5 32.5 32.5 32.5 32.5 32.5 70 Hydroxypropylmethylcellulose (viscosity 4,000 cps) 75 - - - - - - - - - - Hydroxypropylmethylcellulose (viscosity 15,000 cps) - 75 - - - - - - - - - Hydroxypropylmethylcellulose (viscosity 100,000 cps) - - 75 - - - - - - - - Polyethylene Oxide (Molecular Weight 2,000,000) - - - 75 - - - - - - - Polyethylene oxide (molecular weight 4.000,000 - - - - 75 - - - - - - Polyethylene Oxide (Molecular Weight 7,000,000) - - - - - 75 - - - - - Sodium alginate - - - - - - 75 - - - - Xanthan Gum - - - - - - - 75 - - - Arabian sword - - - - - - - - 75 - - Glyceryl Behenate - - - - - - - - - 75 - Polyvinylpyrrolidone 5 5 5 5 5 5 5 5 5 5 5 Light anhydrous silicic acid 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Magnesium stearate 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Uncoated gross weight 250 250 250 250 250 250 250 250 250 250 250 Opadray AMB 10 10 10 10 10 10 10 10 10 10 10 Tablet total weight 260 260 260 260 260 260 260 260 260 260 260

< Example  7 ~ 17: Western-based  Proportional Ivy leaf  Preparation of Oral Sustained-Release Tablet Containing Extracts>

In the same manner as in Example 1, oral sustained-release preparations containing the ivy leaf extracts of Examples 7 to 17 were prepared using the composition shown in Table 2 below.

ingredient Example 7 8 9 10 11 12 13 14 15 16 17 Content (mg) Ivy Leaf Extract 100 100 100 100 100 100 100 100 100 100 100 Microcrystalline cellulose 7.5 20 20 45 45 57.5 64 7.5 20 45 57.5 Lactose Carb 7.5 20 20 45 45 57.5 63.5 7.5 20 45 57.7 Hydroxypropylmethylcellulose (viscosity 4,000 cps) 125 100 - - - - - - - - - Hydroxypropylmethylcellulose (viscosity 15,000 cps) - - 100 50 - - - - - - - Hydroxypropylmethylcellulose (viscosity 100,000 cps) - - - - 50 25 12.5 - - - - Polyethylene oxide (molecular weight 4.000,000 - - - - - - - 125 100 - - Polyethylene Oxide (Molecular Weight 7,000,000) - - - - - - - - - 50 25 Polyvinylpyrrolidone 5 5 5 5 5 5 5 5 5 5 5 Light anhydrous silicic acid 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Magnesium stearate 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 2.5 Uncoated gross weight 250 250 250 250 250 250 250 250 250 250 250 Opadray AMB 10 10 10 10 10 10 10 10 10 10 10 Tablet total weight 260 260 260 260 260 260 260 260 260 260 260

< Test Example  1> according to Western mechanisms Ivy leaf  Extract of western tablets Ivy leaf  Among the extracts Hederacoside  C component elution evaluation

The dissolution test of Examples 1 to 6 and Comparative Examples 1 to 5 was conducted according to the paddle method of Method 2 of the Korean Pharmacopoeia (10th revised) dissolution test method. Eluent was used as purified water, the eluent was 500 mL, the stirring speed was 50 rpm, the elution temperature was performed at 37 ± 0.5 ℃. At the scheduled time, 1 mL of sample was taken and the same amount of eluent was added. The sample was filtered with a 0.45 um membrane filter and analyzed by HPLC to determine the concentration of Hederacoside C, an indicator of ivy leaf extract.

< Ivy leaf  Among the extracts Hederacoside  C component HPLC  Method>

Column: Spherisorb ^® ODS2 (C18, 5 um, 4.0 × 125 mm, Waters)

Mobile phase: Acetonitrile: 10 mM ammonium acetate (pH 8.5, pH adjusted with triethylamine) = 30: 70 (v / v)

Injection volume: 40 μL

Flow rate: 1.2 mL / min

Detection wavelength: 205 nm

Column temperature: 35 ℃

As a result, as shown in FIG. 1, in Comparative Example 5, which is a general release tablet, all were eluted within 2 hours, whereas in Examples 1 to 3, 5, and 6, continuous release was observed for 24 hours. Also, Comparative Examples 1 and 3 did not delay elution, and about 90% of the elution was performed within 2 hours in a dissolution rate pattern similar to that of Comparative Example 5. In Comparative Example 2, it can be seen that a continuous dissolution rate can be achieved according to the use of xanthan gum, but it did not achieve a dissolution rate of more than 80% in 24 hours. In Comparative Example 4, elution was confirmed using glyceryl behenate, but more than about 80% of elution was performed at 8 hours, and thus sufficient elution was not achieved.

In Examples 1 to 3, 5 and 6 it was confirmed that the dissolution rate is delayed as the viscosity of the hydroxypropyl methyl cellulose and the molecular weight of polyethylene oxide is increased, by adjusting the weight ratio of the sustained-release agent to adjust the dissolution rate to the target aspect Could confirm.

< Test Example  2> according to the amount of the western mechanism Ivy leaf  Elution Evaluation of Sustained-Release Tablets Containing Extracts

This experiment was carried out to confirm the dissolution rate change according to the amount of sustained-release gas. As a result of performing a dissolution test in the same manner as the dissolution test method of Test Example 1 using the tablets prepared in Examples 7 to 17, as shown in FIGS. 2 to 6, the dissolution rate increased as the amount of the sustained-release agent was decreased. It was found that there was a difference in elution rate control depending on the viscosity and molecular weight. Through this, it was confirmed that the tablets prepared in Examples 1, 2 and 6 to 10 exhibited particularly linear sustained release.

< Test Example  3> according to the dissolution paddle speed Ivy leaf  Elution Evaluation of Sustained-Release Tablets Containing Extracts

Using Examples 2 and 6, the dissolution test was conducted according to the paddle method of the tenth revised dissolution test method of the Korean Pharmacopoeia. Among the experimental conditions in the dissolution test method of Test Example 1, the elution was performed by varying the paddle speed to 100 rpm and the dissolution rate change according to the long-term exercise state of the human body was confirmed.

Example 2 Example 6 Elution time 6 8 12 6 8 12 Dissolution rate
(Paddle speed 50 rpm) 31.3 39.8 56.0 33.3 42.7 58.2 Dissolution rate
(Paddle speed 100 rpm) 35.5 42.3 59.3 37.9 46.2 62.4 Dissolution rate
Difference % 13.4 6.3 5.9 13.8 8.2 7.2

As a result, as shown in Figure 7 and Table 3, Examples 2 and 6 had a small dissolution rate difference even if the paddle speed is increased, the dissolution rate of less than 20% as a result of comparing the dissolution rate at the dissolution time 6, 8, 12 hours It was confirmed that the difference appeared. These results reflect the dissolution rate according to the degree of long-term exercise state of the user, and when taking sustained-release tablets in which the dissolution rate difference occurs according to the paddle speed, the dissolution rate is different depending on the long-term exercise state of the doser so that a certain drug is not expressed. Although it may not be, when taking the formulation of the present invention it can be seen that a certain drug can be expressed regardless of long-term exercise state.

< Test Example  4> in different pH solutions Ivy leaf  Elution Evaluation of Extract Sustained-Release Tablets

Example 2 was eluted according to the dissolution test method of Test Example 1 and the elution was evaluated by the paddle method in eluent pH 1.2, 4.0, 6.8, and purified water, and the results are shown in FIG. 8. As shown in Figure 8, the controlled release formulation of Example 2 was confirmed to release the ivy leaf extract at a constant rate regardless of the pH in a wide pH range.

< Test Example  5> Ivy leaf  Elution Evaluation of Sustained-release Tablets According to the Amount of Extract

According to the composition of Example 2, Example 18 was prepared in the same ratio by applying the amount of the ivy leaf extract from 100 mg to 75 mg. The composition was prepared with the composition shown in Table 4 below, and the elution was carried out according to the dissolution test method of Test Example 1 to compare the dissolution patterns with Example 2.

ingredient Example 2 Example 18 Content (mg) Ivy Leaf Extract 100 75 Microcrystalline cellulose 32.5 24.375 Lactose Carb 32.5 24.375 Hydroxypropylmethylcellulose
(15,000 cps) 75 56.25 Polyvinylpyrrolidone 5 3.75 Light anhydrous silicic acid 2.5 1.875 Magnesium stearate 2.5 1.875 Tablet total weight 250 187.5

As a result, as shown in FIG. 9, the dissolution patterns of Example 2 and Example 18 were similar. It was confirmed that even when the invented preparations were applied to ivy leaf extracts of different doses, they showed equivalent dissolution patterns.

Claims (13)

An oral sustained release preparation containing an ivy leaf extract,
An oral sustained release formulation for once-daily administration, comprising a hydrophilic sustained release polymer, a diluent, a lubricant, a hygroscopic agent, and a binder. The method of claim 1,
The ivy leaf extract is an oral sustained release preparation comprising at least 10% by weight of hederacoside C based on the weight of the ivy leaf extract. The method of claim 1,
The preparation is an oral sustained release preparation comprising 50 to 200 mg of ivy leaf extract. The method of claim 1,
The hydrophilic sustained-release polymer is in the group consisting of hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, carboxymethyl cellulose, polyacrylic acid, polyvinylpyrrolidone, polyethylene glycol, and polyethylene oxide Oral sustained-release preparation, characterized in that at least one selected. The method of claim 1,
The hydrophilic sustained release polymer is hydroxypropyl methyl cellulose,
The hydroxypropyl methyl cellulose is contained in 10 to 50% by weight of the total formulation weight, oral sustained release formulation characterized in that it has a viscosity of 3,000 to 120,000cps. The method of claim 1,
The hydrophilic sustained release polymer is polyethylene oxide,
The polyethylene oxide is contained in 10 to 50% by weight of the total weight of the formulation, oral sustained release formulation characterized in that it has a molecular weight of 3,000,000 to 8,000,000. The method of claim 1,
The diluent is oral sustained release preparation, characterized in that at least one of microcrystalline cellulose and lactose. The method of claim 1,
The hygroscopic agent is oral sustained release preparation, characterized in that the hard silicic anhydride. The method of claim 1,
The binder for oral sustained release, characterized in that the polyvinylpyrrolidone. The method of claim 1,
The oral sustained release formulation,
According to the dissolution test method No. 2 of the Korean Pharmacopoeia, the dissolution rate of hederacoside C was 20 to 6 hours in a dissolution test at 37 ± 0.5 ° C, 500 mL of purified water, pH 4.0 and pH6.8 at 50 rpm. Oral sustained release preparation, characterized in that 50%, 80 to 100% in 24 hours. The method of claim 1,
The oral sustained release formulation,
In the dissolution test in 37 ± 0.5 ° C, 500 mL purified water, pH 4.0 and pH6.8 eluate according to the dissolution test method of the Korea Pharmacopoeia, the difference between the dissolution rate at the paddle speed 50rpm and the paddle speed 100rpm was 20 Oral sustained release formulation, characterized in that the% or less. A method for producing an oral sustained release formulation containing the ivy leaf extract according to any one of claims 1 to 11,
(a) mixing the ivy leaf extract, a hydrophilic sustained release polymer, a diluent, and a hygroscopic agent to prepare a mixture;
(b) mixing the mixture of step (a) with a binder to form a powder or granules, and then sizing them to produce a sieved material; And
(c) preparing a tablet by mixing the tablets and the lubricant of step (b) with a tablet;
Containing, method for producing oral sustained release formulation. The method of claim 12,
(d) a method for producing an orally sustained release preparation, characterized in that it further comprises the step of coating by adding a coating agent to the other tablet of step (c).

Images