KR100908193B1 - The method for solubilization of ARTEMISIA extract - Google Patents

Abstract

The present invention relates to a pharmaceutical dosage form, more specifically a tablet, which contains a flax extract as an active ingredient and is capable of reducing a mass deviation and blocking herb-specific odor.

In addition, the present invention provides a preparation having an excellent dissolution rate in the gastrointestinal tract, which is a poorly soluble drug, and thus can be rapidly absorbed into the living body, thereby remarkably increasing the bioavailability and preventing the odor of the herbal medicine It is possible to eliminate discomfort when taking a patient and to take it easily.

Poloxamer, calcium silicate, microcrystalline cellulose, film coating, refining

Description

The method of solubilization of ARTEMISIA extract

The present invention relates to a pharmaceutical dosage form, more specifically a tablet, which contains a flax extract as an active ingredient and is capable of reducing a mass deviation and blocking herb-specific odor.

It is known that the extract is a perennial herbaceous plant belonging to the compositae , and the extract is known to have an effect of prolonging the coagulation time of the blood (Drug 28 (2): 69-77, 1984) Flavobacterium spp .), antifungal activity ( J. Pharm. Bull. 32 (2): 723; 1984), platelet aggregation inhibitory action ( Zhongguo Zhongyao Zazhi , 19 (11), 1993), and has been shown to be effective in the treatment of allergies and inflammation by supporting the host defense system by acting anticoagulant ( Chem. Pharm. Bull. 33 (5): 2028-2034, 1985) ( Indian J. Med. Res. 60, 1972). In addition, the use of eupatilin, which is extracted from leaflets, has been reported to be used for antitumor agents (WO 8803805), psoriasis agents (WO 8803800), allergy treatments (JP 84155314) and aphthous ulcer agents (CA 2065496 AA) .

Korean Patent Application No. 94-00147 discloses a medicinal use for the treatment of gastrointestinal diseases of epothilone extracted from leaves, Korean Patent Application No. 94-39337 discloses a medicament for the treatment of gastrointestinal diseases of the stomach of jaceosidin And Korean Patent Application No. 96-28230 discloses that a lobster extract containing oil tiline and pseudosidein is effective for inflammatory bowel disease.

Korean Patent Application No. 2003-41628 discloses a method of selectively removing harmful substances by maintaining the effective ingredient of a lady's extract as it is, thereby preventing or treating gastrointestinal diseases or inflammatory bowel disease from existing ley extract A far superior lobe extraction method is known.

The lyophilized extract preparation is known as a poorly soluble drug. Therefore, a fast-acting preparation for co-administration with a sustained-release preparation for prevention or treatment of gastrointestinal diseases or inflammatory bowel disease is required. Korean Patent Application No. 2004-23663 discloses a lyophilized extract and a water- A Korean Patent Application No. 2004-23664 discloses a rapid-acting oral formulation of a lysolecule extract comprising a solid dispersion prepared by containing a polymer, and Korean Patent Application No. 2004-23664 discloses a lysozyme extract, oil, surfactant and co- 1: 0.5 to 50: 0.1 to 50: 0.1 to 50 weight ratio, are known.

Conventional herbal extract preparations containing the extracts of the present invention have been developed as oral preparations, but herbal preparations have a high hygroscopicity of the herbal extracts themselves even when they are pulverized, and there are many variations in the capsule filling due to the density, fluidity and adhesive cohesive force of the raw materials However, it is inconvenient in the process of repeatedly charging the capsule in various ways without being charged at one time. In addition, there is a disadvantage in that it is difficult to fill the capsules by using the herbal medicine preparation Due to the nature of the drug in the finished product often smell peculiar herbal medicine, there were many inconveniences.

In addition, the formulation containing the anti-leaf extract may cause various causes such as the kind of the adjuvant contained in the formulation, environmental factors (eg, wet granule production method) or storage environment factors (eg, moisture and temperature) Have the problem that the pharmacologically active substance is easily decomposed in a pharmaceutical dosage form.

Accordingly, the inventors of the present invention have studied a pharmaceutical dosage form to solve the problem of formulation due to hygroscopicity, density of raw material, fluidity, adhesive cohesive force and the like, even when a preparation for oral administration containing a crude drug, And can block the odor of the herbal medicine, thus completing the present invention.

It is an object of the present invention to provide a tablet formulation capable of reducing the mass deviation and blocking odor peculiar to a herbal medicine, in a preparation for oral administration containing a lady extract.

It is another object of the present invention to provide a tablet formulation containing an insecticidal drug, which is an insoluble drug, having an excellent dissolution rate in the gastrointestinal tract.

In order to achieve the above object, the present invention provides a tablet formulation of a lysolecule extract coated with a composition comprising a lysolecule extract, calcium silicate, microcrystalline cellulose, poloxamer and a coating agent described below.

Hereinafter, the present invention will be described in detail.

The present invention relates to a tablet formulation capable of solubilizing the insecticidal drug, a poorly soluble drug, in the gastrointestinal tract.

The present invention contains an extract of Artermisia asiatica Nakai, which is a perennial herbaceous plant belonging to the compositae as an active substance. The bait extract preferably contains 0.8 to 2.40% by weight of the oil tiller (C ₁₈ H ₁₆ O ₇ : molecular weight 344.31) per gram of the bait extract. It is advisable to use 95% (v / v) ethanol (hereinafter referred to as '95% ethanol '), which is a lower alcohol, especially ethanol, as the extraction solvent. Leaf extracts are prepared by soft extraction, filtration, and concentration under reduced pressure at 78 ° C or lower, using 95% ethanol as an extraction solvent.

The present invention specifically relates to a method of preparing a lyophilized solution by dissolving a lysolecule extract and a poloxamer in ethanol to prepare a lyophilized solution and mixing it with other excipient components to prepare a lyophilized formulation, . In the present invention, a tablet formulation containing a fenugreek extract is characterized by using a fenugreek ethanol solution in which poloxamer and a fenugreek extract are dissolved in ethanol.

The present invention contains 0.05 to 1 part by weight, preferably 0.08 part by weight, of poloxamer per 1 part by weight of the hair softening agent 95% ethanol softening extract.

In addition, the present invention relates to a tablet formulation capable of reducing a mass deviation when tableting a lavender extract, which is a herb medicine, tablet.

Since the active ingredient is a hygroscopic material and is unstable in temperature, a pharmaceutical preparation such as tablets or capsules should have a low weight variation so that the composition of the drug should have excellent flowability .

There are several evaluation methods for the flow-mediated determination of drug composition, but the most recently introduced concept is a method of evaluating the motility of a mixture by rotating the mixture in a rotating drum (Chemical Engineering Science, 51, 1996 , p. 4167-4181; AAPS PharmSciTech, 1 (3), 2000, article 21).

The method is classified into six types of rolling, slumping, slipping, cascading, cataracting, and centrifuging, in which the flowability is sequentially But it is described as deteriorating. In the above document, it is judged that the flowability is sufficient to ensure that the flowability corresponding to rolling or at least slumping is secured.

Surprisingly, the present inventors have found that when a mixture of calcium silicate and microcrystalline cellulose is combined with the above-mentioned ethanol solution to form a granular form after drying, it has a slumping or rolling phase flowability and is smoothly manufactured into a tablet formulation without mass deviation .

The present invention contains calcium silicate: microcrystalline cellulose = 0.2 to 1: 1 to 2 parts by weight, preferably 0.3: 1.7 part by weight, based on 1 part by weight of the hair softening agent 95% ethanol.

Further, the present invention relates to a tablet formulation capable of blocking the unpleasant odor of the herbal medicine formulation when tableting the lavender extract, which is a herb medicine agent, into a tablet formulation.

The present invention provides film-coated tablets with the coatings described below.

In the present invention, Coating A, Coating B and Coating C define the following compositions.

Coating agent A is a composition obtained by mixing 54.85% by weight of hydroxypropylmethylcellulose, 22.86% by weight of titanium oxide, 13.72% by weight of ethylcellulose and 8.67% by weight of diethyl phthalate.

Coating agent B was 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 tartarazine aluminum latex (tar pigment of the Korean Food and Drug Administration), Brilliant Blue FCF Aluminum Lake, 3.00% by weight of lecithin, 1.70% by weight of indigocarmin aluminum lake (tar pigment of Korea Food & Drug Administration), and 0.48% by weight of xanthan gum.

Coating agent C is a composition containing 54.16% by weight of carboxymethylcellulose sodium, 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 present invention is coated by a conventional film coating method using each of the coating agents A, B and C in an appropriate amount.

The present invention is a film-coated tablet formulation, which can block the odor of the herbal medicine agent, thereby eliminating the uncomfortable feeling when the patient is taking it.

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

(1) The herbal medicines are prepared and extracted with stirring solvent for an appropriate period of time, cooled, filtered and concentrated to prepare a soft X-ray.

(2) Mix the residue with the soft ice cream of item (1) after making the soft ice cream by the same method as in (1).

(3) In (1) and (2), the mixed soft X and the poloxamer are mixed and dissolved in the solvent ethanol to prepare a lyophilized ethanol solution.

(4) Mix calcium silicate and microcrystalline cellulose. At this time, an excipient and a disintegrant may be included.

(5) The ethanol solution prepared in (3) and the mixture prepared in (4) are combined, dried and set.

(6) Mix granules and lubricants prepared in (5) and mix them.

Each coating is taken in an appropriate amount and mixed with ethanol and water to prepare a coating solution.

The film-coated tablets are prepared by coating with the coating liquid prepared in the nasal spray container prepared in paragraph (6).

The active composition generally comprises one or more pharmaceutically acceptable excipients, carriers or diluents. The particular carrier, diluent or excipient used will depend on the means and purpose for which the active ingredient, ley extract, is applied. Tablet formulations, which generally contain herbal extracts, include materials such as diluents, glidant disintegrants, and mixtures thereof.

The present invention may include excipients, disintegrants, lubricants, and the like, which are any of the ingredients commonly used in the manufacture of tablet formulations in the pharmaceutical arts, such as lactose, starch, lactose, mannitol, kaolin, Sodium chloride), powdered sugar and powdered cellulosic derivatives.

The present invention particularly relates to a granular preparation prepared by mixing a mixture of calcium silicate and a microcrystalline cellulose with a slumping or rolling phase flowability so that it can be easily tableted into a tablet formulation without mass deviation, May include a lubricant. Glidants are typically used in tablet formulations of the present invention to effectively prevent tablets and punches from sticking to the die. Suitable lubricants include talc, sodium stearyl fumarate, stearic acid or its salts and the like. Preferred lubricants in the present invention are talc and magnesium stearate.

The disintegrant can also be added to the composition to disintegrate the tablet formulation after administration and release the lysolecule extract. Suitable disintegrants include croscarmellose sodium, sodium starch glycolate, and the like, with croscarmellose sodium being most preferred.

As described above, the present invention solves the problem of formulation of a herbal medicine containing a moth extract, hygroscopicity, density, flowability, adhesive cohesive force and the like of a raw material and can be produced by slumping or rolling ), And the mass deviation can be reduced.

In addition, the present invention provides a formulation having an excellent dissolution rate in the gastrointestinal tract, so that the tablet preparation containing the insecticidal drug, the insecticidal drug, can be rapidly absorbed into the living body, and the bioavailability can be remarkably increased.

Furthermore, the present invention provides a tablet formulation capable of blocking odor peculiar to herbal medicines, which can alleviate discomfort when taking a patient and can be easily administered.

Hereinafter, the present invention will be described in more detail through examples and test examples. However, the following examples and test examples are provided to illustrate the present invention and do not limit the scope of the present invention.

≪ Example 1 > Preparation of soft palm extract

To 1 ㎏ of each leaf, 8 liters of 95% ethanol was added, and the mixture was cooled at room temperature for 20 hours. After filtration, the same amount of 95% ethanol was added to the residue, followed by cooling for 4 hours. The pre-filtrates were combined and concentrated under reduced pressure at 78 ° C or lower to prepare about 60 g of soft palm kernel extract.

≪ Example 2 > Preparation of tablets coated with a film

5 g of poloxamer prepared in Example 1 was mixed and dissolved in 10 ml of 95% ethanol to prepare an epilating ethanol solution. Separately, 20 g of calcium silicate, 100 g of microcrystalline cellulose, 133 g of lactose and 5 g of croscarmellose sodium were homogeneously mixed, and then the prepared leaf ethanol solution was slowly added to the mixture and dried at 45 캜 to prepare a 24- The granules were prepared by injection into a roller compactor. Magnesium stearate and talc were added to the prepared granules in an appropriate amount, and uniformly mixed. Using a continuous tabletting machine (Erweka, Germany), rectangular tablets having a major diameter of 8.1 mm and a minor axis of 4.1 mm were prepared, and coating agents A, B and C And film-coated in an appropriately sized film-coating apparatus.

Example 3 Preparation of Leaf Film-Coated Tablets Containing No Other Excipients (Lactose and Croscarmellose Sodium)

5 g of poloxamer prepared in Example 1 was mixed and dissolved in 10 ml of 95% ethanol to prepare an epilating ethanol solution. After 20 g of calcium silicate and 100 g of microcrystalline cellulose were homogeneously mixed without containing lactose and croscarmellose sodium, they were then prepared in the same manner as in Example 1.

≪ Comparative Example 1 > Preparation of lagophilic film-coated tablets without mixing calcium silicate and microcrystalline cellulose

5 g of poloxamer prepared in Example 1 was mixed and dissolved in 10 ml of 95% ethanol to prepare an epilating ethanol solution. 133 g of lactose and 5 g of croscarmellose sodium were homogeneously mixed without mixing calcium silicate and microcrystalline cellulose, and thereafter, the same procedure as in Example 2 was followed.

≪ Comparative Example 2 > Preparation of calcium silicate-free lobe film-coated tablets

The soft palm extract prepared in Example 1 was dissolved in 10 ml of 95% ethanol without calcium silicate to prepare a soft palm leaf ethanol solution, and the same procedure as in Example 2 was followed.

≪ Comparative Example 3 > Preparation of lyophilized film-coated tablets containing no microcrystalline cellulose

The soft palm extract prepared in Example 1 was dissolved in 10 ml of 95% ethanol to prepare a low-molecular ethanol solution, which was prepared in the same manner as in Example 2 without microcrystalline cellulose.

≪ Comparative Example 4 > Preparation of a film coated tablet without lyophil mixed with poloxamer, calcium silicate and microcrystalline cellulose

The soft palm extract prepared in Example 1 was dissolved in 10 ml of 95% ethanol without mixing poloxamer to prepare an epilated ethanol solution. Thereafter, it was prepared in the same manner as in Comparative Example 1.

≪ Comparative Example 5 > Preparation of lobe-coated tablet without poloxamer

The soft palm extract prepared in Example 1 was dissolved in 10 ml of 95% ethanol without mixing poloxamer to prepare a soft palm leaf ethanol solution, which was prepared in the same manner as in Example 2.

≪ Experimental Example 1 >

The film-coated tablets in Examples 2 and 3 and Comparative Examples 1 to 5 were subjected to a dissolution test at 50 rpm according to the second general method of the Japanese Pharmacopoeia in accordance with General Methods for General Methods 2 and 3 at 5, 10, 15, 30, and 60 minutes The eluate was analyzed by liquid chromatography. The results of the dissolution test are shown in Table 1.

Examples 2 and 3 and Comparative Examples 1 to 3 are film-coated tablets prepared by mixing poloxamer with an insecticidal drug, a soft soluble drug, and a softened extract solution with other ingredients, It is a film-coated tablet prepared without sour.

As can be seen from the following Table 1, in Examples 2 and 3 and Comparative Examples 1 and 3, the dissolution rate was more than 85% in 30 minutes, and in Comparative Example 4 and 5 in which poloxamer was not contained, 60 minutes elapsed And showed a dissolution rate of 50% or less.

Therefore, it can be understood that the present invention, which is a tablet formulation containing poloxamer as an insoluble drug and a lysolecithin as a solubilizing agent, has an excellent dissolution rate in the gastrointestinal tract.

≪ Experimental Example 2 > Flowability of the mixture containing the leaf extract and preparation test of the tablet

The flowability was evaluated by rotating the mixed composition containing the leaf extract before the preparation by tablet machine in Examples 2 and 3 and Comparative Examples 1 to 5 in a rotating drum. It was also examined whether the tablets could be manufactured using a continuous tablet machine (Erweka, Germany).

Examples 2 and 3 and Comparative Example 5 are mixtures prepared by mixing calcium silicate and microcrystalline cellulose in a mixed composition containing a lyophilized extract, and Comparative Examples 1 to 4 are calcium silicate and / or microcrystalline cellulose Without mixing.

As can be seen from the following Table 2, Examples 2 and 3 and Comparative Example 5 exhibit slumping or rolling flowability which can be prepared by tablet, and can be easily prepared by tableting. However, in Comparative Examples 1 to 4, the final mixture exhibited very poor slipping flowability, which resulted in defective tablets having large mass deviations during production into tablet formulations.

Therefore, the present invention is a tablets tableted with granules prepared by associating a lanolin-ethanol solution, a calcium silicate and a microcrystalline cellulose mixture, and has slumping or rolling-phase flowability, have.

<Experiment 3> Mass deviation test

In each of Examples 2 and 3 and Comparative Examples 1 to 5, 20 tablets made by tablets were randomly taken, and weight was measured to determine the degree of the weight deviation. The weight deviations are shown in Table 3. The test evaluation was based on the mass deviation test standard described in the Korean Pharmacopoeia.

Mass deviation test evaluation criterion: When calculating the average mass with 20 looms, the deviation between the value and individual mass is more than 2 but not more than 2 times.

As can be seen from the following Table 3, Examples 2 and 3 and Comparative Example 5 were tablets prepared by combining calcium silicate and a microcrystalline cellulose mixture with a leaf extract and tabletted as granules, However, all of Comparative Examples 1 to 4 prepared by mixing calcium silicate and / or microcrystalline cellulose without mixing were all suitable.

Therefore, in the present invention, granulated tablets prepared by combining a solution of a low viscosity ethanol with a solution of calcium silicate and a microcrystalline cellulose have a slumping or rolling phase flowability, so that they can be smoothly purified into a tablet formulation Can be manufactured.

<Experimental Example 4> The sensory test

The discomfort degree of the film-coated tablets and the discomfort after taking 50 tablets of each of the applicants suffering from gastrointestinal diseases in Examples 2 and 3 was tested and shown in Table 3. As a control, non-film-coated tablets were used in Examples 2 and 3.

As can be seen from the following Table 4, the film-coated tablets prepared in Example 2 and Example 3 showed almost no unpleasant feeling, and most of them were used in the test group taking the noodles used as the control group, but they were very uncomfortable Some of them showed severe vomiting after taking.

Therefore, the present invention is a film-coated tablet formulation, which can block the odor of the herbal medicine, and can eliminate the uncomfortable feeling when the patient is taking it.

Claims (1)

In the elution method of tablets containing the anti- Essentially, the step of preparing the leaf ethanol solution by dissolving the leaf extract and the poloxamer in 95% (v / v) ethanol; Preparing a granule by adding a calcium silicate and a microcrystalline cellulose to the epilating ethanol solution and mixing a pharmaceutically acceptable excipient; Mixing and granulating the granules with a lubricant; And Wherein the tablets are coated by a coating agent and formulated to improve the dissolution rate of the film-coated tablets containing the tablets extract.