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    • 专利摘要:
    The present invention is 1.0 to 2.0% by weight of biphenyl dimethyl dicarboxylate, liver disinfectant, 1.0 to 5.0% by weight of dissolution aid, 60.0 to 95.0% by weight of polyethylene glycol, 1.0 to 5.0% by weight of water and 0.1% of surfactant or polymer compound Provided is a biphenyl dimethyldicarboxylate soft capsule containing a transparent solution comprising 5.0 wt%, gelatin, and preservatives, and a method for preparing the same.
    公开号:KR19980054904A
    申请号:KR1019960074101
    申请日:1996-12-27
    公开日:1998-09-25
    发明作者:이상순；정연복
    申请人:김명섭；구주제약 주식회사；
    IPC主号:
    专利说明:

    Soft capsule agent of biphenyl dimethyl dicarboxylate
    1: Comparison table of dissolution rate in artificial gastric juice of PMC raw materials, conventional tablets and hard capsules.
    2: Comparison of dissolution rate in artificial intestine solution of PMC raw materials, conventional tablets and hard capsules.
    3: Chromatogram obtained according to the HPLC method.
    4: Trend in concentration of PMC in serum after oral administration of 8 capsules.
    Figure 5: Graph of Area under the serum concentration curves (AUC).
    Figure 6: Graph of Maximum Serum Concentration (Cmax).
    Figure 7: Graph of Time for Maximum Serum Concentration (Tmax).
    [Industrial use]
    The present invention relates to a soft capsule containing biphenyl dimethyl carboxylate (hereinafter referred to as PMC), which is a therapeutic agent for liver disease, which is formulated into a soft capsule after preparing a stable PMC solution without crystal precipitation.
    Conventional Technology and His Challenges
    Biphenyl dimethyl carboxylate (PMC), the main ingredient of the present invention, has a property of being almost insoluble in water having the following structural formula (I), and is a drug first developed by a Chinese medical school.
    PMC has been shown to protect against toxic liver damage caused by carbon tetrachloride or thioaceramide in animal studies [Chem. Biol. Interactions, 41, 39-47 (1982)], PMC's hepatic damage inhibitory action inhibits the formation of lipid peroxide [Chem. Biol, Interactions, 78, 77-84 (1991)], appears to inhibit the binding of lipids to carbon tetrachloride metabolism of the microsomes of the liver [Chem. Biol, Interactions, 39, 301-314 (1982). In addition, clinically, short-term treatment studies for chronic hepatitis patients have been shown to have an effect of lowering serum ALT level or bilirubin level, but have no side effects. [Korean Journal of Internal Medicine, 40, 172 ~ 178 (1990] )].
    In Korea, 25mg tablets and 7.5mg hard capsules are widely used clinically as internal medicines containing PMC. However, PMC's own raw material is poorly soluble in water, so the dissolution rate is 3.33% after 2 hours in artificial gastric juice. Intestinal fluid was 2.27%, PMC tablet was 5.94% in artificial gastric juice, 9.72% in artificial intestinal fluid, and hard capsules showed low dissolution rate, 22.14% in artificial gastric juice and 28.64% in artificial intestinal fluid, although the dissolution rate was improved. In the case of tablets, absorption was poor during oral administration, resulting in a bioavailability of only 25-30% and slow absorption (see Table 1, FIG. 1 and FIG. 2).
    TABLE 1
    Dissolution rate by time in artificial gastric juice and artificial intestine for PMC raw materials, conventional tablets and hard capsules (%)

    * A.G.J. ; artificial gastric juice,
    A.I.J. ; artificial intestinal juice
    * Numbers in parentheses denote standard errors (n = 3)
    Therefore, it is urgently needed to improve the dissolution rate of PMC to increase the bioavailability and rapid absorption, and thus attempted to soften the capsule as a subject of the research.
    Generally, soft capsules are prepared by suspending the main liquid in vegetable oil such as soybean oil or by dissolving the filling solution dissolved in a base such as polyethylene glycol.However, in case of preparing a soft capsule containing PMC as a main component in vegetable oil, the dissolution rate This low absorption is not good, and when dissolved in polyethylene glycol and filled in soft capsules because crystal precipitation occurs it was necessary to develop a composition that can prevent this to maximize the efficacy of the PMC.
    [Means to solve this problem]
    In order to improve the dissolution rate and bioavailability of PMC, which is poorly soluble, the present inventors have made the formulation of PMC a soft capsule, and while studying various types of formulations, it has been found that PMC is solubilized into a stable transparent solution in which crystals do not precipitate. As a result, filling the soft capsules and confirming the preparation test by in vivo and in vitro test, the dissolution rate was increased and the bioavailability was increased, and the stability test result confirmed that the crystal did not precipitate and the content did not fall. The invention has been completed.
    The content of the soft capsule of the present invention is a biphenyl dimethyldicarboxylate (PMC), a pharmacologically active ingredient, a mixed solution of a polyethylene glycol base and water containing a dissolution aid, and one of a surfactant or a polymer compound. In detail, 1.0 to 2.0% by weight of the active ingredient PMC, 1.0 to 5.0% by weight of the dissolution aid, 60.0 to 95.0% by weight of polyethylene glycol, 1.0 to 5.0% by weight of water, 0.1 to 5.0 It is a soft capsule agent contained in a weight% ratio.
    In the method for preparing the soft capsule of the present invention, 1.0 to 5.0% by weight of a dissolving aid is added to 60.0 to 95.0% by weight of polyethylene glycol as a base, 1.0 to 5.0% by weight of water is added after mixing and then heated to 70 ° C. 0.1 to 5.0% by weight of one of them is added to dissolve, and then 1.0 to 2.0% by weight of PMC as an active ingredient is added to the solution, followed by stirring and dissolving to produce a clear PMC solution.
    In the present invention, as the dissolution aid, one selected from glycerin, concentrated glycerin, propylene glycol, and propylene carbonate is used within the range of 1.0 to 5.0% by weight, and preferably, concentrated glycerin is most preferable in terms of PMC dissolution rate. Do.
    In addition, the solubilizing base is 60.0 to 95.0% by weight of polyethylene glycol (PEG), it is preferable to use mainly selected from the liquid phase PEG-300, PEG-400 and PEG-600 at room temperature, in terms of elution of PMC as an active ingredient PEG-400 was preferred.
    In the present invention, to increase the solubility of PMC, to prevent crystallization, and to stabilize the formulation, one of 1.0 to 5.0% by weight of water and a surfactant or a polymer compound is selected and used within the range of 0.1 to 5.0% by weight, Specific examples of the surfactant include 0.5 to 1.0 wt% of polyethylene hardened castor oil (HCO-40, -50, -60, etc., manufactured by Nippon Nippon Co., Ltd.), polyethylene glycol capriate / caprate (Labrasol et al., CATTEFOSSE, France) 0.5 to 2.0% by weight, glycerin fatty acid ester (Myvacet 9-45, etc., manufactured by Koyo Co., Ltd.) 0.3 to 1.0% by weight, or polysorbate (tween 80) 0.1 to 1.0% by weight, used as a polymer compound 0.5 to 5.0% by weight of polyvinylpyrrolidone (PVP K-25, -K-30, -K-90, -CL BASF, etc.) is used.
    First, the PMC solubility experiment was conducted to find the preferred base of the present invention. As a result of measuring the solubility by adjusting the content of various polyethylene glycol (PEG) bases, the results of PMC in Formulation Example 8 of the PEG 400 base as shown in the following Table 2 are as follows. Solubility was highest.
    TABLE 2
    Supersaturation Solubility of PMC with Various PEG Concentrations

    * Stirred at 500 ° C. for 1 hour at 70 ° C.
    In other words, as a result of measuring the supersaturation solubility of PMC solution according to the test conditions in order to measure the solubility of PMC according to the concentration of various PEG bases, it was found that PMC solubility was the highest in the prescription of PEG400 base, and the concentration of PEG As increased, the solubility of PMC did not increase significantly.
    Table 3 shows the results of measuring the PMC solubility according to the PEG concentration of various PEG and glycerin mixtures.
    TABLE 3
    Effect of Mixed PEG and Glycerin on PMC Solubility

    * Stirred at 500 ° C. for 1 hour at 70 ° C.
    In other words, as a result of measuring the PMC solubility according to the concentration of PEG in the mixed solution of PEG and glycerin, the solubility of the mixture of PEG400 and glycerin was the highest, and the PMC solubility according to the concentration of PEG400 was 580.5mg and 680.5mg When there is no significant difference in the PEG 60.0 ~ 95.0% by weight it can be seen that all within the range, among them, the prescription of prescription (prescription example 7) containing 580.5 mg of PEG400 and 12 mg of glycerin as a basic prescription and the weight of the capsule Was determined to 600 mg to proceed with the formulation design of the soft capsule.
    Meanwhile, Table 4 shows the results of experiments on the solubility of PMC using propylene glycol or propylene carbonate instead of glycerin.
    TABLE 4
    Effect of Glycerin, Propylene Glycol, and Propylene Carbonate on PMC Solubility

    * Stirred at 500 ° C. for 1 hour at 70 ° C.
    As a result of the above experiments, it can be seen that the dissolution aids glycerin, propylene glycol or propylene carbonate are preferably in the range of 1.0 to 5.0% by weight, and more preferably in the case of containing glycerin. It is recognized that the most preferred in terms of solubility, and to set the basic prescription as shown in the experimental results described in Table 3.
    Next, we examined the solubility and crystallization of PMC according to the water concentration of 1.0 ~ 10.0% by weight in the basic prescription. As can be seen in Table 5, 1-5% of water of Formulation Examples 2. 3. 4. was good, and Formula 4 had the highest content of PMC and no crystallization.
    TABLE 5
    PMC content according to water concentration in basic prescription

    * Stirred at 500 ° C. for 1 hour at 70 ° C.
    * The solution prepared for each prescription was filtered and observed for 30 days at 3-5 ℃.
    Distinct precipitation: ◎
    Opaque cloudy: ○
    Transparent solution: ×
    As shown in Table 5, Formulations 2, 3, and 4 with 1.0 to 5.0% by weight of water are higher than Formula 1 without water, and Formula 5 with 10.0% by weight of water is distinct over time. A precipitate formed. Therefore, the proper concentration of water is preferably 1.0 to 5.0% by weight.
    Next, the PMC content and the crystallization of different PMC contents in the grade of polyvinylpyrrolidone (PVP), which is a high molecular compound in the basic prescription of PEG, and the results are shown in Table 6 below.
    TABLE 6
    PMC content according to polyvinylpyrrolidone grade of basic prescription

    * Stirred at 500 ° C. for 1 hour at 70 ° C.
    As a result of considering PMC content and crystallization according to grade of polyvinylpyrrolidone, a high molecular compound in basic prescription, as shown in Table 6, Formula 2 containing PVP K-30 had the highest content and did not have crystallization. It became.
    Next, look at the PMC content and crystallization according to the concentration of PVP K-30 in the basic prescription, as shown in Table 7.
    TABLE 7
    PMC content according to PVP K-30 concentration in basic prescription

    * Stirred at 500 ° C. for 1 hour at 70 ° C.
    That is, as a result of considering the PMC content according to the concentration of PVP K-30 in the basic prescription, it is possible to obtain a clear solution at the concentration of Formulation Example 1 (1.0% by weight) as shown in Table 7 and Formulation Examples 2 to 5 (2 -5 wt%), it turns out that it is preferable to change the color to yellow to 1 wt%.
    Next, look at the PMC content and crystallization according to the combined concentration of water and PVP K-30 in the basic prescription, as shown in Table 8.
    TABLE 8
    PMC content according to water concentration in basic prescription with PVP K-30

    * Stirred at 500 ° C. for 1 hour at 70 ° C.
    * The solution prepared for each prescription was filtered and observed for 30 days at 3-5 ℃.
    Distinct precipitation: ◎
    Opaque cloudy: ○
    Transparent solution: ×
    In the above experiment, the water of the capsule film is transferred to the contents, so that the crystals may be precipitated. Therefore, the prescription of water was added to prevent this and increase the content, and 1% by weight of PVP K-30 was added to the basic prescription of water. As a result of considering the effect of concentration, Prescription Examples 2, 3, and 4 with 1-5% by weight of water were also preferred, and Prescription Example 4 with 5% by weight of water had the highest PMC content and crystallization. It was not even found that it is a preferred prescription example.
    1 wt% of PVP K-30 and 5 wt% of water were added to the basic prescription, and the results of experiments on crystal precipitation according to the concentration of PMC are shown in Table 9 below.
    TABLE 9
    PMC content and crystallization according to the concentration of PMC in basic prescription with PVP K-30 and purified water

    * Stirred at 500 ° C. for 1 hour at 70 ° C.
    As a result of examining the content of PVC K-30 and purified water in the basic prescription for dissolving PMC, as shown in Table 10, it was confirmed that up to 12 mg of PMC can be dissolved as a transparent solution without crystallization as shown in Table 4. As can be seen, in the present invention it is possible to obtain a transparent solution without crystal precipitation within the content range of PMC.
    The soft capsule prepared according to the present invention is a transparent soft capsule containing colorless and transparent contents containing 7.5 mg of biphenyldimethyldicarboxylate (PMC), which is a drug per capsule, and is usually due to chronic hepatitis, persistent hepatitis or drugs. One capsule once per adult is orally administered three times a day for hepatitis with elevated transaminase.
    Hereinafter, examples of the present invention, experimental examples on stability, experimental examples on bioavailability, and the like are listed.
    Example 1

    1.2 kg of concentrated glycerin (pharmaceutical) was added to 58.05 kg of polyethylene glycol 400 (Pharmacopoeia), stirred and mixed, and warmed to about 70 ° C. Then, 0.75 kg of biphenyldimethyldicarboxylate (notified) was added thereto, followed by vigorous stirring to completely dissolve it. Degassing under reduced pressure then gives a clear solution. When the gelatin was 100, the above-mentioned transparent liquid was encapsulated by 600 mg per capsule by a general method, using a gelatin coating formulated with a weight ratio of concentrated glycerin 45, methyl paraben 0.375, and propyl paraben 0.675, and 100,000 soft capsules. Was prepared.
    Example 2

    The above formulation was prepared in accordance with Example 1 to obtain a soft capsule.
    Example 3

    The above formulation was prepared in accordance with Example 1 to obtain a soft capsule.
    Example 4


    After adding 1.2 kg of concentrated glycerin (pharmaceutical) to 57.45 kg of polyethylene glycol-400 (pharmaceutical), stirring and mixing, and adding 0.6 kg of HCO-40 to warm it to about 70 ° C., 0.75 kg of biphenyldimethyldicarboxylate (notified) was added. The solution was added vigorously to complete dissolution and then degassed under reduced pressure to obtain a clear solution. Then, using the same gelatin membrane as in Example 1 to prepare a soft capsule.
    Example 5

    1.2 kg of concentrated glycerin (pharmaceutical) was added to 54.45 kg of polyethylene glycol 400 (pharmaceutical), stirred and mixed, 3.0 kg of purified water was added thereto, warmed to about 70 ° C., and 0.6 kg of HCO-40 was added to completely dissolve it. 0.75 kg of a carboxylate (notified) was added, vigorously stirred to complete dissolution, and then degassed under reduced pressure to obtain a clear solution. Next, a soft capsule was prepared using the same gelatin membrane as in Example 1.
    Example 6


    The above formulation was prepared in accordance with Example 4 to obtain a soft capsule.
    Example 7

    In the above-described prescription, an internal solution was prepared in accordance with Example 5 to obtain a soft capsule.
    Example 8
    t18
    In the above-described prescription, an internal solution was prepared according to Example 4, and the soft capsule was used.
    Example 9


    In the above-described prescription, an internal solution was prepared in accordance with Example 5 to obtain a soft capsule.
    Example 10

    In the above-described prescription, an internal solution was prepared according to Example 4, and the soft capsule was used.
    Example 11

    In the above-described prescription, an internal solution was prepared in accordance with Example 5 to obtain a soft capsule.
    Example 12

    In the above-described prescription, an internal solution was prepared according to Example 4, and the soft capsule was used.
    Example 13

    In the above-described prescription, an internal solution was prepared in accordance with Example 5 to obtain a soft capsule.
    Example 14

    In the above-described prescription, an internal solution was prepared according to Example 4, and the soft capsule was used.
    Example 15

    In the above-described prescription, an internal solution was prepared in accordance with Example 5 to obtain a soft capsule.
    Example 16

    In the above-described prescription, an internal solution was prepared according to Example 4, and the soft capsule was used.
    Example 17

    In the above-described prescription, an internal solution was prepared in accordance with Example 5 to obtain a soft capsule.
    [Stability experiment]
    Table 10 shows the results of salping the solubility and the properties of the contents prepared according to the Examples of the present invention.
    TABLE 10
    PMC content and crystal precipitation in each example

    * Manufactured by stirring at 500rpm at 70 ℃ for 1 hour
    * Observed by storing the soft capsule prepared for each example prescription for 30 days at 3-5 ℃
    Distinct precipitation: ◎
    Opaque cloudy: ○
    Transparent solution: ×
    As a result of measuring the solubility of the PMC solution according to the test conditions, it can be seen that the content was maintained in Examples 10-12, and Examples 14-17 and there was no crystal precipitation, and the best results were obtained in Example 17.
    Next, the stability test of each formulation was performed.
    The short-term stability test results of the three lot products prepared according to Example 1 and Example 17 under severe conditions are shown in Table 11, and the results of the long-term storage test of the products prepared according to Example 17 for three years are shown in Table 12. It described in -16.
    A) stability test under severe conditions
    TABLE 11
    Short term stability test

    * Description: N.C.-Not changed
    ppt-sedimentation
    As a result of performing the short-term stability test of Example 1 and Example 17 of each Example, the crystal | crystallization did not precipitate in Example 17 and the best result which the dissolution rate and content did not change was obtained.
    B) 3-year long-term preservation test
    Samples: Three Lot products (92001, 92002, 92003) according to Example 17 were stored under shading conditions at room temperature for 3 years.
    Test Method: At the start of the test, each item was tested for 6, 12, 18, 24, 30, and 36 months.
    TABLE 12

    Test Results: As a result of the long-term preservation test, the product according to the present invention obtained satisfactory results satisfying the criteria in all the test items. It can be seen that the quality can be guaranteed for the validity period of the product for 3 years.
    TABLE 13
    Biphenyl Dimethyl Dicarboxylate (P.M.C.) Content

    TABLE 14
    Preservative test of P.M.C soft capsule
    1) M-Paraben

    Table 14 Continued
    2) P-Paraben

    TABLE 15
    P.M.C soft capsule disintegration

    TABLE 16
    Weight Variation of P and M.C Soft Capsules

    (Bioavailability assessment)
    Next, a bioavailability evaluation experiment was performed between a product prepared according to the present invention and a commercial PMC-containing hard capsule, and the results were described.
    1. Test Title
    Relative Bioavailability Evaluation of PMC Soft Capsules (Biphenyl Dimethyl Dicarboxylate Soft Capsules)
    2. Purpose of test
    The bioavailability of the structural PMC soft capsule (Kuju Pharmaceutical Co., Ltd.), which is a test agent, was relatively evaluated using a commercially available hard capsule (K Pharmaceutical Co., Ltd.) as a control agent.
    3. Test method
    1) Test and Control
    ① Ingredients and content: 7.5mg as biphenyl dimethyl dicarboxylate
    ② Name: Test formulation-PMC soft capsule (Koju Pharmaceutical)
    Control Agents-D Capsule (K Pharmaceutical)
    2) Recruitment of applicants
    Through the announcement, 29 volunteers who had no history of digestive system, liver, kidney and blood diseases and who are not currently taking any other medicines were recruited by a medical doctor (Notice 96-16, Article 9 paragraph 3) was implemented. Among them, 16 patients who were determined to be healthy in blood and urine tests were selected and tested.
    3) Test subject
    The subjects were 20-26 year old healthy male volunteers at the University of Pharmacy.
    4) Classification of test subject Jesus and test subject group
    Sixteen subjects were randomly divided into eight groups per group, as shown in Table 17 below. The soft capsules were administered, the second phase was reversely administered, and the dosage was 8 capsules (60 mg as biphenyl dimethyldicarboxylate) in each formulation.
    TABLE 17
    Dose plan according to group in crossover test by Latin blast method

    5) Test Method and Medication Plan
    As a cross test method according to the Latin Exploration method, as shown in Table 18, a dosing plan was established and 16 subjects to be administered were randomly divided into 8 subjects per group. In order to rule out the effects of the meal, the dog was fed at 8 am in the state of fasting more than 12 hours before dosing, the fasting state was maintained for 6 hours after dosing, and blood was collected over time until 12 hours. In addition, the drug-absence period was 3 hours and half-life 86.6 minutes in Tmax of biphenyldimethyldicarboxylate tablets (Han et al., J. Kor. Pharm. Sci., 24 (2), 67-72 (1994). ), Kim ○○, pp. 42, Seoul National University Master's Thesis (1995)), and Article 96-16 (October 31, 1996) of the Food and Drug Safety Headquarters. According to the estimation criteria, the half-life is at least three times longer than the half-life.
    All the subjects placed a scalp-vein set in the vein of the arm or hand and collected 8 ml of blank blood each. In order to prevent the coagulation of the blood remaining in the scalp-vein set after the blood collection, the injection of physiological test solution containing injection heparin (25 u / ㎖) was injected into the blood vessel.
    Eight capsules (60 mg as PMC) of each of the treaties and test drugs were administered orally with 200 ml of water, respectively, to the subjects who had fasted for 12 hours or more in group I (8) and group 2 (8). It was. Differences in medication duration between subjects were taken at intervals of 2,3,2,3,2,3,2,3 minutes in consideration of the blood collection time. A seven-day washout period was carried out in the same manner across the tests of Stage II.
    Sampling time interval was 3 hours, half-life of 86.6 minutes, and blood collection was done up to 8 hours in the above literature. In this study, the blood collection time was 0.33, 0.67, 1, 2, 3, 4, 6, 8, 10 and 8 ml of blood were collected at every time point at 12 hours. In order to prevent unintentional fluctuations in blood collection time, blood collection schedules were distributed to pre-trial blood collectors (clinics and physicians) and subjects.
    No meals were provided until 6 hours after dosing, and 1.5 servings of gimbap and 200 ml of drinking water were supplied at the end of blood collection at 6 hours (2 pm). There was no meal until after the last blood collection.
    After the blood collection, all subjects received antibiotics (250 ml of amoxicillin capsules) to prevent any possible harm from contamination.
    In order to completely remove the remaining heparin-treated saline in 23 gauge scalp-vein, approximately 2.0 ml of blood was drawn out each time and 8.0 ml of blood was drawn with a new syringe. The collected blood was placed in a Vacutainet tube, left in the refrigerator for 20 minutes, and centrifuged at 3000 rpm for 15 minutes to separate serum. Next, only serum was taken and transferred to sterile vials, which were stored in a freezer at -20 ° C until analysis.
    Other blood collection sites devoted more than 20 pyeong to the Department of Clinical Pathology, University Medical Center, in consideration of the management of blood collection, the activities of subjects and the space required for blood collection. A total of 10 people participated in the blood collection and management, including 2 blood collection managers, 3 doctors, 2 blood collection assistants, 2 investigators and 1 investigator.
    6) Sample processing and analysis method
    ① Main equipment and devices
    -Liquid Chromatography Device: Hitachi Co., Ltd, Model: L-6000 Pump, L-6200
    Intelligent pump, Detecter: L-4200 UV / VIS Detector
    -pH meter: Dong-woo Medical System, pH / ION meter DP-880
    -Centrifuge: Beckman Instruments, INC, MODEL TJ-6
    ② HPLC conditions
    Pretreated plasma samples were quantified under the following HPLC conditions. HPLC (Model L-6000 Pump, L-6200 Intelligent pump) from Hitachi Co., Ltd., L-4200 UV / VIS Detector for detector, reversed-phase C-18 Column (5) Μm, 4.6 × 250mm, Alltech) and D-2500 Chromato Integrator as data processing device and Precolumn Module (Alltech) with Lichrosorb RP-18 5U as a precolumn. As a mobile phase, a mixture of methanol, water, and acetonitrile (58: 37: 5 v / v) was used and quantified at a flow rate of 1.0 ml / min and a extraction wavelength of 254 nm.
    ③ Create calibration curve
    Biphenyl dimethyl carboxylate was dissolved in methanol, and a small amount of the diluted solution with water was added to 1.0 ml of serum so that the final drug concentration in the serum was 0.05, 0.1, 0.2 and 0.5 µg / ml. 100 μl of a cortisol solution (100 μg / ml) dissolved in methanol was added as an internal standard and mixed by vortexing for 3 seconds. Then Eter. 10 ml of a mixture of CHCl 3 (3: 7 v / v) was added, extracted by vortexing for 10 minutes, and centrifuged at 3000 rpm for 15 minutes. The larvae were transferred to cornical tubes and completely evaporated with nitrogen gas. 100 μl of methanol was added thereto, followed by vortexing for 1 minute, and 40 μl was injected into HPLC. From the obtained chromatogram, the ratio of the peak area of the biphenyl dimethyl carboxylate to the peak area of the internal standard was determined and plotted on the vertical axis, and the concentration as the biphenyl dimethyl dicarboxylate was plotted on the horizontal axis to prepare a calibration curve. .
    ④ Plasma Sample Treatment
    The frozen serum obtained from the subject was left at room temperature to dissolve and vortexed for 1 minute, and then 1.0 ml of this serum was added with 100 μl of cortisol solution (100 μg / ml) dissolved in methanol as an internal standard and vortexed for 3 seconds. Next to Ether. 100 ml of CHCL 3 mixture (3: 7 v / v) was added, extracted by vortexing for 10 minutes, and centrifuged at 3000 rpm for 15 minutes. The larvae were transferred to a cornical tube and completely evaporated with nitrogen gas. 100 μl of methanol was added thereto, followed by vortexing for 1 minute, and 40 μl was injected into HPLC. From the obtained chromatogram, the ratio of the peak area of biphenyldimethyldicarboxylate to the peak area of the internal standard was determined, and the concentration of drug in serum was calculated from the calibration curve.
    ⑤ Calculation
    From the obtained chromatogram, the peak area ratio (At / Ai) of biphenyldimethyldicarboxylate to the peak area of the internal standard was obtained, and the concentration of biphenyldimethyldicarboxylate in serum (ng / ml) was calculated from a calibration curve prepared in advance. ) Was obtained. Where At represents the peak area of biphenyldimethyldicarboxylate and Ai represents the peak area of the internal standard.
    4. Test result
    1) Establishment of analysis conditions
    The chromatogram obtained when the sample was analyzed by HPLC as in the test method of 6-3) was the same as in the third degree. Under the analysis conditions, biphenyl dimethyl dicarboxylate (PMC) and internal standard were well separated from the peaks of other serum components. It became. The calibration curve was y = 2.7278x + 0.0013 (r = 0.9999), showing good linearity at 0.05-0.5 µg / ml as in the fourth degree.
    2) Concentration of biphenyl dimethyl dicarboxylate (PMC) in serum by time of each subject
    The drug concentration-time curve in serum was shown in FIG. 4 after administration of the nineteen drug subjects, PMC soft capsule (test preparation) and K drug D capsule (control).
    TABLE 18
    PMC concentration in serum of each subject after administration of the control agent (K Pharmaceutical D-Capsule) (ng / ml)

    TABLE 19
    PMC concentration in serum of each subject (ng / ml) after administration of test agent (European drug PMC soft capsule)

    3) Statistical processing and evaluation of test results
    The non-categorical items for evaluation between the test drug and the reference drug were, in principle, the area under the blood concentration time curve (AUC), the peak blood concentration (Cmax), and the peak blood concentration reaching time (Tmax) calculated by bioavailability. These calculations were expressed as mean standard deviation, and the test for the difference between the drugs was judged to be significant only in case of P0.1 in unpaired Student's t-test.
    ① Area under the drug concentration-time curve in serum (AUC)
    The AUCs of the 16 control and test formulations are shown in Table 20. The average AUC of the test formulation (PMC soft capsule) was 48% greater than that of the control formulation (K pharmaceutical D capsule).
    5 is a graph showing this.
    TABLE 20
    AUC (ng hr / ml) for each subject

    * Significantly different from the Control (P0.1)
    ② Maximum blood concentration (Cmax)
    The Cmax of the control and test formulations of 16 subjects is shown in Table 21. The average Cmax of the test formulation (PMC soft capsule) was 55% greater than that of the control formulation (K pharmaceutical D capsule). This is shown in the graph of FIG. 6.
    TABLE 21
    Cmax (ng / ml) for each subject

    * Significantly different from the Control (P0.05)
    ③ Time to reach drug concentration in maximum serum (Tmax)
    The Tmax of the control and test formulations of 16 subjects is shown in Table 22. The mean Tmax of the test formulation (PMC soft capsule) was 56% lower than that of the control formulation (K pharmaceutical D capsule). In other words, the peak serum concentration was reached at an early time. 7 shows a graph of this.
    Table 22
    Tmax (hr) for each subject

    * Significantly different from the Control (P0.01)
    5. Conclusion
    PMC is a synthetic homolog of Schizandrin C, one of the active ingredients isolated from Schizandra chinensis, and is used for chronic hepatitis. The bioavailability was evaluated using D capsule of K Pharmaceutical, a PMC capsule that is licensed and manufactured in Korea, as a control agent, and received PMC soft capsules prepared according to the clinical trial management criteria from the test client. A cross-test was performed by a second-tier Latin bombardment test in healthy adult male volunteers. Statistics on AUC, Cmax, and Tmax were obtained by measuring the change in serum concentrations in each subject for 12 hours after each drug administration. Treatment was considered. In the AUC and Cmax criteria items, the difference in the mean value was 48% and 55%, respectively, and the test agent showed a higher value than the control agent. In the Tmax standard, the difference in the mean value was 56%, which was lower than that of the control. In other words, Cmax appeared at an early time.
    The statistical results showed significant differences in the AUC, Cmax and Tmax items at the significance levels of P0.1, 0.05 and 0.01, respectively.
    In conclusion, the soft capsules, which were the test agent, showed 48% and 55% higher values in the AUC and Cmax items, and 56% lower in the Tmax item than the capsules, which were the control agent (see Table 23).
    TABLE 23

    In view of the above experimental results, it can be seen that the soft capsule according to the present invention is a pharmaceutical formulation very stable, it is superior to the conventional hard capsules in terms of bioavailability and proved to be an industrially useful invention.
    权利要求:
    Claims (6)
    [1" claim-type="Currently amended] 1.0-2.0% by weight of biphenyldimethyldicarboxylate, 1.0-5.0% by weight of dissolution aid, 60.0-95.0% by weight of polyethylene glycol, 1.0-5.0% by weight of water and 0.1-5.0% by weight of surfactant or polymer compound A soft capsule of biphenyl dimethyldicarboxylate containing a solution, gelatin and a preservative.
    [2" claim-type="Currently amended] The soft capsule according to claim 1, wherein the dissolution aid comprises one of glycerin, concentrated glycerin, propylene glycol, and propylene carbonate.
    [3" claim-type="Currently amended] The method of claim 1, wherein the surfactant is selected from one of polyethylene hardened castor oil, polyethylene glycol caprate / caprate, glycerin fatty acid ester or polysorbate, and polyvinyl pyrrolidone is used as the polymer compound. The soft capsule product characterized by the above-mentioned.
    [4" claim-type="Currently amended] 60.0-95.0% by weight of polypropylene glycol was added 1.0-5.0% by weight of the dissolution aid, 1.0-5.0% by weight of purified water, followed by warming, and dissolved by adding 0.1-5.0% by weight of surfactant or polymer compound. 1.0-2.0% by weight of dimethyldicarboxylate is added, followed by stirring and dissolving to produce a clear solution. A method of producing a soft capsule of biphenyldimethyldicarboxylate, characterized by forming a gelatinous coating.
    [5" claim-type="Currently amended] The method of claim 4, wherein the dissolution aid is one of glycerin, concentrated glycerin, propylene glycol, and propylene carbonate.
    [6" claim-type="Currently amended] The method of claim 4, wherein one selected from polyethylene hardened castor oil, polyethylene glycol caprate / caprate, glycerin fatty acid ester, or polysorbate, and polyvinyl pyrrolidone is used as the polymer compound. A method for producing a soft capsule, characterized in that.
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    同族专利:
    公开号 | 公开日
    KR100196431B1|1999-06-15|
    引用文献:
    公开号 | 申请日 | 公开日 | 申请人 | 专利标题
    法律状态:
    1996-12-27|Application filed by 김명섭, 구주제약 주식회사
    1996-12-27|Priority to KR1019960074101A
    1998-09-25|Publication of KR19980054904A
    1999-06-15|Application granted
    1999-06-15|Publication of KR100196431B1
    优先权:
    申请号 | 申请日 | 专利标题
    KR1019960074101A|KR100196431B1|1996-12-27|1996-12-27|Soft capsules formulations of biphenyl dimethyl dicarboxylate|
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