Background
The pain relieving tincture is a reddish brown clear liquid, has slight fragrance and pungent taste, has the effects of dispelling wind and eliminating dampness, and activating blood circulation to relieve pain, is mainly used for stomachache, traumatic injury and rheumatism osteodynia, and has obvious curative effect. The traditional preparation method of the Ketongding tincture comprises the following steps: pulverizing the rest 18 medicinal materials except Camphora and Mentholum into coarse powder; then mixing 16 medicinal materials except Camphora, Mentholum, Scutellariae radix and fructus Gardeniae, adding 80% ethanol, and sealing and soaking for 10 days; filtering the extractive solution, collecting filtrate, distilling the residue with steam, and collecting distillate; mixing the distillate and the filtrate, controlling alcohol content at 55-65%, adjusting to 400ml, adding Camphora, oleum Menthae Dementholatum, fructus Gardeniae and Scutellariae radix coarse powder in corresponding parts, stirring, sealing, soaking for 10 days, standing, and filtering. The extraction method is long in time consumption, and 80% ethanol is soaked for 10 days, so that not only the effective components but also a plurality of fat-soluble impurities are dissolved in 80% ethanol, so that the pain relieving tincture contains more impurities, suspended matters or precipitates can be generated after long-term storage, and the stability is poor; the subsequent high-temperature distillation extraction is adopted, so that the active ingredients in the medicinal materials are easily damaged, and the extraction is incomplete. Therefore, a simple and rapid preparation method of the tincture for treating the pain is urgently needed, can effectively extract the effective components in the medicinal materials, and can ensure that the tincture for treating the pain has good stability.
The principle of the supercritical carbon dioxide fluid extraction separation process is carried out by utilizing the relation between the dissolving capacity and the density of the supercritical fluid, namely, the influence of pressure and temperature on the dissolving capacity of the supercritical fluid. In the supercritical state, the supercritical fluid is contacted with the substance to be separated, so that the components with polarity, boiling point and molecular weight are selectively extracted in turn.
Chinese patent application CN1899567A discloses a kaleidoscope oil spray for traumatic injury and a preparation method thereof, the medicinal part of the kaleidoscope oil spray for traumatic injury is prepared by extracting 77 medicinal materials with supercritical carbon dioxide to obtain a fat-soluble extract and mixing the fat-soluble extract with the following medicaments, wherein the extraction conditions of the supercritical extraction are as follows: the extraction pressure is 15-40M Pa, the separation pressure is 3-8MPa, the extraction temperature is 30-60 ℃, the separation temperature is 30-40 ℃, and the flow is 26-32Kg/h for extraction for 1-5 h. The method adopts supercritical extraction of 77 medicinal materials, each of which has different effective components, and many traditional Chinese medicine effective components such as flavonoid glycosides, alkaloids, proteins, etc. with high molecular weight and water soluble substances are difficult to extract or have low extraction rate.
Although the supercritical carbon dioxide extraction has the advantages of convenient separation, low toxicity, little or even no solvent residue, and the like, and can be operated at normal temperature, the supercritical carbon dioxide extraction also has the defect of poor dissolving capacity to strong polarity, and an entrainer needs to be added. The entrainer is also called as carrying agent, and is a substance which is added into the supercritical fluid solvent, has strong affinity with the extracted substance, can be mixed with the fluid solvent, has volatility between the extracted substance and the supercritical component, and mainly aims at improving the selectivity and the solubility of the extracted substance.
Chinese patent application CN105396069A discloses a preparation method of a traditional Chinese medicine for treating chronic gastritis, the traditional Chinese medicine composition is prepared from 19 medicinal materials such as coptis chinensis, pinellia ternate, herba eupatorii, fructus amomi, salvia miltiorrhiza and the like, a preparation method combining supercritical extraction, ultrasonic extraction and reflux extraction is adopted, the content of effective components in the composition is comprehensively improved, the curative effect of a final preparation is further improved, and the traditional Chinese medicine composition has the characteristics of controllable curative effect, controllable quality and the like. However, the composition adopts 3 extraction methods, so that the active ingredients of 19 medicinal materials can be extracted to a great extent, and the method is complicated. Wherein, ethanol is selected as entrainer in the supercritical extraction, but the extracted dregs of a decoction are added with ethanol for reflux extraction, which indicates that the effective components of the medicinal materials are not completely extracted out by the supercritical carbon dioxide extraction with ethanol as entrainer.
In order to solve the technical problems, the pain relieving tincture with good stability and remarkable efficacy needs to be provided, and the preparation method of the pain relieving tincture with simple operation and high extraction rate of effective components is provided.
Disclosure of Invention
The invention aims to provide the pain relieving tincture for promoting blood circulation to arrest pain with good stability and remarkable efficacy, and the preparation method of the pain relieving tincture for promoting blood circulation to arrest pain, which is simple and convenient to operate and high in extraction rate of effective components.
In order to achieve the purpose, the invention adopts the following technical scheme:
the pain relieving tincture for promoting blood circulation to arrest pain comprises the following preparation raw materials in parts by weight: 15-25 parts of black tiger root, 8-15 parts of rhizoma cyperi, 8-15 parts of cablin potchouli herb, 8-15 parts of black bean ginger, 4-12 parts of cortex periplocae, 4-12 parts of pepper, 4-12 parts of murraya jasminorage, 4-12 parts of chicken bone, 4-12 parts of rhizoma acori graminei, 8-15 parts of galangal, 2-6 parts of rhizoma zedoariae, 2-6 parts of rhizoma sparganii, 0.5-1.8 parts of asarum, 1-5 parts of radix zanthoxyli, 0.5-1.8 parts of euonymus fortunei, 1-5 parts of dalbergia wood, 1-5 parts of radix scutellariae, 1-5 parts of gardenia, 1-5 parts of camphor and 0.1-0.3 part of menthol.
Further, the pain relieving tincture comprises the following preparation raw materials in parts by weight: 19.5 parts of black tiger root, 11.7 parts of nutgrass galingale rhizome, 11.7 parts of cablin potchouli herb, 11.7 parts of black bean ginger, 8.0 parts of cortex periplocae, 7.8 parts of pepper, 7.8 parts of murraya paniculata, 7.8 parts of chicken bone, 7.8 parts of grassleaf sweelflag rhizome, 11.7 parts of galangal, 3.9 parts of zedoary, 3.9 parts of rhizoma sparganii, 1.2 parts of asarum, 2.0 parts of zanthoxylum nitidum, 1.2 parts of euonymus fortunei, 2.0 parts of dalbergia wood, 2.0 parts of baical skullcap root, 2.0 parts of cape jasmine fruit, 2.0 parts of camphor and 0.2.
Further, the preparation method of the tincture for treating the pain comprises the following steps:
s1, respectively crushing the raw materials except camphor and menthol, sieving the crushed raw materials by a No. 5 pharmacopeia sieve to obtain raw material fine powder, and uniformly mixing the raw material fine powder in parts by weight to obtain raw material mixed fine powder;
s2, putting the raw material mixed fine powder obtained in the step S1 into an extraction kettle of a 1L supercritical carbon dioxide extraction instrument, adding 50-200ml of entrainer, soaking for 1-2h, setting the temperature of the extraction kettle to be 30-50 ℃, the temperature of a separation kettle I to be 25-45 ℃ and the temperature of a separation kettle II to be 20-35 ℃;
s3, opening a valve of a carbon dioxide gas tank, setting the flow of carbon dioxide to be 10-30L/min, the pressure of an extraction kettle to be 15-32MPa, the pressure of a separation kettle I to be 10-25MPa and the pressure of a separation kettle II to be 8-15MPa, and starting to perform circulating extraction after the extraction kettle reaches the required temperature and pressure for 2-5 hours;
s4, collecting the extract, adding 750ml of ethanol with volume fraction of 55-65% and 450-.
Further, the entrainer in the step S2 includes the following raw materials and their mass fractions: 5-10% of sucrose fatty acid ester, 2-5% of coconut oil fatty acid diethanolamide and 85-92% of absolute ethyl alcohol.
Further, the sucrose fatty acid ester has an HLB value of 5 to 15.
Further, the preparation method of the Ketongding tincture comprises the following steps:
A) respectively crushing the raw materials except camphor and menthol, sieving the crushed raw materials by a No. 5 pharmacopeia sieve to obtain raw material fine powder, and uniformly mixing the raw material fine powder in parts by weight to obtain raw material mixed fine powder;
B) taking the mixed fine powder of the raw materials obtained in the step A, putting the mixed fine powder into an extraction kettle of a supercritical carbon dioxide extraction instrument with the specification of 1L, adding 50-200ml of entrainer, soaking for 1-2h, setting the temperature of the extraction kettle to be 30-50 ℃, the temperature of a separation kettle I to be 25-45 ℃, and the temperature of a separation kettle II to be 20-35 ℃;
C) opening a valve of a carbon dioxide gas tank, setting the flow of carbon dioxide to be 10-30L/min, setting the pressure of an extraction kettle to be 15-32MPa, the pressure of a separation kettle I to be 10-25MPa and the pressure of a separation kettle II to be 8-15MPa, and starting to perform circulating extraction when the temperature and the pressure of the extraction kettle reach required values for 2-5 hours;
D) collecting the extract, adding 750ml of ethanol with volume fraction of 55-65% and 450-.
The contact area between the medicinal materials and the supercritical fluid can be increased by pulverizing the medicinal materials into fine powder, and the extraction efficiency is improved. The 18 medicinal materials are extracted in the extraction kettle together, the effective components of each medicinal material are different, the extraction under the same condition is easy to cause incomplete extraction of the effective components of part of the medicinal materials, and the extraction rate of the effective components of the water-soluble, alkaloid and flavonoid glycoside traditional Chinese medicines can be improved by adding entrainer ethanol. Incidentally, the applicant surprisingly found that the extraction rate can be significantly improved by adding specific amounts of sucrose fatty acid ester and coconut oil fatty acid diethanolamide to the entrainer, and experiments prove that the extraction rate can be reduced by about 10% by singly using ethanol, without adding sucrose fatty acid ester or without adding coconut oil fatty acid diethanolamide. However, the mechanism of the two methods for improving the extraction rate is not clear, and the solubility of the active ingredient in the supercritical fluid may be improved. Dissolving the supercritical extract, camphor and menthol in 55-65% ethanol, and sealing and ultrasonic treating to accelerate the dissolution of the extract, camphor and menthol into a stable and uniform mixture.
Moreover, stability tests prove that the tincture for treating pain prepared by the method has no change in state, color and smell after being placed for 12 months at the temperature of 25 +/-2 ℃ and the relative humidity of 60 +/-10%, and the tincture for treating pain has good stability and can be placed for a long time. Meanwhile, the pain relieving tincture prepared by the method has obvious effect of relieving the gall. Experiments prove that the pain-relieving tincture prepared by the method has an extremely obvious inhibiting effect on mouse ear swelling caused by dimethylbenzene, and the inhibition rate of the pain-relieving tincture is increased by more than 25% compared with that of the pain-relieving tincture prepared by the traditional method; has extremely obvious inhibiting effect on the plantar swelling caused by hot plate scald of a mouse, and the inhibition rate of the kelong tincture prepared by the traditional method is increased by more than 20 percent.
The invention has the following advantages:
1) the pain relieving tincture has obvious effect, and the inhibition rate of the pain relieving tincture on swelling and pain is increased by more than 20% compared with the pain relieving tincture prepared by the traditional preparation method.
2) The preparation of the tincture for treating pain adopts supercritical fluid extraction, is convenient and simple, has short extraction time and high extraction efficiency, and can extract effective components in medicinal materials to the maximum extent.
3) The Ketongding tincture provided by the invention has good stability, and can still keep specific smell, is clear and transparent after stability test, and has no precipitate.
Detailed Description
The present invention will be described in further detail with reference to the following examples. It should not be understood that the scope of the above-described subject matter of the present invention is limited to the following examples.
The reagents used in the invention are all common reagents and can be purchased by reagent production enterprises.
Example 1A tincture for promoting blood circulation and relieving pain
An analgesic tincture for promoting blood circulation and relieving pain is prepared from the following raw materials in parts by weight: 19.5 parts of black tiger root, 11.7 parts of nutgrass galingale rhizome, 11.7 parts of cablin potchouli herb, 11.7 parts of black bean ginger, 8.0 parts of cortex periplocae, 7.8 parts of pepper, 7.8 parts of murraya paniculata, 7.8 parts of chicken bone, 7.8 parts of grassleaf sweelflag rhizome, 11.7 parts of galangal, 3.9 parts of zedoary, 3.9 parts of rhizoma sparganii, 1.2 parts of asarum, 2.0 parts of zanthoxylum nitidum, 1.2 parts of euonymus fortunei, 2.0 parts of dalbergia wood, 2.0 parts of baical skullcap root, 2.0 parts of cape jasmine fruit, 2.0 parts of camphor and 0.2.
The preparation method comprises the following steps:
A) respectively crushing the raw materials except camphor and menthol, sieving the crushed raw materials by a No. 5 pharmacopeia sieve to obtain raw material fine powder, and uniformly mixing the raw material fine powder in parts by weight to obtain raw material mixed fine powder;
B) taking the mixed fine powder of the raw materials obtained in the step A), putting the mixed fine powder into an extraction kettle of a supercritical carbon dioxide extraction instrument with the specification of 1L, adding 50ml of entrainer, soaking for 1.5h, setting the temperature of the extraction kettle to be 40 ℃, the temperature of a separation kettle I to be 30 ℃, and the temperature of a separation kettle II to be 20 ℃;
C) opening a valve of a carbon dioxide gas tank, setting the flow of carbon dioxide to be 25L/min, the pressure of an extraction kettle to be 30MPa, the pressure of a separation kettle I to be 20MPa and the pressure of a separation kettle II to be 10MPa, starting to perform circulating extraction after the extraction kettle reaches the required temperature and pressure, and setting the extraction time to be 4 hours;
D) collecting extract, adding 650ml of ethanol with volume fraction of 60% and the camphor and the menthol with the weight parts, and sealing and ultrasonically treating for 1h to obtain the traditional Chinese medicine.
The entrainer in the step B) is prepared from the following raw materials in percentage by mass: 8% of sucrose fatty acid ester (H LB ═ 7), 3% of coconut oil fatty acid diethanolamide and 89% of absolute ethyl alcohol.
Example 2A tincture for promoting blood circulation and relieving pain
An analgesic tincture for promoting blood circulation and relieving pain is prepared from the following raw materials in parts by weight: 16.0 parts of black tiger root, 12.0 parts of nutgrass galingale rhizome, 10.0 parts of cablin potchouli herb, 10.0 parts of black bean ginger, 7.0 parts of cortex periplocae, 8.0 parts of pepper, 8.0 parts of murraya paniculata, 5.0 parts of chicken bone, 10.0 parts of grassleaf sweelflag rhizome, 12.0 parts of galangal, 5.0 parts of zedoary, 5.0 parts of common burreed rhizome, 1.0 part of asarum, 3.0 parts of shinyleaf pricklyash root, 1.5 parts of eupolyphaga sinensis root, 3.0 parts of dalbergia wood, 3.0 parts of baical skullcap root, 2.0 parts of cape jasmine fruit, 3.0 parts of camphor and 0.2.
The preparation method comprises the following steps: the difference from example 1 is that the HLB value of sucrose fatty acid ester in example 2 is 5, and the rest of the parameters and operations are referred to in example 1.
Example 3A tincture for promoting blood circulation and relieving pain
An analgesic tincture for promoting blood circulation and relieving pain is prepared from the following raw materials in parts by weight: 20.0 parts of black tiger root, 8.0 parts of nutgrass galingale rhizome, 9.0 parts of cablin potchouli herb, 10.0 parts of black bean ginger, 10.0 parts of cortex periplocae, 9.0 parts of pepper, 8.0 parts of murraya paniculata, 7.0 parts of chicken bone, 7.0 parts of grassleaf sweelflag rhizome, 10.0 parts of galangal, 5.0 parts of zedoary, 4.0 parts of common burreed rhizome, 0.8 parts of asarum, 3.0 parts of shinyleaf pricklyash root, 1.5 parts of eupolyphaga sinensis rhizome, 4.0 parts of dalbergia wood, 3.0 parts of baical skullcap root, 3.0 parts of cape jasmine fruit, 3.0 parts of camphor and 0.2.
The preparation method comprises the following steps: the difference from example 1 is that the HLB value of sucrose fatty acid ester in example 3 is 10, and the rest of the parameters and operations refer to example 1.
Comparative example 1 Ketongding for promoting blood circulation and relieving pain
The difference from example 1 is that the entrainer of comparative example 1 is absolute ethanol and the rest of the parameters and operation refer to example 1.
Comparative example 2 Ketongding for promoting blood circulation and relieving pain
The difference from the example 1 is that the entrainer of the comparative example 2 is prepared from the following raw materials in percentage by mass: sucrose fatty acid ester (HLB ═ 7) 11% and absolute ethanol 89%, the rest of the parameters and the procedure refer to example 1.
Comparative example 3 Ketongding for promoting blood circulation and relieving pain
The difference from the example 1 is that the entrainer of the comparative example 3 is prepared from the following raw materials in percentage by mass: coconut oil fatty acid diethanolamide 11% and absolute ethanol 89%, the rest parameters and the operation refer to example 1.
Comparative example 4 Ketongding for promoting blood circulation and relieving pain
Comparative example 4 the same procedure as in example 1 was followed to prepare:
pulverizing the rest 18 medicinal materials except Camphora and Mentholum into coarse powder; then mixing the rest 16 medicinal materials except Camphora, Mentholum, Scutellariae radix and fructus Gardeniae, adding 80% ethanol, and sealing and soaking for 10 days; filtering the extractive solution, collecting filtrate, distilling the residue with steam, and collecting distillate; mixing the distillate and the filtrate, controlling alcohol content at 60%, adjusting to 400ml, adding Camphora, oleum Menthae Dementholatum, fructus Gardeniae and Scutellariae radix coarse powder in corresponding parts, stirring, sealing, soaking for 10 days, standing, and filtering.
Comparative example 4 is different from example 1 in that a tincture for treating pain was prepared by a conventional method.
Test example 1 measurement of extraction Rate
1. Test materials: the supercritical extracts prepared in examples 1 to 3 and comparative examples 1 to 3.
2. The test method comprises the following steps: the supercritical extracts prepared in examples 1 to 3 and comparative examples 1 to 3 were recorded and the extraction rate was calculated.
3. And (3) test results:
TABLE 1 measurement results of extraction ratio
Group of
|
Medicinal materials (g)
|
Extract (g)
|
Extraction ratio (%)
|
Example 1
|
125.85
|
33.10
|
26.3
|
Example 2
|
124.70
|
30.93
|
24.8
|
Example 3
|
125.50
|
32.50
|
25.9
|
Comparative example 1
|
125.85
|
17.24
|
13.7
|
Comparative example 2
|
125.85
|
22.13
|
17.6
|
Comparative example 3
|
125.85
|
19.38
|
15.4 |
As can be seen from Table 1, the extraction rates of examples 1-3 are all high, which indicates that the preparation method of the present invention can effectively extract the effective components of the medicinal materials, wherein the extraction rate of example 1 is the highest and is the best example of the present invention. While comparative examples 1-3 show a significant reduction in extraction yield, indicating that sucrose fatty acid ester and coconut oil fatty acid diethanolamide as entrainers can significantly improve extraction yield.
Test example 2 Effect of paraxylene on ear swelling in mice
1. Test materials: the tincture prepared in example 1 and comparative example 4.
2. Test subjects: NIH mice, SPF grade, body weight (20 ± 2) g.
3. The test method comprises the following steps:
30 mice were selected and randomly divided into 3 groups, namely a blank control group (60% ethanol), an example 1 group and a comparative example 4 group, and each group contains 10 mice. 0.03mL of xylene is uniformly applied to the right auricle of each mouse to cause inflammation, the left auricle is used as a control, and 0.04mL of corresponding liquid medicine is respectively applied to the right auricle 1min, 30min and 60min after causing inflammation. The mice were sacrificed by removing the cervical vertebrae 2h after the inflammation, the same part of the ears was cut off in equal area by a punch with a diameter of 8mm, and weighed by a precision electronic balance, and the difference between the weights of the left and right ears was taken as the swelling degree.
4. And (3) test results:
TABLE 2 Effect of tincture of pain on ear swelling in mice caused by Paralyne
Group of
|
Dosage (ml)
|
Quantity (only)
|
Swelling degree (mg)
|
Inhibition ratio (%)
|
Blank control group
|
0.04×3
|
10
|
15.2±3.9
|
—
|
EXAMPLE 1 group
|
0.04×3
|
10
|
6.5±4.3** |
57.24
|
Comparative example 4 group
|
0.04×3
|
10
|
10.5±4.5* |
30.92 |
Note: compared with the blank control group, the composition of the composition,**P<0.01,*P<0.05。
as can be seen from table 2, the tincture for treating myalgia prepared in example 1 has a very significant inhibitory effect on the swelling of mouse ears caused by xylene. In contrast, comparative example 4 showed a significant decrease in the rate of inhibition of ear swelling in mice by p-xylene.
Test example 3 Effect on mouse Hot plate Scald model
1. Test materials: the tincture prepared in example 1 and comparative example 4.
2. Test subjects: NIH mice, SPF grade, body weight (20 ± 2) g.
3. The test method comprises the following steps:
30 healthy mice were selected, half of each male and female, and randomly divided into 3 groups, namely a blank control group (60% ethanol), an example 1 group and a comparative example 4 group, and 10 mice in each group were selected. Before scald, the normal volume of the right hind foot of each group of mice is measured according to a capillary amplification measuring method, then the right hind foot sole of the mice is scalded by a constant temperature hot plate at 55 +/-0.5 ℃ for 30s, and 0.05mL of corresponding liquid medicine is respectively coated on the right hind foot sole of the mice 1min, 30min and 60min after scald. The volume of the right hind foot is measured 2h and 5h after the scald, and the difference between the volume of the front and the hind foot of the scald is taken as the swelling degree.
4. And (3) test results:
TABLE 3 Effect of Ketongding on mouse Hot plate Scald model
Note: compared with the blank control group, the composition of the composition,**P<0.01,*P<0.05。
as can be seen from table 3, the tincture for treating pain prepared in example 1 has a very significant inhibitory effect on hot plate scald-induced plantar swelling in mice. In contrast, comparative example 4 showed a significantly reduced rate of inhibition of hot plate scald injury to the foot sole of the mouse.
Test example 4 stability test of tincture for pain
1. Test materials: the tincture prepared in example 1 and comparative example 4.
2. The test method comprises the following steps: the tincture of Ketongcing prepared in example 1 and comparative example 4 was placed at 25 ℃. + -. 2 ℃ and 60%. + -. 10% relative humidity for 12 months, and sampled every 3 months, and the condition, color and smell of the tincture were intensively examined.
3. And (3) testing results:
TABLE 4 stability test results of Ketongding
As is clear from Table 4, in example 1, the state, color and smell were not changed and the stability was good after the storage for 12 months at a temperature of 25 ℃ C. + -. 2 ℃ and a relative humidity of 60%. + -. 10%. Comparative example 4 the tincture for treating pain prepared by the conventional method had a small amount of suspended substances at month 6, and the color and smell were changed to some extent, and even the tincture for treating pain became more precipitated brown solution at month 12, the smell was reduced, and the state was significantly different from that of month 0, indicating that the tincture for treating pain prepared by the conventional method was unstable.
Test example 5 skin irritation test
1. Test materials: the pain-relieving tincture prepared in example 1.
2. Test subjects: healthy rabbits were 4, weighing (2.1 + -0.2) kg, and half female and half male.
3. The test method comprises the following steps:
taking healthy rabbits, and removing hair on two sides of animal spine with 10% sodium sulfide solution 48h before administration, wherein the area of each side is about 50cm2After unhairing, 24h, the skin was examined for injury due to unhairing. The left and right sides of the same body are controlled by self, and the pain relieving tincture and 60% ethanol 2mL are respectively given to the left and right side unhairing areas. Twice a day, continuously administering for one week, and washing residual test medicine and 60% ethanol with warm water on day 8. Observing the condition of the administration site for 1h, 24h, 48h and 72h after removing the medicine respectively, and observing whether the applied site is hyperpigmented,Bleeding points, rough skin or thin skin, and the like, the occurrence and recovery of the disease and the time were recorded and scored according to Table 5.
TABLE 5 skin irritation response score
4. And (3) test results:
TABLE 6 Ketongding rabbit irritation test results (n ═ 4)
As can be seen from Table 6, in the observation period, the skin of the tested rabbit has no abnormal reactions such as erythema, edema and the like, no other poisoning symptoms are found, and the highest stimulation score is 0 at each observation time point in the test, so the skin stimulation test shows that the blood-activating and pain-relieving tincture has no stimulation to the whole skin.
The foregoing embodiments are merely illustrative of the principles and utilities of the present invention and are not intended to limit the invention. Any person skilled in the art can modify or change the above-mentioned embodiments without departing from the spirit and scope of the present invention. Accordingly, it is intended that all equivalent modifications or changes which can be made by those skilled in the art without departing from the spirit and technical spirit of the present invention be covered by the claims of the present invention.