Drug and preparation method thereof
Technical field
The present invention relates to drug fields, more particularly to drug and preparation method thereof.
Background technology
Hypertension is to continue the disease of hyperpiesia, can cause the diseases such as apoplexy, heart disease, hemangioma, kidney failure, high blood
Pressure is a kind of characterized by angiosthenia increases, can be functional with heart, blood vessel, brain and kidney and other organs or organic change
Systemic disease, it is divided into essential hypertension and secondary hypertension.There are many reason of hypertension incidence, can be divided into heredity
With two aspects of environment.In unused antihypertensive, systolic pressure >=139mmHg and/or diastolic pressure >=89mmHg, by blood
Hypertension is divided into 1,2,3 grades by voltage levels.Systolic pressure >=140mmHg and diastolic pressure<90mmHg is single-row for isolated systolic height
Blood pressure.Patient previously has history of hypertension, currently uses antihypertensive, although blood pressure is less than 140/90mmHg, should also examine
Break as hypertension.
By onset emergency and disease progression, chronic type and rapidly progressive type can be divided into, it is common with chronic type.Benign hypertension
It shows as:(1) early stage shows:How asymptomatic early stage is, finds that blood pressure increases when physical examination once in a while, fire is nervous, excited
Or the symptoms such as dizziness, headache, dim eyesight, tinnitus, insomnia, weak, absent minded are felt after fatigue, may be higher mental function
Caused by imbalance.Early stage blood pressure only temporarily increases, and is persistently increased with disease progression blood pressure, internal organs involvement.(2) brain shows:Head
Bitterly, dizzy common.Mostly due to excited, over fatigue, climate change or deactivated depressor and induce.The hurried raising of blood pressure.
Severe headache, vision disorder, Nausea and vomiting, twitch, stupor, transient hemiplegia, aphasia etc..(3) Cardiac Manifestation:In early days, the heart
Heart failure occurs for functional compensation, symptom unobvious, later stage, heart function decompensation.(4) kidney shows:Long-term hypertension causes
Renal arteriolosclerosis.When renal hypofunction, enuresis nocturna can be caused, contain albumen, cast and red blood cell in diuresis, urine.Urine concentrating power
Lowly, phenol red excretion and urea clearance obstacle.There is azotemia and uremia.(5) artery changes.(6) Fundus oculi changes.It is anxious
Into type hypertension:Also referred to as accelerated hypertension accounts for the 1% of high blood pressure, can suddenly be changed by chronic type from, also can onset.It dislikes
Property hypertension can be happened at any age, but be most common with 30-40 Sui.Blood pressure is significantly raised, and diastolic pressure is mostly in 17.3Kpa
More than (130mmHg), there are weak, the symptoms such as thirsty, diuresis.Eyesight declines rapidly, and there are retinal hemorrhage and exudation, Chang You in eyeground
Bilateral papilledema.There is albuminuria, blood urine and renal insufficiency rapidly.Also heart failure, hypertensive cerebral can occur
Disease and hypertensive crisis, disease progression rapidly more dies of uremia.
Telmisartan is a kind of novel blood-pressure drug, is that a kind of specific blood vessels Angiotensin Ⅱ receptor (AT1 types) is short of money
Anti-agent.It is high with AT1 receptor subtypes (known angiotensinⅡ action site) that Telmisartan substitutes angiotensin-ii-receptor
Compatibility combines.Telmisartan is in AT1 acceptor sites without any position agonist effect, Telmisartan selectivity and AT1 receptors
In conjunction with the combination is lasting.Decompression stabilization does not cause to cough.
Use the ethyl alcohol of high concentration, security risk higher in the preparation process of Telmisartan at present;And in process of production
Dust from flying, material loss is serious and is unfavorable for the health of operating personnel.In addition, tablet is yellow-white, treatment is not met
Standard requirement.
Therefore it provides a kind of telmisartan tablet and preparation method thereof has important practical significance.
Invention content
In view of this, a kind of drug of present invention offer and preparation method thereof.The formula and preparation method improve production effect
Rate reduces production hour, reduces testing cost, reduces production energy consumption, and concentration of alcohol is reduced to by 80%
27%, dosage is reduced to 56.5kg by 98.4kg, that is, reduces 42.58%.The higher fluidized drying of safety is used again, significantly
Reduce shop safety risk.Lactose dosage is increased, is used in combination microcrystalline cellulose to replace starch, and use particle drying to half
Whole grain when dry, greatly reduces dust from flying.Not only loss, but also protection operation room environmental sanitation had been reduced.In addition, also improving production
Quality:Remove starch in formula, so that tablet is become present milky from original yellow-white, more meet quality criteria requirements;
Remove povidone k30 (i.e. 80% ethanol solution of 7% povidone k30) in formula, uses 27% ethanol solution instead and be more conducive to drug
Release plays drug effect;Supplementary product consumption is reduced, piece weight (0.167g/ pieces → 0.162g/ pieces) is reduced, reduces dose.
In order to achieve the above-mentioned object of the invention, the present invention provides following technical scheme:
The present invention provides a kind of drugs, including Telmisartan and ethyl alcohol, and do not include povidone.
In some specific embodiments of the present invention, a concentration of 27% (v/v) of ethyl alcohol.
In some specific embodiments of the present invention, the drug further includes pharmaceutically acceptable auxiliary material;It is described can
The auxiliary material of receiving includes adhesive (pregelatinized starch, ethyl alcohol), filler (lactose, microcrystalline cellulose), disintegrant (carboxymethylstarch
Sodium), mixture more than one or both of lubricant (magnesium stearate).
The present invention some specific embodiments in, the auxiliary material include lactose, microcrystalline cellulose, carboxyrnethyl starch sodium,
Mixture more than one or both of pregelatinized starch or magnesium stearate.
In some specific embodiments of the present invention, in terms of mass parts, the drug includes following component:
In some specific embodiments of the present invention, in terms of mass parts, the drug includes following component:
The present invention also provides the preparation methods of the drug, include the following steps:
Step 1:95% ethyl alcohol is taken to be mixed to prepare the ethanol water that volumetric concentration is 27% with water;
Step 2:It takes 9~27 parts of lactose, microcrystalline cellulose, pregelatinized starch and the carboxyrnethyl starch sodium of recipe quantity, replace meter Sha
Smooth dry-mixed, the ethanol water for being 27% with volumetric concentration made from step 1 mixes, 1450~2850r/min shearings, granulation;
Step 3:Take material fluidized drying made from step 2, whole grain;It repeats the above steps;
Step 4:The magnesium stearate of material made from step 3 and recipe quantity and the carboxyrnethyl starch sodium of surplus are taken, is mixed, pressure
Piece, packing.
In some specific embodiments of the present invention, the dry-mixed time described in step 2 is 10~50min;The shearing
Time be 1~10min.
In some specific embodiments of the present invention, the temperature of fluidized drying described in step 3 is 30~90 DEG C, and the time is
10~50min.Preferably, the time of fluidized drying is 18~30min.
In some specific embodiments of the present invention, the time mixed described in step 4 is 1~30min.
The present invention provides a kind of drugs, including Telmisartan and ethyl alcohol, and do not include povidone.Production efficiency improves:
Every 2,000,000 foreshorten to 12h by 32h, and production hour reduces:Every 2,000,000 foreshorten to 48h by 128h;Testing cost reduces by 1/
2.Original formulation technique:Every batch of 1,000,000 is examined 1 time, and 2,000,000 need to detect 2 times;New Recipe:Every batch of 2,000,000 only needs to examine
It tests 1 time;Energy consumption reduces by 60.59%.Concentration of alcohol is reduced to 27% by the present invention by 80%, and dosage is reduced to by 98.4kg
54.08kg reduces 45.04%.The higher fluidized drying of safety is used again, greatly reduces shop safety risk.Increase
Added lactose dosage, microcrystalline cellulose be used in combination to replace starch, but use particle drying to it is half-dried when whole grain, greatly reduce powder
Dirt is flown upward.Not only loss, but also protection operation room environmental sanitation had been reduced.In addition, also improving product quality:Remove and forms sediment in formula
Powder makes tablet become present milky from original yellow-white, more meets quality criteria requirements;Remove povidone k30 in formula
(i.e. 80% ethanol solution of 7% povidone k30) uses 27% ethanol solution instead and is more conducive to drug release, plays drug effect;It reduces auxiliary
Expect dosage, reduce piece weight (0.167g/ pieces → 0.162g/ pieces), reduces dose.
Specific implementation mode
The invention discloses a kind of drug and preparation method thereof, those skilled in the art can use for reference present disclosure, suitably
Modified technique parameter is realized.In particular, it should be pointed out that all similar substitutions and modifications are for a person skilled in the art
It will be apparent that they are considered as being included in the present invention.The method of the present invention and application are carried out by preferred embodiment
Description, related personnel obviously can not depart from the content of present invention, in spirit and scope to method described herein and application into
Row change is suitably changed and is combined, to realize and apply the technology of the present invention.
Raw materials used, auxiliary material and reagent are available on the market in drug provided by the invention and preparation method thereof.
With reference to embodiment, the present invention is further explained:
Embodiment 1
2000000/batches
Formula:Telmisartan 40.00kg lactose 104.00kg microcrystalline cellulose 128.00kg carboxyrnethyl starch sodiums 20.00kg is pre-
95% ethyl alcohol 54.08kg purified waters 136.20kg of gelling starch 30.00kg magnesium stearates 2.00kg
Preparation method:1, claim to match:According to raw material principle after first auxiliary material, lactose, microcrystalline cellulose, pre- glue are weighed respectively according to formula
Change starch and carboxyrnethyl starch sodium (18kg), Telmisartan, is uniformly mixed;Weigh magnesium stearate and carboxyrnethyl starch sodium respectively again
(2kg), another device preserve.
2, adhesive is prepared:95% ethyl alcohol of formula ratio is uniformly mixed with purified water, that is, 27% ethanol solution is made.
3, it pelletizes, is dry:By above-mentioned material equal portions at 12 parts, every part of 26.67kg.Two parts of 53.34kg are taken to set wet granulation
In machine, be switched on dry-mixed 30min, and 27% ethanol solution 31.36kg, booting stirring and 1450r/min high speed shear 3min is added, goes out
Material is sieved with 20 mesh and is pelletized, and (half-dried) taking-ups of fluidized drying (65 DEG C of temperature of blowing) about 18min, with 18 mesh sieves, reboiling is dry
Dry (65 DEG C of temperature of blowing) about 30min (i.e. particle temperature rises to about 42 DEG C), takes out.Remaining 5 pots material are prepared with method, are added stearic
Sour magnesium and carboxyrnethyl starch sodium 2kg, set in three-dimensional mixer, mix 5min, take out, tabletting (theoretical piece weight 0.162g/ pieces), packaging
To obtain the final product.
4, tabletting, packaging:Be pressed into circle plain film of 0.162g/ pieces (theoretical value), it is aluminum-plastic packaged to obtain the final product.
Embodiment 2
1250000/batches
Formula:Telmisartan 25.00kg lactose 125.00kg microcrystalline cellulose 145.00kg carboxyrnethyl starch sodiums
95% ethyl alcohol 70kg purified waters 246.30kg of 10.00kg pregelatinized starch 15.00kg magnesium stearates 3.00kg.
Preparation method:1, claim to match:According to raw material principle after first auxiliary material, weighs lactose, microcrystalline cellulose, pregelatinated according to formula and form sediment
Powder and carboxyrnethyl starch sodium (9kg), Telmisartan are uniformly mixed;Magnesium stearate and carboxyrnethyl starch sodium (1kg) are weighed again, and another device is protected
It deposits.
2, adhesive is prepared:95% ethyl alcohol of formula ratio is uniformly mixed with purified water, that is, 27% ethanol solution is made.
3, it pelletizes, is dry:By above-mentioned material equal portions at 12 parts, every part of 26.58kg.Two parts of 53.16kg are taken to set wet granulation
In machine, be switched on dry-mixed 10min, and 27% ethanol solution 50.12kg, booting stirring and 2150r/min high speed shear 10min is added,
Discharging is sieved with 20 mesh and is pelletized, (half-dried) taking-ups of fluidized drying (30 DEG C of temperature of blowing) about 50min, with 18 mesh sieves, reboiling
Dry (30 DEG C of temperature of blowing) about 50min (i.e. particle temperature rises to about 43 DEG C), takes out.Remaining 5 pots material are prepared with method, are added hard
Fatty acid magnesium and carboxyrnethyl starch sodium 1kg, set in three-dimensional mixer, mix 30min, take out, tabletting (theoretical piece weight 0.258g/ pieces),
It packs to obtain the final product.
4, tabletting, packaging:Be pressed into circle plain film of 0.258g/ pieces (theoretical value), it is aluminum-plastic packaged to obtain the final product.
Embodiment 3
2750000/batches
Formula:Telmisartan 55.00kg lactose 80.00kg microcrystalline cellulose 90.00kg carboxyrnethyl starch sodiums 30.00kg
95% ethyl alcohol 30kg purified waters 105.56kg of pregelatinized starch 45.00kg magnesium stearates 1.00kg.
Preparation method:1, claim to match:According to raw material principle after first auxiliary material, weighs lactose, microcrystalline cellulose, pregelatinated according to formula and form sediment
Powder and carboxyrnethyl starch sodium (27kg), Telmisartan are uniformly mixed;Magnesium stearate and carboxyrnethyl starch sodium (3kg) are weighed again, and another device is protected
It deposits.
2, adhesive is prepared:95% ethyl alcohol of formula ratio is uniformly mixed with purified water, that is, 27% ethanol solution is made.
3, it pelletizes, is dry:By above-mentioned material equal portions at 12 parts, every part of 24.75kg.Two parts of 49.50kg are taken to set wet granulation
In machine, be switched on dry-mixed 50min, and 27% ethanol solution 22.50kg, booting stirring and 2850r/min high speed shear 1min is added, goes out
Material is sieved with 20 mesh and is pelletized, and (half-dried) taking-ups of fluidized drying (90 DEG C of temperature of blowing) about 10min, with 18 mesh sieves, reboiling is dry
Dry (90 DEG C of temperature of blowing) about 10min (i.e. particle temperature rises to about 45 DEG C), takes out.Remaining 5 pots material are prepared with method, are added stearic
Sour magnesium and carboxyrnethyl starch sodium 3kg, set in three-dimensional mixer, mix 1min, take out, tabletting (theoretical piece weight 0.1075g/ pieces), packet
It fills to obtain the final product.
4, tabletting, packaging:Be pressed into circle plain film of 0.1075/ (theoretical value), it is aluminum-plastic packaged to obtain the final product.Comparative example
1000000/batches
Formula:Telmisartan 20.00kg lactose 20.00kg starch 112.00kg carboxyrnethyl starch sodiums 10.00kg
95% ethyl alcohol 49.20kg purified waters 9.26kg of povidone k30 4.40kg magnesium stearates 1.00kg
Preparation method:1, claim match, be sieved:According to raw material principle after first auxiliary material, lactose, starch, carboxymethylstarch are weighed according to formula
Sodium, magnesium stearate, povidone k30 and Telmisartan (in addition to magnesium stearate, povidone k30) are uniformly mixed and cross 80 mesh sieve.
2, adhesive is prepared:80% ethyl alcohol that povidone k30, ethyl alcohol and purified water are configured to 7% povidone k30 is molten
Liquid;
3, it pelletizes, is dry:By above-mentioned material equal portions at 6 parts, every part of 27kg.Portion is taken to set in wet granulator, booting is mixed
10min is closed, the 80% ethanol solution 10.48kg of 7% povidone k30 is added, booting stirring 5min is cut until being opened simultaneously when 4min
Broken high speed gear switch shreds 1min, the sieve granulation of 20 mesh, 60 ± 5 DEG C of drying about 2h of baking oven, 18 mesh sieves, taking-up, remaining 5 pots material
It is prepared with method.Magnesium stearate is added, sets in three-dimensional mixer, mixes 30min, takes out, tabletting is packed to obtain the final product.
4, tabletting, packaging:Be pressed into round plain film (theoretical piece weight 0.167g/ pieces), it is aluminum-plastic packaged to obtain the final product.
Embodiment 4
1, cost reduction:
(1) production efficiency improves:Every 2,000,000 foreshorten to 12h by 32h
Original formulation technique:Every batch of 1,000,000 takes 2 days, and 2 batches 2,000,000 take 4 days (i.e. 4 days × 8h=32h);
New Recipe:Every batch of 2,000,000 takes 1.5 days (i.e. 1.5 days × 8h=12h).
(2) production hour reduces:Every 2,000,000 foreshorten to 48h by 128h
Original formulation technique:Every 2 batches 2,000,000,4 people take 4 days, that is, need 4 people × 4 day of working hour × 8h=128h);
New Recipe:Every batch of 2,000,000,4 people take 1.5 days, that is, need 4 people × 1.5 day of working hour × 8h=48h).
(3) testing cost reduces by 1/2:
Original formulation technique:Every batch of 1,000,000 is examined 1 time, and 2,000,000 need to detect 2 times;
New Recipe:Every batch of 2,000,000 need to only be examined 1 time.
(4) energy reduces:
Original formulation technique:Wet granulator:1/4h × 6 pot × 2 batch × 23kw=69.0kw
Former baking oven needs to use:6h × 2 × 2 batch × (36.45kw+12.45kw)=1173.6kw
Three-dimensional mixer:(1/6+1/6) h × 7.5kw=2.5kw
Air-conditioning system need to use 32h (wind cabinet 58.5kw+ handpiece Water Chilling Units 116.1kw)=32h × 152.6kw=5587.2kw
Energy consumption is total:6831.7kw (produces 2,000,000 power consumption)
New Recipe:Wet granulator:(30/60+3/60) h × 6 pot × 23kw=75.9kw
Boiling drier (18/60+30/60) h × 6 pot × 108.5kw=520.8kw
Three-dimensional mixer:5/60 × 7.5kw=0.625kw
Air-conditioning system:12h (wind cabinet 58.5kw+ handpiece Water Chilling Units 116.1kw)=2095.2kw
Energy consumption is total:2692.53kw (produces 2,000,000 power consumption)
Energy consumption reduces:(2692.53-6831.7)/6831.7 × 100%=-60.59%
2, security risk is reduced:
Concentration of alcohol is reduced to 27% by 80%, and dosage is reduced to 54.08kg by 98.4kg, that is, reduces 45.04%.Again
Using the higher fluidized drying of safety, shop safety risk is greatly reduced.
3, dust from flying is reduced:
Due to increasing lactose dosage, microcrystalline cellulose is used in combination to replace starch, but use particle drying to it is half-dried when it is whole
Grain, greatly reduces dust from flying.Not only loss, but also protection operation room environmental sanitation had been reduced.
4, product quality is improved:
(1) remove starch in formula, so that tablet is become present milky from original yellow-white, more meet quality standard and want
It asks.
(2) remove povidone k30 (i.e. 80% ethanol solution of 7% povidone k30) in formula, use 27% ethanol solution instead
More conducively drug release, performance drug effect.
(3) new Recipe reduces supplementary product consumption, reduces piece weight (0.167g/ pieces → 0.162g/ pieces), reduces dose.
Table 1
5 dissolution rate of embodiment detects
Telmisartan Tablets (20mg) dissolution detection method:
Source:State food pharmaceuticals administration general bureau national drug standards WS1-(X-081)-2011Z【It checks】Dissolution
Degree
(1) this product is taken, according to dissolution rate and drug release determination method (four the second methods of P121 of Chinese Pharmacopoeia version in 2015), with phosphorus
Hydrochlorate buffer solution (pH7.5) (takes potassium dihydrogen phosphate 13.6g, water 800ml is added to make dissolving, with 2mol/L sodium hydroxide solution tune
Save pH to 7.5, add water to 1000ml, shake up to get) 900ml be dissolution medium, rotating speed be 75 turns per minute, operate in accordance with the law, pass through
It at 30 minutes, taking solution appropriate, filters, precision measures subsequent filtrate 5ml, sets in 10ml measuring bottles, scale is diluted to dissolution medium,
It shakes up, according to UV-VIS spectrophotometry (four P38 of Chinese Pharmacopoeia version in 2015), extinction is measured at the wavelength of 296nm
Degree;It is another to take Telmisartan reference substance about 10mg, it is accurately weighed, it sets in 100ml measuring bottles, adds 0.005mol/L sodium hydroxide methanol molten
Liquid dissolves and is diluted to scale, shakes up, and precision measures 5ml, sets in 50ml measuring bottles, is diluted to scale with dissolution medium, shakes up, together
Method measures, and calculates every stripping quantity, and limit is the 80% of labelled amount, should meet regulation.
(2) this product is taken, according to dissolution rate and drug release determination method (four the second methods of P121 of Chinese Pharmacopoeia version in 2015), with
0.1mol/L hydrochloric acid solutions 900ml is dissolution medium, and rotating speed is 50 turns per minute, is operated in accordance with the law, when through 30 minutes, takes solution suitable
Amount, filtration, precision measure subsequent filtrate 5ml, set in 10ml measuring bottles, be diluted to scale with dissolution medium, shake up, according to ultraviolet-visible
Spectrophotometry (four P38 of Chinese Pharmacopoeia version in 2015) measures absorbance at the wavelength of 290nm;Separately take Telmisartan pair
It is accurately weighed according to product about 10mg, add dissolution medium to dissolve and be diluted to the solution containing about 10 μ g in every 1ml, shake up, is surveyed with method
It is fixed, every stripping quantity is calculated, limit is the 80% of labelled amount, should meet regulation.
2 Telmisartan Tablets 20mg dissolution rates of table detect initial data
2 Telmisartan Tablets 20mg dissolution rates of table detect initial data (Continued)
Batch number |
Dissolution rate (%) |
Batch number |
Dissolution rate (%) |
Batch number |
Dissolution rate (%) |
Batch number |
Dissolution rate (%) |
170701 |
97 |
170801 |
99 |
170904 |
97 |
171103 |
94 |
170702 |
97 |
170802 |
98 |
170905 |
98 |
171104 |
98 |
170703 |
96 |
170803 |
97 |
171001 |
98 |
171201 |
97 |
170704 |
95 |
170804 |
97 |
171002 |
99 |
171202 |
97 |
170705 |
98 |
170805 |
96 |
171003 |
99 |
171203 |
98 |
170706 |
97 |
170901 |
96 |
171004 |
99 |
—— |
—— |
170707 |
100 |
170902 |
96 |
171101 |
96 |
|
|
170708 |
99 |
170903 |
99 |
171102 |
97 |
|
|
3 Telmisartan Tablets 20mg dissolution rates of table detect initial data
Dissolution rate detects primary data analysis
△ 2013 is annual (original formulation technique):
73 batches are produced altogether
One, average value is calculated
Remove two maximum values (100%, 99%), remove two minimum values (89%, 90%)
Average value=6643/ (73-4)=96.27%
Two, standard deviation, variance are calculated
(1) arithmetic mean of instantaneous value is calculated
Arithmetic mean of instantaneous value=7021/73=96.18%
(2) standard deviation is calculated
Standard deviation sigma=2.3115
(3) variance is calculated
Variances sigma2=5.3430
△ 2015 is annual (new Recipe):
58 batches are produced altogether
One, average value is calculated
Remove two maximum values (101%, 101%), remove two minimum values (94%, 95%)
Average value=5300/ (58-4)=98.15%
Two, standard deviation, variance are calculated
(1) arithmetic mean of instantaneous value is calculated
Arithmetic mean of instantaneous value=5691/58=98.12%
(2) standard deviation is calculated
Standard deviation sigma=1.6970
(3) variance is calculated
Variances sigma2=2.8798
△ 2016 is annual (new Recipe):
62 batches are produced altogether
One, average value is calculated
Remove two maximum values (101%, 101%), remove two minimum values (94%, 95%)
Average value=5715/ (62-4)=98.53%
Two, standard deviation, variance are calculated
(1) arithmetic mean of instantaneous value is calculated
Arithmetic mean of instantaneous value=6106/62=98.48%
(2) standard deviation is calculated
Standard deviation sigma=1.6767
(3) variance is calculated
Variances sigma2=2.8113
△ 2017 (new Recipe):
62 batches are produced altogether
One, average value is calculated
Remove two maximum values (100%, 100%), remove two minimum values (94%, 94%)
Average value=5657/ (62-4)=97.53%
Two, standard deviation, variance are calculated
(1) arithmetic mean of instantaneous value is calculated
Arithmetic mean of instantaneous value=6045/62=97.50%
(2) standard deviation is calculated
Standard deviation sigma=1.4621
(3) variance is calculated
Variances sigma2=2.1377
△ data analyses
Table 4
Data above shows that not only batch increases 1 times, dissolution rate (drug release) mean value using after new formula, new process
At least increase by 1.28 percentage points, and the stability of drug-eluting greatly improves.
Explanation:Dissolution Value illustrates that drug release is better closer to 100%, and dissolution rate variance yields is smaller illustrates that drug is released
It is more steady to put curve, the more stable drug effect the more reliable.
The above is only a preferred embodiment of the present invention, it is noted that for the ordinary skill people of the art
For member, various improvements and modifications may be made without departing from the principle of the present invention, these improvements and modifications are also answered
It is considered as protection scope of the present invention.