CN107303395B - Pharmaceutical composition containing pronase and preparation method thereof - Google Patents

Pharmaceutical composition containing pronase and preparation method thereof Download PDF

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Publication number
CN107303395B
CN107303395B CN201610241579.XA CN201610241579A CN107303395B CN 107303395 B CN107303395 B CN 107303395B CN 201610241579 A CN201610241579 A CN 201610241579A CN 107303395 B CN107303395 B CN 107303395B
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pronase
sodium
pharmaceutical composition
acid
composition according
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CN107303395A (en
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卢迪
高莹
吴昀
赵焰平
周丽莹
刘亚男
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Beijing Tide Pharmaceutical Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K49/00—Preparations for testing in vivo
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2009—Inorganic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2095—Tabletting processes; Dosage units made by direct compression of powders or specially processed granules, by eliminating solvents, by melt-extrusion, by injection molding, by 3D printing

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  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Chemical & Material Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
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  • Inorganic Chemistry (AREA)
  • Medicinal Preparation (AREA)

Abstract

The invention discloses a new dosage form of a pronase-containing pharmaceutical composition, which simultaneously contains active ingredients of pronase and sodium bicarbonate, so that a patient can directly use the pharmaceutical composition.

Description

Pharmaceutical composition containing pronase and preparation method thereof
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pronase-containing pharmaceutical composition and a preparation method thereof.
Background
Gastroscopy is an important method for diagnosing upper gastrointestinal diseases, and as mucus is contained in the stomach, and saliva exists in the patient during the gastroscopy process, the endoscope is easily interfered by foam-like mucus in the esophagus and the stomach during the examination process, the visual field definition is reduced, and the detection of tiny focuses is not facilitated. Thereby increasing the missed diagnosis and misdiagnosis rate of diseases and prolonging the examination time. The diagnosis experience of early-stage gastric cancer in Japan is summarized by Yamaga pill, more than 50% of the early-stage gastric cancer is found to have no clinical symptoms, the diagnosis is mainly carried out by gastroscopy, but the detection rate of the early-stage gastric cancer in China is low, and has a larger difference with the detection rate of more than 50% of the early-stage cancer in Japan, wherein the meticulous degree of gastroscopy is an important factor influencing the detection of the early-stage gastric cancer. Therefore, the stomach preparation before examination is important, but because the stomach contains natural foam mucus, when the gastric mucosa is diseased, the mucus and foam in the stomach cavity are more, so that the examination effect is influenced, the small pathological changes and the atypical pathological changes are easy to miss diagnosis, and the stomach is repeatedly washed or attracted by saline, so that the examination time is prolonged, and the quality of the gastroscopy can be improved and the examination time can be shortened by orally taking an effective defoaming agent before the examination. Currently used anti-foaming agents are lidocaine mucilage, dyclonine, and pronase particles.
Lidocaine mucilage is also commonly used in domestic gastroscopy, and the medicine contains a certain amount of simethicone, but the function of eliminating foam in the stomach is not ideal. The dyclonine is used as a novel anesthetic for mucous membranes or skins, has quick response, deep strength and low toxicity, and is not easy to influence central nerves. The dyclonine foaming agent can reduce the surface tension of foam after entering the intestinal tract and encountering the foam, so that the foam can be rapidly broken. The edible essence and the sweetening agent contained in the dyclonine can reduce the rejection feeling of patients and reduce adverse reaction conditions such as nausea, vomiting and the like. Pronase is a proteolytic enzyme, can cut off gastric mucin peptide bond and effectively dissolve gastric mucus, improves gastroscopy visibility, and because it is stable and shows activity under the environment of pH 7-10, should take sodium bicarbonate as gastric acid neutralizer simultaneously, it is completely different with the mechanism of action of traditional defoaming agent, can really dissolve and remove gastric mucus, brings clearer vision for gastroscopy, improves the detectable rate of gastroscope to tiny pathological changes, especially early gastric cancer. Thus, an increasing number of people tend to use pronase particles for gastroscopy.
Currently, the commercially available pronase is granule, and 20000 units of pronase (1 bag) and 1g of sodium bicarbonate are added into 50-80ml of drinking water (20-40 ℃) 15-30min before gastroscopy, and are orally taken after shaking and dissolving, so the usage is troublesome and is not beneficial to patients. Therefore, the development of a new pronase dosage form is urgently needed in clinic, so that the medication method is improved, and the compliance of patients is improved.
Disclosure of Invention
Aiming at the defects of the prior art, the invention provides the pharmaceutical composition containing pronase and sodium bicarbonate, and the pharmaceutical composition is prepared into a solid preparation which can be directly used, thereby being greatly convenient for clinical medication of patients. The purpose of the invention can be realized by the following technical scheme:
a pharmaceutical composition containing pronase comprises active ingredients of pronase, acid source substance, alkali source substance, lubricant and other pharmaceutically acceptable excipients, wherein sodium bicarbonate in the alkali source substance of the composition is an essential ingredient, and the contents of other components in the composition are as follows:
9.24% -35.00% of pronase (specific gravity)
Sodium bicarbonate (proportion) 11.5% -68.14%
The acid source substance (specific gravity) is 12.28-25.9%
3.37-45.3% of alkali source substances (specific gravity) except sodium bicarbonate
The lubricant (specific gravity) is 1.47-9.50%.
The pronase pharmaceutical composition provided by the invention is rapidly disintegrated after being put into water, and the pH of the water solution is 7.0-10.0, preferably 7.5-9.5.
The acid source substance in the composition is selected from one or a mixture of more of anhydrous citric acid, tartaric acid, fumaric acid, malic acid and acidic amino acid, wherein the acidic amino acid can be aspartic acid or glutamic acid, and the dosage of the acidic amino acid is preferably 14.71-23.26% by weight; the alkaline source substance can also contain one or a mixture of more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium bicarbonate, calcium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate and basic amino acid besides the necessary component of sodium bicarbonate, wherein the basic amino acid can be lysine, arginine or histidine, and the dosage of the basic amino acid is preferably 5.00-44.10 percent.
The lubricant in the composition is selected from a water-soluble lubricant, a water-insoluble lubricant or a mixture of the water-soluble lubricant and the water-insoluble lubricant, wherein the water-soluble lubricant can be polyethylene glycol, sodium dodecyl sulfate, magnesium dodecyl sulfate, L-leucine, sodium benzoate, sodium oleate, sodium chloride, sodium acetate and boric acid, preferably the polyethylene glycol and the sodium dodecyl sulfate, the dosage of the water-soluble lubricant is controlled to be 1.0-6.50%, and can be further optimized to be 1.47-5.00%, and the water-insoluble lubricant can be magnesium stearate, talcum powder, silica gel micropowder, sucrose fatty acid ester, sodium stearate fumarate and fumed silica, wherein the dosage of the talcum powder, the silica gel micropowder, the sodium stearate fumarate and the fumed silica is preferably 0.47-3.00%, and can be further optimized to be 0.99-2.50%.
The pharmaceutical composition can also contain a filler, an adhesive, a foaming agent and the like, wherein the filler can be selected from lactose, mannose, sucrose, glucose, starch, microcrystalline cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, dextrin, sugar powder and the like, the dosage of the filler is 1.00-6.00%, and the adhesive can be selected from hydroxypropyl methylcellulose aqueous solution, polyvinylpyrrolidone ethanol (water) solution, olefine acid resin aqueous solution, starch slurry, ethanol, syrup, polyvinylpyrrolidone and polyvinyl acetate copolymer, isopropanol, ethanol solution of polyethylene glycol (12000-20000) or low molecular weight polyethylene glycol (4000-6000).
The composition can also be added with a proper amount of flavoring agent, sweetening agent, essence or pigment for improving the taste and enhancing the compliance of patients, wherein the flavoring agent can be selected from menthol, peppermint oil, artificial vanilla, cinnamon and various fruit flavors, the sweetening agent can also be aspartame, honey, fructose, acesulfame potassium and the like, and the flavoring agent with various flavors can also be added, such as lemon flavor, orange flavor and the like, wherein the total dosage of the flavoring agent, the sweetening agent, the essence or the pigment and other additives is not more than 3%.
The dosage form of the composition prepared by the invention is a solid preparation, and can be tablets, granules or capsules.
The invention can adopt a dry granulation process, a wet granulation process or a direct tabletting process to prepare the pronase solid preparation, wherein the wet granulation process can adopt an acid-base mixed granulation process, an acid-base separate granulation process and an acid-base mixed non-aqueous granulation process, the dry granulation process or the direct tabletting process is preferred to prepare the pronase preparation, and the water content of the composition prepared by the invention is lower than 3 percent because pronase is extremely sensitive to water.
Detailed Description
Example 1
Prescription:
Figure 902065DEST_PATH_IMAGE001
the preparation method comprises the following steps: the pronase, sodium bicarbonate, polyethylene glycol, gas phase silicon dioxide, dipotassium hydrogen phosphate and anhydrous citric acid with the prescription dose are put into a self-sealing bag, mixed evenly and tabletted directly.
Example 2
Prescription:
Figure 881523DEST_PATH_IMAGE002
the preparation method comprises the following steps: placing the formula amounts of pronase, sodium bicarbonate, polyethylene glycol, micropowder silica gel, lysine and anhydrous citric acid in a self-sealing bag, mixing uniformly, and directly tabletting.
Example 3
Prescription:
Figure 474309DEST_PATH_IMAGE003
the preparation method comprises the following steps: placing the pronase, the sodium bicarbonate, the sodium dodecyl sulfate, the fumed silica, the dipotassium hydrogen phosphate and the citric acid with the prescription dose into a self-sealing bag, uniformly mixing, and directly tabletting.
Example 4
Prescription:
Figure 931835DEST_PATH_IMAGE004
the preparation method comprises the following steps: the pronase, sodium bicarbonate, polyethylene glycol, talcum powder, anhydrous citric acid and sodium carbonate are put into a self-sealing bag according to the prescription dose, mixed evenly and tabletted directly.
Example 5
Prescription:
Figure 949470DEST_PATH_IMAGE005
the preparation method comprises the following steps: placing the formula amounts of pronase, sodium bicarbonate, sodium carbonate, micropowder silica gel, glutamic acid and polyethylene glycol into a self-sealing bag, mixing uniformly, and directly tabletting.
Example 6
Prescription:
Figure 77658DEST_PATH_IMAGE006
the preparation method comprises the following steps: placing the formula amounts of pronase, sodium bicarbonate, polyethylene glycol, sodium stearate fumarate, disodium hydrogen phosphate and citric acid in a self-sealing bag, mixing uniformly, and directly tabletting.
Example 7
Prescription:
Figure 407008DEST_PATH_IMAGE007
the preparation method comprises the following steps: uniformly mixing the formula amounts of pronase, sodium bicarbonate, aspartic acid, arginine, 0.0225g of polyethylene glycol and 0.0075g of fumed silica; pulverizing and sieving; mixing the sieved granules with the rest polyethylene glycol, fumed silica, and prescription amount of menthol, pigment, glucose, and lemon essence, and tabletting.
Example 8
Prescription:
Figure 684536DEST_PATH_IMAGE008
the preparation method comprises the following steps: uniformly mixing the formula amounts of pronase, sodium bicarbonate, dipotassium hydrogen phosphate, glutamic acid, 0.01g of polyethylene glycol and 0.015g of sodium stearate fumarate; pulverizing and sieving; mixing the sieved granules with the rest polyethylene glycol, fumed silica and artificial vanilla, pigment, sucrose and orange essence according to the prescription amount, and tabletting.
Example 9
Prescription:
Figure 415732DEST_PATH_IMAGE009
the preparation method comprises the following steps: uniformly mixing the formula amounts of pronase, sodium bicarbonate, dipotassium hydrogen phosphate, anhydrous citric acid, 0.01125g of polyethylene glycol and 0.0075g of micropowder silica gel; pulverizing and sieving; and uniformly mixing the sieved particles, the rest of polyethylene glycol, the gas phase silicon dioxide, the aspartame and the saccharin according to the prescription amount, and tabletting.
Comparative example 1
Prescription:
Figure 720680DEST_PATH_IMAGE010
the preparation method comprises the following steps: the pronase, sodium bicarbonate, polyethylene glycol, gas phase silicon dioxide, dipotassium hydrogen phosphate and anhydrous citric acid with the prescription dose are put into a self-sealing bag, mixed evenly and tabletted directly.
Comparative example 2
Prescription:
Figure 537327DEST_PATH_IMAGE011
the preparation method comprises the following steps: placing the formula amounts of pronase, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, sodium dodecyl sulfate and micro-powder silica gel into a self-sealing bag, uniformly mixing, and directly tabletting.
Comparative example 3
Prescription:
Figure 352967DEST_PATH_IMAGE012
the preparation method comprises the following steps: mixing the formula amounts of pronase, sodium bicarbonate, disodium hydrogen phosphate, aspartic acid, 0.0075g of polyethylene glycol and 0.0035g of magnesium stearate uniformly; pulverizing and sieving; and uniformly mixing the sieved granules, the rest polyethylene glycol and magnesium stearate and the menthol and glucose according to the prescription amount, and tabletting.
Test example 1
The samples prepared in examples 1 to 9 and comparative examples 1 to 3 were examined to examine the appearance and disintegration of the samples, the pH of the solution after disintegration, and the water content of the samples, and the results are shown in table 1.
TABLE 1 test results of appearance and disintegration of samples, pH of the solution after disintegration, and water content of the samples
Figure DEST_PATH_IMAGE013
The results in table 1 show that the solid preparation of pronase prepared by the invention has smooth surface, the tablet can be rapidly disintegrated in water and completely dissolved, the pH value after disintegration is in the activity range of the medicine pronase, the drug effect of pronase is ensured, the water content of the preparation is low, the prepared tablet can be stably stored for a long time, and the safety of medication is further ensured.
Test example 2 enzyme potency assay
Preparation of control solutions: an appropriate amount of tyrosine control product dried at 105 deg.C for 3 hr is precisely weighed, dissolved in 0.2mol/L hydrochloric acid solution, and diluted to obtain a solution containing 25 μ g of tyrosine per 1ml (fresh preparation).
Preparing a test sample stock solution: taking 0.5g of the product, accurately weighing, placing in a 100ml measuring flask, adding phosphate buffer solution (weighing 1.80g of monopotassium phosphate, 7.57g of anhydrous disodium hydrogen phosphate and about 500ml of water for dissolving, taking 0.035g of calcium acetate and 50ml of water for dissolving, mixing the two solutions, adding water to 1000ml for dissolving, dissolving and diluting to scale, shaking uniformly, accurately weighing 1ml, placing in a 100ml measuring flask, and adding phosphate buffer solution for diluting to scale.
Preparation of casein substrate solution: taking 1g of milk casein, precisely weighing, drying at 105 ℃ for 2 hours, and measuring the drying weight loss. Weighing 1.0g of milk casein in terms of dry product, adding 40ml of the phosphate buffer solution, heating in warm water to dissolve, cooling, adjusting pH to 7.4 with sodium hydroxide solution, adding 50ml of the phosphate buffer solution, shaking up, and preheating to 40 +/-1 ℃ for later use (fresh preparation).
The determination method comprises the following steps: precisely adding 1ml of a sample stock solution into 3 test tubes respectively, precisely adding 1ml of a casein substrate solution preheated to 40 +/-1 ℃ after preserving heat in a water bath at 40 +/-1 ℃ for 5 minutes, shaking up, timing, precisely reacting in the water bath at 40 +/-1 ℃ for 10 minutes, immediately precisely adding 2ml of a trichloroacetic acid solution (taking 1.63g of trichloroacetic acid, 2.72g of sodium acetate and 1.20g of glacial acetic acid, adding a proper amount of water for dissolving and diluting to 100 ml), shaking up, precisely placing in the water bath at 40 +/-1 ℃ for 20 minutes, filtering, and taking a subsequent filtrate as a sample solution. Precisely adding 1ml of the stock solution of the sample into 2 test tubes respectively, keeping the temperature in a water bath at 40 +/-1 ℃ for 5 minutes, precisely adding 2ml of trichloroacetic acid solution, shaking up, precisely adding 1ml of casein substrate solution preheated to 40 +/-1 ℃, shaking up, precisely placing in a water bath at 40 +/-1 ℃ for 20 minutes, filtering, and taking the subsequent filtrate as the blank solution of the sample.
Precisely measuring the above sample solution, blank solution of sample, reference solution, and 0.2mol/L hydrochloric acid solution 1ml respectively, placing into test tubes, precisely adding sodium carbonate solution (anhydrous sodium carbonate 4.24g, and water 100ml for dissolution) 5ml respectively, precisely adding Fulin test solution (1 → 3) 1ml, standing at 40 deg.C + -1 deg.C for 20 min, cooling to room temperature, performing ultraviolet-visible spectrophotometry (four parts of the Chinese pharmacopoeia 2015 0401) within 4 hr, and measuring absorbance of the above 4 solutions at 660nm wavelength (sequentially as A)1、A2、A3、A4) Calculated as follows:
per 1mg of streptokinase-containing protease activity (unit) = (A)1- A2）×Ws×ns×1000/（A3- A4) X W x n x 10 x 1/4 wherein: ws and W are respectively the sampling amount (g) ns of the reference substance and the sample to be tested, and n is the dilution times of the reference substance and the sample to be tested.
TABLE 2 results of enzyme potency test
Figure 515833DEST_PATH_IMAGE014
Note: the streptokinase-containing activity per 1mg should be 135-165 units.
The results in Table 2 show that the active substance pronase contained in the pronase preparation prepared by the invention can keep the effective activity of the pronase through enzyme titer determination, thereby ensuring the drug effect of the pronase preparation and the treatment effect of the drug.
Test example 3 stability test
The stability test determination method comprises the following steps: the product is taken to simulate to be packaged on the market (aluminum plastic packaging and medicinal drying agent are packaged into an aluminum plastic composite bag) according to the test method in the drug stability test guiding principle in the technical guiding principle of chemical drug stability research and the drug stability test guiding principle in the four departments of the national pharmacopoeia 2015 edition compiled by the State Committee, the product is placed in 60 +/-2 ℃ and RH75 +/-5% for continuous 0, 7, 14 and 21 days for sampling, the enzyme activity of the active ingredients in the preparation is inspected to change along with the time by adopting an enzyme titer determination method, and the result is shown in Table 3.
TABLE 3 stability test results
Figure DEST_PATH_IMAGE015
The percentage in Table 3 is the percentage of enzyme activity of the solid preparation of pronase. As can be seen from the data in Table 3, the pronase preparation prepared by the invention has good stability, solves the problems of easy deterioration and instability of the main drug due to moisture absorption and physicochemical properties, and the harsh test results show that the enzyme activity of the preparation prepared by the invention is reduced more slowly in the period of validity, thereby improving the effectiveness in clinical application.

Claims (10)

1. A pharmaceutical composition containing pronase, which contains pronase as an active ingredient, a disintegrating agent, a lubricant and other pharmaceutically acceptable excipients, and is characterized in that the composition contains sodium bicarbonate as an alkali source substance as an essential component, and the contents of other components in the composition are as follows:
9.24% -35.00% of pronase (specific gravity)
Sodium bicarbonate (proportion) 17.65% -66.67%
14.71 to 23.26 percent of acid source substance (specific gravity)
The alkali source substances (specific gravity) except sodium bicarbonate is 5.0-44.1%
1.47 to 5.00 percent of lubricant (specific gravity),
the water content of the composition is less than 3%;
and the pharmaceutical composition is a tablet.
2. The pronase-containing pharmaceutical composition according to claim 1, wherein the pronase pharmaceutical composition rapidly disintegrates after being placed in water, and the pH of the aqueous solution is 7.5 to 9.5.
3. The pronase-containing pharmaceutical composition according to claim 1, wherein the acid source is selected from the group consisting of citric acid anhydrous, citric acid, tartaric acid, adipic acid fumarate, malic acid, and acidic amino acids.
4. The pronase-containing pharmaceutical composition according to claim 1, wherein the alkaline source is selected from one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, calcium carbonate, disodium hydrogen phosphate, sodium dihydrogen phosphate, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, and basic amino acids.
5. The pronase-containing pharmaceutical composition according to any of claims 1-3, wherein the acid source is selected from the group consisting of citric acid anhydrous, acidic amino acids, citric acid.
6. The pronase-containing pharmaceutical composition according to any of claims 1-4, wherein the alkaline source is selected from the group consisting of dipotassium hydrogen phosphate, potassium dihydrogen phosphate, basic amino acids, sodium carbonate.
7. The pronase-containing pharmaceutical composition according to claim 1, wherein the lubricant is selected from water-soluble lubricant, water-insoluble lubricant or their mixture, the water-soluble lubricant is selected from one or more of polyethylene glycol, sodium dodecyl sulfate, magnesium dodecyl sulfate, L-leucine, sodium benzoate, sodium oleate, sodium chloride, sodium acetate and boric acid, and the water-insoluble lubricant is selected from one or more of magnesium stearate, talc, silica gel micropowder, sucrose fatty acid ester, sodium fumarate stearate, and fumed silica.
8. The pronase-containing pharmaceutical composition according to claim 1, wherein the composition comprises a filler, a binder or a foaming agent, wherein the filler is selected from lactose, mannose, sucrose, glucose, starch, microcrystalline cellulose, carboxymethyl cellulose, sodium carboxymethyl cellulose, dextrin or sugar powder, and the binder is selected from hypromellose aqueous solution, polyvinylpyrrolidone ethanol solution, olefine acid resin aqueous solution, starch slurry, ethanol, syrup, polyvinylpyrrolidone-polyvinyl acetate copolymer, isopropanol or ethanol solution of polyethylene glycol with molecular weight of 12000-20000, or polyethylene glycol with molecular weight of 4000-6000.
9. The pronase-containing pharmaceutical composition according to claim 1, wherein the composition comprises menthol, peppermint oil, artificial vanilla, cinnamon aspartame, honey, fructose or acesulfame potassium.
10. The pronase-containing pharmaceutical composition according to any of claims 1-9, wherein the composition is prepared by a direct compression process.
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Citations (1)

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Publication number Priority date Publication date Assignee Title
EP0958833A1 (en) * 1998-05-20 1999-11-24 Erasmus Universiteit Rotterdam Methods and means for preventing or treating inflammation

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0958833A1 (en) * 1998-05-20 1999-11-24 Erasmus Universiteit Rotterdam Methods and means for preventing or treating inflammation

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Title
"链霉蛋白酶用于胃镜检查前胃内黏液清洗的效果观察";杨静 等;《上海护理》;20150930;第15卷;摘要，第45页左栏最后1段 *

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