CN110960682B - Method for enhancing drug load in molten state for long time after high pressure of pH-regulated gel - Google Patents
Method for enhancing drug load in molten state for long time after high pressure of pH-regulated gel Download PDFInfo
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
- A61K31/05—Phenols
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/335—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
- A61K31/365—Lactones
- A61K31/375—Ascorbic acid, i.e. vitamin C; Salts thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- A61K38/38—Albumins
- A61K38/385—Serum albumin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
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- A—HUMAN NECESSITIES
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- 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
- A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
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- 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
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/02—Nutrients, e.g. vitamins, minerals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P39/00—General protective or antinoxious agents
- A61P39/06—Free radical scavengers or antioxidants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P7/00—Drugs for disorders of the blood or the extracellular fluid
- A61P7/06—Antianaemics
Abstract
A method for enhancing drug loading by the length of time of a melting state of a pH-regulated gel after high pressure relates to the technical field of drug loading. Dissolving high ester pectin in PBS buffer solution, standing overnight at room temperature, heating in water bath, adding sucrose, reacting, pouring into soft food packaging bag, vacuum packaging, molding, taking out, and performing ultrahigh pressure treatment to obtain liquid gel; mixing with the specified medicine on a super clean bench, and stirring to obtain gel tablets; pouring the mixture into a tablet mold, standing for molding, and drying in a drying dish at room temperature to constant weight to obtain a gel sheet; and soaking the obtained gel sheet in the solution A for 5-10 s, quickly transferring the gel sheet to the solution B for 5-10 s, then transferring the gel sheet from the solution B to the solution A for 5-10 s, taking out the gel sheet after film coating, placing a tablet placing rack table, and completing the long-time enhancement of the drug load of the pH-regulated gel in a molten state after high pressure. The time of the pectin-sucrose gel in a melting state after ultrahigh pressure is prolonged by about 10 times, and the quality of the gel drug-loaded tablet is convenient to improve.
Description
Technical Field
The invention relates to the technical field of drug loading, in particular to a method for enhancing drug loading by regulating the length of time of a gel in a molten state after high pressure through pH.
Background
The ultrahigh pressure technology has excellent microbial inactivation effect in the aspect of food processing, can directionally improve the quality of food, and avoids the loss of food flavor brought by the traditional heat sterilization, and the technology is more and more applied to the aspect of food processing. The ultrahigh pressure treatment technology of the food is to treat the food by adopting pressure of 100-1000 MPa, and the influence degree of the ultrahigh pressure technology on molecules in the food mainly stays on the interaction of non-covalent bonds, and mainly relates to van der Waals force, hydrogen bonds, hydrophobic interaction and ionic bonds. The purpose of improving the food processing quality is achieved by ultrahigh pressure treatment and directional enhancement or weakening of intermolecular interaction and even the configuration of biomacromolecules.
Disclosure of Invention
The invention aims to solve the problems that pectin-sucrose gel subjected to ultrahigh pressure treatment has a high recovery speed, so that the medicine is difficult to disperse uniformly, the quality of eye drops seriously and the like, and provides a method for prolonging the time of the pectin-sucrose gel in a molten state after ultrahigh pressure and improving the time of the molten state of the pH regulation gel after high pressure in a medicine embedding operation space to enhance the medicine load.
The invention comprises the following steps:
1) dissolving high-ester pectin in PBS (phosphate buffer solution) with the pH value of 2.3-2.8, stirring, standing overnight at room temperature, heating a water bath kettle to 80-90 ℃, adding sucrose after the temperature is stable, pouring into a soft food packaging bag after reaction, carrying out vacuum packaging, and standing in a low-temperature refrigerator to obtain a formed pectin gel sample;
2) taking out the gel sample molded in the step 1), putting the gel sample into an ultrahigh pressure container for ultrahigh pressure treatment, and converting the gel state from a solid state to a molten state to obtain liquid gel;
3) taking the liquid gel obtained in the step 2), mixing the liquid gel with the specified medicine on a super clean bench according to a certain proportion, and stirring to obtain gel tablets;
4) pouring the sample obtained in the step 3) into a tablet mould for standing and forming, and then drying in a drying dish at room temperature to constant weight so as to dehydrate pectin gel to obtain a gel sheet;
5) soaking the gel sheet obtained in the step 4) in the solution A for 5-10 s, quickly transferring the gel sheet to the solution B for 5-10 s, then transferring the gel sheet from the solution B to the solution A for 5-10 s, taking out the gel sheet after film coating, placing a tablet placing table, and completing the process of regulating the gel pressure by pH, and then enhancing the drug load by the time length of a melting state; the preparation method of the solution A comprises the following steps: preparing a gellan gum aqueous solution in a high-temperature water bath, and cooling to room temperature for later use while stirring; the preparation method of the solution B comprises the following steps: the 3% acetic acid solution dissolves low concentration chitosan and low concentration calcium chloride.
In the step 1), the pH value of the PBS buffer solution is 2.6-2.8; the ratio of the high-ester pectin to the PBS buffer solution to the sucrose is (1.8-2.0): 45-50): 40-50); the high-ester pectin is food-grade high-ester pectin with an esterification degree of 50-80%, preferably high-ester pectin with an esterification degree of 66%; the high-ester pectin can be derived from citrus, grapefruit, apple, etc.; the sucrose is analytically pure or commercially available food grade; the reaction time can be 5-10 min; the low temperature refrigerator may be left for 24 hours.
In the step 2), the ultrahigh pressure treatment can be carried out for 8-10 min under the pressure of 550-650 MPa; the precision of the ultrahigh pressure treatment equipment is +/-10 MPa.
In the step 3), the specified medicine comprises various substances such as protein, microorganisms, polyphenol and the like, particularly heat-intolerant nutrient substances, and 20-50% of effective components can be prevented from being damaged by bypassing the heat treatment process of gel formation (ascorbic acid test); the stirring time can be 30-50 min; the stirring time is controlled within 50min to ensure that the gel structure is not destroyed while the medicine is dispersed uniformly.
In the step 5), the concentration of the gellan gum in the gellan gum aqueous solution can be 0.15-0.2%; the mass percentage concentration of the chitosan can be 0.4-0.6%, and the mass percentage concentration of the calcium chloride can be 2-4%.
The drug can be directly poured into a tablet mould without secondary ultrahigh pressure treatment after being embedded, and the drug-loading rate of each gel is the same (+/-1%) through later-stage drug release detection.
Compared with the prior art, the invention has the following outstanding advantages:
1. a pH buffer system is introduced in the primary gelling stage, so that the time of pectin-sucrose gel in a molten state after ultrahigh pressure is greatly prolonged by about 10 times, a great operation space is provided in the aspect of medicine mixing and dispersing, and the quality of gel drug-loaded tablets is conveniently improved.
2. After the process is optimized, the release rate of the medicine-carrying gel tablet treated by ultrahigh pressure is improved, and the proportion of structural water is increased.
3. The adjustable and controllable range of the pH is confirmed, the formation of gel and the state transition of the gel after the ultrahigh pressure treatment can be met, and the cost control and the subsequent improvement of the tablet quality are facilitated.
4. A method for improving the quality of the tablets through environmental conditions is explored and used for guiding the further optimization direction of the later process.
Drawings
FIG. 1 shows the appearance of pectin gel treated under ultrahigh pressure without introducing a pH adjusting system.
FIG. 2 is the appearance of pectin gel after the introduction of pH adjusting system and ultra-high pressure treatment.
FIG. 3 is a graph showing stability analysis of gels loaded with ascorbic acid at different melt states.
Fig. 4 is a graph of the rheological recovery kinetics of pectin gels at different pH.
FIG. 5 is a graph of the in vitro release kinetics of loaded pectin gels at various pH.
Fig. 6 is a graph of the two-stage thermogravimetric water loss of pectin gels at different pH.
Detailed Description
The following examples will further illustrate the present invention with reference to the accompanying drawings.
Example 1
A process for embedding resveratrol based on ultrahigh pressure melting gel comprises the following steps:
(1) preparing pectin gel: dissolving 1.8g of high ester pectin (food grade, esterification degree of 66%) in 48g of PBS buffer solution with pH of 2.3, stirring for 24h, heating to 80 deg.C in water bath, adding 50g of sucrose (analytically pure) after temperature is stabilized, pouring into soft food packaging bag after 8min, and vacuum packaging. And standing overnight in a low-temperature refrigerator for 24h for molding.
(2) Gel melting by ultrahigh pressure treatment: and (3) taking out the gel sample molded in the step (1), placing the gel sample into an ultrahigh pressure container, setting the processing pressure to be 600MPa, and processing for 8min to convert the gel state from a solid state to a molten state.
(3) Embedding of the drug: and (3) taking out the liquid gel obtained in the step (2), mixing the liquid gel with 100mg of resveratrol in an ultra-clean bench, and automatically stirring for 50min, wherein as shown in fig. 4, the upper limit of the operation time of medicine mixing depends on the pH value of the gel environment regulated by people, the pH value is too low, so that the storage modulus and the loss modulus are crossed prematurely and are solidified in advance, and the condition shown in fig. 3 is caused when the time after phase change is maintained is not enough, so that the medicine distribution is very uneven, and the quality of tablets is influenced.
(4) Tablet forming: and (4) pouring the sample obtained in the step (3) into a tablet mould, standing for 24h and forming.
(5) Dehydrating the gel sheet: and (5) drying the gel tablet obtained in the step (4) in a drying dish at room temperature to constant weight.
(6) Coating a film by pectin gel: solution A: preparing a gellan gum aqueous solution with a certain mass concentration in a high-temperature water bath, stirring and cooling to room temperature for later use, wherein the liquid B comprises the following components: the 3% acetic acid solution dissolves 0.4% chitosan and 2% calcium chloride. And (3) soaking the gel sheet obtained in the step (5) in the solution A for 5-10 s, quickly transferring to the solution B for 5-10 s, and then transferring from the solution B to the solution A for 5-10 s. Taking out and placing the tablet placing rack.
The resveratrol loaded at this time is a gastric treatment drug, the embedding condition is mild, the characteristics of the drug can be well protected, and meanwhile, as shown in fig. 5, the purpose of slowly releasing the drug in the gastrointestinal tract can be realized as far as possible by adjusting the pH, the period of the drug exerting the effect is prolonged, and the pH 2.3 has the best drug release performance.
Example 2
The process for melting gel embedded ascorbic acid based on ultrahigh pressure comprises the following steps:
(1) preparing pectin gel: dissolving 2.0g of high ester pectin (food grade, esterification degree of 66%) in 48g of PBS buffer solution with pH of 2.7, stirring for 24h, heating to 80 deg.C in water bath, adding 50g of sucrose (analytically pure) after temperature is stabilized, pouring into soft food packaging bag after 5min, and vacuum packaging. And (3) standing the mixture in a low-temperature refrigerator overnight for 24 hours, and forming, wherein the gel structure is compact as shown in figure 1.
(2) Gel melting by ultrahigh pressure treatment: and (3) taking out the gel sample molded in the step (1), placing the gel sample into an ultrahigh pressure container, setting the processing pressure to be 550MPa, and processing for 10min to convert the gel state from a solid state to a molten state.
(3) Embedding of the drug: dissolving 100mg ascorbic acid with 2ml deionized water, taking out the liquid gel obtained in step (2), mixing with ascorbic acid solution in a super clean bench, and automatically stirring for 50 min.
(4) Tablet forming: and (4) pouring the sample obtained in the step (3) into a tablet die, standing for 24h for molding, wherein as can be seen from fig. 2, the gel environment structure of the drug is greatly changed compared with the prior art, and the sucrose layer generates an obvious gathering phenomenon.
(5) Dehydrating the gel sheet: and (5) drying the gel tablet obtained in the step (4) in a drying dish at room temperature to constant weight.
(6) Coating a film by pectin gel: solution A: preparing a gellan gum aqueous solution with a certain mass concentration in a high-temperature water bath, stirring and cooling to room temperature for later use, wherein the liquid B comprises the following components: the 3% acetic acid solution dissolves 0.6% chitosan and 3% calcium chloride.
And (3) soaking the gel sheet obtained in the step (5) in the solution A for 5-10 s, quickly transferring to the solution B for 5-10 s, and then transferring from the solution B to the solution A for 5-10 s. Taking out and placing the tablet placing rack.
The ascorbic acid has important effects of preventing iron deficiency anemia, resisting oxidation, participating in collagen synthesis and the like, is usually absorbed by a human body in the intestinal tract in a large amount, is easily oxidized and decomposed, and can be effectively fixed and protected until being absorbed by the human body.
Example 3
A process for melting gel embedded Bovine Serum Albumin (BSA) based on ultrahigh pressure comprises the following steps:
(1) preparing pectin gel: dissolving 1.9g of high ester pectin (food grade, esterification degree of 66%) in 49g of PBS buffer solution with pH of 2.8, stirring for 24h, heating to 80 deg.C in water bath, adding 49g of sucrose (analytically pure) after temperature is stabilized, pouring into soft food packaging bag after 10min, and vacuum packaging. The mixture was left in a low temperature refrigerator overnight for 24 h.
(2) Gel melting by ultrahigh pressure treatment: taking out the gel sample molded in the step (1), placing the gel sample into an ultrahigh pressure container, setting the processing pressure to be 650MPa, and processing for 9min to convert the gel state from a solid state to a molten state.
(3) Embedding of the drug: and (3) taking out the liquid gel obtained in the step (2), mixing the liquid gel with 100mg of BSA in a super clean bench, and automatically stirring for 50 min.
(4) Tablet forming: and (4) pouring the sample obtained in the step (3) into a tablet mould, standing for 24h and forming.
(5) Dehydrating the gel sheet: and (5) drying the gel tablet obtained in the step (4) in a drying dish at room temperature to constant weight.
(6) Coating a film by pectin gel: solution A: preparing a gellan gum aqueous solution with a certain mass concentration in a high-temperature water bath, stirring and cooling to room temperature for later use, wherein the liquid B comprises the following components: the 3% acetic acid solution dissolves 0.5% chitosan and 4% calcium chloride.
And (3) soaking the gel sheet obtained in the step (5) in the solution A for 5-10 s, quickly transferring to the solution B for 5-10 s, and then transferring from the solution B to the solution A for 5-10 s. Taking out and placing the tablet placing rack.
BSA as an embedding material of protein can generate the mutual action in the aspects of hydrogen bond and the like with pectin gel, the diffusion speed is obviously limited in the in-vitro simulated digestion process, and the slow release effect is enhanced.
FIG. 6 shows the two-stage thermogravimetric water loss profile of pectin gels at different pH.
The gel system used in the invention is a pectin-sucrose system without other cross-linking substances, the pectin-sucrose is used as natural polysaccharide and disaccharide, has no toxic and harmful effects on organisms, and the pectin also has good biocompatibility and health care effect and is often used as a delivery carrier of human oral drugs. Traditional gels are largely divided into two major systems: chemical gels and physical gels, chemical gels refer to three-dimensional network structures formed by internal cross-linking of chemical bonds, and generally have no reversibility; the physical gel has a three-dimensional structure formed by crosslinking through hydrogen bonds, hydrophobic interaction and the like, and can realize reversible transformation in a gel process under certain conditions. For example, the pectin sucrose system gel in the invention is realized through the interaction of hydrogen bonds and hydrophobic properties, and through ultrahigh pressure treatment, after the pressure breaks through a threshold value, the interaction of the hydrogen bonds and the hydrophobic properties in the gel can be influenced to a certain extent, so that the purpose of converting the gel from a solid state to a liquid state is realized.
In the process of loading the medicine, because the liquid gel after pressure relief can be quickly recovered to the solid state, the mixed loading of the medicine is not facilitated, the medicine is easily dispersed unevenly, the quality of the tablet is influenced, and in order to solve the problem, the time for maintaining the gel in the liquefied state needs to be prolonged.
The invention is based on the application of the phenomenon of melting pectin gel under ultrahigh pressure in the aspect of drug embedding, and the situation of uneven distribution of embedded drugs is easily caused in the practical operation process of the application, so that the quality of tablets is reduced. The method comprises the steps of preparing pectin-sucrose gel under a buffer system, then melting the pectin gel under ultrahigh pressure, and finally embedding the medicine and coating a film. In the preparation stage of the pectin gel, the pH value of the environment for preparing the gel is regulated and controlled by introducing the buffer system, so that the time for maintaining the melting state of the gel after ultrahigh pressure treatment is prolonged by more than 10 times, the operation space of drug loading is greatly improved, the drug distribution is more uniform than that before optimization, no adverse effect is caused on the sustained release effect of the drug, and the quality of the gel tablet is effectively improved.
Claims (8)
1. A method for enhancing drug loading in a molten state for a long time after high pressure of a pH-controlled gel is characterized by comprising the following steps:
1) dissolving high-ester pectin in PBS (phosphate buffer solution) with the pH value of 2.3-2.8, stirring, standing overnight at room temperature, heating a water bath kettle to 80-90 ℃, adding sucrose after the temperature is stable, pouring into a soft food packaging bag after reaction, carrying out vacuum packaging, and standing in a low-temperature refrigerator to obtain a formed pectin gel sample;
2) taking out the gel sample molded in the step 1), putting the gel sample into an ultrahigh pressure container for ultrahigh pressure treatment, and converting the gel state from a solid state to a molten state to obtain liquid gel; the ultrahigh pressure treatment is carried out for 8-10 min under the pressure of 550-650 MPa; the precision of the ultrahigh pressure treatment equipment is +/-10 MPa;
3) mixing the liquid gel obtained in the step 2) with a specified medicine on a super clean bench according to a certain proportion, and stirring to obtain a mixture of the liquid gel and the medicine; the stirring time is 30-50 min; the stirring time needs to be controlled within 50min to ensure that the gel structure is not damaged while the medicine is dispersed uniformly;
4) pouring the mixture obtained in the step 3) into a tablet mould for standing and forming, and then drying in a drying dish at room temperature to constant weight so as to dehydrate pectin gel to obtain gel sheets;
5) soaking the gel sheet obtained in the step 4) in the solution A for 5-10 s, quickly transferring the gel sheet to the solution B for 5-10 s, then transferring the gel sheet from the solution B to the solution A for 5-10 s, taking out the gel sheet after film coating, placing a tablet placing table, and completing the process of regulating the gel pressure by pH, and then enhancing the drug load by the time length of a melting state; the preparation method of the solution A comprises the following steps: preparing a gellan gum aqueous solution in a high-temperature water bath, and cooling to room temperature for later use while stirring; the preparation method of the solution B comprises the following steps: the 3% acetic acid solution dissolves low concentration chitosan and low concentration calcium chloride.
2. The method for increasing the duration of drug loading in a high-pressure post-thaw state of a pH-controlled gel according to claim 1, wherein in step 1), the pH of the PBS buffer is 2.6-2.8.
3. The method for increasing drug load in the high-pressure post-melting state of the pH-controlled gel according to claim 1, wherein in the step 1), the ratio of the high-ester pectin to the PBS buffer to the sucrose is (1.8-2.0): 45-50): 40-50.
4. The method for enhancing drug loading of the pH-controlled gel according to claim 1, wherein in step 1), the high ester pectin is food-grade high ester pectin with an esterification degree of 50-80%; the high-ester pectin is derived from citrus, grapefruit or apple.
5. The method for increasing drug loading of pH-controlled gel during post-high pressure melt state according to claim 4, wherein the high ester pectin is a high ester pectin having a degree of esterification of 66%.
6. The method for enhancing drug loading according to claim 1, wherein in step 1), the sucrose is analytically pure or commercially available food grade; the reaction time is 5-10 min; the low-temperature refrigerator is placed for 24 h.
7. The method for controlling the duration of the high-pressure post-thawing state of the gel to enhance the drug loading according to claim 1, wherein in the step 3), the specified drugs comprise proteins, microorganisms and polyphenols, and 20-50% of the effective ingredients are prevented from being damaged by bypassing the heat treatment process of gel formation.
8. The method for increasing the drug load according to the length of time that the pH control gel melts after high pressure according to claim 1, wherein in the step 5), the concentration of gellan gum in the gellan gum aqueous solution is 0.15% to 0.2%; the mass percentage concentration of the chitosan is 0.4-0.6%, and the mass percentage concentration of the calcium chloride is 2-4%.
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