Menthol-camphor eutectic nanoemulsion in-situ gel preparation
Technical Field
The invention belongs to the field of pharmaceutical preparations, and particularly relates to a nasal nano-emulsion in-situ gel of a menthol crystal-camphor eutectic mixture and a preparation method thereof.
Background
The compound menthol nose drops is a common preparation for treating rhinitis sicca and atrophic rhinitis, and comprises the main active components of menthol and camphor with equal mass, and the solvent is liquid paraffin. The menthol selectively acts on the cold receptors of the mucous membrane to generate cold feeling, and the emission effect of the receptors can reduce vasoconstriction and edema, thereby relieving the uncomfortable feeling of inflammation. The camphor also has the function of stimulating cold receptors like menthol, and also has the functions of easing pain and relieving itching.
Menthol and camphor have been described as eutectic mixtures in the prior art, but menthol and camphor are used only as auxiliary materials and are generally used as carriers for topical application. Due to the change of properties such as microstructure after the menthol and the camphor form the eutectic, whether the menthol and the camphor form the eutectic and have the active function of the menthol and/or the camphor is unpredictable, so that the prior art does not prepare the menthol and the camphor used as active ingredients into the eutectic, and on the contrary, the menthol and the camphor tend to be prevented from forming the eutectic in the preparation process for the stability of the preparation and the controllability of the preparation process in the field.
The nano emulsion is also called microemulsion and is a homogeneous dispersion system which is formed by water, oil, surfactant and the like, has nanometer-scale particle size, is thermodynamically stable, isotropic, transparent or semitransparent. However, the nano-emulsion has high requirements on the property stability of the auxiliary materials and the active ingredients due to the nano-scale particles. The properties of the menthol and camphor eutectic are not fully revealed by the prior art in this field, in particular its stability, more particularly in the nanoemulsion, is not known to the skilled person, and therefore the skilled person would hardly expect nor would he expect the menthol and camphor eutectic as an oil phase of the nanoemulsion.
In situ gel, also called in vivo gel, refers to a semisolid or solid preparation formed by reversible transformation of dispersion state or conformation in response to external stimuli (change of temperature, pH value, ion species and concentration, illuminance and the like of an application site) at the application site after a high molecular material is applied in a solution or semisolid state. The preparation is widely applied to eye mucosa, nasal mucosa, oral mucosa, rectal mucosa, injection administration parts and the like. However, it is not uncommon in the art to prepare the nanoemulsion into the in-situ gel, and particularly in the process of preparing the gel, the gel components are very likely to generate various interactions with the active ingredient or the auxiliary material, so that the stability of the active ingredient or the preparation is influenced.
In addition, although the compound menthol crystal nasal drops have good treatment effect on rhinitis sicca and atrophic rhinitis, the original formula and process are backward, the existing administration mode is still directly administered through nasal drops, and the following defects mainly exist: 1) the original preparation contains a large amount of liquid paraffin (98%), which influences the transmucosal absorption of menthol and camphor; 2) a large amount of liquid paraffin in the original preparation causes the deviation and the change of the drug peak shape in the determination process, and the determination of the drug content is greatly interfered. 3) The original preparation is liquid with strong fluidity, has short detention time in the nasal cavity, causes the defects of low bioavailability and poor patient compliance caused by frequent use, and limits the development of the prescription to a certain extent; 4) the original preparation contains volatile camphor and menthol, and has unstable property. Therefore, the eutectic characteristics of the menthol crystal and the camphor in the prescription are utilized to prepare the nanoemulsion, and the nanoemulsion is further used as a nasal drop by combining the in-situ gel property, so that the prescription dosage of the original preparation is kept, and the characteristics of small particle size of the nanoemulsion, easy transmucosal absorption and long residence time of the gel preparation in a nasal cavity are simultaneously achieved, the defects of unstable storage and inaccurate content measurement of the original preparation can be overcome, the residence time of the medicine in the local nasal cavity and the permeation performance of the nasal mucosa can be obviously prolonged, and the improvement of bioavailability, the improvement of curative effect and the convenience for patients are facilitated.
Disclosure of Invention
The invention aims to prepare a nano-emulsion by taking a menthol-camphor eutectic mixture as an oil phase, and provides a nano-emulsion in-situ gel preparation for treating rhinitis sicca and atrophic rhinitis by combining with an in-situ gel preparation, so as to promote the transmucosal absorption of a medicament and prolong the detention time of the medicament in a nasal cavity, thereby reducing the administration times, and improving the curative effect and the compliance of patients.
The inventors have surprisingly found that menthol and camphor have better mucosal absorption after forming a eutectic mixture. In-vitro release and in-vitro transmucosal experiment show that the menthol-camphor (1: 1) eutectic nanoemulsion can improve the in-vitro release and in-vitro transmucosal effect by 3 times or more than 3 times when being compared with the original preparation in 100 min.
The present inventors have also surprisingly found that a eutectic of menthol and camphor can exist stably as an oil phase in a nanoemulsion. The nanoemulsion prepared by taking the eutectic as the oil phase is centrifuged for 30min at 20000 rpm, and the eutectic formed by the menthol and the camphor can stably exist as the oil phase in the nanoemulsion, which is shown in figure 6.
The inventors have more surprisingly found that the eutectic of menthol and camphor 3:1-1:1 (by weight) has better stability and is particularly suitable for use as the oil phase of a nanoemulsion. Preferably, menthol-camphor is most stable under 7:3 conditions.
The inventors have also surprisingly found that a nanoemulsion with a menthol-camphor eutectic as the oil phase has better stability when made into an in situ gel, and particularly compared with a nanoemulsion with a menthol-camphor eutectic as the oil phase, the inventors have found that the stability is improved by more than 40% through similar experimental studies in experimental example 2. Furthermore, when the average particle size of the nanoemulsion is about 135nm, the prepared in-situ gel has good stability, which can be seen in fig. 7.
The inventor also unexpectedly discovers that the nano-emulsion in-situ gel prepared by using tween 80 as an emulsifier, glycerin as a co-emulsifier, deacetylated gellan gum as a gel material and sodium alginate as a thickening agent has better stability. The inventor finds that the stability of the composition is obviously superior to that of the composition of other auxiliary materials through similar experimental research of experimental example 2.
Specifically, the invention relates to the following technical scheme:
a nasal nanoemulsion in situ gel, characterised by consisting of an active ingredient and a co-adjuvant, wherein the active ingredient consists of menthol and camphor, and the menthol and camphor form a eutectic which acts as the oil phase of the nanoemulsion, the co-adjuvant comprises an emulsifier, a gel material and water, and the active ingredient and co-adjuvant are by weight: 1-4 parts of eutectic, 1-10 parts of emulsifier, 0.4-23 parts of gel material and 63-97.6 parts of water.
The weight ratio of the menthol to the camphor is 3:1-1: 1.
Preferably, the weight ratio of the menthol to the camphor is 7: 3.
The auxiliary materials also comprise 1-5 parts of auxiliary emulsifier and 0.1-1 part of thickening agent.
The emulsifier is Tween 80, polyethylene glycol octyl phenyl ether and D-α-One or more of vitamin E polyethylene glycol succinate, polyoxyethylene castor oil, poloxamer 188 and lecithin.
The auxiliary emulsifier is one or a mixture of more of absolute ethyl alcohol, n-butanol, polyglycerol ester, propylene glycol, ethylene glycol, glycerol and polyethylene glycol 400.
The gel material is one or more of deacetylated gellan gum, carbomer P974, chitosan and poloxamer 407.
The thickener is one or more of carbomer, sodium alginate, hydroxypropyl methylcellulose, polyvidone, sodium carboxymethylcellulose, and methylcellulose.
The average particle size of the nanoemulsion is less than or equal to 200nm, the PI is less than 0.25, and the pH is neutral.
The average particle size of the nanoemulsion is approximately equal to 135 nm.
The in situ gel is in a fluid state in vitro and is converted to a gel having a viscosity greater than 5 pas in the nasal cavity.
More specifically, the purpose of the invention is realized by the following technical scheme:
the nasal nano-emulsion in-situ gel containing the menthol crystal-camphor eutectic mixture comprises the following components in percentage by mass: 1.0-4.0% of eutectic, 1.0-5.0% of emulsifier, 0.1-5% of co-emulsifier, 0.1-2.0% of gel material, 0.1-1% of thickening agent and the balance of water.
The preparation method of the menthol-camphor eutectic liquid adopts a grinding method, the eutectic liquid is colorless transparent liquid and fragrant in smell, and the prepared nano-emulsion is semitransparent liquid with opalescence.
The emulsifier is Tween 80, polyethylene glycol octyl phenyl ether, D-α-one or a mixture of vitamin E polyethylene glycol succinate, polyoxyethylene castor oil, poloxamer 188 and lecithin.
The auxiliary emulsifier is one or more of anhydrous alcohol, n-butanol, polyglycerol ester, propylene glycol, ethylene glycol, glycerol and polyethylene glycol 400.
The gel material is one or more of deacetylated gellan gum, chitosan, polyvidone and poloxamer 407;
the thickener is one or more of carbomer, sodium alginate, hydroxypropyl methylcellulose, sodium carboxymethylcellulose, and methylcellulose.
The preparation method of the eutectic nasal nano-emulsion in-situ gel comprises the following steps: taking the eutectic mixture as an oil phase, and uniformly mixing the oil phase with an emulsifier and a co-emulsifier; gradually adding water into the mixture, and uniformly performing vortex oscillation to prepare the nanoemulsion; adding the gel matrix into a certain amount of water to prepare a gel solution; adding the nanoemulsion into the gel solution, mixing uniformly, and adding water to full dose to prepare the nasal nanoemulsion in-situ gel of the eutectic mixture.
The nanoemulsion prepared by the method has the average particle size of about 200nm and the PI of less than 0.25.
In the application of the eutectic nasal nano-emulsion in-situ gel, the gel preparation is administrated through a nasal cavity in a nasal drop form, and is quickly converted into a gel state after being mixed with an artificial nasal liquid.
The invention has the beneficial effects that:
the invention comprehensively utilizes the technology of the nano-emulsion and the in-situ gel preparation, and the eutectic is prepared into the nano-emulsion, thereby greatly improving the dispersibility and the stability of the medicament, promoting the medicament to be absorbed through mucous membrane, and further preparing the in-situ gel liquid for nasal drip. The in-situ gel system is low-viscosity fluid in vitro, and the solution-gel phase transformation occurs under physiological conditions, so that the residence time of the preparation in the nose is prolonged, and the drug absorption is further improved.
The eutectic nasal nano-emulsion in-situ gel provided by the invention is still administrated in a nasal drop form according to the original method, but the preparation can be quickly subjected to phase transition and gelation in a nasal cavity after being administrated, so that the retention time of a medicine in a nasal mucosa is prolonged, the bioavailability of the medicine is increased, and the patient compliance is good. Compared with the common nasal drops and common gels, the invention has the following advantages: (1) the menthol-camphor eutectic mixture is directly used as an oil phase to prepare the nanoemulsion, the average grain diameter of the nanoemulsion is below 200nm, and the menthol and the camphor have good mucous membrane permeation promoting function and are beneficial to being absorbed through nasal mucous membranes; (2) the in-situ gel system carrying the nano-emulsion has low viscosity, can be instantly converted into gel after being dropped into a nasal cavity, obviously prolongs the detention time of the nasal cavity, reduces the use frequency, increases the compliance of a patient and is convenient to use; (3) the selected high molecular material emulsifier and auxiliary emulsifier and the like hardly have irritation and side effect on the nasal cavity; (4) the nasal drop is stable in storage at normal temperature and 4 ℃, and has uniform content.
Furthermore, the invention needs to be emphasized to remarkably improve the technology that 1) the invention greatly improves the absorption effect of the medicine through the mucous membrane while keeping basically the same medicine content, 2) the invention overcomes the defects that the medicine content in the compound menthol nasal drops (original preparation) is difficult to measure and is easy to be interfered by liquid paraffin, can easily establish a method for measuring the content of the medicine HP L C in the nano-emulsion gel, has the advantages of low detection limit and no interference by other substances, 3) the invention overcomes the defect that the original preparation is volatile in the placement process, and the nano-emulsion combines the gel technology to effectively solve the instability of the medicine in the prescription, 4) the invention overcomes the defects that the original preparation is easy to lose and has poor absorption under physiological conditions (in the nasal cavity), greatly improves the detention time of the medicine in the nasal cavity, can effectively reduce the administration frequency, improve the compliance of a patient, and has the specific effect as shown in figure 8.
The above advantages of the present invention will be further described with reference to the accompanying drawings and specific embodiments, but it is to be understood that the following specific embodiments are not intended to limit the invention, the scope of which is defined by the claims.
Drawings
Fig. 1 is a photograph of the nanoemulsion in situ gel of example 5 before and after mixing with an artificial nasal solution. Wherein A is the preparation of example 5 before adding the artificial nasal solution, and is in a flowing liquid state; b is the formulation of example 5 after the addition of artificial nasal fluid, measured as a gel with a viscosity greater than 5Pa · s.
Fig. 2 is a particle size distribution diagram and a TEM image of the nanoemulsion prepared in example 1.
Fig. 3 is a graph of the in vitro transmucosal release of the nanoemulsion in situ gel and compound menthol crystal nasal drops (original preparation group) in example 1. Wherein the menthol-camphor (1: 1) eutectic nanoemulsion has at least 3 times of in vitro transmucosal effect improvement compared with the original preparation.
Fig. 4 is the in vitro release profile of the nanoemulsion in situ gel and compound menthol crystal nasal drops (original preparation group) in example 1. Wherein the menthol-camphor (1: 1) eutectic nanoemulsion has at least 5 times higher in vitro release effect than the original preparation.
FIG. 5 is a H & E staining pathological section of the nanoemulsion in-situ gel and compound menthol nasal drops (original preparation group) in rat nasal mucosa irritation experiment in example 1. Wherein A is a nano-emulsion group, B is an original preparation group, and the nano-emulsion in-situ gel has lower irritation to nasal mucosa.
FIG. 6 is a graph of the stability of the nanoemulsion prepared by using the eutectic as the oil phase in example 1 after being centrifuged at 20000 rpm for 30 min. It can be seen that the nanoemulsion prepared by using the eutectic as the oil phase is centrifuged for 30min at 20000 rpm, and the eutectic formed by the menthol and the camphor can stably exist as the oil phase in the nanoemulsion.
FIG. 7 is a diagram showing the layering of the nanoemulsion in-situ gel with the particle size of 135nm prepared in example 7 and the nanoemulsion in-situ gel with the particle size of 465 nm prepared from the same auxiliary materials after centrifugation at 5000 rpm for 30min at 60 ℃. Wherein the particle diameter of A is 135nm, and the particle diameter of B is 465 nm.
Fig. 8 is a comparison of the nasal retention of the nanoemulsion in situ gel of example 1 and compound menthol nasal drops (raw formulation group). In the figure, A is an original preparation group, B is a nano-emulsion in-situ gel group, and the result of a small animal living body imaging experiment shows that the original preparation basically does not remain in the nasal cavity of a rat after 30min, the nano-emulsion in-situ gel is quickly converted into a gel form with higher viscosity after being dripped into the nasal cavity of the rat, and more remains after 240 min, which shows that the nano-emulsion in-situ gel can effectively prolong the retention time of a medicament in the nasal cavity.
Detailed Description
The technical solution of the present invention is further explained by embodiments in the following with reference to the accompanying drawings:
example 1:
weighing 2.00 g of eutectic mixture as an oil phase, adding 4.00 g of tween-80 and 2.00 g of glycerol, uniformly mixing, gradually adding 20m L of water into the mixture, uniformly mixing to prepare a nano-emulsion, adding 0.50g of deacetylated gellan gum into 50 m L of deionized water, adding 0.20 g of sodium alginate to prepare a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m L, and measuring the nano-emulsion in the system to be sample 1, wherein the specific parameters are shown in table 1.
Example 2:
weighing 1.00 g of eutectic mixture as an oil phase, adding 5.00 g of polyethylene glycol octyl phenyl ether and 5.00 g of propylene glycol, uniformly mixing, gradually adding 20m L of water into the mixture, uniformly mixing to prepare nano-emulsion, adding 22 g of poloxamer 407 into 50 m L of deionized water, adding 0.10 g of sodium carboxymethyl cellulose to prepare a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m L, and measuring the nano-emulsion in the system to be a sample 2, wherein the specific parameters are shown in table 1.
Example 3:
weighing 4.00 g of eutectic mixture as an oil phase, adding 5.00 g of polyoxyethylene castor oil and 5.00 g of polyethylene glycol 400, uniformly mixing, gradually adding 20m L of water into the mixture, uniformly mixing to prepare nano-emulsion, adding 0.4g of carbomer 974 into 50 m L of deionized water, adding 0.10 g of sodium carboxymethyl cellulose, adding the nano-emulsion into a gel solution, uniformly mixing, adding water to 100 m L, and obtaining the nano-emulsion marked as sample 3 in the system, wherein the specific parameters are shown in table 1.
Example 4:
weighing 2.50 g of eutectic as oil phase, adding 1.00 g D-αUniformly mixing vitamin E polyethylene glycol succinate and 3.00 g of n-butanol, gradually adding 20m L of water into the mixture, uniformly mixing to prepare a nano-emulsion, standing and dissolving 3.00 g of chitosan in 50 m L of water, adding 0.50g of polyvinylpyrrolidone, standing overnight to obtain a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m L, and measuring the nano-emulsion in the system to be a sample 4, wherein the specific parameters are shown in table 1.
Example 5:
weighing 3.00 g of eutectic mixture as an oil phase, adding 3.50 g of lecithin and 3.50 g of ethylene glycol, uniformly mixing, gradually adding 20m L of water into the mixture, uniformly mixing to prepare nano-emulsion, heating and dissolving 0.50g of deacetylated gellan gum in 50 m L of water, adding 0.50g of sodium alginate, standing overnight to obtain a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m L, and obtaining the nano-emulsion in the system, wherein the specific parameters are shown in table 1.
Example 6:
weighing 2.00 g of eutectic mixture as an oil phase, adding 5.33 g of tween 80 and 2.67 g of ethanol, uniformly mixing, gradually adding 20m L of water into the mixture, uniformly mixing to prepare nano-emulsion, dissolving 20 g of poloxamer 407 in 50 m L of water at 50 ℃ by heating, adding 0.30 g of polyvinylpyrrolidone, standing overnight to obtain a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m L, and obtaining the nano-emulsion in the system, wherein the specific parameters are shown in table 1.
Example 7:
weighing 4.00 g of eutectic mixture as an oil phase, adding 4.00 g of polyoxyethylene castor oil 2.00 g of polyglycerol ester, uniformly mixing, gradually adding 20m L of water into the mixture, uniformly mixing to prepare nano-emulsion, dissolving 0.60 g of carbomer P974 in 50 m L of water, adding 1.00 g of ethyl cellulose, standing overnight to obtain a gel solution, adding the nano-emulsion into the solution, uniformly mixing, adding water to 100 m L, and obtaining the nano-emulsion in the system, wherein the specific parameters are shown in table 1.
Example 8:
weighing 2.00 g of eutectic mixture as an oil phase, adding 3.00 g of poloxamer 188 and 2.00 g of propylene glycol, uniformly mixing, gradually adding 20m L of water into the mixture, uniformly mixing to prepare a nano-emulsion, dissolving 0.50g of deacetylated gellan gum in 50 m L of water at 90 ℃, adding 0.20 g of sodium alginate, standing overnight to obtain a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m L, and obtaining the nano-emulsion in the system, wherein the specific parameters are shown in table 1.
Example 9:
weighing 2.00 g of eutectic mixture as an oil phase, adding 5.33 g of Tween 80 and 2.67 g of propylene glycol, uniformly mixing, gradually adding 20m of L water into the mixture, uniformly mixing to prepare nano-emulsion, dissolving 20 g of poloxamer 407 in 50 m of L water at 50 ℃ by heating, adding 1.00 g of sodium carboxymethylcellulose, standing overnight to obtain a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m of L, and obtaining the nano-emulsion in the system, wherein the specific parameters are shown in table 1.
Example 10:
weighing 2 g of eutectic mixture as an oil phase, adding 1.00 g of Tween 80 and 2.00 g of glycerol, uniformly mixing, gradually adding 20m of L water into the mixture, uniformly mixing to prepare a nano-emulsion, dissolving 0.50g of deacetylated gellan gum in 50 m of L water at 90 ℃ in a water bath, standing to room temperature, adding 0.20 g of sodium alginate, standing overnight at 4 ℃ to obtain a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m of L, and measuring the nano-emulsion in the system to be a sample 10, wherein the specific parameters are shown in table 1.
Example 11:
weighing 3.00 g of eutectic mixture as an oil phase, adding 1.20 g of polyethylene glycol octyl phenyl ether and 0.60 g of glycerol, uniformly mixing, gradually adding 1.10 m of L water into the mixture, uniformly mixing to prepare a nano-emulsion, dissolving 0.60 g of deacetylated gellan gum in 50 m of L water under the condition of 90 ℃ water bath, standing to room temperature, adding 0.30 g of sodium alginate, standing overnight at 4 ℃ to obtain a gel solution, adding the nano-emulsion into the gel solution, uniformly mixing, adding water to 100 m of L, and measuring the nano-emulsion in the system to be a sample 11, wherein the specific parameters are shown in table 1.
Experimental example 1
Comparison experiment of dissolution effect or absorption effect of eutectic and non-eutectic
In vitro release, namely taking freshly prepared artificial nasal solution as a release medium, precisely measuring 4.0 m L compound menthol nanoemulsion gel liquid in a dialysis bag, placing the dialysis bag in a conical flask with a cover, adding 50 m L release medium at the rotating speed of 100 rpm (35 +/-0.5) DEG C, sequentially sampling at different time points, adding the release medium with the same volume, filtering by using a microporous membrane, and determining the content of the medicine by using HP L C.
And (3) a transmucosal absorption experiment, namely adding artificial nasal liquid (5% of Tween 80 and 5% of glycerol are added to achieve the condition of a medicament leakage groove) into a receiving pool by adopting a medicament transdermal diffusion tester, fixing the mucosa between a supply chamber and a diffusion chamber, balancing the mucosa in a water bath constant temperature oscillator with the temperature of 35 +/-0.5 ℃, uniformly covering the mucosa with 2.5 m L in-situ gel at the rotating speed of 300 rpm, sampling from the receiving pool at different time points respectively, adding the artificial nasal liquid with the same volume after each sampling, filtering by using a microporous filter membrane, and measuring the medicament content by using HP L C.
The results are shown in fig. 3 and 4, and it can be seen from the experimental results that menthol and camphor have better mucosal absorption effect after forming eutectic solution. In vitro release and in vitro transmucosal experiment show that the menthol-camphor (1: 1) eutectic nanoemulsion has at least 3 times of in vitro transmucosal effect improvement compared with the original preparation; the menthol-camphor (1: 1) eutectic nanoemulsion has at least 5 times higher in-vitro release effect than the original preparation.
Experimental example 2
Experiment of standing stability of eutectic mixtures with different proportions at 4 DEG C
The menthol-camphor eutectic mixtures with different ratios are placed at 4 ℃, and the time from the placement to the crystallization is observed, and the results are shown in table 2:
from the above experiments, it can be seen that the eutectic of menthol and camphor 3:1-1:1 (by weight) has better stability, and is particularly suitable for use as the oil phase of a nanoemulsion. Preferably, menthol-camphor is most stable under 7:3 conditions.
Experimental example 3
The inventors further examined the accelerated stability of the semi-finished nanoemulsions of samples 1 to 11 and example 1 prepared in examples 1 to 11.
Each sample was sealed in a glass bottle and left at (40. + -.2) ° C and relative humidity (75. + -.5)% to examine the time taken for the appearance of each sample to change (turbidity, floating, settling, etc.), and the results are shown in Table 3:
from the above results, it was found that the nanoemulsion having a menthol-camphor eutectic as an oil phase has better stability when made into an in-situ gel, and particularly, the stability is improved by more than 40% compared with the nanoemulsion having a menthol-camphor eutectic as an oil phase.
And the nano-emulsion in-situ gel prepared when the emulsifier is Tween 80, the co-emulsifier is glycerol, the gel material is deacetylated gellan gum and the thickener is sodium alginate has better stability.