CN112851726A - Arbutin-carbamide eutectic crystal and preparation method, preparation and application thereof - Google Patents

Arbutin-carbamide eutectic crystal and preparation method, preparation and application thereof Download PDF

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CN112851726A
CN112851726A CN202110073418.5A CN202110073418A CN112851726A CN 112851726 A CN112851726 A CN 112851726A CN 202110073418 A CN202110073418 A CN 202110073418A CN 112851726 A CN112851726 A CN 112851726A
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强悠悠
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Abstract

The application relates to an arbutin-carbamide eutectic and a preparation method, a preparation and application thereof, wherein XRD characteristic diffraction peaks of the arbutin-carbamide eutectic appear at 8.379 degrees +/-0.2 degrees, 14.896 degrees +/-0.2 degrees, 16.734 degrees +/-0.2 degrees, 17.361 degrees +/-0.2 degrees, 22.402 degrees +/-0.2 degrees, 25.342 degrees +/-0.2 degrees, 31.018 degrees +/-0.2 degrees and 34.179 degrees +/-0.2 degrees; the preparation method comprises the following steps: putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): 1g of m (mixed powder) in a volume of 15mL, ultrasonically mixing at the temperature of 20-30 ℃ for 20-30min, continuously stirring at a constant speed for 20-30min at the rotation speed of 25-30rmp, finally reducing the rotation speed to 10-12rmp and the temperature to 5-10 ℃, continuously stirring at a constant speed for 10-15min, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying to obtain the arbutin-carbamide eutectic. The arbutin-carbamide eutectic provided by the application has good stability and improved solubility, and is beneficial to improving the bioavailability of arbutin drugs.

Description

Arbutin-carbamide eutectic crystal and preparation method, preparation and application thereof
Technical Field
The application belongs to the technical field of pharmaceutical co-crystals, and particularly relates to an arbutin-carbamide co-crystal, and a preparation method, a preparation and an application thereof.
Background
Arbutin, also known as arbutin, arbutin or myricitrin, is a skin whitening active substance which integrates the concepts of 'green', 'safe' and 'high efficiency' into a whole because it is originally derived from natural green plants. It can rapidly penetrate into skin, effectively inhibit tyrosinase activity in skin and block melanin formation while not affecting skin cell proliferation concentration, and accelerate melanin decomposition and excretion by combining with tyrosinase, thereby reducing skin pigmentation and removing mottle and freckle. It has no toxic side effect, irritation, sensitization, etc. on melanocyte, and also has the functions of moistening skin, healing wound, killing bacteria and resisting inflammation. The traditional Chinese medicine containing arbutin is commonly used for treating tracheitis, infectious urinary system diseases, skin diseases, allergy and inflammatory diseases.
Pharmaceutical co-crystals, or multicomponent crystals, are a new structure formed by self-assembly of co-crystal former (CCF) and pharmaceutical active ingredient (API) through hydrogen bonds, or non-covalent bonds with saturation and directionality (such as van der waals force of aromatic hydrocarbon or benzene ring, pi-conjugation and halogen bond), all of which are solid at normal temperature, and there is a fixed stoichiometric ratio between each component. The formation of hydrogen bonds or other non-covalent bonds in the pharmaceutical co-crystal structure does not change the properties of the molecule itself, nor does it destroy inherent covalent bonds within the molecule. The proper CCF and the API are selected to form the eutectic crystal, so that various physical and chemical properties and pharmaceutical properties of the medicament, such as melting point, solubility, bioavailability, hygroscopicity and chemical stability, can be changed to a great extent. Cocrystals enable a drug to be more in solid form, especially for amorphous, non-dissociative or low pKa active pharmaceutical ingredients, which is an important means of altering the solid form of a drug. In recent years, the eutectic technology becomes a new approach for drug development, and the synthesis and properties of the pharmaceutical cocrystal make the pharmaceutical cocrystal show attractive application prospects in the fields of pharmacology and biomedicine, but at present, almost no report about the pharmaceutical cocrystal of arbutin exists.
Disclosure of Invention
In order to solve the problems in the background art, the application provides an arbutin-carbamide eutectic crystal in a first aspect, which comprises arbutin and a eutectic ligand carbamide in a molar ratio of 1: 1; and the XRD characteristic diffraction peak of the arbutin-carbamide eutectic appears at 8.379 degrees +/-0.2 degree, 14.896 degrees +/-0.2 degree, 16.734 degrees +/-0.2 degree, 17.361 degrees +/-0.2 degree, 22.402 +/-0.2 degree, 25.342 +/-0.2 degree, 31.018 +/-0.2 degree and 34.179 +/-0.2 degree.
The second aspect of the application provides a preparation method of the arbutin-carbamide eutectic crystal, which comprises the following steps:
putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): 1g of m (mixed powder) in a volume of 15mL, ultrasonically mixing at the temperature of 20-30 ℃ for 20-30min, continuously stirring at a constant speed for 20-30min at the rotation speed of 25-30rmp, finally reducing the rotation speed to 10-12rmp and the temperature to 5-10 ℃, continuously stirring at a constant speed for 10-15min, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying to obtain the arbutin-carbamide eutectic.
As further explained in the present application, the preparation method of the arbutin-carboxamide eutectic preferably comprises the following steps:
placing mixed powder consisting of arbutin and carbamide in a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): and m (mixed powder) is 15mL and is 1g, ultrasonic mixing is carried out for 30min at the temperature of 25 ℃, uniform stirring is carried out for 30min at the rotation speed of 30rmp, the rotation speed is reduced to 12rmp, the temperature is reduced to 8 ℃, uniform stirring is carried out for 15min, standing is carried out for 24 h, the solvent is removed by rotary evaporation under reduced pressure, and drying is carried out to obtain the arbutin-carbamide eutectic crystal.
As a further illustration of the present application, the volume ratio of the water to the ethanol in the mixed solvent is 1: 1.
as a further illustration of the present application, the drying conditions are drying under vacuum pressure of 45Pa at a temperature of 55 ℃ for 1 h.
As a further explanation of the application, the ultrasonic mixing condition is ultrasonic power of 250W and ultrasonic frequency of 40 KHz.
In a second aspect, the present application provides a pharmaceutical preparation comprising the arbutin-carboxamide eutectic and a pharmaceutically acceptable excipient.
As further illustration of the application, the pharmaceutical preparation comprises the arbutin-carbamide eutectic and a proper amount of one or more auxiliary materials of lactose, starch, microcrystalline cellulose, talcum powder, magnesium stearate and 1% of sodium hydroxymethyl cellulose.
As a further illustration of the present application, the pharmaceutical preparation is one of arbutin tablet, arbutin capsule, arbutin pill, arbutin granule or arbutin powder.
The arbutin-carbamide eutectic can be prepared into antibacterial and anti-inflammatory medicines.
Compared with the prior art, the method has the following beneficial technical effects:
the application provides a brand new arbutin-carbamide eutectic, which solves the problems of poor stability and poor solubility of the existing arbutin and arbutin crystals, because the pharmaceutical eutectic is assembled by hydrogen bonds, or non-covalent bonds with saturation and directionality (such as Van der Waals force of aromatic hydrocarbon or benzene rings, pi-conjugate action and halogen bonds) to form a novel structure, and the formation of the hydrogen bonds or other non-covalent bonds in the pharmaceutical eutectic structure can not change the properties of molecules and can not damage inherent covalent bonds in the molecules, so the arbutin-carbamide eutectic obtained by the application can change the melting point, the solubility, the bioavailability, the chemical stability and the like of arbutin to a great extent; therefore, the arbutin-carbamide eutectic provided by the application has high solubility, is beneficial to improving the absorption efficiency of arbutin drugs and improving the bioavailability of the drugs.
The arbutin-carbamide eutectic provided by the invention has good stability and better solubility, and because the ultrasonic stirring dissolution and gradient cooling and speed reduction stirring conditions are adopted in the preparation process, and the adopted solvent is a mixed solvent of ethanol and water instead of a single solvent, the arbutin-carbamide eutectic has good crystallization effect, and finally an arbutin-carbamide eutectic medicine different from arbutin is obtained.
Compared with the common arbutin crystal form and arbutin, the arbutin-carbamide eutectic provided by the invention has a better antibacterial effect on escherichia coli, staphylococcus aureus, propionibacterium acnes and the like in air pollution such as haze and the like, and particularly has an obvious antibacterial effect on propionibacterium acnes, so that the arbutin-carbamide eutectic provided by the application has a better anti-inflammatory and antibacterial effect.
In conclusion, the arbutin-carbamide eutectic provided by the application has good stability, and compared with a crystal form in the prior art, the arbutin-carbamide eutectic has improved solubility, is beneficial to improving the bioavailability of arbutin drugs, and has important significance for improving the curative effect and safety of drugs.
Drawings
FIG. 1 is a representation diagram of X-ray powder diffraction analysis of arbutin-carbamide eutectic, arbutin and carbamide obtained in example 2 of the present application;
fig. 2 is a differential scanning calorimetry analysis characterization diagram of arbutin-carbamide eutectic, arbutin and carbamide provided in embodiment 2 of the application;
FIG. 3 is a Fourier transform infrared spectroscopy characterization chart of arbutin-carbamide co-crystal obtained in example 2 of the present application.
Detailed Description
In order to make the objects, technical solutions and advantages of the embodiments of the present application clearer, the technical solutions in the embodiments of the present application will be clearly and completely described below with reference to the drawings in the embodiments of the present application, and it is obvious that the described embodiments are some embodiments of the present application, but not all embodiments.
Thus, the following detailed description of the embodiments of the present application, presented in the accompanying drawings, is not intended to limit the scope of the claimed application, but is merely representative of selected embodiments of the application. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present application.
The technical solution of the present application will be explained with reference to specific embodiments.
Example 1
A preparation method of arbutin-carbamide eutectic comprises the following steps:
putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): m (mixed powder) is 15mL:1g, and the volume ratio of the water to the ethanol in the mixed solvent is 1: 1;
then ultrasonically mixing for 20min under the conditions of 20 ℃, ultrasonic power of 250W and ultrasonic frequency of 40KHz, continuously stirring for 20min at a constant speed under the condition of a rotating speed of 25rmp, finally reducing the rotating speed to 10rmp and the temperature to 5 ℃, continuously stirring for 10min at a constant speed, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying for 1h under the conditions of vacuum pressure of 45Pa and temperature of 55 ℃ to obtain the arbutin-carbamide eutectic crystal.
Example 2
A preparation method of arbutin-carbamide eutectic comprises the following steps:
putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): m (mixed powder) is 15mL:1g, and the volume ratio of the water to the ethanol in the mixed solvent is 1: 1;
then ultrasonically mixing for 30min under the conditions of 25 ℃, ultrasonic power of 250W and ultrasonic frequency of 40KHz, continuously stirring for 30min at a constant speed under the condition of a rotating speed of 30rmp, finally reducing the rotating speed to 12rmp and the temperature to 8 ℃, continuously stirring for 15min at a constant speed, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying for 1h under the conditions of vacuum pressure of 45Pa and temperature of 55 ℃ to obtain the arbutin-carbamide eutectic crystal.
Example 3
A preparation method of arbutin-carbamide eutectic comprises the following steps:
putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): m (mixed powder) is 15mL:1g, and the volume ratio of the water to the ethanol in the mixed solvent is 1: 1;
then ultrasonically mixing for 25min under the conditions of 30 ℃, ultrasonic power of 250W and ultrasonic frequency of 40KHz, continuously stirring for 25min at a constant speed under the condition of a rotating speed of 28rmp, finally reducing the rotating speed to 11rmp and the temperature to 10 ℃, continuously stirring for 12min at a constant speed, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying for 1h under the conditions of vacuum pressure of 45Pa and temperature of 55 ℃ to obtain the arbutin-carbamide eutectic crystal.
Example 4
A preparation method of arbutin-carbamide eutectic comprises the following steps:
putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): m (mixed powder) is 15mL:1g, and the volume ratio of the water to the ethanol in the mixed solvent is 1: 1;
then carrying out ultrasonic mixing for 27min under the conditions of 22 ℃, ultrasonic power of 250W and ultrasonic frequency of 40KHz, then continuing to stir at constant speed for 22min under the condition of the rotating speed of 25rmp, finally reducing the rotating speed to 11rmp and the temperature to 10 ℃, continuing to stir at constant speed for 12min, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying for 1h under the conditions of vacuum pressure of 45Pa and temperature of 55 ℃ to obtain the arbutin-carbamide eutectic crystal.
Example 5
A preparation method of arbutin-carbamide eutectic comprises the following steps:
putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): m (mixed powder) is 15mL:1g, and the volume ratio of the water to the ethanol in the mixed solvent is 1: 1;
then ultrasonically mixing for 23min under the conditions of 28 ℃, ultrasonic power of 250W and ultrasonic frequency of 40KHz, continuously stirring for 27min at a constant speed under the condition of a rotating speed of 27rmp, finally reducing the rotating speed to 12rmp and the temperature to 8 ℃, continuously stirring for 11min at a constant speed, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying for 1h under the conditions of vacuum pressure of 45Pa and temperature of 55 ℃ to obtain the arbutin-carbamide eutectic crystal.
Example 6
A preparation method of arbutin-carbamide eutectic comprises the following steps:
putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): m (mixed powder) is 15mL:1g, and the volume ratio of the water to the ethanol in the mixed solvent is 1: 1;
then carrying out ultrasonic mixing for 23min under the conditions of 24 ℃, ultrasonic power of 250W and ultrasonic frequency of 40KHz, then continuing to stir at constant speed for 26min under the condition of the rotating speed of 26rmp, finally reducing the rotating speed to 10rmp and the temperature to 7 ℃, continuing to stir at constant speed for 13min, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying for 1h under the conditions of vacuum pressure of 45Pa and temperature of 55 ℃ to obtain the arbutin-carbamide eutectic crystal.
The three samples of arbutin-carbamide eutectic, arbutin and carbamide obtained in the above example 2 are characterized, and the specific results are as follows:
(1) x-ray powder diffraction analysis
And (3) testing conditions are as follows: cu/k alpha (lambda is 1.5418nm) is used as a radiation source, the scanning speed and the step length are respectively 0.1s/step and 0.02 degrees, the scanning is carried out within the range of 5-50 degrees, and the working condition of a power supply is 40kV and 40 mA.
The results of X-ray powder diffraction analysis of three samples of arbutin, carbamide and arbutin-carbamide eutectic are shown in fig. 1, and it can be seen from the figure that characteristic peaks of arbutin are at 12.968, 18.407, 19.516 and 25.971 °, especially a strong peak at 25.971 °; characteristic peaks of the carbamide are 22.404, 29.529, 32.846, 35.689, 37.359, 45.631 and 49.590 degrees, and strong peaks are positioned at 22.404 degrees; the characteristic peaks of arbutin and carbamide in the arbutin-carbamide eutectic basically disappear, and new characteristic peaks appear at 8.379 degrees +/-0.2 degrees, 14.896 degrees +/-0.2 degrees, 16.734 degrees +/-0.2 degrees, 17.361 degrees +/-0.2 degrees, 22.402 +/-0.2 degrees, 25.342 +/-0.2 degrees, 31.018 +/-0.2 degrees and 34.179 +/-0.2 degrees, which indicates that the arbutin and the carbamide form the eutectic rather than the simple superposition of two substances.
(2) Differential scanning calorimetry
And (3) testing conditions are as follows: respectively weighing 10mg of arbutin and carbamide as reference substances in a blank crucible, weighing 10mg of arbutin-carbamide eutectic sample prepared in example 2, recording DSC curves of the three samples at 15-600 ℃ at a heating rate of 10 ℃/min under the protection of nitrogen, and collecting the DSC graphs on TA Q200.
As shown in FIG. 2, the melting point of arbutin is 198-; the melting point of the carbamide is 132.7 ℃, and a characteristic absorption peak appears at 140 ℃; in a DSC curve of the arbutin-carbamide eutectic, a characteristic peak of arbutin disappears, the strength of the carbamide peak is obviously reduced, and a new endothermic peak appears at about 117 ℃ and 187 ℃, and the result can further illustrate the existence of the eutectic and show that the melting point of arbutin is reduced due to the formation of the arbutin-carbamide eutectic.
(3) Elemental analysis:
instruments and drugs: 1 stage of vario EL III element analyzer; 1 computer with vario EL III program; CHNS model-aminobenzenesulfonic acid (Sul) standard sample; o mode-Benzoic Acid (ben) standard; example 2 the sample obtained.
Setting temperature of the heating furnace: CHNS mode: 1150 ℃ for Furnace 1 (right); 850 ℃ for Furnace 2 (therein); furnace3 (left): 0 ℃. An O mode: 1150 ℃ for Furnace 1 (right); 0 ℃ for Furnace 2 (the); furnace3 (left): 0 ℃.
CHNS mode: according to the use instruction of a vario EL III element analyzer, sequentially carrying out a blank test, a conditioning test, an aminobenzenesulfonic acid standard sample test, a sample obtained in example 2 and the aminobenzenesulfonic acid standard sample test;
an O mode: according to the use instruction of the vario EL III element analyzer, a blank test, a conditioning test, a benzoic acid standard sample test, the sample obtained in the example 2 and the benzoic acid standard sample test are carried out in sequence.
The final results were: elemental analysis (C12H16O7 · CH4N 2O): 50.03 percent of C; 0.06 percent of H; 0.10 percent of N; 0.43 percent of O; (theoretical: C50.00%; H0.06%; O0.41%; N0.09%) has a molecular weight of 329.23.
(4)IR(KBr，cm-1) And (3) analysis:
the eutectic prepared in the embodiment 2 of the application is subjected to KBr tabletting method to measure infrared spectrum, Shimadzu Fourier transform infrared spectrometer, Shimadzu FTIR-8400; the infrared spectrum analysis result is shown in figure 3, and in the infrared spectrum, 3370cm appears-1Absorption peak of hydroxyl group (b); 1750cm-1And 1512cm-1Typical absorption peaks of benzene ring(s); 1622cm-1And 1463cm-1Deformation vibration of NH at (b); 1680cm-1Stretching vibration of carbonyl group; 1223cm-1Stretching vibration of carbon-hydrogen bond in Ar-O bond; 1085cm-1And 1045cm-1Characteristic absorption of the acetal bond C-O-C; 8955cm of pyran ring representing glucose-1Bending vibration of point C1-H; 831cm-1Bending vibration of p-substituted benzene; thus, the co-crystal contains arbutin and carbamide at the same time.
(5) And (3) moisture determination:
the water content of the eutectic sample obtained in example 2 was 0.23% as measured by the Karl-Fischer method, and the theoretical water content was 1.9% if the substance was a monohydrate, and it can be seen from the water content result that the eutectic sample obtained in example 2 did not contain crystal water, was not a hydrate, and the water content thereof was only adsorbed water.
(6) HPLC determination of component content:
reagent: arbutin and carbamide (urea), w is more than or equal to 99.0 percent;
the instrument comprises the following steps: agilent 1260 high performance liquid chromatograph;
chromatographic conditions are as follows: ZORBAX SB-C18Columns (4.6 mm. times.250 mm, 5 μm); the column temperature is 25 ℃; mobile phase: phosphate buffer (containing 0.05mol/L phosphoric acid)Potassium dihydrogen, 0.01mol/L sodium dodecyl sulfate, 1% acetic acid and 0.4% triethylamine, pH adjusted to 3.0 with phosphoric acid) -methanol (50: 50); the flow rate is 1 mL/min; detection wavelength: 235 nm; sample introduction amount: 20 μ L.
And (3) detecting a mixed reference substance: taking an appropriate amount of arbutin reference substance and carbamide reference substance, dissolving with a small amount of phosphate buffer solution (0.2mol/L sodium dihydrogen phosphate solution-0.2 mol/L disodium hydrogen phosphate solution (39: 61), diluting with a mobile phase to prepare solutions containing 1mg of arbutin and carbamide in each 1ml, thus obtaining mixed reference substance solutions, injecting 10 mu L of the mixed reference substance solutions into a liquid chromatograph under the conditions, recording a chromatogram, completely separating arbutin and carbamide peaks under the chromatographic conditions, and calculating the theoretical plate number according to the arbutin peak to be not less than 3000.
And (3) testing the test article: accurately weighing 100mg of the sample in the embodiment 2 and the external standard respectively, placing the sample in a 200ml measuring flask, adding a mobile phase for dissolving and diluting the sample into 1ml of solution containing 1mg of the sample to be detected, accurately weighing 10 mu L of the solution, injecting the solution into a liquid chromatograph under the conditions, and calculating by peak area according to an external standard method to obtain the sample in the embodiment 2, wherein each mg of the sample contains arbutin and carbamide respectively 794.6 mu g and 174.1 mu g, and the molar ratio of arbutin to carbamide is 1.007: 1.
the above measurement results show that the arbutin-carbamide eutectic prepared in example 2 of the present application contains arbutin-carbamide eutectic with a molar ratio of 1:1 arbutin and carbamide.
The X-ray powder diffraction analysis of the arbutin-carbamide eutectic samples obtained in the above examples 1 and 3-6 can obtain the same result as the X-ray powder diffraction analysis obtained in the example 2, which shows that the arbutin-carbamide eutectic can be obtained by the preparation methods provided in the examples 1 and 3-6.
Comparative example 1
The arbutin-carbamide eutectic and the pure arbutin prepared in the embodiment 2 are respectively treated with the drug with the pH value of 1.8
Figure BDA0002906721550000081
SGF (simulated artificial gastric juice), FaSSIF (artificial intestinal juice in a fasting state) with pH of 6.5 is prepared into a saturated solution, and the content of a sample in the saturated solution is determined by a High Performance Liquid Chromatography (HPLC) method after 1 hour and 4 hours.
The results of the experiment are shown in the table above:
as can be seen from the above table, the arbutin-carboxamide eutectic obtained in example 2 of the present application has significantly higher solubility than arbutin after being placed in SGF and FaSSIF for 1 hour and 4 hours.
Example 7
A preparation method of a combined medicine tablet uses the pure arbutin-carbamide eutectic product prepared in example 2 as a raw material medicine of a combined medicine, uses the following excipients as auxiliary ingredients for preparing the combined medicine tablet, and prepares a tablet sample with the medicine content of 10-200 mg in each tablet according to a certain proportion, and the proportion of the formula of the tablets is given in the following table:
Figure BDA0002906721550000091
the preparation process of the tablet is as follows: mixing the excipient in the above table with pure arbutin-carbamide eutectic crystal, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into soft material, sieving, granulating, oven drying, sieving, grading, adding magnesium stearate and pulvis Talci, mixing, and tabletting.
Example 8
A preparation method of a combined medicine capsule uses the arbutin-carbamide eutectic pure product prepared in example 2 as a raw material medicine of a combined medicine and uses the following excipients as auxiliary ingredients for preparing the combined medicine capsule, and each capsule sample with the medicine content of 10-200 mg is prepared according to a certain proportion, and the proportion of the formula of the capsules is given in the following table:
Figure BDA0002906721550000092
Figure BDA0002906721550000101
the preparation process of the capsule comprises the following steps: mixing excipient and pure arbutin-carbamide eutectic crystal, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into wet granules, oven drying, sieving, grading, adding magnesium stearate, mixing, and making into capsule; or directly mixing pure arbutin-carbamide eutectic with several excipient adjuvants, sieving, and directly encapsulating without granulating.
Example 9
A preparation method of combined medicine powder uses the pure arbutin-carbamide eutectic product prepared in example 2 as a raw material medicine of a combined medicine, uses the following excipients as auxiliary material components for preparing the combined medicine powder, powder samples containing 10-200 mg of medicine are prepared according to a certain proportion, and the proportion of the formulas of the powder is given in the following table:
Figure BDA0002906721550000102
the preparation process of the powder is as follows: mixing the excipient in the above table and pure arbutin-carbamide eutectic crystal uniformly, adding appropriate amount of 1% sodium carboxymethylcellulose solution, making into wet material, oven drying, grinding, pulverizing, and sieving.
The administration dosage requirements of the arbutin-carbamide eutectic combined pharmaceutical preparation prepared in the above examples 7-9 are as follows:
administration dose 1 (tablet) of arbutin-carbamide eutectic combination drug:
the arbutin-carbamide eutectic is used as the active ingredient of the medicine, the daily administration dosage is 30mg, and the arbutin-carbamide eutectic can be respectively prepared into 1 tablet of 10mg common tablets 3 times a day, 2 times a day, 1 tablet of 15mg common tablets or 1 tablet of 30mg tablet types 1 time a day.
Administration dose 2 (capsule) of arbutin-carbamide eutectic combination drug:
the arbutin-carbamide eutectic is used as the active ingredient of the medicine, the daily administration dosage is 60mg, and the arbutin-carbamide eutectic can be respectively prepared into 1 capsule with 30mg for 1 capsule for 1 time and 1 capsule with 60mg for 1 time.
Administration dose 2 (powder) of arbutin-carbamide eutectic combined medicine:
the arbutin-carbamide eutectic is used as the active ingredient of the medicine, the daily administration dosage is 60mg, and the medicine can be prepared into powder of 60mg 1 bag 1 time per day.
It should be noted that: the arbutin-carbamide eutectic combined pharmaceutical preparation provided by the application has many factors on the administration dosage of the effective components, such as: the use for prevention and treatment varies with the daily dosage; the nature and severity of the disease cause different daily doses; the difference of sex, age, body surface area of patients, administration route, administration frequency and treatment purpose causes the difference of daily dosage; when in use, different arbutin-carbamide eutectic active ingredient total dosage schemes are made according to different requirements of actual prevention and treatment on different conditions, and the administration can be completed in a multi-time or one-time mode.
Evaluation of bacteriostatic Properties
Adding a proper amount of deionized water into the arbutin-carbamide eutectic drug prepared in the example 2, the beta-arbutin crystal III pure product prepared in the patent with the patent application number of 201310121528.X and the arbutin combination drug sold in the market respectively to prepare a sample to be detected 1 (arbutin-carbamide eutectic drug), a sample to be detected 2 (beta-arbutin crystal III drug) and a sample to be detected 3 (arbutin drug); the amounts of the deionized water in the samples to be detected 1, 2 and 3 are all consistent.
Oxford cup method: preparing corresponding culture medium according to different test strains, and sterilizing at 121 deg.C for 20min with high pressure steam. Preparing a solid culture medium plate, pouring about 20mL of culture medium into each culture dish, after the culture medium is solidified, taking 100 mu L of bacterial liquid (bacterial suspension with the concentration determined by the Mach turbidimetry) by using a liquid transfer gun, dripping the bacterial suspension into the culture dish, and uniformly coating the bacterial suspension on the solid culture medium by adopting a plate coating method. Directly and vertically placing an Oxford cup (a round small tube with the inner diameter of 6mm, the outer diameter of 8mm and the height of 10 mm) on the surface of the culture medium, and slightly pressurizing to ensure that the Oxford cup is in contact with the culture medium without a gap. Three oxford cups were placed per petri dish. 200 mul of samples to be tested are added into each Oxford cup, and the culture dish of the bacteria is lightly placed in a bacteria incubator to be cultured for about 16 hours at 37 ℃.
Note: the bacteriostatic action is judged to be very good if the diameter of the bacteriostatic circle is more than or equal to 30mm, the bacteriostatic action is judged to be very good if the diameter of the bacteriostatic circle is more than or equal to 20mm and less than 30mm, the bacteriostatic action is judged to be very good if the diameter of the bacteriostatic circle is more than or equal to 30mm, and the bacteriostatic action is high if the diameter of the bacteriostatic circle is more than or equal to 15mm and less than 20 mm; the bacteriostatic diameter less than 15mm and less than 10mm is the medium sensitivity '+'; the diameter of the bacteriostatic agent is less than 10mm, and the bacteriostatic agent is judged to have no bacteriostatic action. Wherein, the larger the zone of inhibition, the better the inhibition effect.
The bacteriostatic effect is shown in the following table:
Figure BDA0002906721550000111
Figure BDA0002906721550000121
the antibacterial experimental effect obtained in the table shows that the arbutin-carbamide eutectic combined drug provided by the application has better antibacterial effect on escherichia coli, staphylococcus aureus and propionibacterium acnes appearing in air pollution such as haze, and the antibacterial effect is also obviously superior to that of beta-arbutin crystal III type combined drug and arbutin combined drug.
The embodiments given above are preferable examples for implementing the present application, and the present application is not limited to the above-described embodiments. Any non-essential addition or replacement made by a person skilled in the art according to the technical features of the technical solution of the present application falls within the scope of the present application.

Claims (10)

1. An arbutin-carbamide eutectic is characterized by comprising arbutin and eutectic ligand carbamide in a molar ratio of 1: 1; and the XRD characteristic diffraction peak of the arbutin-carbamide eutectic appears at 8.379 degrees +/-0.2 degree, 14.896 degrees +/-0.2 degree, 16.734 degrees +/-0.2 degree, 17.361 degrees +/-0.2 degree, 22.402 +/-0.2 degree, 25.342 +/-0.2 degree, 31.018 +/-0.2 degree and 34.179 +/-0.2 degree.
2. A method for preparing an arbutin-carboxamide cocrystal according to claim 1, comprising the steps of:
putting mixed powder consisting of arbutin and carbamide with a molar ratio of 1:1 into a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): 1g of m (mixed powder) in a volume of 15mL, ultrasonically mixing at the temperature of 20-30 ℃ for 20-30min, continuously stirring at a constant speed for 20-30min at the rotation speed of 25-30rmp, finally reducing the rotation speed to 10-12rmp and the temperature to 5-10 ℃, continuously stirring at a constant speed for 10-15min, finally standing for 24 hours, carrying out reduced pressure rotary evaporation to remove the solvent, and drying to obtain the arbutin-carbamide eutectic.
3. The method for preparing an arbutin-carbamide eutectic crystal according to claim 2, comprising the steps of:
placing mixed powder consisting of arbutin and carbamide in a mixed solvent consisting of water and ethanol, wherein V (mixed solvent): and m (mixed powder) is 15mL and is 1g, ultrasonic mixing is carried out for 30min at the temperature of 25 ℃, uniform stirring is carried out for 30min at the rotation speed of 30rmp, the rotation speed is reduced to 12rmp, the temperature is reduced to 8 ℃, uniform stirring is carried out for 15min, standing is carried out for 24 h, the solvent is removed by rotary evaporation under reduced pressure, and drying is carried out to obtain the arbutin-carbamide eutectic crystal.
4. The method for preparing an arbutin-carbamide co-crystal according to claim 2, wherein the volume ratio of the water to the ethanol in the mixed solvent is 1: 1.
5. the method for preparing the arbutin-carbamide co-crystal according to claim 2, wherein the drying condition is vacuum pressure of 45Pa and temperature of 55 ℃ for 1 h.
6. The method for preparing the arbutin-carbamide eutectic crystal according to claim 2, wherein the ultrasonic mixing condition is ultrasonic power of 250W and ultrasonic frequency of 40 KHz.
7. A pharmaceutical preparation comprising the arbutin-carboxamide cocrystal according to claim 1 and a pharmaceutically acceptable excipient.
8. The pharmaceutical preparation according to claim 7, wherein the pharmaceutical preparation comprises arbutin-carboxamide cocrystal according to claim 1 and a suitable amount of one or more excipients selected from lactose, starch, microcrystalline cellulose, talc, magnesium stearate and 1% sodium hydroxymethyl cellulose.
9. The pharmaceutical preparation according to claim 7 or 8, wherein the pharmaceutical preparation is one of arbutin tablet, arbutin capsule, arbutin pill, arbutin granule or arbutin powder.
10. Use of an arbutin-carboxamide co-crystal as claimed in claim 1 for the preparation of a medicament for antibacterial and anti-inflammatory use.
CN202110073418.5A 2021-01-20 2021-01-20 Arbutin-carbamide eutectic crystal and preparation method, preparation and application thereof Pending CN112851726A (en)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894583A (en) * 2023-02-17 2023-04-04 天津大学 Arbutin solvent compound and crystallization preparation method thereof
CN118160567A (en) * 2024-04-10 2024-06-11 上海永大菌业有限公司 Organic strain planting method

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115894583A (en) * 2023-02-17 2023-04-04 天津大学 Arbutin solvent compound and crystallization preparation method thereof
CN118160567A (en) * 2024-04-10 2024-06-11 上海永大菌业有限公司 Organic strain planting method

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