CN115381798B - Compound preparation containing diammonium glycyrrhizinate for improving liver function and preparation method thereof - Google Patents
Compound preparation containing diammonium glycyrrhizinate for improving liver function and preparation method thereof Download PDFInfo
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Abstract
The invention relates to a compound preparation containing diammonium glycyrrhizinate for improving liver functions and a preparation method thereof, belonging to the technical field of pharmaceutical compositions. In order to solve the problems that the blood concentration of the existing diammonium glycyrrhizinate preparation is difficult to control, and the clinical dose is difficult to adjust and control, the invention provides a compound preparation containing diammonium glycyrrhizinate for improving liver function, wherein the compound preparation is a hydrogel patch, and comprises a release protective layer, a drug-loaded hydrogel layer and a backing layer from top to bottom in sequence, and the drug-loaded hydrogel layer comprises diammonium glycyrrhizinate, carbomer, sodium carboxymethylcellulose, polyvinyl alcohol, gelatin and water for injection. The invention ensures that the diammonium glycyrrhizinate penetrates through the skin at a constant rate to enter the systemic circulation by a transdermal administration mode, thereby maintaining relatively stable blood concentration. The hydrogel containing diammonium glycyrrhizinate is externally applied to a liver region, so that damaged and necrotic hepatocytes can be recovered or regenerated, and the improvement of liver functions is realized.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical compositions, and particularly relates to a compound preparation containing diammonium glycyrrhizinate for improving liver functions and a preparation method thereof.
Background
Diammonium glycyrrhizinate is an effective component extracted from traditional Chinese medicine liquorice, is a third-generation extract of the effective component of the liquorice, and has stronger effects of resisting inflammation, protecting liver cells and improving liver functions. Diammonium glycyrrhizinate can obviously prevent serum alanine amino group transfer aminotransferase ALT from increasing caused by galactosamine, carbon tetrachloride and thioacetamide, and improve damaged tissues of liver. The liver tissue section shows that diammonium glycyrrhizinate can resist damage of liver cell mitochondria and nucleolus caused by galactosamine, increase the content of hepatic glycogen and nucleic acid, reduce liver cell necrosis and accelerate liver cell recovery.
Diammonium glycyrrhizinate has enterohepatic circulation and complex in vivo process, and the blood concentration change of the medicine and its metabolites has close relationship with enterohepatic circulation and protein combination. Diammonium glycyrrhizinate is incompletely absorbed by oral administration, reaches blood concentration about 8 hours after oral administration, and disappears after 52 hours; the blood concentration decayed rapidly 1 hour after intravenous injection and was at a low level 24 hours later. The curative effect of the diammonium glycyrrhizinate oral preparation is worse than that of intravenous drip, which is related to the low bioavailability. The blood concentration of diammonium glycyrrhizinate is difficult to control in a treatment window, and the clinical dosage is difficult to adjust and control, so that not only can the treatment of patients be delayed, but also the patients can be injured by the medicine.
Disclosure of Invention
In order to solve the problems that the existing diammonium glycyrrhizinate preparation is difficult to control the blood concentration and the clinical dosage is difficult to adjust and control, the invention provides a compound preparation containing diammonium glycyrrhizinate for improving the liver function and a preparation method thereof.
The technical scheme of the invention is as follows:
the utility model provides a compound preparation for improving liver function contains diammonium glycyrrhizinate, compound preparation is the aquogel patch, is from top to bottom in proper order from type protective layer, medicine carrying hydrogel layer and back sheet, medicine carrying hydrogel layer includes the component of following mass percent content:
the rest is water for injection; the diammonium glycyrrhizinate component is diammonium glycyrrhizinate or diammonium glycyrrhizinate drug-loaded liposome.
Further, the diammonium glycyrrhizinate drug-loaded liposome comprises the following components in parts by mass:
1 part of diammonium glycyrrhizinate,
20 to 30 portions of egg yolk lecithin,
8-12 parts of cholesterol.
Further, the preparation method of the diammonium glycyrrhizinate drug-loaded liposome comprises the following steps:
dissolving diammonium glycyrrhizinate in purified water, dissolving egg yolk lecithin and cholesterol in a proper amount of absolute ethyl alcohol, mixing the egg yolk lecithin and cholesterol with the obtained diammonium glycyrrhizinate aqueous solution, performing rotary evaporation to remove the solvent, performing vacuum drying overnight to obtain a lipid membrane, adding DEPC (diethyl ammonium phosphate) normal saline to dissolve and hydrate the lipid membrane, performing ultrasonic treatment and membrane treatment on the obtained hydration system, and dialyzing to obtain the diammonium glycyrrhizinate drug-loaded liposome.
Further, the ultrasonic treatment condition is that the ultrasonic power is 300-500W for 5-8 min; the condition of the membrane treatment is that the polycarbonate membrane with the aperture of 100nm repeatedly extrudes the hydration system after the ultrasonic treatment for 10 to 15 times; the particle size of the diammonium glycyrrhizinate drug-loaded liposome is 100-150 nm.
Further, the diammonium glycyrrhizinate drug-loaded liposome comprises the following components in parts by mass:
further, the preparation method of the diammonium glycyrrhizinate drug-loaded liposome comprises the following steps:
dissolving diammonium glycyrrhizinate in DEPC physiological saline, dissolving yolk lecithin, cholesterol and DSPE-PEG-MAL in absolute ethyl alcohol, removing the solvent through reduced pressure rotary evaporation to obtain a first lipid membrane, redissolving the obtained first lipid membrane with absolute ethyl alcohol, removing the solvent through rotary evaporation again to obtain a second lipid membrane, dissolving and hydrating the obtained second lipid membrane with DEPC physiological saline containing diammonium glycyrrhizinate, performing ultrasonic treatment and membrane treatment on the obtained hydration system, and dialyzing to obtain the MAL modified diammonium glycyrrhizinate drug-loaded liposome.
Further, the ultrasonic treatment condition is that the ultrasonic power is 300-500W for 5-8 min; the condition of the membrane treatment is that the polycarbonate membrane with the aperture of 100nm repeatedly extrudes the hydration system after the ultrasonic treatment for 10 to 15 times; the particle size of the diammonium glycyrrhizinate drug-loaded liposome is 100-150 nm.
A preparation method of a compound preparation containing diammonium glycyrrhizinate for improving liver function comprises the following steps:
step 1, completely dissolving carbomer, sodium carboxymethylcellulose, polyvinyl alcohol and gelatin by using water for injection, and uniformly mixing to obtain a hydrogel system;
step 2, adding diammonium glycyrrhizinate into the hydrogel system obtained in the step 1, stirring at 100rpm under an ultrasonic condition to uniformly dissolve diammonium glycyrrhizinate into the hydrogel system to obtain a medicine-containing system, and sequentially homogenizing and irradiating the medicine-containing system for crosslinking to obtain medicine-carrying hydrogel;
and 3, coating the drug-loaded hydrogel obtained in the step 2 on a back lining layer by using a coating machine, wherein the coating thickness is 5mm, blowing cold air to form the drug-loaded hydrogel while coating, cutting the obtained forming material into pieces according to the required size, covering a release protective layer on the surface of the drug-loaded hydrogel, and sealing an aluminum foil bag or a plastic bag.
Furthermore, the back sheet is medical non-woven fabrics or polyurethane semipermeable membrane, it is PE membrane to leave type protective layer.
Further, the ultrasonic condition of the water of step 2 is that the ultrasonic frequency is 50KHz, and the ultrasonic power is 30-80W; the homogeneous pressure is 30MPa, and the irradiation crosslinking condition is that the irradiation crosslinking is carried out for 20min by using 500GY/s electron beams.
The invention has the beneficial effects that:
the compound preparation containing diammonium glycyrrhizinate for improving liver function provided by the invention takes diammonium glycyrrhizinate as a main medicinal ingredient to prepare a hydrogel patch preparation, and diammonium glycyrrhizinate penetrates through skin at a constant rate to enter systemic circulation through a transdermal administration mode to maintain relatively stable blood concentration. When the hydrogel containing diammonium glycyrrhizinate is used, the hydrogel can generate local treatment effect by being externally applied to a liver area, so that damaged and necrotic hepatocytes are recovered or regenerated, and the improvement of liver function is realized.
The invention prepares diammonium glycyrrhizinate into liposome preparation, which can ensure that the medicine has larger penetration amount of cuticle, improve the medicine absorption capacity, reduce the biological metabolism, prolong the half-life period of the medicine, efficiently deliver diammonium glycyrrhizinate to the action part and solve the problem that the dosage of diammonium glycyrrhizinate is difficult to regulate and control.
The diammonium glycyrrhizinate is further prepared into an MAL modified diammonium glycyrrhizinate drug-loaded liposome preparation, the diammonium glycyrrhizinate drug-loaded liposome can be delivered to the liver in a targeted manner through the MAL modification, the uptake of liver cells is increased, the repairing and regenerating effects on the liver cells are further enhanced, and the preparation method has the advantages of strong targeting property, high efficiency and safety.
Detailed Description
The technical solutions of the present invention are further described below with reference to the embodiments, but the present invention is not limited thereto, and any modifications or equivalent substitutions made to the technical solutions of the present invention without departing from the spirit and scope of the technical solutions of the present invention should be covered in the protection scope of the present invention. The process equipment or apparatus not specifically mentioned in the following examples are conventional in the art, and if not specifically mentioned, the raw materials and the like used in the examples of the present invention are commercially available; unless otherwise specified, the technical means used in the examples of the present invention are conventional means well known to those skilled in the art.
Example 1
The embodiment provides diammonium glycyrrhizinate drug-loaded liposome and a preparation method thereof.
In the embodiment, the diammonium glycyrrhizinate drug-loaded liposome comprises the following components in parts by mass:
1 part of diammonium glycyrrhizinate,
25 parts of egg yolk lecithin,
10 parts of cholesterol.
The preparation method of the diamine glycyrrhizinate drug-loaded liposome in the embodiment is as follows:
dissolving diammonium glycyrrhizinate in purified water, dissolving egg yolk lecithin and cholesterol in a proper amount of absolute ethyl alcohol, slowly mixing the egg yolk lecithin and cholesterol with the obtained diammonium glycyrrhizinate aqueous solution, rotationally evaporating the mixture in a warm water bath at 20 ℃ to remove a solvent, drying the mixture overnight under vacuum to obtain a lipid membrane, adding DEPC (diethyl phthalate) normal saline to dissolve and hydrate the lipid membrane, hydrating the lipid membrane in a shaker at 20 ℃ for 1h, treating the obtained hydration system for 5min by using 500W ultrasonic power to fully disperse the liposome in the hydration system, performing membrane treatment on the ultrasonically treated hydration system through a polycarbonate membrane with the aperture of 100nm, repeatedly extruding the obtained liposome mixed solution for 15 times, then placing the obtained liposome mixed solution in a dialysis bag with the molecular weight cutoff of 30kDa, dialyzing the obtained mixed solution for 30min by using the normal saline, removing free diammonium glycyrrhizinate which is not encapsulated in a permeation solution, and collecting liquid in the dialysis bag to obtain the diammonium glycyrrhizinate drug-loaded liposome with the particle size of 100-150 nm.
Example 2
The embodiment provides an MAL modified diammonium glycyrrhizinate drug-loaded liposome and a preparation method thereof.
In the embodiment, the MAL modified diammonium glycyrrhizinate drug-loaded liposome comprises the following components in parts by mass:
the DSPE-PEG-MAL used in this example, fully known as dipalmitoylphosphatidylethanolamine-polyethylene glycol-maleimide, available from New Biotech, inc. of Senakai, and having a PEG molecular weight of 2000.
The preparation method of the MAL-modified diammonium glycyrrhizinate drug-loaded liposome in this embodiment is as follows:
dissolving diammonium glycyrrhizinate in DEPC physiological saline, dissolving egg yolk lecithin, cholesterol and DSPE-PEG-MAL in absolute ethyl alcohol, removing the solvent by reduced pressure rotary evaporation to obtain a first lipid membrane, re-dissolving the obtained first lipid membrane with absolute ethyl alcohol, and removing the solvent by rotary evaporation again to obtain a second lipid membrane, dissolving and hydrating the obtained second lipid membrane with DEPC physiological saline containing diammonium glycyrrhizinate, hydrating for 1h in a shaker at 20 ℃, treating the obtained hydrated system for 5min by using 500W ultrasonic power to fully disperse the liposome in the hydrated system, performing membrane treatment on the hydrated system after ultrasonic treatment through a polycarbonate membrane with the aperture of 100nm, repeatedly extruding for 15 times, placing the obtained liposome mixed solution in a dialysis bag with the molecular weight of 30kDa, dialyzing for 30min with physiological saline, removing unencapsulated free diammonium glycyrrhizinate in the permeation solution, and collecting the liquid in the dialysis bag to obtain the diammonium glycyrrhizinate drug-loaded liposome with the particle size of 100-150 nm.
The encapsulation efficiency and the particle size of the liposomes obtained in example 1 and example 2 were measured, respectively, and the specific measurement method of the encapsulation efficiency was as follows:
2mL of each liposome obtained in example 1 and example 2 was centrifuged at 20000 Xg for 30 minutes, and the supernatant was retained. Using 25 parts of yolk lecithin and 10 parts of cholesterol to prepare a blank liposome centrifugal supernatant as a reference, detecting the absorbance value of diammonium glycyrrhizinate by using a fluorescence spectrophotometer, drawing a standard absorption curve, and calculating the encapsulation efficiency according to the following formula:
encapsulation efficiency = (total addition of diammonium glycyrrhizinate-amount of diammonium glycyrrhizinate in supernatant)/total addition of diammonium glycyrrhizinate × 100%.
The results of the encapsulation efficiency and particle size measurement of the liposomes are shown in Table 1.
TABLE 1
| Detecting items | Average particle diameter (nm) | Encapsulation efficiency (%) |
| EXAMPLE 1 liposomes | 135.6±2.54 | 88.16％ |
| EXAMPLE 2 liposomes | 143.9±5.12 | 83.58％ |
As can be seen from the data in Table 1, the average particle size of the liposomes prepared in examples 1 and 2 was 100 to 150nm, and the encapsulation efficiency was 80% or more.
The diammonium glycyrrhizinate liposomes prepared in example 1 and example 2 were continuously placed for three months, and the liposomes were observed not to be settled within three months, and had good stability.
Example 3
The embodiment provides a compound preparation containing diammonium glycyrrhizinate for improving liver functions and a preparation method thereof.
The compound preparation containing diammonium glycyrrhizinate for improving liver function in the embodiment is a hydrogel patch, and is sequentially provided with a release protective layer, a drug-loaded hydrogel layer and a back lining layer from top to bottom, wherein the release protective layer is a PE (polyethylene) film, and the back lining layer is a polyurethane semipermeable film.
The medicine-carrying hydrogel layer comprises the following components in percentage by mass:
the preparation method of the compound preparation containing diammonium glycyrrhizinate for improving liver functions in the embodiment comprises the following steps:
step 1, completely dissolving carbomer, sodium carboxymethylcellulose, polyvinyl alcohol and gelatin by using water for injection, and uniformly mixing to obtain a hydrogel system;
step 2, adding diammonium glycyrrhizinate into the hydrogel system obtained in the step 1, stirring at 100rpm under the conditions that the ultrasonic frequency is 50KHz and the ultrasonic power is 30-80W to uniformly dissolve the diammonium glycyrrhizinate into the hydrogel system to obtain a medicine-containing system, homogenizing the medicine-containing system at the homogenizing pressure of 30MPa, performing irradiation crosslinking treatment on the medicine-containing system after homogenizing is completed, and performing irradiation crosslinking for 20min by using 500GY/s electron beams to obtain medicine-carrying hydrogel;
and 3, coating the drug-loaded hydrogel obtained in the step 2 on a back lining layer by using a coating machine, wherein the coating thickness is 5mm, blowing cold air to form the drug-loaded hydrogel while coating, cutting the obtained forming material into pieces according to the required size, covering a release protective layer on the surface of the drug-loaded hydrogel, and sealing an aluminum foil bag or a plastic bag.
Example 4
The embodiment provides a compound preparation containing diammonium glycyrrhizinate for improving liver functions and a preparation method thereof.
The compound preparation containing diammonium glycyrrhizinate for improving liver function in the embodiment is a hydrogel patch, and is sequentially provided with a release protective layer, a drug-loaded hydrogel layer and a back lining layer from top to bottom, wherein the release protective layer is a PE (polyethylene) film, and the back lining layer is a polyurethane semipermeable film.
The medicine-carrying hydrogel layer comprises the following components in percentage by mass:
the preparation method of the compound preparation containing diammonium glycyrrhizinate for improving liver functions in the embodiment comprises the following steps:
step 1, completely dissolving carbomer, sodium carboxymethylcellulose, polyvinyl alcohol and gelatin by using water for injection, and uniformly mixing to obtain a hydrogel system;
step 2, adding diammonium glycyrrhizinate into the hydrogel system obtained in the step 1, stirring at 100rpm under the conditions that the ultrasonic frequency is 50KHz and the ultrasonic power is 30-80W to uniformly dissolve the diammonium glycyrrhizinate into the hydrogel system to obtain a medicine-containing system, homogenizing the medicine-containing system at the homogenizing pressure of 30MPa, performing irradiation crosslinking treatment on the medicine-containing system after homogenizing is completed, and performing irradiation crosslinking for 20min by using 500GY/s electron beams to obtain medicine-carrying hydrogel;
and 3, coating the drug-loaded hydrogel obtained in the step 2 on a back lining layer by using a coating machine, wherein the coating thickness is 5mm, blowing cold air to form the drug-loaded hydrogel while coating, cutting the obtained forming material into pieces according to the required size, covering a release protective layer on the surface of the drug-loaded hydrogel, and sealing an aluminum foil bag or a plastic bag.
Example 5
The embodiment provides a compound preparation containing diammonium glycyrrhizinate for improving liver functions and a preparation method thereof.
The compound preparation containing diammonium glycyrrhizinate for improving liver functions in the embodiment is a hydrogel patch, and comprises a release protective layer, a drug-loaded hydrogel layer and a back lining layer from top to bottom in sequence, wherein the release protective layer is a PE film, and the back lining layer is a polyurethane semipermeable film.
The drug-loaded hydrogel layer comprises the following components in percentage by mass:
the preparation method of the compound preparation containing diammonium glycyrrhizinate for improving liver functions in the embodiment comprises the following steps:
step 1, completely dissolving carbomer, sodium carboxymethylcellulose, polyvinyl alcohol and gelatin by using water for injection, and uniformly mixing to obtain a hydrogel system;
step 2, adding the diammonium glycyrrhizinate drug-loaded liposome prepared in the example 1 into the hydrogel system obtained in the step 1, stirring at 100rpm under the conditions that the ultrasonic frequency is 50KHz and the ultrasonic power is 30-80W to uniformly dissolve diammonium glycyrrhizinate into the hydrogel system to obtain a drug-loaded system, homogenizing the drug-loaded system at the homogenizing pressure of 30MPa, performing irradiation crosslinking treatment on the drug-loaded system after homogenizing is completed, and performing irradiation crosslinking for 20min by using 500GY/s electron beams to obtain drug-loaded hydrogel;
and 3, coating the drug-loaded hydrogel obtained in the step 2 on a backing layer by using a coating machine, wherein the coating thickness is 5mm, blowing cold air to form the drug-loaded hydrogel while coating, cutting the obtained forming material into pieces according to the required size, covering a release protective layer on the surface of the drug-loaded hydrogel, and sealing an aluminum foil bag or a plastic bag.
Example 6
The embodiment provides a compound preparation containing diammonium glycyrrhizinate for improving liver functions and a preparation method thereof.
The compound preparation containing diammonium glycyrrhizinate for improving liver function in the embodiment is a hydrogel patch, and is sequentially provided with a release protective layer, a drug-loaded hydrogel layer and a back lining layer from top to bottom, wherein the release protective layer is a PE (polyethylene) film, and the back lining layer is a polyurethane semipermeable film.
The drug-loaded hydrogel layer comprises the following components in percentage by mass:
the preparation method of the compound preparation containing diammonium glycyrrhizinate for improving liver functions in the embodiment comprises the following steps:
step 1, completely dissolving carbomer, sodium carboxymethylcellulose, polyvinyl alcohol and gelatin by using water for injection, and uniformly mixing to obtain a hydrogel system;
step 2, adding the diammonium glycyrrhizinate drug-loaded liposome prepared in the example 1 into the hydrogel system obtained in the step 1, stirring at 100rpm under the conditions that the ultrasonic frequency is 50KHz and the ultrasonic power is 30-80W to uniformly dissolve diammonium glycyrrhizinate into the hydrogel system to obtain a drug-loaded system, homogenizing the drug-loaded system at the homogenizing pressure of 30MPa, performing irradiation crosslinking treatment on the drug-loaded system after homogenizing is completed, and performing irradiation crosslinking for 20min by using 500GY/s electron beams to obtain drug-loaded hydrogel;
and 3, coating the drug-loaded hydrogel obtained in the step 2 on a backing layer by using a coating machine, wherein the coating thickness is 5mm, blowing cold air to form the drug-loaded hydrogel while coating, cutting the obtained forming material into pieces according to the required size, covering a release protective layer on the surface of the drug-loaded hydrogel, and sealing an aluminum foil bag or a plastic bag.
Example 7
The embodiment provides a compound preparation containing diammonium glycyrrhizinate for improving liver functions and a preparation method thereof.
The compound preparation containing diammonium glycyrrhizinate for improving liver function in the embodiment is a hydrogel patch, and is sequentially provided with a release protective layer, a drug-loaded hydrogel layer and a back lining layer from top to bottom, wherein the release protective layer is a PE (polyethylene) film, and the back lining layer is a polyurethane semipermeable film.
The drug-loaded hydrogel layer comprises the following components in percentage by mass:
the preparation method of the compound preparation containing diammonium glycyrrhizinate for improving liver functions in the embodiment comprises the following steps:
step 1, completely dissolving carbomer, sodium carboxymethylcellulose, polyvinyl alcohol and gelatin by using water for injection, and uniformly mixing to obtain a hydrogel system;
step 2, adding the diammonium glycyrrhizinate drug-loaded liposome prepared in the example 2 into the hydrogel system obtained in the step 1, stirring at 100rpm under the conditions that the ultrasonic frequency is 50KHz and the ultrasonic power is 30-80W to uniformly dissolve diammonium glycyrrhizinate into the hydrogel system to obtain a drug-loaded system, homogenizing the drug-loaded system at the homogenizing pressure of 30MPa, performing irradiation crosslinking on the drug-loaded system after homogenizing is completed, and performing irradiation crosslinking for 20min by using 500GY/s electron beams to obtain drug-loaded hydrogel;
and 3, coating the drug-loaded hydrogel obtained in the step 2 on a backing layer by using a coating machine, wherein the coating thickness is 5mm, blowing cold air to form the drug-loaded hydrogel while coating, cutting the obtained forming material into pieces according to the required size, covering a release protective layer on the surface of the drug-loaded hydrogel, and sealing an aluminum foil bag or a plastic bag.
Example 8
The embodiment provides a compound preparation containing diammonium glycyrrhizinate for improving liver functions and a preparation method thereof.
The compound preparation containing diammonium glycyrrhizinate for improving liver functions in the embodiment is a hydrogel patch, and comprises a release protective layer, a drug-loaded hydrogel layer and a back lining layer from top to bottom in sequence, wherein the release protective layer is a PE film, and the back lining layer is a polyurethane semipermeable film.
The drug-loaded hydrogel layer comprises the following components in percentage by mass:
the preparation method of the compound preparation containing diammonium glycyrrhizinate for improving liver functions in the embodiment comprises the following steps:
step 1, completely dissolving carbomer, sodium carboxymethylcellulose, polyvinyl alcohol and gelatin by using water for injection, and uniformly mixing to obtain a hydrogel system;
step 2, adding the diammonium glycyrrhizinate drug-loaded liposome prepared in the embodiment 2 into the hydrogel system obtained in the step 1, stirring at 100rpm under the conditions that the ultrasonic frequency is 50KHz and the ultrasonic power is 30-80W to uniformly dissolve diammonium glycyrrhizinate into the hydrogel system to obtain a drug-loaded system, homogenizing the drug-loaded system at the homogenizing pressure of 30MPa, performing irradiation crosslinking treatment on the drug-loaded system after homogenizing is completed, and performing irradiation crosslinking for 20min by using 500GY/s electron beams to obtain drug-loaded hydrogel;
and 3, coating the drug-loaded hydrogel obtained in the step 2 on a back lining layer by using a coating machine, wherein the coating thickness is 5mm, blowing cold air to form the drug-loaded hydrogel while coating, cutting the obtained forming material into pieces according to the required size, covering a release protective layer on the surface of the drug-loaded hydrogel, and sealing an aluminum foil bag or a plastic bag.
Experiment one, the curative effect of the compound preparation containing diammonium glycyrrhizinate prepared in example 3, example 5 and example 7 on improving liver function is examined.
(one) subject:
100 patients meeting the diagnosis standard of impaired liver function are aged 37-65 years, wherein 62 men and 38 women have the course of disease for 6-18 months. Patients all passed the diagnostic criteria for impaired liver function: dull pain in the liver area with asthenia; mild or moderate elevations of alanine Aminotransferase (ALT) and glutamyl transpeptidase (GGT); the course of the disease is more than half a year.
(II) survey group:
100 patients are randomly divided into 4 groups, each group is 25 patients, and each group of cases has no significant difference after statistical treatment on sex, age, disease course, symptoms and the like, and has comparability and statistical significance.
Group 1 was example 3, group 2 was example 5, group 3 was example 7, group 4 was orally available diammonium glycyrrhizinate capsules, and the hydrogel patches prepared in example 3, example 5 and example 7 were applied to the liver area one by one daily for 14 days; group 4 was orally administered 150mg (3 capsules) once, 3 times a day.
(III) evaluation standard of symptom curative effect:
the liver function mainly observes the most sensitive indexes of the liver function, namely glutamic-pyruvic transaminase ALT and glutamic-transpeptidase GGT, and adopts a rate method for detection.
The effect is shown: the dull pain of the liver area disappears, and the liver functions of glutamic-pyruvic transaminase ALT and glutamic-transpeptidase GGT are reduced to the normal range;
the method has the following advantages: the dull pain of the liver area is obviously relieved, and the liver function glutamic-pyruvic transaminase ALT and glutamic-transpeptidase GGT are reduced by more than 50 percent;
and (4) invalidation: the liver area has no improvement on the dull pain, and the liver function of glutamic pyruvic transaminase ALT and glutamic transpeptidase GGT is reduced by less than 30 percent.
(IV) therapeutic results
The patients in each group were as shown in table 2, and the effective rate = (effective number + significant number)/total number × 100%.
TABLE 2
| Experimental groups | The effect is shown: human being | The method has the following advantages: human being | And (4) invalidation: human being | High efficiency |
| Group 1 | 8 | 14 | 3 | 88％ |
| Group 2 | 17 | 8 | 0 | 100％ |
| Group 3 | 23 | 2 | 0 | 100％ |
| Group 4 | 7 | 12 | 6 | 76％ |
As shown by the comparison of effective rate data in Table 2, the hydrogel patch containing diammonium glycyrrhizinate provided by the invention can improve the state of impaired liver function, and the effect is superior to that of oral diammonium glycyrrhizinate capsules. The result shows that the hydrogel patch preparation enables diammonium glycyrrhizinate to permeate the skin at a constant rate to enter systemic circulation through a transdermal drug delivery mode, so that relatively stable blood concentration is maintained, the effect of recovering or regenerating damaged and necrotic hepatocytes by diammonium glycyrrhizinate is enhanced, and the improvement of liver functions is realized. The diammonium glycyrrhizinate in the liposome preparation prepared in example 3 further enhances the transdermal absorption capacity of the medicine, has a slow release effect, reduces the biological metabolism, prolongs the half-life period of the medicine, and delivers the diammonium glycyrrhizinate to the action site more efficiently. Example 5 the MAL-modified diammonium glycyrrhizinate drug-loaded liposome delivers diammonium glycyrrhizinate drug-loaded liposome to the liver in a targeted manner, increasing the uptake of liver cells, and further enhancing the repair and regeneration efficacy of liver cells. No adverse toxic or side effects of the hydrogel patch of the invention were found in clinical observation, indicating that the drug is a safe and effective external preparation.
Claims (5)
1. The utility model provides a compound preparation for improving liver function contains diammonium glycyrrhizinate, a serial communication port, compound preparation is the aquogel patch, from top to bottom is in proper order from type protective layer, medicine carrying hydrogel layer and back sheet, medicine carrying hydrogel layer includes the component of following mass percent content:
0.01 to 60 weight percent of diammonium glycyrrhizinate,
2.0 to 4.0 weight percent of carbomer,
3.0 to 5.0 weight percent of sodium carboxymethyl cellulose,
1.5 to 3.5 weight percent of polyvinyl alcohol,
10.0 to 15.0 weight percent of gelatin,
The rest is water for injection; the diammonium glycyrrhizinate component is diammonium glycyrrhizinate drug-loaded liposome;
the diammonium glycyrrhizinate drug-loaded liposome comprises the following components in parts by mass:
1 part of diammonium glycyrrhizinate,
20 to 30 portions of egg yolk lecithin,
8 to 12 portions of cholesterol,
5-8 parts of DSPE-PEG-MAL;
the preparation method of the diammonium glycyrrhizinate drug-loaded liposome comprises the following steps:
dissolving diammonium glycyrrhizinate in DEPC physiological saline, dissolving yolk lecithin, cholesterol and DSPE-PEG-MAL in absolute ethyl alcohol, removing the solvent through reduced pressure rotary evaporation to obtain a first lipid membrane, redissolving the obtained first lipid membrane with absolute ethyl alcohol, removing the solvent through rotary evaporation again to obtain a second lipid membrane, dissolving and hydrating the obtained second lipid membrane with DEPC physiological saline containing diammonium glycyrrhizinate, performing ultrasonic treatment and membrane treatment on the obtained hydration system, and dialyzing to obtain the MAL modified diammonium glycyrrhizinate drug-loaded liposome.
2. The compound preparation containing diammonium glycyrrhizinate for improving liver function according to claim 1, wherein the ultrasonic treatment condition is 300-500W ultrasonic power treatment for 5-8 min; the condition of the membrane treatment is that the polycarbonate membrane with the aperture of 100nm repeatedly extrudes the hydration system after the ultrasonic treatment for 10 to 15 times; the particle size of the diammonium glycyrrhizinate drug-loaded liposome is 100-150 nm.
3. A method for preparing the diammonium glycyrrhizinate-containing compound preparation for improving liver function according to claim 1, comprising the steps of:
step 1, completely dissolving carbomer, sodium carboxymethylcellulose, polyvinyl alcohol and gelatin by using water for injection, and uniformly mixing to obtain a hydrogel system;
step 2, adding a diammonium glycyrrhizinate component into the hydrogel system obtained in the step 1, stirring at 100rpm under an ultrasonic condition to uniformly dissolve diammonium glycyrrhizinate into the hydrogel system to obtain a drug-containing system, and sequentially homogenizing and irradiating for crosslinking the drug-containing system to obtain a drug-loaded hydrogel;
and 3, coating the drug-loaded hydrogel obtained in the step 2 on a back lining layer by using a coating machine, wherein the coating thickness is 5mm, blowing cold air to form the drug-loaded hydrogel while coating, cutting the obtained forming material into pieces according to the required size, covering a release protective layer on the surface of the drug-loaded hydrogel, and sealing an aluminum foil bag or a plastic bag.
4. The method for preparing a diammonium glycyrrhizinate-containing compound preparation for improving liver function according to claim 3, wherein the backing layer is a medical non-woven fabric or a polyurethane semipermeable membrane, and the release protective layer is a PE membrane.
5. The method for preparing a diammonium glycyrrhizinate-containing compound preparation for improving liver functions according to claim 3 or 4, wherein the ultrasonic frequency of water of step 2 is 50KHz, and the ultrasonic power is 30-80W; the homogeneous pressure is 30MPa, and the irradiation crosslinking condition is that the irradiation crosslinking is carried out for 20min by using 500GY/s electron beams.
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