CN110123738B - Polyacrylate hydrogel suppository for rectal delivery of puerarin and preparation method thereof - Google Patents
Polyacrylate hydrogel suppository for rectal delivery of puerarin and preparation method thereof Download PDFInfo
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- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
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Abstract
The invention discloses a polyacrylate hydrogel suppository for puerarin rectal delivery and a preparation method thereof, wherein puerarin is taken, N' -methylene bisacrylamide, hydroxyethyl methacrylate and methacrylic acid are added, 1, 2-propylene glycol is added as a solvent, and the ultrasonic treatment is carried out until the puerarin is completely dissolved to obtain a transparent homogeneous oil phase; taking sodium bisulfite and ammonium persulfate, adding deionized water, and then performing ultrasonic treatment until the sodium bisulfite and the ammonium persulfate are completely dissolved to obtain a water phase; and (3) completely dissolving the water phase and the oil phase by ultrasonic waves, pouring the mixture into a suppository mold, and heating the mixture for 6 hours at the temperature of 37 ℃ in an oil bath to form colorless transparent gel. The polyacrylate hydrogel suppository for puerarin rectal delivery prepared by the invention has good bioavailability, biocompatibility and higher safety.
Description
Technical Field
The invention belongs to the technical field of preparation processes of traditional Chinese medicine polyacrylate hydrogel suppositories, and particularly relates to a polyacrylate hydrogel suppository for puerarin rectal delivery and a preparation method thereof.
Background
Puerarin (C)21H20O9) Is polyhydroxy micromolecule flavonoid compound, and the main chemical component of the polyhydroxy micromolecule flavonoid compound is 8-beta-D-glucopyranose-4', 7-dihydroxy isoflavone. Modern medical research shows that pueraria flavonoid compound puerarin has the effect of improving blood circulation, is clinically used for treating various cardiovascular and cerebrovascular diseases, has the functions of removing oxygen free radicals, increasing the activity of superoxide dismutase and inhibiting the nonenzymatic glycosylation of protein, and has the advantages of low toxicity and wide safety range.
However, puerarin has a chemical structure of a plurality of benzene rings and polyhydroxy groups, and has low water solubility and fat solubility, so that the puerarin has poor oral absorption and low bioavailability. In order to overcome the problems, clinical puerarin preparations are mainly injections and freeze-dried powder injections, but the patients have poor compliance and are easy to have adverse reactions, so that the wide clinical application of puerarin is limited. Therefore, the development of new puerarin dosage forms is urgently needed to promote the absorption and improve the bioavailability of the puerarin, and a new method and a new way are provided for the wide application of the puerarin.
Rectal administration has a long history, and the rectal administration of traditional Chinese medicines is recorded as early as the Han generation. Because the number of blood vessels and mucous membranes in the rectum is large, 50% -70% of the medicine is directly absorbed by the middle vein, the inferior vein and the anal vein of the rectum in rectal administration, the first pass effect of the liver is avoided, and the blood concentration and the bioavailability of the medicine are improved. In addition, rectal administration has the characteristics of quick absorption, prevention of damage of gastric acid and various enzymes to the medicine, reduction of gastrointestinal stimulation, difficult occurrence of adverse reaction and the like, and has unique treatment effect.
The polymer gel not only has a unique three-dimensional network structure, better biocompatibility and responsiveness to the environment, but also has rich sources and low price, so that the polymer gel is attracting more and more attention of scholars. The polymer gel is widely applied to a drug delivery system because it can respond to changes in external environments such as temperature, pH, solvent composition, and the like, thereby generating significant volume changes. In view of the above, the invention provides a puerarin new dosage form-puerarin polyacrylate hydrogel suppository and a preparation process thereof.
Disclosure of Invention
The invention solves the technical problem of providing a polyacrylate hydrogel suppository for puerarin rectal delivery with good bioavailability and biocompatibility and higher safety and a preparation method thereof.
The invention adopts the following technical scheme for solving the technical problems, and the preparation method of the polyacrylate hydrogel suppository for puerarin rectal delivery is characterized by comprising the following specific steps of:
step S1: taking 3-5 parts by weight of puerarin, adding 6-8 parts by weight of N, N' -methylene bisacrylamide, 15-25 parts by weight of hydroxyethyl methacrylate and 16-24 parts by weight of methacrylic acid, adding 80-120 parts by weight of 1, 2-propylene glycol as a solvent, and performing ultrasonic treatment until the puerarin is completely dissolved to obtain a transparent homogeneous oil phase;
step S2: taking 4-6 parts by weight of sodium bisulfite and 4-6 parts by weight of ammonium persulfate, adding 90-110 parts by weight of deionized water, and then carrying out ultrasonic treatment until the mixture is completely dissolved to obtain a water phase;
step S3: and (3) completely dissolving the water phase obtained in the step S2 and the oil phase obtained in the step S1 by ultrasonic waves, pouring the mixture into a suppository mold, and heating the mixture for 6 hours at 37 ℃ in an oil bath to form colorless transparent gel, namely the polyacrylate hydrogel suppository for rectal delivery of puerarin, wherein the polyacrylate hydrogel suppository has good release performance in a rectal environment with the pH =7.4, and the cumulative release amount within 12 hours reaches 80%.
Preferably, the mass ratio of the puerarin to the N, N' -methylene bisacrylamide to the hydroxyethyl methacrylate to the methacrylic acid to the 1, 2-propylene glycol to the ammonium persulfate to the sodium bisulfite to the deionized water is 4:7:20:20:100:5:5: 100.
The polyacrylate hydrogel suppository for rectal delivery of puerarin is characterized by being prepared by the method.
The polymer gel suppository prepared by the invention has a unique three-dimensional network structure, better biocompatibility and responsiveness to rectal environment, and is a good drug-loading system. In rectal administration, 50-70% of the drug is directly absorbed by the middle, lower and anal veins of the rectum, thus avoiding the first pass effect of the liver and improving the blood concentration, the bioavailability and the medication safety of the drug. In addition, rectal administration has the characteristics of quick absorption, prevention of damage of gastric acid and various enzymes to the medicine, reduction of gastrointestinal stimulation, difficult occurrence of adverse reaction and the like, and has unique treatment effect.
Drawings
FIG. 1 is an infrared spectrum of a polymer gel;
FIG. 2 is a Raman spectrum of a polymer gel;
FIG. 3 is a bar graph of the swelling ratio of polymer gel;
FIG. 4 is a degradation diagram of a polymer gel;
FIG. 5 is a drawing of a section of rat rectal tissue;
FIG. 6 is a bar graph of in vitro release rate of drug loaded polymer gel;
fig. 7 is a bar graph of blood drug concentration of drug-loaded polymer gel in rats.
Detailed Description
The present invention will be further specifically described with reference to the following examples, which are intended to illustrate the present invention and not to limit the contents thereof.
Examples
Puerarin suppository formula and preparation process
(1) The prescription proportion is as follows: 3-5 kg of puerarin, 6-8 kg of N, N' -Methylene Bisacrylamide (MBA), 15-25 parts of hydroxyethyl methacrylate (HA), 16-24 kg of methacrylic acid (MAA), 80-120 kg of 1, 2-propylene glycol, and ammonium persulfate ((NH)4)2S2O6）4-6 kg of sodium bisulfite (NaHSO)3) 4-6 kg and 90-110 kg deionized water; the optimal prescription proportion is as follows: 4 kg of puerarin, 7 kg of N, N' -Methylenebisacrylamide (MBA), 20 kg of hydroxyethyl methacrylate (HA), 20 kg of methacrylic acid (MAA), 100 kg of 1, 2-propanediol, and ammonium persulfate ((NH)4)2S2O6) 5 kg of sodium bisulfite (NaHSO)3) 5 kg and 100 kg deionized water;
(2) the preparation process comprises the following steps: adding puerarin, N' -methylene bisacrylamide, hydroxyethyl methacrylate and methacrylic acid, adding 1, 2-propylene glycol as a solvent, and performing ultrasonic treatment until completely dissolved to obtain a transparent and homogeneous oil phase; taking sodium bisulfite and ammonium persulfate, adding deionized water, and then performing ultrasonic treatment until the sodium bisulfite and the ammonium persulfate are completely dissolved to obtain a water phase; and (3) completely dissolving the water phase and the oil phase by ultrasonic waves, pouring the mixture into a suppository mold, and heating the mixture for 6 hours at the temperature of 37 ℃ in an oil bath to form colorless transparent gel.
Characterization of Polymer gels
In the FTIR spectrum of FIG. 1, at 1720cm-1The bands observed here are caused by flexural vibrations of the carbonyl groups in the hydrogel molecules. The same bands were observed in the spectra of HA, MAA and MBA, whereas the bands in the hydrogel molecules were broader due to their conjugation. Furthermore, 1100cm in HA and MAA-1And 3300cm-1The bands appearing are caused by the oscillation (-OH) of the hydroxyl group, 700cm in MBA-1The nearby bands are caused by out-of-plane stretching vibrations of the secondary amines, and these bands are also detectable in the hydrogel. In conclusion, the polymer gel was successfully synthesized. In the Raman spectrum of FIG. 2, HA, MAA and MBA were found at 1729cm-1Has obvious diffraction peak at the position, and the hydrogel is at 1500cm-1The obvious absorption peak is caused by that when the molecules are crosslinked to form gel, carbonyl and double bond are conjugated to shift the wavelength of the absorption peak to the low wave direction. At 1675cm-1Nearby diffraction peaks were caused by-C = C-double bond vibration, while peaks of double bonds were not observed in the hydrogel. At 2895.7cm-1The existence of strong peaks indicates the existence of-CH 2-and-CH 3-groups. On the upper partThe characteristics of the monomer are also observed in the Raman spectrum of the hydrogel, which again indicates the success of the polymer gel synthesis.
Swelling and degradation experiments of Polymer gels
Using PBS buffer solution (simulated rectal environment) with pH =7.4 as a swelling medium, precisely weighing 3 groups of blank polymer gels, respectively, recording the dry weight Wd of the polymer gel, soaking the blank polymer gels in Phosphate Buffer Solution (PBS) with pH =7.4 in groups, taking out the blank polymer gels every 2h for each group of samples, sucking off PBS attached to the surface by using absorbent paper, and precisely weighing Ws. The equilibrium swelling ratio (ESR = Ws/Wd) of the gel is shown in fig. 3, where the swelling ratio of the polymer gel gradually increases from 2 to 6 hours, and the swelling ratio reaches a maximum of about 230% from 18 to 24 hours, and almost reaches equilibrium. Shows that solvent molecules gradually penetrate into the polymer gel to cause swelling in 2-6h, and the swelling reaches the equilibrium in 18-24 h.
Taking 3 groups of blank gels for degradation experiments, taking PBS buffer solution with pH =7.4 as a gel degradation medium, respectively infiltrating the blank suppositories in penicillin bottles, taking out the blank gels every 2h for each group of samples, absorbing PBS attached to the surface by using absorbent paper, taking pictures, and then putting the pictures back into the original penicillin bottles. As shown in FIG. 4, the gel was not significantly exfoliated from 0-6h, while from 8h, significant exfoliation of the polymer gel was observed. This indicates that the solvent penetrates into the crosslinking voids of the polymer gel at 0-6h without degradation. And the polymer begins to diffuse into the solvent within 6-8h, and degradation occurs.
Biocompatibility test of hydrogel
And (3) respectively administering puerarin drug-loaded hydrogel and blank hydrogel suppository in the rectum of the SD rat, taking the rectal tissue after 24 hours, and carrying out HE staining. In fig. 5-a, which is a section of normal rat rectal tissue and in fig. 5-b, which is a section of rat rectal tissue after rectal administration, it can be seen by comparison that inflammatory cells and distinct lesions are not found in fig. 5-b, indicating that the hydrogel rectal suppository has good biocompatibility and safety.
In vitro and in vivo Release test
In vitro release experiments, PBS buffer solution with pH =7.4 is used as an in vitro release medium, 5 groups of drug-loaded gel are placed into a 50mL centrifuge tube, 50mL of PBS buffer solution is added, the gel is placed into a water bath constant temperature oscillator, water bath constant temperature oscillation is carried out under the conditions that the temperature is 37 +/-1 ℃ and the speed is 100rpm, samples are taken every 2h, and meanwhile, fresh buffer solution with the same amount is supplemented into the centrifuge tube. Standing the sample solution for 1min, taking out 15mL of release solution with disposable syringe, filtering with 0.22 μm filter membrane, and measuring puerarin content by UV spectrum. As shown in figure 6, the in vitro release rate of the drug-loaded polymer gel gradually increases from 0 to 10 hours, gradually reaches the highest after 10 hours, then the release rate becomes slow, and the total release amount of puerarin reaches about 80 percent in 12 hours.
In vivo experiment, 6 SD rats were taken, and rectally administered with puerarin suppository respectively, and at 0.5h, 2h, 4h, 6h, 8h, 10h and 24h, tail vein blood was taken and serum was separated, and blood concentration was determined by HPLC chromatography. As shown in figure 7, the puerarin suppository has the maximum blood concentration in rats after 2h administration, and puerarin is basically not detected in blood after 24h administration.
In conclusion, the puerarin suppository disclosed by the invention is prepared by selecting a medicine formula, is convenient to prepare and simple in process, and has good biocompatibility, bioavailability and higher safety.
Although the present invention has been described with reference to the specific embodiments, it is not intended to limit the scope of the present invention, and various modifications and variations can be made by those skilled in the art without inventive changes based on the technical solution of the present invention.
Claims (3)
1. A preparation method of polyacrylate hydrogel suppository for rectal delivery of puerarin is characterized by comprising the following specific steps:
step S1: taking 3-5 parts by weight of puerarin, adding 6-8 parts by weight of N, N' -methylene bisacrylamide, 15-25 parts by weight of hydroxyethyl methacrylate and 16-24 parts by weight of methacrylic acid, adding 80-120 parts by weight of 1, 2-propylene glycol as a solvent, and performing ultrasonic treatment until the puerarin is completely dissolved to obtain a transparent homogeneous oil phase;
step S2: taking 4-6 parts by weight of sodium bisulfite and 4-6 parts by weight of ammonium persulfate, adding 90-110 parts by weight of deionized water, and then carrying out ultrasonic treatment until the mixture is completely dissolved to obtain a water phase;
step S3: and (3) completely dissolving the water phase obtained in the step S2 and the oil phase obtained in the step S1 by ultrasonic waves, pouring the mixture into a suppository mold, and heating the mixture for 6 hours at 37 ℃ in an oil bath to form colorless transparent gel, namely the polyacrylate hydrogel suppository for rectal delivery of puerarin, wherein the polyacrylate hydrogel suppository has good release performance in a rectal environment with the pH =7.4, and the cumulative release amount within 12 hours reaches 80%.
2. The method of preparing a polyacrylate hydrogel suppository for rectal delivery of puerarin according to claim 1, wherein: the feeding mass ratio of the puerarin, the N, N' -methylene bisacrylamide, the hydroxyethyl methacrylate, the methacrylic acid, the 1, 2-propylene glycol, the ammonium persulfate, the sodium bisulfite and the deionized water is preferably 4:7:20:20:100:5:5: 100.
3. A polyacrylate hydrogel suppository for rectal delivery of puerarin characterized by being prepared by the method of claim 1 or 2.
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| CN110123738B true CN110123738B (en) | 2022-03-25 |
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Non-Patent Citations (4)
| Title |
|---|
| Development of a poloxamer analogs/carbopol-based in situ gelling and mucoadhesive ophthalmic delivery system for puerarin;Hongyi Qi et al.;《International Journal of Pharmaceutics》;20070107;第337卷;第178-187页 * |
| Modulation of the rheological and mucoadhesive properties of thermosensitive poloxamerbased hydrogels intended for the rectal administration of quinine;A.A.Koffi et al.;《European Journal of Pharmaceutical Sciences》;20051231;第27卷;第328-335页 * |
| P（HEMA-co-MAA）纳米凝胶的制备与pH响应性;申迎华 等;《高分子材料科学与工程》;20121031;第28卷(第10期);第133-136页 * |
| 水凝胶角膜给药载体治疗大鼠角膜炎的实验观察;吕红玲 等;《广东药学学报》;20130830;第29卷(第4期);第407-411页 * |
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