CN109745298B - Oral berberine microcapsule nanoparticle chimeric preparation and administration scheme - Google Patents
Oral berberine microcapsule nanoparticle chimeric preparation and administration scheme Download PDFInfo
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Abstract
The invention discloses a preparation method and an oral application method of an oral berberine intestinal tract targeted delivery and long-short double-effect differential integration microcapsule nanoparticle chimeric preparation, and relates to a microcapsule prepared by preparing three components of a berberine small molecular compound, a biodegradable slow-release material and an enteric coating material according to a specific proportion, and a chimeric preparation formulation which is coated with berberine hydrochloride nanoparticles and carries the berberine hydrochloride nanoparticles by the berberine and the biodegradable slow-release material, so that not only can the content be effectively protected, but also a targeted specific intestinal section can play a first-dose effect provided by the microcapsule and a slow-release long-acting differential integration effect provided by the nanoparticles, the drug administration frequency is reduced and the drug administration compliance is improved while the bioavailability and the drug effect of a drug are improved.
Description
Technical Field
The invention relates to an oral chimeric preparation carrying berberine microcapsule-nanoparticles, which belongs to the field of development of intestinal targeted delivery differential integration systems, and particularly relates to a chimeric body formed by berberine hydrochloride and biodegradable sustained-release material-carried berberine nanoparticles which are simultaneously present in an enteric coating microcapsule according to a specific proportion by adopting three components of a biodegradable sustained-release material, an enteric coating material and berberine, so as to play the roles of intestinal targeted delivery and long-and-short double-effect differential integration.
Background
Berberine is a natural quaternary amine isoquinoline alkaloid mainly contained in Coptidis rhizoma of Ranunculaceae, cortex Phellodendri of Rutaceae, and radix Berberidis Amurensis of berberidaceae. Berberine in nature usually exists in the form of quaternary ammonium salt, and hydrochloride, hydroiodide, sulfate and nitrate thereof are all difficult to dissolve in water, and hydrochloride thereof is widely used clinically. Modern pharmacological studies prove that the berberine has multiple effects of resisting bacteria, diminishing inflammation, resisting intestinal infection, resisting arrhythmia, dilating coronary vessels, reducing blood fat, reducing blood sugar, resisting tumors, resisting platelet aggregation, resisting peptic ulcer, promoting bile secretion, exciting cerebral cortex, relaxing vascular smooth muscle, exciting uterus, bladder, bronchus, gastrointestinal smooth muscle and the like. The berberine-containing plant has wide sources, and has the characteristics of broad drug effect composite spectrum and small side effect, so the berberine compound has wide development and application prospects.
The berberine hydrochloride preparation on the market at present mainly takes tablets and capsules. The intravenous injection is used for causing vasodilatation, blood pressure reduction and cardiac arrest, and has the occurrence of an Ass syndrome and even death in severe cases, and the use of the intravenous injection is forbidden. The berberine hydrochloride tablets and capsules have extremely low intestinal absorption rate, liver first-pass effect and poor bioavailability, are difficult to transport to a diseased part or cells, and need to be taken for a long time without interruption, thereby greatly limiting the application and popularization of the berberine hydrochloride tablets and capsules in clinic. Due to the prominent effects of berberine in immunoregulation, inflammation resistance, cancer resistance and the like, the fixed-point delivery in a specific intestinal segment is realized by developing a novel oral berberine preparation, the local bioavailability and the long-acting immune effect in an intestinal immune system are improved, and the berberine preparation has very important significance in promoting the clinical application development of natural small molecular compounds such as berberine and the like.
In order to solve the disadvantage of extremely low intestinal absorption rate of oral berberine and increase water solubility or lipid solubility of berberine, the development of a novel drug delivery system to improve bioavailability becomes the key point of the drug development. Research shows that berberine is coated and prepared into nanoparticles to promote intestinal tract intake[1]In addition, polymer is adopted to encapsulate berberine, so as to prevent intestinal acid and alkali damage, provide slow release effect and play an antibacterial role[2,3]. In addition, soybean phospholipid is adopted to include berberine hydrochloride to form berberine phospholipid complex (BBR-SPC), which greatly improves lipid solubility and encapsulation efficiency of berberine hydrochloride[4]. The nanometer self-emulsifying berberine hydrochloride delivery system (SNEDDS) is prepared by adopting the solubilizer, so that the solubility of the nano self-emulsifying berberine hydrochloride delivery system is effectively improved, and the in-vivo effective utilization rate is increased[5]. The development of biodegradable nanoparticles, microparticles, emulsions, nanoparticles and lipid vehicles based on oral delivery systems has become a new challenge in recent years[6-9]。
Poly (lactic-glycolic acid), PLGA]Has good biocompatibility, no toxicity, encapsulation and film-forming properties, and has wide application in the biomedical field[10]. PLGA has slow release effect, and can prolong the acting time of the medicine on body. Many researches prove that the polymer PLGA and the polyethylene material have certain immunostimulation effect and can assist in activating the immune activation path[11-13]And simultaneously improves the bioavailability and in vivo distribution of the contents. The PLGA is used for simulating the size and the composition of pathogens and cooperating with antigens and adjuvants, so that the immune response of activated CD8+ T cells and B cells can be effectively induced in the intestinal tract[16]. Research on the preparation of a duodenum-targeted pH-sensitive microparticle system (DSM) with a three-layer structure and targeting, mucosa attachment and pH sensitivity by adopting an emulsion coagulation coating method proves that the berberine hydrochloride targeted preparation has the drug concentration which is improved by a plurality of times in the duodenum mucosa compared with the solution of the berberine hydrochloride targeted preparation[17]Provides a new idea for the development of a novel antibacterial preparation.
Polyacrylic acid resin (methacrylate) as a biocompatible enteric material can release contents in small intestine or large intestine according to the change of intestinal pH[18]. The Eudragit entraps the nanoparticles into microspheres, so that the bioavailability is increased, and the microspheres show good targeting effect after passing through the colon[19]. Oral intestinal localization inoculation research finds that the Eudragit FS30D coating system with the characteristic of large intestine schizolysis can release and absorb the coated nano particles in the large intestine mucous membrane, but rarely be absorbed in the small intestine, thereby causing specific large intestine mucous membrane immune protection reaction[20]. These studies indicate that the Eudragit enteric sustained-release material can produce better intestinal targeting effect.
Therefore, the novel oral berberine micro-capsule nano-particle chimeric preparation with intestinal tract targeted delivery and long-and-short double-effect differential integration is prepared by adopting a slow-release material PLGA, an enteric-coated material Eudragit and a berberine small molecular compound according to a specific proportion, so that the purposes of generating a preset intestinal tract first-agent effect and a slow-release long-acting double-effect are achieved, the bioavailability and the drug effect of the medicine are improved, the administration frequency is reduced, the administration compliance is improved, the treatment or function regulation effect of the oral berberine on major diseases such as autoimmune diseases, tumors, cardiovascular diseases, metabolic diseases, infectious diseases and the like is specifically enhanced, and the clinical application and popularization of natural medicines such as the berberine are better promoted.
Disclosure of Invention
The invention provides a prescription research of an oral berberine hydrochloride microcapsule nanoparticle chimeric preparation, which has the functions of intestinal targeted delivery and long-short double-effect differential integration, improves the bioavailability and the drug effect of a drug in a specific intestinal segment, reduces the drug administration times, improves the drug administration compliance, is suitable for people of different ages, and has very wide application prospect.
The invention provides an oral berberine microcapsule nanoparticle chimeric preparation which mainly comprises the following components: the berberine hydrochloride, the biodegradable sustained-release material-loaded berberine hydrochloride nano-particles and the enteric coating material are respectively prepared from the following raw materials in percentage by mass: 1-10: 1-50: 1-200, mixing the enteric coating material and the berberine hydrochloride to form an outer layer of the microcapsule, and carrying the berberine hydrochloride by the biodegradable slow-release material to form nanoparticles to be embedded in the microcapsule.
The oral berberine microcapsule nanoparticle chimeric preparation comprises the following other components: surfactant, organic solvent, skeleton supporting excipient, plasticizer and lubricant.
The outer diameter of the berberine micro-capsule nano-particle chimeric preparation is 1-100 mu m, and the capsule contains nano-particles.
The size of the berberine hydrochloride-loaded biodegradable slow-release material nano particle is 50 nm-1000 nm.
The biodegradable slow-release material in the berberine hydrochloride-loaded biodegradable slow-release material nanoparticle is selected from one or more of poly (lactic acid-glycolic acid) copolymer, starch, cellulose, polysaccharide, chitin, chitosan and derivatives thereof, polyhydroxyalkyl alcohol ester, poly (beta-malate), poly-alpha-hydroxy acid esters, polycaprolactone and polycyanoacrylate; the biodegradable sustained-release material in the berberine hydrochloride-loaded biodegradable sustained-release material nanoparticle is poly (lactic acid-glycolic acid) copolymer.
The enteric coating material can be one or more selected from acrylic resin, shellac, cellulose acetate phthalate, alginate jelly, polyvinyl alcohol acetate phthalate and hydroxypropyl methyl cellulose phthalate.
The surfactant is polyvinyl alcohol, and the concentration of the polyvinyl alcohol is 0.1-10%.
The organic solvent is selected from one or more of acetone, dichloromethane, chloroform, absolute ethyl alcohol and ethyl acetate.
The skeleton supporting excipient is selected from one or more of mannitol, trehalose, lactose, sucrose, sorbitol and glucose, and the mass ratio of the skeleton supporting excipient to the biodegradable sustained-release material berberine hydrochloride nanoparticle-loaded material is 2.5: 1.
The plasticizer is selected from any one of triethyl citrate, polyethylene glycol 6000, tributyl citrate and dibutyl sebacate.
The lubricant is selected from one of talcum powder, magnesium stearate and glyceryl monostearate.
Preferably, the preparation method of the oral berberine microcapsule nanoparticle chimeric preparation is characterized in that the mass ratio of berberine hydrochloride, poly (lactic acid-glycolic acid) berberine hydrochloride nanoparticles prepared by adopting poly (lactic acid-glycolic acid) copolymer and polyacrylic resin as enteric coating material is 1-10: 1-50: 1-200 respectively, and the oral berberine microcapsule nanoparticle chimeric preparation is prepared according to the following steps:
(1) weighing 1-10 parts of berberine hydrochloride, and adding hot water to dissolve to form a water phase;
(2) weighing 1-100 parts of polylactic acid-glycolic acid copolymer, and adding dichloromethane to form an oil phase;
(3) dropwise adding the water phase into the oil phase, and emulsifying to form emulsion;
(4) adding the formed emulsion into 5-50 parts of surfactant solution, continuously emulsifying, volatilizing to remove dichloromethane at room temperature, and curing to form poly (lactic acid-glycolic acid) berberine hydrochloride-loaded nanoparticles;
(5) filtering the formed poly (lactic acid-glycolic acid) berberine hydrochloride nanoparticles through microporous filter membranes of 0.45 mu m and 0.22 mu m to obtain uniform poly (lactic acid-glycolic acid) berberine hydrochloride nanoparticles, adding the poly (lactic acid-glycolic acid) berberine hydrochloride nanoparticles into a framework support excipient, freezing at low temperature, and sublimating in vacuum to remove water in the poly (lactic acid-glycolic acid) berberine hydrochloride nanoparticles to obtain poly (lactic acid-glycolic acid) berberine hydrochloride nanoparticle solid powder;
(6) preparing polyacrylic resin enteric coating solution, and filtering by using a warp mesh to form milky semitransparent enteric coating solution;
(7) adding berberine hydrochloride into the enteric coating solution to form polyacrylic resin berberine hydrochloride-containing enteric coating solution;
(8) adding poly (lactic acid-glycolic acid) berberine hydrochloride nanoparticle solid powder into enteric coating solution, adding plasticizer, lubricant, and warp mesh, filtering, conveying with peristaltic pump, and spray drying to obtain oral berberine microcapsule nanoparticle chimeric preparation.
The preparation method of the poly (lactic acid-glycolic acid) berberine hydrochloride-loaded nanoparticles has the emulsification strength of 10000-35000 rpm; the stirring speed for volatilizing and removing the organic solvent and curing is 300-1000 rpm, and the stirring time is 4-12 h.
The inlet temperature of the spray drying is 40-200 ℃.
The preparation method of the poly (lactic acid-glycolic acid) berberine hydrochloride-loaded nanoparticles is selected from an emulsification method, an emulsification ultrasonic method, a self-assembly method and a film dispersion method.
The invention is also suitable for preparing other two components without nanoparticles, namely preparing the coating material and the berberine hydrochloride into different dosage forms together. The oral berberine hydrochloride microcapsule nanoparticle chimeric preparation has the characteristics of fixed-point delivery of intestinal segments and slow-release long-acting dual action in intestines because the berberine exists in the Eudragit microcapsule outer covering layer and the PLGA nanoparticles at the same time. Therefore, the chimeric system of microencapsulated nanoparticles of the present invention can be administered in cycles and at periodic intervals. The oral preparation is taken once a day in each administration period, and can be taken once or continuously for a plurality of times or for a plurality of times at intervals of 1-2 days. The dosing interval may be 1 week to 2 months. The microcapsule nanoparticle chimeric preparation can be used alternately with intestinal tract targeting microcapsule preparations, such as: alternating use within the dosing cycle, or use at intervals of the dosing cycle.
Because the micro-capsule nano-particle chimeric system has the effects of intestinal targeting and long-term effect, the drug administration frequency is reduced, the drug administration compliance is improved while the bioavailability and the drug effect of the drug are improved, and the clinical popularization and application prospect is very huge.
Drawings
Fig. 1 is a structural diagram of the berberine hydrochloride-bearing microcapsule-nano chimeric preparation for intestinal tract targeted delivery and long-short double-effect differential integration of oral berberine.
Fig. 2 is a schematic administration diagram of the oral berberine sustained-release microcapsule nanoparticle chimeric preparation, and the oral administration strategy adjusts the administration period and dosage according to different applicable populations and the specific conditions of occurrence and development changes of diseases in the prevention and treatment administration process due to different compositions of the novel preparation, so as to guide the administration.
FIG. 3 is an appearance shape chart of PLGA nanoparticles and an oral berberine hydrochloride microcapsule nanoparticle chimeric preparation prepared by the invention (the left is PLGA berberine nanoparticle freeze-dried powder, and the right is the oral berberine hydrochloride microcapsule nanoparticle chimeric preparation).
FIG. 4 is a scanning electron microscope image of PLGA berberine nanoparticles of the present invention.
FIG. 5 is a particle size distribution diagram of PLGA berberine nanoparticles of the present invention.
FIG. 6 is the zeta potential diagram of the PLGA berberine nanoparticle surface in the present invention.
Detailed Description
The present invention will be further described with reference to the following examples, but it should not be construed that the scope of the present invention as defined above is limited to the following examples. Various alterations and modifications can be made without departing from the technical spirit of the invention, and the scope of the invention is intended to be covered by the invention in accordance with the general technical knowledge and common practice in the field.
Example 1
The structural diagram of the microcapsule nanoparticle chimeric preparation is prepared by three components of PLGA, Eudragit FS30D and berberine hydrochloride according to a specific proportion (figure 1). In the invention, an analysis method is established by adopting an ultraviolet spectrophotometer as a detection means for quality control optimization, and the method is feasible and meets the requirements of pharmaceutics. Taking the dosage of the medicine, the dosage of the organic solvent, the dosage of PLGA and the concentration of polyvinyl alcohol as the investigation factors of the prescription, taking the emulsification strength, the emulsification time, the stirring speed and the stirring time as the investigation factors of the process, and optimally designing L9 (3) according to four factors and three levels4) And (4) optimizing the optimal proportion and the optimal process of the prescription by testing to obtain the proper prescription and process.
Weighing 3mg of berberine hydrochloride, and dissolving the medicine by taking water as a solvent to form a water phase; weighing PLGA (50 mg) and dissolving the PLGA in dichloromethane to serve as an oil phase; gradually adding the water phase into the oil phase drop by drop, and emulsifying to obtain primary emulsion; pouring the formed primary emulsion into 5ml of 1% polyvinyl alcohol aqueous solution, emulsifying for 15min at 25000rpm to obtain pre-compounded emulsion, pouring the pre-compounded emulsion into 35ml of 0.5% polyvinyl alcohol aqueous solution, magnetically stirring for 4-12h at room temperature, volatilizing to remove dichloromethane, solidifying, 10000rcf, and centrifuging for 20min to obtain berberine hydrochloride PLGA nanoparticles; centrifuging for 10min at 10000rcf, washing for 3-5 times, manually filtering through needle filter membranes of 0.45 mu m and 0.22 mu m to obtain uniform berberine hydrochloride PLGA nanoparticles, adding a skeleton support excipient with the mass fraction of 5% into the optimally prepared berberine nanoparticle solution, stirring for 3min to dissolve the berberine hydrochloride PLGA nanoparticles, subpackaging 2ml of each bottle into a cillin bottle, pre-freezing for 4h at-40 ℃, carrying out sublimation drying at the pressure of 20Pa, maintaining for 8h at-40 ℃, heating to-30 ℃ for 4h, maintaining for 4h at-15 ℃, maintaining for 4h at 0 ℃, carrying out analysis drying at the pressure of 30Pa, and maintaining for 8h at 25 ℃ to obtain berberine PLGA freeze-dried powder, and observing the form (figure 3).
Weighing Eudragit FS30D 2.67.67 g, adding 39.25g of 95% ethanol solution to prepare 2% Eudragit FS30D coating solution, mixing well, filtering with 40 mesh gauze to obtain uniform enteric coating solution. Weighing 10g of berberine hydrochloride and 200g of enteric coating liquid, and stirring and mixing uniformly to obtain the embedded microcapsule coating liquid.
Weighing 12g of berberine hydrochloride PLGA nano-particles and the embedded microcapsule coating liquid, stirring and mixing, filtering by a 40-mesh gauze, spraying the mixed liquid by spray drying, wherein the air inlet temperature is 42 ℃, the air outlet temperature is 28 ℃, and finally preparing the microcapsule nano-particle embedded preparation containing the berberine nano-particles and the berberine small-molecular compound. The appearance of the novel oral berberine micro-capsule nano-particle chimeric preparation (figure 3).
The freeze-dried powder of the obtained PLGA berberine nanoparticles is directly and uniformly dispersed on a carrying table of conductive adhesive under the vacuum condition, the surface is sprayed with gold, and the morphology of the berberine nanoparticles is observed under a scanning electron microscope at 20mV for 20min (figure 4). At room temperature, the berberine nanoparticle solution prepared according to the optimal formula is diluted with water and placed in a sample cell to measure the size and distribution of the particle size (figure 5). The berberine nanoparticle solution prepared according to the optimal prescription is placed in a sample pool, and the zeta potential of the berberine nanoparticles is measured by a zeta potential analyzer (figure 6).
Citations
1.Chen,W.,et al.,Bioavailability study of berberine and the enhancing effects of TPGS on intestinal absorption in rats.AAPS PharmSciTech,2011.12(2):p.705-11.
2.Yu,S.H.,et al.,Preparation of fucoidan-shelled and genipin-crosslinked chitosan beads for antibacterial application.Carbohydr Polym,2015.126:p.97-107.
3.Chang,C.H.,et al.,Development of novel nanoparticles shelled with heparin for berberine delivery to treat Helicobacter pylori.Acta Biomater,2011.7(2):p.593-603.
4.Yu,F.,et al.,PEG-lipid-PLGA hybrid nanoparticles loaded with berberine-phospholipid complex to facilitate the oral delivery efficiency.Drug Deliv,2017.24(1):p.825-833.
5.Zhu,J.X.,et al.,Development of self-microemulsifying drug delivery system for oral bioavailability enhancement of berberine hydrochloride.Drug Dev Ind Pharm,2013.39(3):p.499-506.
6.Simoes,S.M.,et al.,Polymeric micelles for oral drug administration enabling locoregional and systemic treatments.Expert Opin Drug Deliv,2015.12(2):p.297-318.
7.Agrawal U,S.R.,Gupta M,Vyas SP]Is nanotechnology a boon for oral drug deliveryDrug Discovery Today,2014.19(10):p.1530-46.
8.Zhang,L.W.,S.；Zhang,M.；Sun,J,Nanocarriers for oral drug delivery.J.Drug Targeting,2013.21(6):p.511-27.
9.Kohli,K.,et al.,Self-emulsifying drug delivery systems:an approach to enhance oral bioavailability.Drug Discov Today,2010.15(21-22):p.958-65.
10.Anand,P.,et al.,Design of curcumin-loaded PLGA nanoparticles formulation with enhanced cellular uptake,and increased bioactivity in vitro and superior bioavailability in vivo.Biochem Pharmacol,2010.79(3):p.330-8.
11.Andorko,J.I.,et al.,Intrinsic immunogenicity of rapidly-degradable polymers evolves during degradation.Acta Biomater,2016.32:p.24-34.
12.Andorko,J.I.,K.L.Hess,and C.M.Jewell,Harnessing biomaterials to engineer the lymph node microenvironment for immunity or tolerance.AAPS J,2015.17(2):p.323-38.
13.Sharp,F.A.,et al.,Uptake of particulate vaccine adjuvants by dendritic cells activates the NALP3 inflammasome.Proc Natl Acad Sci U S A,2009.106(3):p.870-5.
14.Zhang,H.Y.,et al.,Ergosterol-loaded poly(lactide-co-glycolide)nanoparticles with enhanced in vitro antitumor activity and oral bioavailability.Acta Pharmacol Sin,2016.37(6):p.834-44.
15.Khemani,M.,M.Sharon,and M.Sharon,Encapsulation of Berberine in Nano-Sized PLGA Synthesized by Emulsification Method.ISRN Nanotechnology,2012.2012:p.1-9.
16.Moon,J.J.,et al.,Antigen-displaying lipid-enveloped PLGA nanoparticles as delivery agents for a Plasmodium vivax malaria vaccine.PLoS One,2012.7(2):p.e31472.
17.Zhu,X.,et al.,A novel microsphere with a three-layer structure for duodenum-specific drug delivery.Int J Pharm,2011.413(1-2):p.110-8.
18.Bott,C.,et al.,In vivo evaluation of a novel pH-and time-based multiunit colonic drug delivery system.Aliment Pharmacol Ther,2004.20(3):p.347-53.
19.Lamprecht,A.,et al.,A pH-sensitive microsphere system for the colon delivery of tacrolimus containing nanoparticles.J Control Release,2005.104(2):p.337-46.
20.Zhu,Q.,et al.,Large intestine-targeted,nanoparticle-releasing oral vaccine to control genitorectal viral infection.Nat Med,2012.18(8):p.1291-6.
Claims (3)
1. An oral berberine microcapsule nanoparticle chimeric preparation is characterized in that the main components of the microcapsule nanoparticle chimeric preparation are as follows: the berberine hydrochloride, the biodegradable sustained-release material-loaded berberine hydrochloride nano-particles and the enteric coating material are respectively prepared from the following raw materials in percentage by mass: 1-10: 1-50: 1-200, mixing the enteric coating material and berberine hydrochloride to form an outer layer of the microcapsule, and carrying the berberine hydrochloride by the biodegradable slow-release material to form nanoparticles which are embedded in the microcapsule;
the biodegradable slow-release material in the berberine hydrochloride-loaded biodegradable slow-release material nanoparticle is selected from one or more of poly (lactic acid-glycolic acid) copolymer, starch, cellulose, polysaccharide, chitin, chitosan and derivatives thereof, polyhydroxyalkyl alcohol ester, poly (beta-malate), poly-alpha-hydroxy acid esters, polycaprolactone and polycyanoacrylate;
the oral berberine microcapsule nanoparticle chimeric preparation comprises the following other components: surfactant, organic solvent, framework support excipient, plasticizer and lubricant; the surfactant is polyvinyl alcohol, and the concentration of the polyvinyl alcohol is 0.1-10%; the organic solvent is selected from one or more of acetone, dichloromethane, chloroform, absolute ethyl alcohol and ethyl acetate; the skeleton supporting excipient is selected from one or more of mannitol, trehalose, lactose, sucrose, sorbitol and glucose, and the mass ratio of the skeleton supporting excipient to the biodegradable sustained-release material berberine hydrochloride nanoparticle-loaded material is 2.5-10: 1; the plasticizer is selected from any one of triethyl citrate, polyethylene glycol 6000, tributyl citrate and dibutyl sebacate;
the lubricant is selected from one of talcum powder, magnesium stearate and glyceryl monostearate;
the enteric coating material is selected from one or more of acrylic resin, shellac, phthalic acid cellulose acetate, seaweed gel, polyvinyl alcohol phthalate acetate and hydroxypropyl methyl cellulose phthalate.
2. The oral berberine microcapsule nanoparticle chimeric preparation according to claim 1, wherein the berberine microcapsule nanoparticle chimeric preparation has an outer diameter of 1 μm to 100 μm and contains nanoparticles inside.
3. The oral berberine microcapsule nanoparticle chimeric preparation of claim 1, wherein the size of the berberine hydrochloride-loaded biodegradable sustained-release material is 50 nm-1000 nm.
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1593504A (en) * | 2004-07-15 | 2005-03-16 | 天津大学 | Microencapsulation method of Chinese traditional medicine |
| CN101006991A (en) * | 2005-09-26 | 2007-08-01 | 刘凤鸣 | Slow release preparation of berberine |
| CN102949375A (en) * | 2012-11-28 | 2013-03-06 | 厦门大学附属第一医院 | Berberine hydrochloride solid lipid nano preparation and preparation method thereof |
| CN103417515A (en) * | 2013-08-07 | 2013-12-04 | 中山大学 | Biodegradable nanoparticle-entrapped oral colon-targeted micro-capsule and preparation method thereof |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN1593504A (en) * | 2004-07-15 | 2005-03-16 | 天津大学 | Microencapsulation method of Chinese traditional medicine |
| CN101006991A (en) * | 2005-09-26 | 2007-08-01 | 刘凤鸣 | Slow release preparation of berberine |
| CN102949375A (en) * | 2012-11-28 | 2013-03-06 | 厦门大学附属第一医院 | Berberine hydrochloride solid lipid nano preparation and preparation method thereof |
| CN103417515A (en) * | 2013-08-07 | 2013-12-04 | 中山大学 | Biodegradable nanoparticle-entrapped oral colon-targeted micro-capsule and preparation method thereof |
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