CN111773181B - Simvastatin-loaded bone-targeting composite lipid nanoparticle and application thereof - Google Patents
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Abstract
The invention provides a simvastatin-loaded bone-targeting composite lipid nano-material and application thereof. Amorphous calcium carbonate nanoparticles are used as a core, and a simvastatin/soybean lecithin compound, glyceryl monostearate and tetracycline stearic acid grafting material are sequentially coated on the surface of the amorphous calcium carbonate nanoparticles. The calcium supplement and the simvastatin can achieve synergistic treatment effects by coating with relatively stable glyceryl monostearate in the gastrointestinal tract, carrying out bone targeting modification with tetracycline stearic acid graft, and carrying a soybean phospholipid/simvastatin complex. The nanoparticle can be orally taken, and the compliance of patients is improved. The bone targeting effect can transport more calcium supplement and simvastatin to the bone tissue part, and the effect of the calcium supplement and the simvastatin for synergistically treating the osteoporosis is realized.
Description
Technical Field
The invention belongs to the field of pharmacy, and relates to simvastatin-loaded bone-targeting composite lipid nanoparticles and application thereof in preparation of a medicament for treating osteoporosis.
Background
Osteoporosis is a disease of the skeletal system characterized primarily by a degenerative change in the microstructure of bone tissue, increased bone fragility, decreased bone mass, and an increased risk of secondary fractures. The most serious symptom of osteoporosis is fracture, different from common fracture, osteoporosis fracture is brittle fracture with low energy, and short-term treatment is difficult to take effect while the probability of comminuted fracture is greatly increased, thus seriously affecting the life quality of patients. The elderly population and postmenopausal women are high-incidence population of osteoporosis, the incidence rate of the osteoporosis is higher and higher along with the increasing aging of population, and the situation of preventing and treating the osteoporosis in China is very severe.
The existing medicines for treating osteoporosis are common calcium supplements such as calcium tablets, and are bone resorption inhibitors such as estrogen, calcitonin, bisphosphonate and the like, which can only properly relieve the symptoms of osteoporosis, but can not reverse bone mass and repair damaged bone tissues. The drugs that promote bone formation are undoubtedly the focus of current research. Simvastatin is the first choice of medicine in clinic for hyperlipidemia diseases. Mundy et al found that simvastatin can increase bone morphogenetic protein expression of osteoblasts in rats after a series of in vivo experiments on rats, and has strong capacity of inducing osteoblast differentiation. This provides a completely new direction for the treatment of osteoporosis. However, the traditional administration mode has difficulty in reaching the bone tissue to exert the effect with high efficiency because of the poor permeability of the bone tissue. High dose administration tends to increase systemic toxic side effects. The targeted modified Drug Delivery System (DDS) can improve the delivery efficiency of hydrophobic compounds by increasing the solubility of drugs; the efficacy of drugs with short biological half-lives is prolonged by sustained release of the drug; and limits the absorption of nonspecific cells to drugs by reducing the phagocytosis of macrophages; the medicine can be concentrated at the diseased Du part to realize targeted therapy.
Calcium carbonate, a natural, non-toxic biomaterial, has been widely used in the biomedical field due to its advantages of good biocompatibility, low cost, simple chemical composition, etc. By means of two-phase permeation process, reversed microemulsion process, chemical precipitation process, gas diffusion process and other processes, superfine (below 50 nm) to several micron size calcium carbonate particle may be obtained to meet different medicine feeding requirement. Calcium carbonate has been successfully used today as a delivery vehicle for drugs, genes and proteins. Amorphous calcium carbonate, a special member of the calcium carbonate family, also has the above advantages, but its water stability is relatively low. The composite calcium carbonate nanoparticles can further optimize the size and performance of the nanoparticles due to the combination of the advantages of organic-inorganic materials, and can greatly improve the treatment potential of a calcium carbonate-based drug delivery system. Early-stage research in a laboratory discovers that the surface of the amorphous calcium carbonate nanoparticle can be subjected to appropriate lipid modification, so that the stability of the amorphous calcium carbonate nanoparticle in a water environment is realized, and the amorphous calcium carbonate nanoparticle can be used as a carrier with the function of a calcium supplement. Therefore, the invention takes simvastatin as a model drug, takes lipid-modified amorphous calcium carbonate nanoparticles as a carrier and a calcium supplement, and carries out surface modification on bone targeting group tetracycline to prepare the bone targeting composite lipid nanoparticles, thereby realizing the combined treatment of osteoporosis by calcium and SIM. Finally, in view of the need of disease treatment, the present invention continues to explore lipid nanocarriers that can be orally administered based on the previous combination therapy in order to improve patient compliance. Because the glyceryl monostearate is relatively stable in the gastrointestinal tract, the lipid-modified amorphous calcium carbonate nanoparticles are loaded into the glyceryl monostearate, and the bone targeting group tetracycline is modified to obtain the oral bone targeting composite lipid nanoparticles, which have good treatment effect on osteoporosis.
Disclosure of Invention
The invention provides a simvastatin-carrying bone-targeting composite lipid nanoparticle, which takes an amorphous calcium carbonate nanoparticle as a core, and the surface of the nanoparticle is sequentially coated with a simvastatin/soybean lecithin compound, glyceryl monostearate and tetracycline stearic acid graft.
The second purpose of the invention is to provide a preparation method of simvastatin-loaded bone-targeting complex lipid nanoparticles, which comprises the following steps:
1. mixing the ethanol solution of the soybean lecithin and the ethanol solution of the simvastatin according to the weight ratio of the simvastatin to the soybean lecithin of 1: 2-1: 4, and volatilizing the ethanol by a rotary evaporator to obtain the simvastatin/soybean lecithin compound. Wherein the weight ratio of simvastatin to soybean lecithin is optimal to be 1: 3.
2. After the simvastatin/soybean lecithin compound is dispersed in ethanol, adding the mixture into an ethanol solution of amorphous calcium carbonate according to the weight ratio of the amorphous calcium carbonate to the soybean lecithin of 1:1, stirring and compounding, and centrifuging to remove large particles to obtain the simvastatin-loaded composite lipid nanoparticle ethanol solution.
3. Carrying out simvastatin composite lipid nanoparticle-loaded ethanol solution and glyceryl monostearate ethanol solution according to the weight ratio of glyceryl monostearate: and mixing the simvastatin-loaded composite lipid nanoparticles in a weight ratio of 0.5: 1-2: 1, adding an ethanol solution of the tetracycline stearic acid graft (the tetracycline stearic acid graft: glyceryl monostearate: 0.2:1, w/w), stirring, injecting into water with a volume more than 9 times of that of the mixture, and continuously stirring for 5min to obtain the simvastatin-loaded bone-targeted composite lipid nanoparticle suspension. Wherein glyceryl monostearate: the weight ratio of the simvastatin-loaded composite lipid nanoparticle is 1:1, which is optimal.
The third purpose of the invention is to provide the application of the simvastatin-loaded bone-targeting composite lipid nanoparticle in the preparation of the osteoporosis treatment drug. The administration route of the medicament is oral administration.
The invention has the advantages that: the simvastatin-loaded bone-targeting composite lipid nanoparticle is coated by glyceryl monostearate which is relatively stable in gastrointestinal tract, and the tetracycline stearic acid graft is used for bone-targeting modification, and meanwhile, the soybean phospholipid/simvastatin composite is carried, so that the synergistic treatment effect of a calcium supplement and simvastatin can be realized. Simvastatin has strong transport capacity across cell membranes and duodenum after being coated by lipid materials. Both simvastatin and calcium supplements have a greater combined therapeutic effect in increasing bone mass than monotherapy. The simvastatin-loaded bone-targeting composite lipid nanoparticle can restore bone mass to the same level as that of a healthy rat, has the maximum gastrointestinal transport amount and the fastest speed, can be orally taken, improves the compliance of a patient, and can transport more calcium supplements and simvastatin to bone tissue parts under the action of bone targeting, thereby realizing the effect of synergistically treating osteoporosis.
Drawings
Fig. 1 shows the transport amount of simvastatin-loaded bone-targeting complex lipid nanoparticles across single-layer membranes of MDCK cells.
FIG. 2 shows the transduodenal transport amount of simvastatin-loaded bone-targeting complex lipid nanoparticles.
FIG. 3 is a bone density quantitative analysis of simvastatin-loaded bone-targeting complex lipid nanoparticles (E) and normal group (A), castration group (B), simvastatin group (C), calcium supplement group (D).
Fig. 4 bone tomography images of simvastatin-loaded bone-targeting complex lipid nanoparticles (E) and normal group (a), castration group (B), simvastatin group (C), calcium supplement group (D).
Detailed Description
The invention is further illustrated by means of examples and figures.
Example one
(1) Preparation of simvastatin-loaded bone-targeted composite lipid nanoparticles
Taking 200mg of CaCl2Precisely weighing, dissolving in 300 μ L of ultrapure water, dripping the solution into 100mL of absolute ethanol, placing in a round-bottomed flask, and sealing the round-bottomed flask with a sealing film. After reserving a little air hole on the sealing film, the round bottom flask is filled with 3g of (NH)4)2CO3The glass bottles are placed in a dryer together, and gas diffusion reaction is carried out in a constant temperature and humidity box at the temperature of 30 ℃. After reacting for 2-3 days, the anhydrous ethanol in the round-bottom flask is centrifuged (15000rpm for 10min) to obtain white precipitated amorphous calcium carbonate nanoparticles. Dispersing the obtained amorphous calcium carbonate nanoparticles by using a proper amount of absolute ethyl alcohol, and then dispersing by using a probe ultrasonic instrument (400W, working for 2s, stopping for 3s, and performing ultrasonic treatment for 20 times) for later use. Putting the ethanol solution of the soybean lecithin and the ethanol solution of the simvastatin into a round-bottom flask according to a certain proportion, putting the round-bottom flask on a reduced-pressure rotary evaporator, and obtaining the compound of the simvastatin and the soybean lecithin after the ethanol is completely volatilized. Re-dispersing the complex with ethanol, adding into ethanol solution of amorphous calcium carbonate (amorphous calcium carbonate: soybean lecithin ═ 1:1, w/w), stirring at 37 deg.C overnight for compounding, centrifuging at 3000rpm to remove large particles, and obtaining the simvastatin-loaded composite lipid nanoparticles. Mixing the ethanol solution carrying the simvastatin composite lipid nanoparticles and the ethanol solution of the glyceryl monostearate according to a certain proportion, adding the ethanol solution of the tetracycline stearic acid graft (the tetracycline stearic acid graft: the glyceryl monostearate is 0.2:1, w/w), stirring at 60 ℃ for 5min, injecting into 9 times of volume of water, and continuing stirring for 5 min. And (3) placing the newly prepared emulsion to room temperature to obtain the simvastatin bone-loaded targeted composite lipid nanoparticle for oral administration.
(2) Physicochemical property of simvastatin-loaded bone-targeting composite lipid nanoparticle
Oral simvastatin-carrying bone-targeting composite lipid nanoparticles with the concentration of about 1mg/mL are prepared by the method, deionized water is diluted to 100 mu g/mL, and the particle size and the potential of the Zetasizer 3000HS microparticles are measured by a surface potential analyzer.
And measuring the content of simvastatin in the drug-loaded composite lipid nanoparticles by adopting a high performance liquid chromatography. Breaking the oral dispersion liquid carrying the simvastatin bone targeting complex lipid nanoparticles by using an extracting solution (0.6M HCl: ethanol ═ 1:1, v/v), centrifuging at 20000rpm for 15 minutes, and determining the concentration of simvastatin in a supernatant by using a high performance liquid chromatography. The drug loading (DL%) of simvastatin was calculated according to the following formula.
DL％＝Wa/(W0+W)×100％
W0: dosage, Wa: content of free drug in supernatant after centrifugation, W: the quality of the drug-loaded composite lipid nanoparticles.
The physicochemical properties of simvastatin-loaded composite lipid nanoparticles prepared from Simvastatin (SIM), soybean Phospholipid (PL), and Glycerol Monostearate (GMS) at different ratios are shown in tables 1, 2, and 3.
TABLE 1 Simvastatin (SIM), soya lecithin (PL), Glycerol Monostearate (GMS) in different proportions
Particle size of prepared simvastatin-loaded composite lipid nanoparticle (SIM/PL/ACC)
TABLE 2 simvastatin carriers prepared with simvastatin, soya lecithin, glyceryl monostearate in different proportions
Potential of composite lipid nanoparticles
TABLE 3 simvastatin, soy phospholipid, and glycerol monostearate in various ratios
Drug loading of composite lipid nanoparticles
Example two bone targeting composite lipid nanoparticles (TC/GMS/ACC) transport amount across single-layer membrane of MDCK cell
Taking simvastatin and soybean lecithin 1:3, carrying out a single-layer membrane transport test on the ratio of 0.5: 1-2: 1 of the glyceryl monostearate to the bone targeting composite lipid nanoparticles. MDCK cells were seeded on Transwell's polyester membrane and cultured for 7 days to form a cell monolayer. After the HBSS washes a cell monolayer for three times, 0.5mL of oral complex lipid nanoparticles with 1mg/mL of fluorescent marker is added into an upper Transwell chamber for transmembrane transport for 4 hours, then all liquid in a lower chamber is taken out, and the transport amount of the oral complex lipid nanoparticles in the lower chamber is measured by a fluorescence spectrophotometer. As a result, as shown in FIG. 1, when the mass ratio of Glycerol Monostearate (GMS) to complex lipid nanoparticles (PL/ACC) was 1:1, 138.68. mu.g of nanoparticles were transported to the Transwell substrate side (the total amount of nanoparticles charged was 500. mu.g), and the transport amount was the greatest.
EXAMPLE III bone-targeting Complex lipid nanoparticles (TC/GMS/ACC) for oral administration Transduodenal Transporter
Taking simvastatin and soybean lecithin 1:3, carrying out duodenal transport amount research on the ratio of the glyceryl monostearate to the bone targeting composite lipid nano-particles of 0.5: 1-2: 1. Female SD rats (180-200g) are randomly divided into 3 groups, each group comprises 3 animals, and the animals are fasted for 12h (without water prohibition) before experiments. Rats were anesthetized with ether, decapitated, the abdominal cavity was opened, the duodenum about 10cm in length was quickly removed, immediately placed in Krebs-Ringer (K-R) enteral nutrient solution at 4 ℃, and the small intestine was inverted after brief washing. Ligating the everted intestinal segments with operation thread to obtain small bags with a length of about 10cm (one end is tied and the other end is fixed on a plastic tubule for sampling and supplementing fresh intestinal nutritionLiquid). Adding about 2mL of K-R intestinal nutrient solution into each small capsule, then placing the small capsules into a water bath shaking table at 37 ℃ for balancing for 10min, then respectively placing the turning-out intestinal capsules into a release pipe containing the K-R intestinal nutrient solution of the orally-taken composite lipid nanoparticles marked by fluorescence, and carrying out an ex-vivo small intestine transfer absorption experiment under the conditions of 37 ℃, 75rpm and continuous oxygen introduction (keeping the activity of the ex-vivo small intestine). Sampling 0.5mL from a plastic tube at preset time points of 15 min, 30 min, 45 min, 60 min, 80 min, 100 min and 120min respectively, simultaneously adding equal volume of fresh K-R intestinal nutrient solution, and finally measuring the fluorescence value of the sample by using a fluorescence spectrophotometer so as to calculate the unit intestinal area accumulation transport volume of the oral composite lipid nanoparticles at each time point. The transport time is used as a horizontal coordinate, the accumulated transport amount of the unit intestinal area is used as a vertical coordinate, and the transport condition of the oral composite lipid nanoparticles in the duodenum in vitro small intestine is mapped. The results are shown in figure 2, the transport amount of GMS modified bone targeting composite lipid nanoparticles through intestinal mucosa increases with time, and when GMS: PL/ACC is 1:1, the absorption transport amount is maximum and reaches 7.45 mu g/cm2. In addition, when GMS: PL/ACC is 1:1, the transport rate through the intestinal mucosa is maximized to 0.06. mu.g/cm2Permin, GMS: PL/ACC ═ 0.5:1 (0.0457. mu.g/cm), respectively2Permin) and GMS PL/ACC 2:1 (0.0445. mu.g/cm)21.31 times and 1.35 times/min).
Example four therapeutic effects of oral simvastatin-loaded bone-targeting complex lipid nanoparticles on osteoporosis
Castrated female SD rats were used as osteoporosis models. The drug administration is started 4 weeks after castration, all drugs are administered in an oral gavage mode, after 8 weeks, all SD rats are subjected to neck removal and killed, the total length of thighbone is taken, soft tissues are removed, 4% paraformaldehyde is fixed for 24 hours, then microcomputer tomography is carried out, bone density is analyzed, and CT Vox and dataviewer are used for reconstructing three-dimensional (3D) and two-dimensional (2D) images. Referring to fig. 3 and 4, it can be seen that the recovery of bone mass was improved to various degrees in both the simvastatin group and the calcium supplement group, regardless of the quantitative analysis of bone density or the qualitative observation of 2D and 3D. Wherein the simvastatin and calcium supplement combination treatment group has synergistic effect in bone mass recovery, and reaches the same level as the normal group.
Claims (4)
1. A suspension carrying simvastatin bone-targeting composite lipid nanoparticles is characterized in that the nanoparticles take amorphous calcium carbonate nanoparticles as a core, and the surfaces of the nanoparticles are sequentially coated with a simvastatin/soybean lecithin compound, glyceryl monostearate and a tetracycline stearic acid graft, and the suspension is realized by the following steps:
(1) mixing the ethanol solution of the soybean lecithin and the ethanol solution of the simvastatin according to the weight ratio of the simvastatin to the soybean lecithin of 1: 2-1: 4, and volatilizing the ethanol by a rotary evaporator to obtain a simvastatin/soybean lecithin compound;
(2) after the simvastatin/soybean lecithin compound is dispersed in ethanol, adding the mixture into an ethanol solution of amorphous calcium carbonate according to the weight ratio of the amorphous calcium carbonate to the soybean lecithin of 1:1, stirring and compounding, and centrifuging to remove large particles to obtain an ethanol solution carrying simvastatin composite lipid nanoparticles;
(3) carrying out simvastatin composite lipid nanoparticle-loaded ethanol solution and glyceryl monostearate ethanol solution according to the weight ratio of glyceryl monostearate: and mixing the simvastatin-loaded composite lipid nanoparticles in a weight ratio of 0.5: 1-2: 1, adding an ethanol solution of a tetracycline stearic acid graft, wherein the tetracycline stearic acid graft is glycerol monostearate =0.2:1, and w/w, stirring, injecting into water with a volume more than 9 times of that of the mixture, and continuously stirring for 5min to obtain the simvastatin-loaded bone-targeted composite lipid nanoparticle suspension.
2. The simvastatin bone-targeting complex lipid nanoparticle-loaded suspension according to claim 1, wherein the weight ratio of simvastatin to soybean lecithin in the step (1) of preparing the suspension is 1: 3.
3. The simvastatin bone-targeting complex lipid nanoparticle-loaded suspension according to claim 1, wherein the preparation of the suspension comprises the following steps (3): the weight ratio of the simvastatin-loaded composite lipid nanoparticle is 1: 1.
4. The application of the simvastatin bone-targeting complex lipid nanoparticle-loaded suspension disclosed by claim 1 in preparation of a medicine for treating osteoporosis.
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| 《Calcium Supplement by Tetracycline guided amorphous Calcium Carbonate potentiates Osteoblast promotion for Synergetic Osteoporosis Therapy》;Jianwei Wang et al.;《Theranostics》;20200709;第10卷(第19期);第8593页，摘要 * |
| 《固体脂质纳米粒作为药物载体》;李欣玮;《化学进展》;20070131(第1期);第1.2节 * |
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