CN109077994B - Small molecular hydrogel-nanoparticle composite drug carrier and application thereof in skin/mucosa drug delivery system - Google Patents
Small molecular hydrogel-nanoparticle composite drug carrier and application thereof in skin/mucosa drug delivery system Download PDFInfo
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Abstract
本发明公开了一种小分子水凝胶‑纳米粒复合药物载体及其在皮肤/粘膜给药系统中的应用，所述小分子水凝胶‑纳米粒复合药物载体包括载药纳米粒和小分子水凝胶，载药纳米粒分散在小分子水凝胶中，在载药纳米粒表面修饰有细胞穿膜肽。本发明的小分子水凝胶‑纳米粒复合载体用于皮肤/粘膜给药，通过在纳米粒表面修饰穿膜肽，可以显著提高药物的皮肤/粘膜及病灶部位的渗透性，小分子水凝胶解决了溶液剂型给药，药物易流失的问题。
The invention discloses a small-molecule hydrogel-nanoparticle composite drug carrier and its application in a skin/mucosal drug delivery system. The small-molecule hydrogel-nanoparticle composite drug carrier comprises drug-loaded nanoparticles and small Molecular hydrogel, drug-loaded nanoparticles are dispersed in small molecule hydrogel, and cell-penetrating peptides are modified on the surface of drug-loaded nanoparticles. The small-molecule hydrogel-nanoparticle composite carrier of the present invention is used for skin/mucosal administration. By modifying the penetrating peptide on the surface of the nanoparticle, the permeability of the drug to the skin/mucosal and the lesion site can be significantly improved. The glue solves the problem of solution dosage form administration and easy loss of drugs.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical preparations, and particularly relates to a small-molecular hydrogel-nanoparticle composite drug carrier and application thereof in a skin/mucosa drug delivery system.
Background
Skin/mucosal administration refers to the application of drugs through the skin or mucous membranes of various cavities (such as oral cavity, nasal cavity, lung, etc.). The administration mode can avoid the damage of the gastrointestinal tract to the medicine and the irritation of the medicine to the gastrointestinal tract, and compared with intravenous administration, the administration mode can directly administer the medicine at the skin/mucous membrane part of the focus, so that the medicine can quickly reach the focus part, the medicine concentration of the focus part is obviously improved, and the distribution of non-target tissues is reduced. Thus a simple, fast and patient-friendly route of administration. But the manner of dermal/mucosal administration also presents challenges: the drugs are absorbed through the skin or the surface of the mucous membrane and pass through the hydrophobic area of the cell lipid membrane, the hydrophobic structure has a limiting effect on the penetration of the drugs, and the outermost layer of the skin is a compact stratum corneum, so that the strong hydrophobic structure creates a larger barrier for the penetration of the drugs.
The passive diffusion of the drug penetrating through the biological membrane has close relation with the lipid solubility of the drug, the lipid solubility of the drug is generally measured by an oil/water partition coefficient, and the lipid solubility is large if the oil/water partition coefficient is large, so that the transmembrane transport of the drug is facilitated. The passive absorption rate of the medicine is related to the diffusion coefficient of the medicine, and the medicine with large molecular weight has large diffusion resistance and slow diffusion rate and is difficult to penetrate through skin, the surface biomembrane of the pulmonary alveoli, nasal mucosa and the like. Drugs suitable for transdermal/mucosal administration should have a large oil-water partition coefficient, and should not exceed a molecular weight of 1000, and thus are limited in kind.
The variety of transdermally delivered drugs can be expanded by increasing the drug permeability by some means. At present, there are many methods for improving the transdermal efficiency of drugs, which are mainly divided into an active type and a passive type, and the passive type method is a method using a chemical penetration enhancer, a biological peptide and a pharmaceutical preparation carrier, such as: lipid nanoparticles (liposomes), metal nanoparticles, polymer nanoparticles, and the like; active methods are those that disturb or disrupt the skin's barrier by physical means, such as microneedles, microwaves, iontophoresis, electroporation, sonophoresis, magnetic introduction, laser, etc.
However, the method of improving drug permeability by using drug preparation carriers such as lipid nanoparticles (liposomes), metal nanoparticles, polymer nanoparticles, and the like generally has the problems of short retention time of the preparation at the skin/mucosa administration site and frequent administration.
Disclosure of Invention
The invention aims to provide a small-molecular hydrogel-nanoparticle composite drug carrier and application thereof in a skin/mucosa drug delivery system.
The small molecular hydrogel-nanoparticle composite drug carrier comprises drug-loaded nanoparticles and small molecular hydrogel, wherein the drug-loaded nanoparticles are dispersed in the small molecular hydrogel; cell-penetrating peptide is modified on the surface of the drug-loaded nanoparticles.
Further, the drug-loaded nanoparticles are selected from liposomes, transfersomes, solid lipid nanoparticles, nanoemulsions, microemulsions, vesicles, dendrimers, micelles, polymeric nanoparticles or inorganic nanoparticles, such as carbon nanotubes, gold nanoparticles, quantum dots and the like.
Further, the drug loaded by the drug-loaded nanoparticles is selected from small molecule drugs, such as adriamycin, paclitaxel, hamporfin, ereoxib, vemurafenib and the like; or biological macromolecular drugs such as polypeptides, proteins, enzymes, hormones, vaccines, cell growth factors, monoclonal antibodies, glycans, and nucleic acids.
Further, the cell-penetrating peptide is selected from td (acssspskhcg), tat (grkkrrqrrrpq), T2(LVGVFH), 11R (rrrrrrrrrrrrrrr), R8H3(RRRRRRRRHHH), and the like.
Further, the small molecule hydrogel is formed by ordered arrangement and spontaneous aggregation of a gelator with the molecular weight of less than 2000 under the action of non-covalent bonds. Self-assembly of the system to form small molecule hydrogels can be initiated by changing pH, temperature, electric field, magnetic field, ionic strength, addition of chemicals, introduction of light or enzymes.
The application of the small molecular hydrogel-nanoparticle composite drug carrier in a skin/mucosa drug delivery system.
A small molecular hydrogel-transfersome composite drug carrier is composed of a drug-loaded transfersome and a small molecular hydrogel, wherein the drug-loaded transfersome is dispersed in the small molecular hydrogel;
the drug-loaded carrier is prepared from phospholipid, sodium deoxycholate and tween, and loads paclitaxel or coumarin 6, the surface of the drug-loaded carrier is modified with cell-penetrating peptide which is stearic acid modified octa-arginine tri-histidine (Stearylated-octaarginin-trihistine, Ste-RRRRRRRRHHH, Ste-R8H 3);
the micromolecular hydrogel is prepared from gel precursors including fluorenylmethyloxycarbonyl-phenylalanine and phenylalanine-dihydroxyphenylalanine.
The preparation method of the small molecular hydrogel-carrier composite drug carrier comprises the following steps:
step 1, preparing a carrier by a thin film dispersion method: dissolving soybean lecithin, a surfactant and a fat-soluble drug in an organic solvent, removing the organic solvent by vacuum rotary evaporation, adding double distilled water for hydration, and filtering after ultrasonic treatment to obtain a carrier;
step 3, preparing the small molecular hydrogel-carrier composite drug carrier: dissolving the gel precursor in distilled water, adjusting pH to 7.4, adding transfersome, adding enzyme solution, mixing, and reacting in 37 deg.C incubator for 4 h.
A transfersome: also known as elastoliposomes (flexible nanoliposomes), in 1992 the Cevc group described the transfersome for the first time as a liposome for transdermal administration, which is more deformable and elastic than conventional liposomes. The carrier is an artificial carrier composed of phospholipids and surfactants, also known as Edge Activators (EA), which determine the morphology of the carrier. Transdermal mechanism of the transfersome: the carrier can self-polymerize, can transmit the drug to restore the original shape after penetrating the skin, has better elasticity than the traditional liposome, and the high deformability ensures that the carrier can penetrate through the pores with the grain diameter 5-10 times smaller than the self grain diameter through deformation, thereby being a new transdermal drug transmission carrier. The mechanism for enhancing transdermal drug delivery is not clear at this stage, and two mechanisms have been reported: 1) the transfersome is used as a drug carrier and can keep an intact shape after penetrating through the skin; 2) the carrier acts as a permeation enhancer, interfering with the highly ordered intercellular lipids of the stratum corneum, thereby facilitating the penetration of the drug through and across the stratum corneum.
The small molecule hydrogel is a three-dimensional network structure formed by self-assembly of small molecules to form supramolecular chains and then cross-linking and winding of each chain to wrap water molecules in the middle. Methods for initiating self-assembly to form hydrogels can be broadly divided into two categories: one is to start self-assembly by adjusting the system environment, such as changing pH, temperature, electric field, magnetic field, ionic strength, chemical substances, etc.; another is the stimulation of precursors that are not capable of self-assembly to form gel elements that are capable of self-assembly, such as photo-or enzymatic catalysis. The small molecular hydrogel can be used as a new biological material to be applied to tissue engineering, cell culture matrixes, drug delivery and the like. Moreover, the three-dimensional network structure formed by self-assembly can wrap water molecules, other bioactive molecules (nutrients and proteins) and medicines, and can be used as a medicine sustained and controlled release carrier.
Cell Penetrating Peptides (CPPs) are short peptides that have the ability to penetrate the Cell membrane. In 1988, the HIV transactivator tat (GRKKRRQRRPQ) of the transcription protein is firstly discovered to have the capability of passing through a plasma membrane and entering cells. Since 1994 first delivered exogenous short peptides using cell-penetrating peptides as carriers, various cell-penetrating peptides have emerged, which are capable of successfully delivering proteins, nucleic acids, small molecule drugs, antibodies, nanocarriers, and the like. Santan Patra and the like connect oligoarginine to cholesterol to synthesize the membrane-penetrating peptide modified liposome, and in vivo and in vitro experiments show that the modification of the membrane-penetrating peptide can obviously improve the skin permeability of curcumin, thereby proving that the membrane-penetrating peptide plays an important role in skin permeation and transdermal release.
The micromolecular hydrogel-nanoparticle composite carrier is used for skin/mucosa administration, the permeability of the skin/mucosa and focus parts of the medicine can be obviously improved by modifying the surface of the nanoparticle with the cell-penetrating peptide, and the micromolecular hydrogel solves the problem that the medicine is easy to lose when being administered in a solution dosage form.
Drawings
FIG. 1 is a schematic diagram of the preparation of a small molecule hydrogel-carrier composite drug carrier in example 1;
FIG. 2 is a graph showing the distribution of the particle size of the cell-penetrating peptide-modified carrier in example 1;
FIG. 3 is a comparison of the in vitro cumulative skin penetration of the drug of the transfersomes, cell-penetrating peptide modified transfersomes and liposomes of example 1;
FIG. 4 is SEM image of lyophilized sample of the small molecule hydrogel-carrier composite drug carrier in example 1, wherein the scale in FIG. a is 100 μm and the scale in FIG. b is 1 μm;
FIG. 5 shows the in vitro cumulative transdermal rate of the small molecule hydrogel-carrier composite drug carrier of example 1.
Detailed Description
Example 1
Preparation of blank transfersomes: transfersome was prepared by thin film dispersion method, phospholipid (SPC), sodium deoxycholate and surface active ingredient (EA) were dissolved in chloroform according to the ratio of table 1: methanol 2: 1 at 40 deg.C, removing the organic solvent by vacuum rotary evaporation to form lipid film on the bottle wall, and vacuum drying overnight to remove residual organic solvent. Addition of ddH2O hydration for 10min, dispersing the lipid suspension by using a probe type cell ultrasonicator to perform ice bath ultrasound for 5min, and passing the ultrasound liposome suspension through a 0.22 mu m cellulose ester film to obtain a carrier (Ts) with uniform particle size. Conventional liposomes (Ls) were also prepared as controls.
Preparing a drug-loaded carrier: the preparation of the carrier carrying Paclitaxel (PTX) or coumarin 6(Cou6) only needs to dissolve PTX (or Cou6) and lipid components in an organic solvent and prepare the carrier by the method, wherein the loading amount of PTX is 3.3 percent of the total mass of the lipid components, and the loading amount of coumarin 6 is 0.2 percent of the total mass of the lipid components. And preparing traditional medicine-carrying liposome (Ls).
TABLE 1 composition of the different liposomes
Preparation of cell-penetrating peptide modified transfersome: adding cell-penetrating peptide solution with lipid content of 2.5 mol% into the obtained transfersome, and incubating at 4 deg.C for 40 min;
the particle size of the paclitaxel-loaded cell-penetrating peptide-modified carrier is measured by a dynamic light scattering method, and the result is shown in fig. 2, which shows that the particle size distribution is about 75nm, the particle size is normally distributed, and the distribution is uniform.
In vitro transdermal test: the transdermal capacity of Cou6-CTs was examined using a transdermal diffusion apparatus, male nude mice at 6-7 weeks were sacrificed and then excised from the abdominal skin, and the subcutaneous tissue was removed with scissors and then the adherent adipose layer and connective tissue were removed with isopropanol, taking care not to damage the skin during this procedure, and finally washed with 0.9% NaCl for future use. Setting the stirring speed at 500rpm, fixing the treated skin on a Franz diffusion cell, wherein the stratum corneum of the skin faces to a dosing cell, the inner layer of the skin is contacted with a buffer solution in a sample receiving cell, and the buffer solution is prepared from ethanol: PBS 1: 3, and is used after ultrasonic bubble removal treatment. 300 μ L of different liposome samples were uniformly added to the dosing reservoir to give a dosing area of 3.14cm2800 μ L of sample was taken from the sample receiving well at 0.5, 1, 2, 4, 6, 8, 12h, and the same volume of buffer was replenished after each sampleAnd (6) flushing liquid. The cumulative drug permeability was calculated as follows:
a is the dose, V is the volume of the receiving solution, Cn is the concentration of the sample sampled at the nth time, Ci is the concentration of the sample in the receiving solution at the ith time, and Vi is the sampling volume.
The cumulative release rate calculation is shown in FIG. 3: transdermal results show that the transfersomes (Ts, CTs) have good transdermal effect compared with the traditional liposomes (Ls), and the transdermal efficiency of the transfersomes is obviously improved after the CPP is added, and compared with the traditional liposomes, the transdermal efficiency of the transfersomes CTs in the experimental design is improved by nearly 4 times.
Preparing a small molecular hydrogel-carrier composite carrier: taking a certain amount of 10mM fluorenylmethoxycarbonyl-phenylalanine (Fmoc-F) and 20mM phenylalanine-dihydroxyphenylalanine (F-F-DOPA) as gel precursors, fully dissolving the gel precursors in distilled water, then uniformly mixing the gel precursors with 250 mu L of transfersome (CTs) after the pH is about 7.4, then adding 200 mu L of WQ9-2 enzyme solution (1mg/mL, strain Bacillus WQ9-2(CN102021125A), wherein the produced protein WQ9-2 has the performance of catalyzing and synthesizing hydrogel factors), uniformly mixing, placing in a 37 ℃ incubator, and reacting for 4 hours.
Fig. 4 is an SEM image of a small molecule hydrogel-carrier composite carrier lyophilized sample, wherein the SEM after vacuum freeze-drying of the sample can be used for observing a three-dimensional network structure formed after the gelator is wound and aggregated by a self-assembly manner. From figure a it can be seen that the three-dimensional skeleton of the hydrogel is cross-linked by a dendritic structure to form a porous structure. The size of the skeleton is about 10-30 μm, the porous scaffold structure provides skeleton support for the gel on one hand and can be loaded with drugs on the other hand, and the partial enlargement of the figure b (namely the figure b) can see that the transfersome is loaded in the gel gap structure and the size of the transfersome is about 100 nm.
Small molecule hydrogel-transfersome in vitro transdermal test: the operation method and the in vitro transdermal test of the carrier, the calculation result of the cumulative release rate is shown in figure 5: the 12h transdermal results for the small molecule hydrogel-transfersome were about 12%, indicating that the small molecule hydrogel as a depot may slow the transdermal speed of the transfersome.
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