CN111012734A - Drug-loaded reticular in-situ phase-change gel sustained-release system and preparation method thereof - Google Patents

Drug-loaded reticular in-situ phase-change gel sustained-release system and preparation method thereof Download PDF

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CN111012734A
CN111012734A CN201811171012.5A CN201811171012A CN111012734A CN 111012734 A CN111012734 A CN 111012734A CN 201811171012 A CN201811171012 A CN 201811171012A CN 111012734 A CN111012734 A CN 111012734A
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phospholipid
mucopolysaccharide
ethanol
solution
derivative
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CN111012734B (en
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龚涛
罗静雯
张培
宋旭
张志荣
孙逊
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Sichuan University
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Abstract

The invention provides a drug-loaded in-situ reticular gel sustained-release preparation taking phospholipid and mucopolysaccharide derivatives as matrixes, and provides a preparation method of the preparation.

Description

Drug-loaded reticular in-situ phase-change gel sustained-release system and preparation method thereof
Technical Field
The invention relates to an in-situ phase-change reticular gel sustained-release system which takes phospholipid and mucopolysaccharide derivatives as matrixes and biocompatible organic solvent as solvent and is suitable for wide medicines, belonging to the technical field of medicines.
Background
The water-soluble chemical medicine has prominent and irreplaceable important effects on human health, and has the characteristics of clear physicochemical properties, quick dissolution in vivo, quick absorption and quick elimination, so that the maintenance time of the curative effect is short. Some low permeability water soluble molecular drugs, due to their poor permeability, result in poor tissue affinity. The blood concentration of the fat-soluble medicine after administration has obvious peak value and valley value, so that the toxic and side effect is larger, the drug effect is reduced, for chronic diseases, continuous injection or intravenous drip is needed to ensure the curative effect of the medicine, and the physical, psychological and economic burden of patients is increased. Therefore, the drug can be slowly released through the sustained-release preparation, the stable blood concentration is obtained, and the key point of reducing the peak valley value is that the toxicity is reduced, the effect is increased, and the drug compliance of patients is increased. It is therefore desirable to develop an injectable sustained release delivery system.
The currently marketed sustained-release drug delivery system for injection is mainly PLGA (polylactic-co-glycolic acid) microspheres. Among a plurality of drug sustained-release preparations, risperidone sustained-release microspheres for injection are one of the most successful varieties. Risperidone is one of drugs for treating psychosis, long-acting risperidone microsphere injection (called "risperidone microsphere" for short) is developed and produced by american poplar company under the trade name constant (Consta), and is successively marketed in the united states and europe in 2003 and enters the chinese market in 2006, so that the risperidone can be slowly released for 7 weeks. The risperidone sustained release microsphere intramuscular injection formulation (LY 3004) developed by green leaf pharmacy for the treatment of schizophrenia, which required only one injection every two weeks for convenient use, had completed 3 critical phase I clinical trials in 172 us patients. Although the PLGA microspheres have good slow release effect, the preparation process is complex, the drug loading is low, the organic solvent used in the preparation process is remained in the preparation, and in addition, the lactic acid and the glycolic acid generated in the degradation process can cause the reduction of the pH value of an injection part, thereby causing inflammatory reaction. The above disadvantages limit the application of PLGA microspheres.
Vesicle Phospholipid Gel (VPG) is a semisolid dispersion of phospholipids that can encapsulate water-soluble, lipid-soluble, amphiphilic drugs. Patent CN102697741A develops an oxaliplatin vesicular phospholipid gel injection, which is prepared from oxaliplatin, soybean lecithin, cholesterol, PEG and glucose according to a specific weight ratio, and improves the stability of the preparation. And the problems of sedimentation, aggregation and the like easily occur in the storage process, the stability of the preparation is influenced, and the storage and the transportation of the preparation are not facilitated.
The laboratory develops an in-situ phase-change gel sustained-release preparation (CN 102526753A) which takes high-concentration phospholipid as a main matrix and adds a small part of vegetable oil and an in-situ phase-change gel sustained-release system (CN 107049932A) which takes phospholipid and span as matrixes and ethanol as a solvent and is suitable for medicines. The former has the advantages of good biocompatibility, obvious sustained-Release effect, good in-vivo degradability and the like, has good sustained-Release effect when applied to protein polypeptide drugs, for example, octreotide acetate can be stably and slowly released in rats, rabbits and dogs for about one month, and the burst Release of the drug is less and superior to that of a commercial octreotide acetate microsphere (MX Wang, et al. pharmaceutical and pharmaceutical synthetic plasmid of a phosphopeptide-based pharmaceutical formulation for on a month administration of octreotide, Journal of controlled Release 230 (2016) 45-56); exenatide acetate phospholipid Gel has almost no burst release, is slowly released in rats for up to one month, and can maintain stable blood sugar reducing effect for more than 20 days (M Hu, et al Long-activating phospholipid Gel of exogenous for Long-Term therapy of Type II Diabetes, PharmRes 33 (2016): 1318-1326). The latter has better slow release effect and smaller burst release when applied to the encapsulation of part of fat-soluble chemical drugs, such as ipiprazole, 2, 4-dinitrophenol phospholipid gel and the like, which can be continuously released in animals for more than half a month (GF Wei, et al. However, in the research, the inventor also finds that the effect is not ideal enough when a plurality of chemical drugs are encapsulated by the phospholipid gel preparation, and although the phospholipid gel preparation has a certain slow release effect, the slow release time can only last for several days, the long-term effective blood concentration cannot be maintained, and the burst release condition is serious. First, some of the drugs with strong water solubility have short action time, presumably because the human subcutaneous tissue is aqueous environment, and the water-soluble drugs are entrapped in the small molecule gel system, lack barrier and easily diffuse out through body fluid. Secondly, part of the drugs with strong lipid solubility have good compatibility with phospholipid, and are easy to permeate and diffuse in a phospholipid carrier to release, so that the drug release rate is obviously accelerated, the sustained release time is relatively short, the burst release is more, and the safety problem can be caused for some drugs with narrow treatment window.
Therefore, for a wide range of chemical drugs, a drug carrier with wide application range, small burst release and long sustained-release time needs to be searched to solve the problem of long-acting sustained release for injection.
Disclosure of Invention
The invention aims to overcome the defects in the prior art and provide an in-situ gel sustained-release system which has wide application range, can not only enable water-soluble medicines to be slowly released for a long time after being injected, but also can be suitable for fat-soluble medicines. The in-situ gel sustained-release system can obviously reduce the burst release of the drug.
It has been unexpectedly found in research that high concentrations of a mixture of phospholipids and mucopolysaccharide derivatives can form flowable injectable liquids in biocompatible organic solvents. When the mixture is injected into water, a gel preparation having a network shape can be rapidly and spontaneously formed. According to this property, the inventors conceived that when a drug is dissolved or dispersed in a solution containing phospholipids and mucopolysaccharide derivatives, the phospholipids and mucopolysaccharide derivatives spontaneously form a semisolid network gel at the injection site due to the relatively high content of water in the body after injection into the body, and the mixture further solidifies as the solvent exudes, becoming a carrier and a barrier for drug release, effectively controlling the drug release.
According to the above unexpected findings, the inventors prepared an ethanol solution containing 10% of a mucopolysaccharide derivative and 60% of a phospholipid by using ivermectin as a model drug, and after 0.6 ml of the ethanol solution was subcutaneously injected into rats, the drug was smoothly released for 30 days or more. At the same dose, Cmax raw drug≈2857.43 μg/mL，Cmax high concentration phospholipid gel(prepared according to patent CN 102526753A). apprxeq. 703.28. mu.g/mL, Cmax mucopolysaccharide derivative phospholipid gelAbout 514.86 mug/mL, and the original drug group can only be released for 5 days, the common phospholipid gel can be released for 15 days, and the mucopolysaccharide derivative gel can be released for more than 30 days. The toxicity test result shows that the phospholipid mucopolysaccharide derivative gel can effectively reduce the toxic and side effects of high-dose ethanol diffusion. Therefore, for the medicine with narrow therapeutic window, the preparation can effectively reduce the toxic and side effects.
Based on the above studies, we have surprisingly found that a phospholipid mucopolysaccharide derivative reticulated gel sustained release formulation can significantly reduce drug burst and prolong the release time. We believe that we have prepared novel gel sustained release systems that reduce burst release and allow sustained release for longer periods of time than conventional gel formulations. We select water-soluble drugs such as doxorubicin hydrochloride and fat-soluble drugs such as ipiprazole as model drugs to carry out further research, and the results show that gel preparations of the drugs such as doxorubicin hydrochloride and ipiprazole can be always in a relatively stable release state and almost have no burst release phenomenon.
The mucopolysaccharide derivative is an amphiphilic derivative formed by connecting long-chain macromolecular mucopolysaccharide and fatty amine or fatty acid, and has better biocompatibility and biodegradability. The inventors have found that by incorporating a partially mucopolysaccharide derivative into the formulation, the gel formulation cures immediately upon exposure to water and has a distinct network structure. On one hand, the curing time of the phospholipid gel can be shortened; on the other hand, the sustained release tablet has good sustained release effect on both fat-soluble chemical drugs and water-soluble chemical drugs in-vivo and in-vitro release tests. Thereby expanding the application of the phospholipid gel preparation and providing possibility for the sustained release application of a wide range of medicines.
It is an object of the present invention to provide a reticulated gel sustained release system suitable for use with pharmaceuticals.
It is an object of the present invention to provide a reticulated gel sustained release system that significantly reduces burst release of the drug. It is an object of the present invention to provide a reticulated gel sustained release system comprising a phospholipid and a mucopolysaccharide derivative.
In a specific embodiment, the reticular gel sustained-release system capable of obviously reducing the burst release of the drug can be added with a proper amount of oil for injection, so that the dosage of the organic solvent is reduced.
In a specific embodiment, the above-described reticulated gel sustained release system capable of significantly reducing drug burst further comprises a biocompatible organic solvent.
The invention aims to provide a high-concentration phospholipid mucopolysaccharide derivative sustained-release preparation prepared from phospholipid, mucopolysaccharide derivatives and pharmaceutical active ingredients, namely the in-situ injection phase-change gel sustained-release system or the in-situ injection phase-change gel sustained-release preparation.
The invention aims to provide a phospholipid mucopolysaccharide derivative sustained-release preparation which has good sustained-release effect, effectively reduces the burst release of the medicament, has high phospholipid content and is easy to inject and contains bioactive components.
Mucopolysaccharide derivatives suitable for use in the phospholipid mucopolysaccharide derivative sustained release formulations of the present invention include, but are not limited to, chondroitin sulfate-fatty amine conjugates, hyaluronic acid-fatty amine conjugates, heparin-fatty amine conjugates, dermatan sulfate-fatty amine conjugates, heparan sulfate-fatty amine, keratan sulfate-fatty amine, and chitosan-fatty acid in combination with one or more of them, preferably chondroitin stearylamine conjugates.
The mucopolysaccharide derivatives suitable for use in the present invention have a degree of fatty amine or fatty acid substitution of from 1 to 50% and a molecular weight in the range of from 10 to 20,000 kDa.
The phospholipids suitable for use in the high concentration phospholipid mucopolysaccharide derivative sustained release formulations of the present invention include, but are not limited to, a combination of one or more of natural phospholipids, semi-synthetic phospholipids, and synthetic phospholipids.
The natural phospholipid includes, but is not limited to, egg yolk lecithin, soybean lecithin or combination thereof.
The semi-synthetic phospholipid includes, but is not limited to, hydrogenated egg yolk lecithin, hydrogenated soybean lecithin, or a combination thereof.
The synthetic phospholipid includes, but is not limited to, one or more of dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidic acid, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine, dimyristoylphosphatidylcholine, and the like.
In a particular embodiment, the preferred phospholipid of the present invention is soy phospholipid S100.
Further, the gel sustained-release preparation of the present invention may further comprise an oil for injection.
The oil for injection includes, but is not limited to, soybean oil, corn oil, sesame oil, tea oil, fish oil, medium-chain fatty glyceride, cottonseed oil, ethyl oleate, and combinations thereof.
In a specific embodiment, the phospholipid sustained-release preparation comprises 30-80 parts of phospholipid and 1-20 parts of mucopolysaccharide derivative based on the weight parts of the preparation.
The active pharmaceutical ingredients suitable for preparing the phospholipid sustained-release preparation include, but are not limited to, anticancer drugs, anti-inflammatory drugs, analgesic drugs, anti-infective drugs, antidiabetic drugs, immunomodulatory drugs, antihypertensive drugs, antiepileptic drugs, antidepressant drugs, antipsychotic drugs, antiobesity drugs, uropathy drugs and cardiotonic drugs.
Pharmaceutically active ingredients suitable for use in the present invention include, but are not limited to, the following:
the composition can be administered in the form of a composition containing epipiprazole, olanzapine, viscerasin, epinastine, oxyphenbutamin, oxyphenbutazone, norgestrel, valprohormone, or the composition containing the vasopressin, or the composition containing the active substance, such as a vasopressin, the hormone, the drug for which is selected from the composition, the drug is selected from the composition, the drugs such as a, the drug, the vasopressin, the drug (s, the drug is a, the drug is a, the drug-s, the drug, the vasopressin, the drug is a, the drug, the vasopressin, the drug such as a, the drug, the hormone, the drug is a, the drug is a, the drug, the hormone, the drug, the hormone, the prodrug, the hormone, the prodrug, the hormone, the prodrug, the hormone, the prodrug, the hormone, the prodrug.
Further, the chemical agent may be in the form of a pharmaceutically acceptable salt, including but not limited to hydrochloride, sulfate, acetate, salicylate, sulfonate, citrate, and other pharmaceutically acceptable salt forms.
The phospholipid mucopolysaccharide derivative sustained-release preparation comprises, by weight, 0.01-20 parts of a pharmaceutical active ingredient, 30-80 parts of phospholipid and 1-20 parts of a mucopolysaccharide derivative. The sustained-release preparation can also comprise oil for injection, and the phospholipid mucopolysaccharide derivative sustained-release preparation contains 5-40 parts by weight of oil for injection.
The sustained-release preparation further comprises a biocompatible organic solvent, and the phospholipid mucopolysaccharide derivative sustained-release preparation contains 7-30 parts by weight of the biocompatible organic solvent. The phospholipid mucopolysaccharide derivative sustained-release preparation comprises, by weight, 0.01-20 parts of a pharmaceutical active ingredient, 30-80 parts of phospholipid, 1-20 parts of a mucopolysaccharide derivative and 7-30 parts of a biocompatible organic solvent. The concentration range of the biocompatible organic solvent is 50-100% (v/v).
The composition further comprises 30-80 parts by weight of phospholipid and 1-20 parts by weight of mucopolysaccharide derivative, preferably 3-10 parts by weight.
Wherein the biocompatible organic solvent can be selected from one or more of absolute ethanol, ethanol solution, N-propanol, isopropanol, N-butanol, isobutanol, sec-butanol, tert-butanol, propylene glycol, glycerol, polyethylene glycol, N-pentane, isopentane, neopentane, N-hexane, methyl formate, ethyl acetate, dimethyl sulfoxide, N-dimethylformamide, and formamide, and the ethanol solution is preferably one or more of ethanol-water solution, ethanol-dimethyl sulfoxide solution, ethanol-N, N-dimethylformamide solution, ethanol-formamide solution, ethanol-N-hexane, ethanol-physiological saline solution, ethanol-phosphate buffer solution, ethanol carbonate buffer solution, ethanol-succinate buffer solution, ethanol-citrate buffer solution, and ethanol-lactate buffer solution, wherein the concentration of ethanol can be 50% -100% (v/v).
The in-situ injection phase-change gel slow-release system taking the phospholipid mucopolysaccharide derivative as the matrix is a novel dosage form, the active pharmaceutical ingredient can be dissolved in a phospholipid mucopolysaccharide derivative-biocompatible organic solvent to form liquid with good fluidity, after the phospholipid and the mucopolysaccharide derivative are injected into a body, semisolid mesh gel wrapping the active pharmaceutical ingredient can be immediately formed by the phospholipid and the mucopolysaccharide derivative, and the slow-release effect is good.
The pharmaceutically active ingredient may also be dispersed in the form of fine particles in a phospholipid mucopolysaccharide derivative-biocompatible organic solvent as long as the preparation's penetration is maintained.
The active pharmaceutical ingredient and the blank phospholipid mucopolysaccharide derivative matrix can be stored respectively and administered after being dissolved or dispersed uniformly before use.
In a specific embodiment, the method of preparing the in situ gel formulation of the present invention may comprise the steps of:
(1) dissolving the active components in proper amount of biocompatible organic solvent, filtering with microporous membrane for sterilization to obtain medicinal solution;
(2) mixing phospholipid and mucopolysaccharide derivative with the medicinal solution obtained in step (1) under aseptic condition, stirring for mixing, standing for a while to remove air bubbles in the preparation, packaging, and sealing.
In a specific embodiment, the method of preparing the in situ gel formulation of the present invention may comprise the steps of:
(1) under the aseptic condition, the active ingredients of the medicine are taken to prepare medicine particles by a common crystallization or pulverization mode in pharmaceutics.
(2) Mixing phospholipid and mucopolysaccharide derivative with biocompatible organic solvent under aseptic condition, and stirring to mix well;
(3) and (3) uniformly mixing the drug particles in the step (1) and the carrier solution prepared in the step (2) under the aseptic condition, standing for a moment to remove air bubbles in the preparation, subpackaging and sealing to obtain the traditional Chinese medicine preparation.
The in-situ injection phase-change gel sustained-release preparation can be used for injection administration, preferably subcutaneous administration; it can also be used for other administration forms such as topical administration.
The in-situ injection phase change gel sustained-release preparation can also be used for repairing and expanding soft and/or hard tissues.
The invention prepares the phospholipid mucopolysaccharide derivative sustained-release preparation by creative research and by taking the phospholipid mucopolysaccharide derivative, ethanol solution and the like as main raw materials and taking ivermectin, doxorubicin hydrochloride, ipiprazole and the like as model medicines. The obtained preparation has good fluidity, is easy to inject and administer, and has good slow release effect proved by animal in vivo experiments. The result of examining the irritation of the phospholipid mucopolysaccharide derivative sustained-release preparation to the injection site shows that the preparation has better biocompatibility and less irritation to the administration site.
Therefore, the invention can realize the slow release of various medicaments generally, well solves the technical problem of strong burst release performance of the existing medicament in-situ gel preparation, and has good application prospect.
Advantages of the invention
The phospholipid mucopolysaccharide derivative sustained-release preparation contains a small amount of biocompatible organic solvent which can be completely mutually dissolved with water, after the phospholipid and mucopolysaccharide derivative sustained-release preparation is injected into a human body, a mixture of the phospholipid and the mucopolysaccharide derivative can be immediately solidified, the macromolecular mucopolysaccharide derivative forms a network structure for binding micromolecular phospholipid, and the biocompatible organic solvent can be quickly diffused to body fluid, so that the gel preparation is further solidified to become a carrier for drug sustained release and control the release of the drug. Animal in vivo experiments prove that the preparation has good slow release effect, and the burst effect is small or even no burst. The phospholipid mucopolysaccharide derivative sustained-release preparation has the advantages of good fluidity, easy injection administration and the like. In addition, the medicine can be dissolved by selecting a proper solvent or a solvent combination according to the solubility of the medicine to be encapsulated so as to prepare a uniform and transparent stable preparation. The drug may also be uniformly dispersed in the formulation in particulate form. In addition, the phospholipid mucopolysaccharide derivative sustained-release preparation does not contain water or has low water content, and the preparation contains a biocompatible organic solvent, so that the growth of microorganisms can be effectively inhibited, the storage of the preparation is facilitated, and the application range of the phospholipid mucopolysaccharide derivative preparation is expanded.
Drawings
FIG. 1 is a graph showing the comparison between the phospholipid mucopolysaccharide derivative sustained-release preparation before and after gelation.
FIG. 2 is a transmission electron microscope image of phospholipid mucopolysaccharide derivative reticular sustained-release preparations of different formulas of ivermectin.
Fig. 3 is an in vitro release profile of the phosphomucopolysaccharide derivative sustained release formulation, high concentration phospholipid sustained release formulation and solution set of ivermectin.
Fig. 4 is a graph showing the time course of a phospholipid mucopolysaccharide derivative sustained-release preparation, a high-concentration phospholipid sustained-release preparation and a solution group injected subcutaneously with ivermectin.
Figure 5 is an observation of the appearance of skin irritation of a sustained release formulation of a phospholipid mucopolysaccharide derivative of ivermectin.
FIG. 6 is a H & E staining pattern of skin irritant slices of the phosphomucopolysaccharide derivative sustained release formulation of ivermectin.
FIG. 7 is a graph showing the time course of the sustained-release formulation of the phospholipid mucopolysaccharide derivative of doxorubicin hydrochloride, the sustained-release formulation of high-concentration phospholipid, and the solution group.
FIG. 8 is a time course of the sustained release formulation of the phospholipid mucopolysaccharide derivative of brexpiprazole and the sustained release formulation of a high concentration phospholipid.
Detailed Description
The following examples are further illustrative of the present invention and are in no way intended to limit the scope of the invention. The present invention is further illustrated in detail below with reference to examples, but it should be understood by those skilled in the art that the present invention is not limited to these examples and the preparation method used. Also, equivalent substitutions, combinations, improvements or modifications of the invention may be made by those skilled in the art based on the description of the invention, but these are included in the scope of the invention.
Example 1
Dissolving 100mg of ivermectin in 2.0 g of ethanol, filtering by a 0.22-micron microporous filter membrane to obtain a medicinal solution, adding injection-grade soybean phospholipid S1006.0 g, injection-grade medium-chain fatty glyceride 1.0 g and chondroitin sulfate octadecylamine coupler 1.0 g under an aseptic condition, magnetically stirring for about 1 hour under an aseptic condition until S100 is uniformly mixed to obtain a liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the product.
Example 2
And (3) grinding and crushing a proper amount of doxorubicin hydrochloride in a mortar under aseptic conditions to obtain doxorubicin hydrochloride powder. Taking 1.5g of absolute ethyl alcohol, 806.5 g of injection-grade egg yolk phospholipid E, 0.5g of chondroitin sulfate octadecylamine coupling compound and 1.5g of soybean oil, magnetically stirring for about 1 hour under an aseptic condition until the mixture is uniformly mixed, taking 20 mg of doxorubicin hydrochloride powder and uniformly mixing with the liquid under the aseptic condition to obtain liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging and sealing to obtain the product.
Example 3
Under the aseptic condition, taking a proper amount of brexpiprazole, grinding and crushing in a mortar to obtain brexpiprazole powder. Taking 1.5g of absolute ethyl alcohol, 1.0 g of hyaluronic acid hexadecylamine coupling compound and 1007.5 g of injection-grade soybean phospholipid, and magnetically stirring for about 1 hour under the aseptic condition until the absolute ethyl alcohol, the hyaluronic acid hexadecylamine coupling compound and the injection-grade soybean phospholipid are uniformly mixed to obtain a milky yellow liquid containing a large amount of bubbles. And (3) taking 200mg of brexpiprazole powder under aseptic conditions, uniformly mixing with the liquid, standing until bubbles disappear completely, subpackaging, and sealing to obtain the brexpiprazole powder.
Example 4
Dissolving theophylline 100mg in 3.0 g of 80% (v/v) ethanol-pH 7.6 phosphate buffer to obtain a medicinal solution, filtering with 0.22 μm microporous membrane, adding injection-grade hydrogenated yolk phospholipid 4.0 g and hyaluronic acid octadecylamine 2.0 g under aseptic condition, magnetically stirring under aseptic condition for about 1 hr until hydrogenated yolk phospholipid is uniformly mixed to obtain a liquid containing a large amount of bubbles, standing until the bubbles completely disappear, packaging, and sealing.
Example 5
Dissolving 10.0 mg of dexamethasone in 1.7 g of absolute ethanol to obtain a drug solution, filtering with a 0.22-micron microporous membrane, adding 6.0g of injection-grade dipalmitoyl phosphatidylethanolamine, 1.3 g of heparin octadecylamine coupling compound and 1 g of medium-chain fatty glyceride under an aseptic condition, magnetically stirring for about 1 h under an aseptic condition until the dipalmitoyl phosphatidylethanolamine is uniformly mixed to obtain a liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the pharmaceutical composition.
Example 6
Dissolving aspirin 100mg in 2.0 g of 80% (v/v) ethanol-pH 7.6 phosphate buffer to obtain a medicinal solution, filtering with a 0.22 μm microporous membrane, adding injection-grade egg yolk lecithin E806.0 g and chitosan dodecanoic acid conjugate 1.9 g under aseptic condition, magnetically stirring under aseptic condition for about 1 h until E80 is uniformly mixed to obtain a liquid containing a large amount of bubbles, standing until the bubbles disappear completely, subpackaging, and sealing to obtain the product.
Example 7
Taking cimetidine 200mg, dissolving in 90% (v/v) ethanol-pH 7.6 phosphate buffer solution of 2.8g to obtain a drug solution, filtering with a 0.22 mu m microporous membrane, adding injection-grade dipalmitoyl phosphatidylethanolamine 6.0g and hyaluronic acid tetradecylamine conjugate 1.0 g under an aseptic condition, magnetically stirring for about 1 h under an aseptic condition until the dipalmitoyl phosphatidylethanolamine is uniformly mixed to obtain liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the product.
Example 8
Dissolving 40 mg of donepezil hydrochloride in 2.5 g of 70% (v/v) ethanol-n-hexane to obtain a medicinal solution, filtering with a 0.22 mu m microporous filter membrane, adding 6.0g of injection-grade hydrogenated soybean phospholipid and 1.5g of hyaluronic acid octadecylamine coupling under aseptic conditions, magnetically stirring for about 0.5 h under aseptic conditions until the hydrogenated soybean phospholipid is uniformly mixed to obtain a liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the finished product.
Example 9
Under the aseptic condition, taking a proper amount of risperidone, grinding and crushing in a mortar to obtain risperidone powder. Taking 2.0 g of absolute ethyl alcohol solution, 1.5g of hyaluronic acid hexadecylamine coupling compound, 5.5 g of hydrogenated yolk phospholipid and 1 g of corn oil, and stirring the mixture for about 0.5 h under a magnetic force under an aseptic condition until the hydrogenated yolk phospholipid is uniformly mixed to obtain a milky yellow liquid containing a large number of bubbles. Taking 150 mg of risperidone powder under aseptic conditions, mixing with the liquid uniformly, standing until bubbles disappear completely, subpackaging, and sealing to obtain the final product.
Example 10
Dissolving captopril 200mg in 90% (v/v) ethanol-water solution 1.5g to obtain a medicinal solution, filtering with a 0.22 mu m microporous membrane, adding injection-grade egg yolk lecithin E806.5 g and chondroitin sulfate tetradecylamine conjugate 2.0 g under aseptic condition, magnetically stirring for about 0.5 h under aseptic condition until E80 is uniformly mixed to obtain a cream yellow liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the final product.
Example 11
Dissolving diazepam 100mg in 75% (v/v) ethanol-water 2.0 g to obtain a medicinal solution, filtering with a 0.22 μm microporous membrane, adding injection-grade dimyristoyl phosphatidylcholine 5.5 g, chondroitin sulfate octadecylamine conjugate 1.5g and fish oil 1.0 g under aseptic condition, magnetically stirring under aseptic condition for about 0.5 h until dimyristoyl phosphatidylcholine is uniformly mixed to obtain a creamy yellow liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the final product.
Example 12
Dissolving 80mg of promethazine in 2.0 g of 70% (v/v) ethanol-water to obtain a drug solution, filtering with a 0.22 mu m microporous membrane, adding 1006.5 g of soybean phospholipid S, 1.0 g of tea oil and 0.5g of heparin tetradecylamine coupling under aseptic conditions, magnetically stirring for about 0.5 h under aseptic conditions until S100 is uniformly mixed to obtain a cream yellow liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the compound.
Example 13
Dissolving 70 mg of aclarubicin in 2.0 g of 80% (v/v) ethanol-water to obtain a drug solution, filtering with a 0.22 mu m microporous membrane, adding egg yolk lecithin E806.5 g and heparin hexadecylamine coupling compound 1.5g under aseptic condition, magnetically stirring for about 0.5 h under aseptic condition until E80 is uniformly mixed to obtain a creamy yellow liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the medicine.
Example 14
Dissolving 90 mg of carmustine in 2.5 g of 80% (v/v) ethanol-water to obtain a drug solution, filtering with a 0.22 mu m microporous filter membrane, adding 5.5 g of dioleoyl phosphatidylethanolamine and 2.0 g of heparan octadecylamine coupling under an aseptic condition, magnetically stirring for about 0.5 h under an aseptic condition until the dioleoyl phosphatidylethanolamine is uniformly mixed to obtain a cream yellow liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the carmustine.
Example 15
Dissolving risperidone 40 mg in isopropanol 3.0 g to obtain a medicinal solution, filtering with a 0.22 μm microporous membrane, adding egg yolk lecithin E804.0 g, tea oil 1.0 g and heparin hexadecylamine coupling substance 2.0 g under aseptic condition, magnetically stirring for about 0.5 h under aseptic condition until E80 is uniformly mixed to obtain cream yellow liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the product.
Example 16
Dissolving 100mg of diethylstilbestrol in 3.0 g of n-hexane to obtain a medicinal solution, filtering with a 0.22-micron microporous filter membrane, adding 4.5 g of soybean phospholipid, 1.0 g of corn oil and 1.5g of heparin-tetradecylamine coupling under an aseptic condition, magnetically stirring for about 0.5 h under an aseptic condition until the mixture is uniform and uniform to obtain a cream yellow liquid containing a large amount of bubbles, standing until the bubbles completely disappear, subpackaging, and sealing to obtain the medicine.
Example 17
Under aseptic conditions, taking a proper amount of silybin, and grinding and crushing the silybin in a mortar to obtain silybin powder. Taking 2.0 g of absolute ethyl alcohol, 1.0 g of hyaluronic acid octadecylamine coupler, 1004.0 g of injection-grade soybean phospholipid and 1.0 g of medium-chain fatty glyceride, and magnetically stirring for about 1 hour under the aseptic condition until the components are uniformly mixed to obtain a milky yellow liquid containing a large amount of bubbles. Mixing silybin powder 2.0 g with the above liquid under aseptic condition, standing until bubbles disappear completely, packaging, and sealing.
Experimental example 1
Samples were prepared according to the preparation method of example 1 to carry out the following tests, replacing the soybean phospholipids prescribed in example 1 (example 1) with egg yolk phospholipids (test example 1), hydrogenated egg yolk lecithin (test example 2), dipalmitoyl phosphatidylethanolamine (test example 3) and no phospholipids (test example 4, replacing phospholipids with medium-chain fatty acid glycerides, which was prepared in the same manner as in example 1). A bulk drug solution group was simultaneously designed, and 50 mg of the drug was dissolved in 5mL of 50% propylene glycol phosphate buffer (pH = 7.6) to prepare a solution having the same concentration as in example 1 (test example 5).
200-220 g of SD rats were randomly divided into five groups of 5 rats, and administered by subcutaneous injection at a dose of 50 mg/kg of ivermectin (example 1, test example 2, test example 3, test example 4 and test example 5), blood was taken from rat orbit at a predetermined time point, the rat orbit was placed in a test tube anticoagulated with heparin sodium, and after the sample was processed, plasma concentration was measured by LC-MS/MS injection, and the results are shown in the following table:
Figure 258868DEST_PATH_IMAGE002
as a result: as can be seen from the above table, the kind of phospholipid has little influence on the large slow release of the drug, and can effectively inhibit the burst release effect of ivermectin.
Example 2
Samples were prepared according to the preparation method of example 1 and subjected to the following tests, in which medium-chain fatty acid glycerides prescribed in example 1 were removed or replaced with soybean oil, corn oil, sesame oil and tea oil. A bulk drug solution group was simultaneously designed, and 50 mg of drug was dissolved in 5mL of 50% propylene glycol phosphate buffer (pH = 7.6) to prepare a solution having the same concentration as in example 1.
200-220 g of SD rats were randomly divided into five groups of 5 rats, and administered by subcutaneous injection at a dose of 50 mg/kg of ivermectin (example 1, test example 2, test example 3, test example 4 and test example 5), blood was taken from rat orbit at a predetermined time point, the rat orbit was placed in a test tube anticoagulated with heparin sodium, and after the sample was processed, plasma concentration was measured by LC-MS/MS injection, and the results are shown in the following table:
Figure 55791DEST_PATH_IMAGE004
as a result: as can be seen from the above table, the presence or absence of the oil for injection in the gel and the kind of the oil added have little influence on the inhibition of the burst release of ivermectin.
Experimental example 3
Samples were prepared according to the preparation method of example 1 to conduct the following tests, and chondroitin sulfate-octadecylamine coupler in the formulation of example 1 was adjusted to 0.5g (test 1) and 0.1 g (test 2). A high concentration phospholipid gel (test example 3, prepared according to patent CN 102526753A) and a bulk drug solution set (test example 4, 100mg of drug was dissolved in 10 mL of propylene glycol-phosphate buffer (pH = 7.6) to prepare a solution of the same concentration as in example 1) were designed at the same time. And a phospholipid mucopolysaccharide gel was set as a control (test example 5, prepared according to the preparation method of example 1, except that the chondroitin sulfate-octadecylamine conjugate was changed to chondroitin sulfate).
The formulation of the high-concentration phospholipid gel sustained-release preparation (patent CN 102526753A) is as follows:
Figure 22610DEST_PATH_IMAGE006
200-220 g of SD rats were randomly divided into five groups of 6 rats, and were subcutaneously injected at a dose of 50 mg/kg of ivermectin (example 1, test example 2, test example 3, test example 4 and test example 5), blood was collected through the orbit of the rat at a predetermined time point, placed in a test tube anticoagulated with heparin sodium, and after the sample was processed, plasma concentration was measured by LC-MS/MS injection, and the results are shown in the following table:
Figure 794257DEST_PATH_IMAGE008
as a result: as can be seen from the above table, the addition of mucopolysaccharide derivatives to phospholipid gels is significantly better than the addition of unmodified mucopolysaccharides, and at the same time, significantly better than that of high concentration phospholipid gels, and can effectively inhibit the burst release of active drugs.
Experimental example 4
The following experiment was carried out according to the preparation method of example 1, and the chondroitin sulfate-octadecylamine coupler in the formulation of example 1 was adjusted to 0.5g (test 1) and 0.1 g (test 2). A high concentration phospholipid gel group was also designed (test example 3). The effect of the mucopolysaccharide derivative content on the appearance of the formulation was examined and the viscosity was determined by a viscometer.
The results are given in the following table:
Figure 213737DEST_PATH_IMAGE010
as a result: with the increase of the addition amount of the mucopolysaccharide derivative, the viscosity of the gel solution is slightly increased, but the fluidity still meets the requirement of injection.
Experimental example 5
Preparing phospholipid mucopolysaccharide derivative sustained-release preparations with different proportions, performing local irritation experiment, and investigating irritation of the anhydrous ethanol dosage to injection part, including red swelling, ulcer, etc.
The results are given in the following table:
table one:
Figure 565084DEST_PATH_IMAGE012
table two:
Figure 134212DEST_PATH_IMAGE014
table three:
Figure 545602DEST_PATH_IMAGE016
table four:
Figure 452378DEST_PATH_IMAGE018
as a result: the ethanol in the formulation exhibited a slightly reversible irritation to the site of administration. However, formulations in which mucopolysaccharide derivatives are present are effective in alleviating irritation, which may be associated with the inflammatory activity of mucopolysaccharides.
Experimental example 6
(1) Gel phase transition process of phospholipid mucopolysaccharide derivatives
The product of example 1 was injected subcutaneously into experimental animals and removed after 30 minutes, and the results are shown in fig. 1, wherein the solution state in fig. 1 is before injection and the semisolid gel state is after injection. Therefore, the phospholipid mucopolysaccharide derivative gel changes from milky yellow transparent liquid to spherical semisolid state, which indicates that the phase change process occurs after ethanol is diffused after the phospholipid mucopolysaccharide derivative gel is injected under the skin.
(2) Gel surface characteristics of phospholipid mucopolysaccharide derivatives
The products of example 1 (IVM-MG-3, ivermectin network gel 3), test example 1 (IVM-MG-2, ivermectin network gel 2), test example 2 (IVM-MG-1, ivermectin network gel 1) and test example 3 (IVM-PG, ivermectin high-concentration phospholipid gel) in experimental example 3 were injected into the experimental animals subcutaneously for 30 minutes and then removed for observation by scanning electron microscopy, and the results are shown in fig. 2: with the increase of the content of the mucopolysaccharide derivative, the nodule on the surface of the preparation is increased, and the network structure is more obvious, which indicates that the mucopolysaccharide derivative can enable the phospholipid gel to have a network barrier.
(3) Results of in vitro Release
The products of example 1 (IVM-MG-3, ivermectin network gel 3), test example 1 (IVM-MG-2, ivermectin network gel 2) in test example 3, test example 2 (IVM-MG-1, ivermectin network gel 1), test example 3 (IVM-PG, ivermectin high-concentration phospholipid gel) and test example 4 (IVM-Sol, test example 4 in test example 3) were packed in dialysis bags, respectively, and then placed in 5ml of 30% ethanol/PBS buffer solution (pH = 7.4) and subjected to in vitro release test in a constant temperature shaker (37 ℃, 100 rmp). 5ml of buffer was removed at the set time point and an equal volume of fresh ethanol/PBS buffer was added and the cumulative drug release rate was calculated. The results are shown in FIG. 3: the gel group of phospholipid mucopolysaccharide derivatives has the characteristic of inhibiting burst release, and the sustained release effect is more obvious along with the increase of the content of the mucopolysaccharide derivatives.
(4) Pharmacokinetic results in vivo
The products of test example 1, test example 2, test example 3 and test example 4 of example 1 and test example 3 were injected subcutaneously into male SD rats, blood was periodically collected, and the content of ivermectin in the plasma was measured by high performance liquid chromatography-mass spectrometry (LC-MS/MS) to examine the sustained release effect.
200-220 g SD rats were randomly divided into five groups, namely a solution group (IVM-Sol, test example 4 of Experimental example 3), a high concentration phospholipid gel group (IVM-PG, test example 3 of Experimental example 3, prepared according to patent CN 102526753A), a reticular gel 1 (IVM-MG-1, test example 2 of Experimental example 3), a reticular gel 2 (IVM-MG-2, test example 1 of Experimental example 3), and a reticular gel 3 (IVM-MG-3, example 1), wherein 6 rats in each group were injected subcutaneously at a dose of 50 MG/kg, blood was collected from rat eyepits at a predetermined time point, the rats were placed in heparin sodium anticoagulated test tubes, and plasma concentration was detected by LC-MS/MS injection after sample treatment.
The pharmacokinetic parameters for each group of formulations were as follows:
Figure 607416DEST_PATH_IMAGE020
the results show that the sustained release capacity of the phospholipid mucopolysaccharide derivative reticular gel is obviously higher than that of the phospholipid gel and the solution with high concentration, and the sustained release time is longer along with the increase of the content of the mucopolysaccharide derivative, which is mainly expressed as CmaxDecrease of t1/2And (5) prolonging. As shown in fig. 4: the high-concentration phospholipid in-situ phase change gel slow release preparation coated with ivermectin has serious burst release and poor slow release effect, and the phospholipid mucopolysaccharide derivative reticular gel preparation can obviously improve the burst release condition of the medicine.
(5) Result of skin toxicity
The product of example 1 was injected subcutaneously into male SD rats, and the morphology inside and outside the skin of the injection site was observed 30 days later, and the results are shown in FIG. 5: the results were the same for normal skin appearance of rats with uniform skin inside and outside.
1 ml of each of test example 1 (IVM-MG-3, ivermectin network gel 3), test example 1 (IVM-MG-2, ivermectin network gel 2) in Experimental example 3, test example 2 (IVM-MG-1, ivermectin network gel 1) and test example 3 (IVM-PG, ivermectin high-concentration phospholipid gel) was injected subcutaneously into rats, and a solution group (IVM-Sol, test example 4 of Experimental example 3) was set as a control, and skin tissues were taken out after one month for H & E staining observation, and as a result, as shown in FIG. 6, the reticular gel preparation was able to significantly reduce its side effects, this is because the preparation has excellent sustained-release and burst-release-suppressing ability, compared with the solution group, the preparation can remarkably reduce irritation reaction caused by ethanol diffusion, thereby improving safety.
Experimental example 7
Pharmacokinetic results in vivo
The product of example 2 was injected subcutaneously into male SD rats, blood was periodically collected, and the content of doxorubicin hydrochloride in plasma was measured by high performance liquid chromatography-mass spectrometry (LC-MS/MS) to examine the sustained-release effect.
SD rats of 200-220 g were randomly divided into two groups of 6 rats, and subcutaneous injections were administered in accordance with a phospholipid chitosan tetradecanoic acid gel group (80 mg/kg, prepared according to example 2, only chondroitin octadecylamine in example 2 was replaced with chitosan tetradecanoic acid) and a high concentration phospholipid gel group (80 mg/kg, prepared according to patent CN102526753A, ivermectin in test example 3 of test example 3 was replaced with 200mg doxorubicin hydrochloride), at a predetermined time point, blood is drawn through the orbit of the rat, placed in a test tube anticoagulated with heparin sodium, the sample is processed, LC-MS/MS sample injection detection of blood concentration shows that the slow release capacity of the phospholipid chitosan myristic acid gel group is obviously higher than that of the high-concentration phospholipid gel and solution group, mainly represented by t1/2 extension, and doxorubicin hydrochloride can maintain higher effective blood concentration. As shown in fig. 7: the high-concentration phospholipid in-situ phase change gel entrapping the water-soluble drug adriamycin hydrochloride has poor slow release effect, and the phospholipid chitosan tetradecanoic acid gel preparation can obviously improve the burst release condition of the drug and has good slow release effect.
The pharmacokinetic parameters for each group of formulations were as follows:
Figure 798095DEST_PATH_IMAGE022
experimental example 8
The product of example 3 was injected subcutaneously into male SD rats, periodically bled, and the amount of ipiprazole in plasma determined by high performance liquid chromatography-mass spectrometry (LC-MS/MS) compared to a high concentration phospholipid gel.
200-220 g of SD rats are randomly divided into two groups, each group comprises 6 rats, subcutaneous injection administration is carried out according to the dosage of a phospholipid hyaluronic acid hexadecylamine gel group (50 mg/kg, prepared according to example 3) and a high-concentration phospholipid gel group (50 mg/kg, prepared according to test example 3 in test example 3, and only 200mg of ivermectin is replaced by ipiprazole), blood is taken from rat eyesockets at a preset time point and is placed in a heparin sodium anticoagulation test tube, and after a sample is treated, LC-MS/MS injection is carried out to detect the blood concentration, and the result shows that the phospholipid hyaluronic acid is capable of being absorbed by human bodiesThe sustained-release capability of the hexadecylamine acid gel group is obviously higher than that of the high-concentration phospholipid gel, and is mainly represented by t1/2And the brexpiprazole can maintain higher effective blood concentration for a long time. As shown in fig. 8, although the high-concentration phospholipid gel can sustain sustained release for 25 days, the phospholipid mucopolysaccharide derivative gel preparation of the present invention has almost no burst release of the drug, has a better sustained release effect, and can sustain sustained release for 45 days.
Figure 911544DEST_PATH_IMAGE024
Experimental example 9
The sustained release preparation of the phospholipid mucopolysaccharide derivative has the sustained release characteristic on other medicines.
The effect of other drugs on suppressing burst release was investigated using in vivo animal experiments. The following drugs were injected subcutaneously into male SD rats with the formulations prepared according to the prescriptions and preparation methods of example 1 (Table 1), example 3 (Table 2) and example 6 (Table 3) except for the active drug, to obtain phospholipid mucopolysaccharide derivatives sustained release formulations and stock solutions of other drugs (each drug is formulated with water for injection, ethanol or DMSO, depending on the specific solubility), periodically blood was collected, and C of each other drug in plasma was measured by high performance liquid chromatography-mass spectrometry (LC-MS/MS)maxThe effect of suppressing the burst release was examined. The results are shown in the following table:
table 1:
Figure 305616DEST_PATH_IMAGE026
table 2:
Figure 998766DEST_PATH_IMAGE028
table 3:
Figure 748678DEST_PATH_IMAGE030
the result shows that the phospholipid mucopolysaccharide derivative reticular gel preparation can obviously improve the burst release condition of the medicament.
In conclusion, the phospholipid mucopolysaccharide derivative in-situ phase change gel can obviously inhibit the burst release of the medicament, prolong the slow release time, reduce the toxicity of the medicament and has good biocompatibility.

Claims (10)

1. An in situ gel formulation comprising a phospholipid, a mucopolysaccharide derivative, a pharmaceutically active ingredient.
2. The in situ gel formulation of claim 1, comprising 0.01 to 20 parts of pharmaceutically active ingredient, 30 to 80 parts of phospholipid, and 1 to 20 parts of mucopolysaccharide derivative.
3. The in situ gel formulation of claim 1, wherein the in situ gel formulation further comprises a biocompatible organic solvent selected from one or more of absolute ethanol, ethanol solution, N-propanol, isopropanol, N-butanol, isobutanol, sec-butanol, tert-butanol, propylene glycol, glycerol, polyethylene glycol, N-pentane, isopentane, neopentane, N-hexane, methyl formate, ethyl acetate, dimethyl sulfoxide, N-dimethylformamide, and formamide, wherein the ethanol solution is preferably ethanol-water solution, ethanol-dimethyl sulfoxide solution, ethanol-N, N-dimethylformamide solution, ethanol-formamide solution, ethanol-N-hexane, ethanol-physiological saline solution, ethanol-phosphate buffer solution, and formamide solution, One or more of ethanol carbonate buffer solution, ethanol-succinate buffer solution, ethanol-citrate buffer solution, and ethanol-lactate buffer solution.
4. The in situ gel formulation of claim 1, further comprising 5-40 parts by weight of an injection oil selected from one or more of soybean oil, corn oil, sesame oil, tea oil, fish oil, medium-chain fatty glyceride, cottonseed oil, and ethyl oleate.
5. The in situ gel formulation of claim 1, wherein the phospholipid is selected from one or more of natural phospholipid selected from egg yolk lecithin, soybean phospholipid; the semisynthetic phospholipid is selected from hydrogenated egg yolk lecithin and hydrogenated soybean phospholipid; the synthetic phospholipid is selected from the group consisting of dipalmitoylphosphatidylethanolamine, dipalmitoylphosphatidic acid, dipalmitoylphosphatidylglycerol, dioleoylphosphatidylethanolamine, dipalmitoylphosphatidylcholine, distearoylphosphatidylcholine and dimyristoylphosphatidylcholine, preferably soybean phospholipid S100.
6. The in situ gel formulation of claim 1, wherein the mucopolysaccharide derivative is prepared from mucopolysaccharide and one or more of fatty amine ligand or fatty acid ligand, wherein the mucopolysaccharide is selected from chondroitin sulfate, hyaluronic acid, heparin, dermatan sulfate, heparan sulfate, keratan sulfate and chitosan or pharmaceutically acceptable salts thereof, the fatty amine ligand or fatty acid ligand is one or more of long-chain, short-chain, saturated, monounsaturated, polyunsaturated fatty amine or fatty acid, the degree of substitution of the fatty amine or fatty acid of the mucopolysaccharide derivative is 1-50%, and the molecular weight of the mucopolysaccharide derivative is 10-20,000 kDa.
7. The in-situ gel preparation according to any one of claims 1-6, wherein the pharmaceutically active ingredient is selected from the group consisting of epipiprazole, olanzapine, veseline, fondaparine, epinastine, oxyphenbutamine, epinastine, oxyphenbutamin, oxyphenbutazone, norgestrel, oxyphenbutazone, norgestrel, oxyphenbutazone, valprohormone, valproor a, valprohormone, or prodrug, or a.
8. A method of preparing an in situ gel formulation according to any one of claims 1 to 7, comprising the steps of:
(1) dissolving the active components in biocompatible organic solvent, filtering with microporous membrane for sterilization to obtain medicinal solution;
(2) mixing phospholipid and mucopolysaccharide derivative with the medicinal solution obtained in step (1) under aseptic condition, stirring for mixing, standing for a while to remove air bubbles in the preparation, packaging, and sealing.
9. A method of preparing an in situ gel formulation according to any one of claims 1 to 7, comprising the steps of:
(1) under the aseptic condition, preparing medicine particles by taking the active ingredients of the medicine through a common crystallization or crushing mode in pharmaceutics;
(2) mixing phospholipid and mucopolysaccharide derivative with biocompatible organic solvent under aseptic condition, and stirring to mix well;
(3) and (3) uniformly mixing the drug particles in the step (1) and the carrier solution prepared in the step (2) under the aseptic condition, standing for a moment to remove air bubbles in the preparation, subpackaging and sealing to obtain the traditional Chinese medicine preparation.
10. Use of the in situ gel formulation of any one of claims 1 to 7 or the process for the preparation of the in situ gel formulation of any one of claims 8 to 9 for the manufacture of a medicament-containing formulation for the inhibition of burst release and for the prolongation of the sustained release time.
CN201811171012.5A 2018-10-09 2018-10-09 Drug-loaded reticular in-situ phase-change gel sustained-release system and preparation method thereof Active CN111012734B (en)

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CN102526753A (en) * 2011-12-15 2012-07-04 成都师创生物医药科技有限公司 In-situ phase change gel slow release system taking phospholipid as substrate and preparation method thereof
CN107049932A (en) * 2017-06-22 2017-08-18 四川大学 A kind of small-molecule drug phase change gel slow-released system in situ and preparation method thereof

Patent Citations (2)

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Publication number Priority date Publication date Assignee Title
CN102526753A (en) * 2011-12-15 2012-07-04 成都师创生物医药科技有限公司 In-situ phase change gel slow release system taking phospholipid as substrate and preparation method thereof
CN107049932A (en) * 2017-06-22 2017-08-18 四川大学 A kind of small-molecule drug phase change gel slow-released system in situ and preparation method thereof

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114560644A (en) * 2022-03-26 2022-05-31 中建西部建设北方有限公司 Modified micro-nano bubble water, preparation method thereof and concrete

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