HK1213812A1 - M10c1 compound and active ingredient-containing composition and preparation method thereof - Google Patents
M10c1 compound and active ingredient-containing composition and preparation method thereof Download PDFInfo
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- HK1213812A1 HK1213812A1 HK16101910.7A HK16101910A HK1213812A1 HK 1213812 A1 HK1213812 A1 HK 1213812A1 HK 16101910 A HK16101910 A HK 16101910A HK 1213812 A1 HK1213812 A1 HK 1213812A1
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- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/7088—Compounds having three or more nucleosides or nucleotides
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/22—Heterocyclic compounds, e.g. ascorbic acid, tocopherol or pyrrolidones
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Abstract
The present invention relates to the field of biological medicine, and specifically relates to a composition comprising an M10C1 compound and an active ingredient, and a preparation method thereof. The active ingredient is siRNA, and calculated in parts by weight, the composition comprises 1-5 parts siRNA, 1-24 parts of the M10C1 compound, and 1-10 parts of cholesterol-polyethylene glycol. The composition of the present invention, which comprises an M10C1 compound and siRNA, can improve pharmacokinetic characteristics of siRNA treatment, change biological distribution, intracellular uptake, targeting and delivery efficiency, reduce adverse reactions, etc.
Description
Technical Field
The invention belongs to the field of medical biology, and particularly relates to a composition containing an M10C1 compound and an active ingredient and a preparation method thereof.
Background
Double-stranded RNA (dsRNA) inhibits protein expression, silences genes, and has wide and potential application in treating human diseases. There are three ways in which dsRNA induces gene silencing: 1. inactivation of transcription function, which is the methylation of DNA or histones under the guidance of RNA; 2. degradation of messenger rna (mrna) induced by small interfering nucleic acids (siRNA); 3. RNA-mediated attenuation of transcription function. However, it is generally believed that dsRNA-induced gene interference (inhibition) refers to RNA degradation in animal cells. Chemically synthesized small RNA, such as siRNA, can enzymatically degrade intracellular mRNA by more than 95% at sub-micromolar concentrations.
The effect of RNAi can last for a long time, even to several generations of cell division, while gene interference is a sequence-specific inhibition. Therefore, RNAi can specifically inhibit gene expression without affecting other mRNA, and the specific inhibition is particularly important in studying gene function and identification of drug targets. siRNA can be used to develop drug therapies: 1. genes that are due to overexpression or not normally expressed; 2. disease caused by mutated gene.
RNAi can be applied to the development of a new class of drugs different from small molecules and proteins, and although long dsRNA causes the interferon response of cells and cannot be directly transmitted to the cells, the application of siRNA is more successful. Has been successfully used in research and has been clinically tested.
The medicine is applied to the treatment aspect, and is firstly used for treating age-related macular degeneration and respiratory syncytial virus. Other reported diseases of treatment, including antiviral HIV, hepatitis a, b, c, cold, measles, etc.; treatment of neurodegenerative diseases, particularly Huntington's disease, such as polyglutamine disease, has also been reported. RNAi can also treat cancer by suppressing the division of tumor cells by inhibiting over-expressed genes. However, a very important field is to develop a safe siRNA delivery technology to ensure the clinical application of RNAi.
Although studies at the cellular level indicate that RNAi is a very promising platform for drug development, whether off-target effects of siRNA can cause some side effects is also of concern, since off-target effects can suppress genes with similar sequences to the target gene. It is calculated that the off-target effect can reach 10%. In mammalian cells, long double stranded siRNA can induce interferon response. Therefore, siRNA or iNA (interfering nucleic acid) must maintain a short sequence to avoid an interferon response. One method that can best design an siRNA or an iNA that does not respond to interferon is to design a therapeutic iNA or siRNA that can act on one or more target genes, or different portions of a target gene, whose structure can be in one orientation, or in different orientations, circular-like, or linear. These several types of iNAORsiRNA differ from commonly used siRNAs in structure. The research shows that: the chemical modification of the siRNA structure and the carrier modification of the siRNA skeleton are two important ways of improving the in vivo delivery stability of siRNA.
The siRNA has high sequence specificity and strong targeting property when playing a role. RNAi has a cascade amplification effect, a very small amount of double-stranded ribonucleic acid (dsRNA) can degrade mRNA with a concentration much higher than that of the dsRNA, but after siRNA is injected into a body, the siRNA must pass through the systemic circulation system after being wrapped, so that the filtering of kidney glomeruli, the phagocytosis of phagocytes, the adsorption of serum proteins and the degradation of endogenous nuclease as far as possible can be avoided, and the siRNA can not reach target cells until the siRNA is retained in a reticuloendothelial system (RES). siRNA has poor stability in serum and is easily degraded by nuclease RNase. After intravenous injection of siRNA, siRNA is distributed to each large organ through blood circulation and eliminated at the same time. The encapsulated siRNA enters the interstitial tissue via the blood vessels (extravasation), then crosses the interstitial tissue to reach the target cell, and is taken up by endocytosis after reaching the target cell. In the process, the encapsulated siRNA is embedded by an endosomal vesicle initiated by the endosome, and must escape from the endosome, be released into cytoplasm, and be loaded to RISC to play a role. The extravasation and penetration ability of siRNA depends on the physical structure of the target tissue, and its intracellular uptake is also related to the surface properties of siRNA and carrier. The biggest obstacles to delivery of siRNA to the target site are entrapment of siRNA and carrier by endosomes and degradation of siRNA and carrier by lysosomes.
Naked siRNA is negatively charged, has large molecular weight and strong polarity, is difficult to pass through cell membranes and vascular endothelium, is easy to be retained in spleen, is easy to be degraded by nuclease in organisms, has short half-life and low transfection efficiency, and even can generate strong inflammatory reaction and the like. Therefore, the in vivo stability of siRNA is crucial for its therapeutic effect. With the aid of various vectors, efficient delivery of siRNA to target cells by different means is the focus of current research.
Disclosure of Invention
The technical scheme of the invention is to provide a composition containing an M10C1 compound and an active ingredient, wherein the structural formula of the M10C1 compound is as follows:
further, the composition also comprises cholesterol-polyethylene glycol, and the active ingredient is siRNA.
Furthermore, the siRNA1-5 parts and the M10C1 compound are 1-24 parts and the cholesterol-polyethylene glycol is 1-10 parts by weight.
Further, the siRNA sequence is HBVsiRNA:
sense strand: [ mC ] CG [ mU ] GUG [ mC ] ACUUCGCCUU [ mC ] A [ dT ] [ dT ];
antisense strand: UGAAGCGAAGUG mC A mC ACGGUC.
Furthermore, the siRNA1 parts of M10C1 compound is 1.5 parts, and the cholesterol-polyethylene glycol is 3 parts by weight.
Further, the cholesterol-polyethylene glycol is one or more selected from cholesterol-PEG 400, cholesterol-PEG 600, cholesterol-PEG 2000, cholesterol-PEG 1000 and cholesterol-PEG 5000.
The present invention also provides a method of preparing a composition comprising an M10C1 compound and an active ingredient, comprising the steps of:
(1) dissolving siRNA in citric acid solution, and obtaining solution I with pH5.0;
(2) taking cholesterol-polyethylene glycol and an M10C1 compound, and dissolving the cholesterol-polyethylene glycol and the M10C1 compound in a solvent to obtain a solution II;
(3) placing the first solution on a magnetic stirrer, slowly dripping the second solution into the first solution while stirring, mixing, adding phosphate buffer, adjusting pH to 6-8, preferably 7, dialyzing, replacing buffer, and concentrating;
(4) and then carrying out high-pressure homogenization and freeze-drying on the concentrated solution to form a dried substance, thus obtaining the composition.
The weight sum of the components in the step (2) and one group or mixture of the components in the siRNA sequence group is 2-10: 1; the volume ratio of the prepared solution I to the prepared solution II is 1: 0.2-1, preferably 1: 0.25-0.8.
Further, the solvent is one or a combination of more than two of methanol, ethanol, chloroform, acetone and ethyl acetate.
The composition containing the M10C1 compound and the active ingredient can improve the pharmacokinetic characteristics of siRNA treatment, change the biodistribution, intracellular uptake, targeting property and transfection efficiency, reduce adverse reactions and the like. The composition of the M10C1 compound and the active ingredient can encapsulate siRNA, deliver the siRNA to target tissues in vivo and stabilize siRNA molecules. M10C1 also plays a key role in the uptake of nanoparticles by endocytosis, entering the endosome of cells. The M10C1 molecule is an amphiphilic macrocyclic lipid molecule. After the nanoparticles are formed, their hydrophilic groups are exposed outside the particles. And the surface charge of the nanoparticles changes with the change of the pH of their environment. In normal blood, the pH is near neutral and its particle surface is uncharged, avoiding binding to plasma proteins and phagocytosis by leukocytes. When entering the cellular endosome, it becomes acidic and positively charged due to its decreased pH (table one). During the flow of hydrogen ions from the outside into the endosome, the endosome is ruptured due to the increase in pressure of the endosome (sponge-like effect). The siRNA is released into the cytoplasm to exert its specific gene suppression function (gene silencing).
Detailed Description
EXAMPLE 1 Synthesis of Compound M10C1
The M10C1 compound is obtained by reacting (1, 4, 7, 10, 13, 16-hexaazacyclooctadecane hexahydrate hydrochloride) and an epoxy compound in a glass bottle with a stirring bar at 90 ℃ without solvent. The reaction time is 24-72 hours at 90 ℃. The ratio (molar ratio) of N, N-di (3-aminopropyl) methylamine to epoxy alkyl compound (alkyl (C12-C14) glycidyl ether, C12-14 glycidyl ether) in the reaction is 1: 4, the result is known to be confirmed by Thin Layer Chromatography (TLC), only one main product exists in the reaction mixture, and the product of the reactant can be used after purification;
example 2
The synthesis method of the cholesterol-polyethylene glycol compound comprises the following steps: placed in a 2000ml round bottom flask was (1S, 2R, 5S, 10S, 11S, 14R, 15R) -2, 15-dimethyl-14- [ (2R) -6-methylheptyl-2 yl ] tetracyclo [8.7.0.0^ 2, 7].0^ 11, 15] ] heptadecan-7-en-5-ol (200 g, 517.26mmol, 1.0 equiv, pyridine (1000 ml.) 4-toluenesulfonyl chloride (148 g, 776.301.50 equiv.) stirred overnight at 50 ℃ in an oil bath, the reaction mixture cooled to a low temperature with a water/ice bath, diluted with 2000ml ether, water 1X1000 and 5X 100020% citric acid were added to the mixture, the resulting mixture was washed with 1X1000mlsat. NaClaq the resulting product was concentrated under vacuum.about 180 g (64%) of a white solid (1S, 2R, 5S, 10S, 11S, 14R, 15R) -2, 15-dimethyl-14- [ (2R) -6-methylheptyl-2-yl ] tetracyclo [8.7.0.0^ 2, 7] 0^ 11, 15] heptadec-7-en-5-yl 4-methylphenyl-1-sulfonate (1S, 2R, 5S, 10S, 11S, 14R, 15R) -2, 15-dimethyl-14- [ (2R) -6-methylheptyl-2-yl ] tetracyclo [8.7.0.0^ 2, 7] 0^ 11, 15] heptadec-7-en-5-yl 4-methylphenyl-1-sulfonate (1700 mL) was placed in a 3000 mL round bottom flask. Mix well and react overnight in an oil bath at 110 ℃. The product was concentrated in vacuo. Dissolve with 2000ml dichloromethane DCM. And then concentrated in vacuo. Eluting with silica gel column and dichloromethane/methanol (100: 1-5: 1). The product was 120 g (65%) of a light brown product: cholesterol oleoyl sulfonate-polyethylene glycol.
Example 3
Carriers for siRNA drugs:
sense strand: CCGUGUGCACUUCGCUUCA [ dT ] [ dT ];
antisense strand: UGAAGCGAAGUGCACACGGUC are provided.
The RNA interference composition also comprises the following components in percentage by weight:
1g of M10C1 Compound obtained in example 1
10002g of cholesterol-polyethylene glycol;
the preparation method of the RNA interference composition for treating the viral hepatitis B comprises the following steps:
(1) dissolving one group in the siRNA sequence group in water containing 0.9 percent of water and 5 percent of cane sugar or pure water to obtain a solution I;
(2) weighing the following components in parts by weight, and dissolving the components in alcohol to obtain a solution II:
M10C1 Compound 1g
10002g of cholesterol-polyethylene glycol;
the weight sum of the components in the step (2) and one group or mixture of the components in the siRNA sequence group is 2-10: 1; the volume ratio of the prepared solution I to the prepared solution II is 1: 0.25-0.8;
(3) mixing the first solution and the second solution uniformly, and performing vacuum filtration at room temperature to gradually evaporate alcohol in the first solution;
(4) homogenizing after most of alcohol is evaporated to obtain suspension with particle size of 5-250 nm;
(5) the suspension is lyophilized to form a white or yellowish dry, RNA interfering composition.
The RNA interference composition is applied by adding a proper amount of water for injection, shaking or dissolving to form a suspension. The preparation method can also be used as a preparation method of other nucleic acid medicaments.
Example 4
Carriers for siRNA drugs:
sense strand: CCGUGUGCACUUCGCUUCA [ dT ] [ dT ];
antisense strand: UGAAGCGAAGUGCACACGGUC are provided.
The RNA interference composition also comprises the following components in percentage by weight:
10g of M10C1 Compound obtained in example 1
100024g cholesterol-polyethylene glycol;
the weight ratio of the sum of the weight of the components to one or the mixture of the siRNA sequence groups is 2-10: 1.
The preparation method of the RNA interference composition for treating the viral hepatitis B comprises the following steps:
(1) solution one: dissolving siRNA in citric acid solution, pH5.0(5mg/ml)
(2) Weighing the following components in parts by weight, and dissolving the components in alcohol to obtain a solution II:
M10C1 Compound 10g
100024g cholesterol-polyethylene glycol;
the volume ratio of the prepared solution I to the prepared solution II is 1: 0.2-1;
(3) the solution one is placed on a magnetic stirrer, and the solution two is slowly dripped into the solution 1 while stirring. After mixing, phosphate buffer was added to adjust the pH to 7. The buffer was replaced by dialysis and concentrated for use as an assay.
Example 5
Carriers for siRNA drugs:
sense strand: CCGUGUGCACUUCGCUUCA [ dT ] [ dT ];
antisense strand: UGAAGCGAAGUGCACACGGUC are provided.
The RNA interference composition also comprises the following components in percentage by weight:
1.5g of M10C1 Compound obtained in example 1
10003g of cholesterol-polyethylene glycol;
the weight ratio of the total weight of the composition to one or the mixture of the siRNA sequence groups is 2-10: 1.
The preparation method of the RNA interference composition for treating the viral hepatitis B comprises the following steps:
1) solution one: dissolving siRNA in citric acid solution, pH5.0(5mg/ml)
2) Weighing the following components in parts by weight, and dissolving the components in alcohol to obtain a solution II:
M10C1 Compound 1.5g
10003g of cholesterol-polyethylene glycol;
3) the solution one is placed on a magnetic stirrer, and the solution two is slowly dripped into the solution 1 while stirring. After mixing, phosphate buffer was added to adjust the pH to 7. The buffer was replaced by dialysis and concentrated for use as an assay.
Example 6
All procedures used in the animal studies conducted were approved by the Institutional Animal Care and Use Committee (IACUC) and were in compliance with applicable regional, state, and federal regulations. RNA interference compositions corresponding to the first to thirteenth siRNA sequence groups were prepared according to the method of example 1, respectively, and the following animal experiments were performed using HBV transgenic mice.
The above siRNA composition dose was 1 mg/kg body weight, one injection, 72 hours later blood sampling to determine HBV surface antigen changes.
Wherein liver HBVDNA analysis is performed by semi-quantitative PCR:
the analysis of HBV surface antigen index of blood is carried out by using a commercial ELISA kit (International immunodiagnosis, Foster City, Calif.) corresponding to the required biochemical index.
TABLE M10C1 anti-hepatitis B siRNA nanoparticle preparation with different batches of particle size, potential and gene inhibition activity
All formulations were nanopreparations at ph6.0 for injection into animals.
Claims (9)
1. A composition comprising an M10C1 compound and an active ingredient, said M10C1 compound having the formula:
2. the composition of claim 1, further comprising cholesterol-polyethylene glycol, wherein the active ingredient is siRNA.
3. The composition of claim 2, wherein the siRNA1-5 parts and the M10C1 compound are 1-24 parts and the cholesterol-polyethylene glycol is 1-10 parts by weight.
4. The composition of claim 1, wherein the siRNA sequence is a hbswirna:
sense strand: [ mC ] CG [ mU ] GUG [ mC ] ACUUCGCCUU [ mC ] A [ dT ] [ dT ];
antisense strand: UGAAGCGAAGUG mC A mC ACGGUC.
5. The composition of claim 2, wherein the siRNA is 1 parts, the M10C1 compound is 1.5 parts, and the cholesterol-polyethylene glycol is 3 parts by weight.
6. The composition of claim 2, wherein the cholesterol-polyethylene glycol is selected from one or more of cholesterol-PEG 400, cholesterol-PEG 600, cholesterol-PEG 2000, cholesterol-PEG 1000, and cholesterol-PEG 5000.
7. A method of preparing the composition of claim 2, comprising the steps of:
(1) dissolving siRNA in citric acid solution, and obtaining solution I with pH5.0;
(2) taking cholesterol-polyethylene glycol and an M10C1 compound, and dissolving the cholesterol-polyethylene glycol and the M10C1 compound in a solvent to obtain a solution II;
(3) placing the first solution on a magnetic stirrer, slowly dripping the second solution into the first solution while stirring, mixing, adding phosphate buffer, adjusting pH to 6-8, preferably 7, dialyzing, replacing buffer, and concentrating;
(4) and then carrying out high-pressure homogenization and freeze-drying on the concentrated solution to form a dried substance, thus obtaining the composition.
8. A process for preparing a composition according to claim 7,
the volume ratio of the solution I to the solution II is 1: 0.2-1, preferably 1: 0.25-0.8.
9. The method for preparing the composition according to claim 7, wherein the solvent in the step (2) is one or a combination of two or more of methanol, ethanol, chloroform, acetone and ethyl acetate.
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510466904.8A CN105079021A (en) | 2015-08-03 | 2015-08-03 | Combination containing M10C1 compound and active ingredient and preparation method of combination |
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| Publication Number | Publication Date |
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| HK1213812A1 true HK1213812A1 (en) | 2016-07-15 |
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| Application Number | Title | Priority Date | Filing Date |
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| HK16101910.7A HK1213812A1 (en) | 2015-08-03 | 2016-02-19 | M10c1 compound and active ingredient-containing composition and preparation method thereof |
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| Country | Link |
|---|---|
| CN (1) | CN105079021A (en) |
| HK (1) | HK1213812A1 (en) |
| WO (1) | WO2017020826A1 (en) |
Families Citing this family (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105079021A (en) * | 2015-08-03 | 2015-11-25 | 厦门成坤生物技术有限公司 | Combination containing M10C1 compound and active ingredient and preparation method of combination |
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2010135207A1 (en) * | 2009-05-16 | 2010-11-25 | Agave Pharma, Incorporated | Compositions comprising cationic amphiphiles and colipids for delivering therapeutics molecules |
| US9233971B2 (en) * | 2010-08-26 | 2016-01-12 | Kunyuan Cui | Lipomacrocycles and uses thereof |
| CN103333890B (en) * | 2012-12-21 | 2015-04-15 | 厦门成坤生物技术有限公司 | RNA interference preparation used for treating viral hepatitis B |
| CN104107437B (en) * | 2013-06-09 | 2015-08-26 | 厦门成坤生物技术有限公司 | A kind of RNA being used for the treatment of hepatitis B disturbs composition and method of making the same |
| CN105079021A (en) * | 2015-08-03 | 2015-11-25 | 厦门成坤生物技术有限公司 | Combination containing M10C1 compound and active ingredient and preparation method of combination |
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2015
- 2015-08-03 CN CN201510466904.8A patent/CN105079021A/en active Pending
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- 2016-02-19 HK HK16101910.7A patent/HK1213812A1/en unknown
- 2016-08-03 WO PCT/CN2016/093007 patent/WO2017020826A1/en not_active Ceased
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| Publication number | Publication date |
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| CN105079021A (en) | 2015-11-25 |
| WO2017020826A1 (en) | 2017-02-09 |
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