CN111249451B - Glycolipid antigen injection and preparation method thereof - Google Patents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/0005—Vertebrate antigens
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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
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/12—Carboxylic acids; Salts or anhydrides thereof
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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
- A61K47/24—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing atoms other than carbon, hydrogen, oxygen, halogen, nitrogen or sulfur, e.g. cyclomethicone or phospholipids
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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
- A61K47/28—Steroids, e.g. cholesterol, bile acids or glycyrrhetinic acid
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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
- A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/08—Solutions
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/10—Dispersions; Emulsions
- A61K9/107—Emulsions ; Emulsion preconcentrates; Micelles
- A61K9/1075—Microemulsions or submicron emulsions; Preconcentrates or solids thereof; Micelles, e.g. made of phospholipids or block copolymers
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/02—Immunomodulators
Abstract
The invention discloses a glycolipid antigen injection, which comprises glycolipid antigen, solubilizer and injection solvent, wherein the weight-volume ratio of the glycolipid antigen to the solubilizer to the injection solvent is 1mg: 10-1000 mg:0.1 to 20ml. The glycolipid antigen injection of the invention prepares the glycolipid antigen (such as alpha-galactosyl ceramide) into the nano micelle through a high molecular auxiliary material, which not only can realize the solubilization of the antigens, but also avoids the problem of NKT failure caused by multiple administration. The glycolipid antigen injection has simple preparation method and is easy to popularize and apply.
Description
Technical Field
The invention belongs to the field of medicines, and particularly relates to a glycolipid antigen injection and a preparation method thereof.
Background
NKT (natural killer T) cells are a distinct subset of T cells with both T cell receptors, TCR, and NK cell receptors, on the surface of a population of cells. NKT cells have the functions of immune regulation and cytotoxicity, and can secrete a large amount of IL-4, IFN-gamma, GM-CSF, IL-13 and other cytokines and chemokines to play the role of immune regulation after being stimulated. Meanwhile, NKT cells are also one of the bridges connecting innate immunity and acquired immunity. Therefore, NKT cells have a great prospect for treating serious diseases such as tumors.
NKT cell therapy one of the implementations: the patient's own blood is extracted for in vitro culture, the white blood cells obtained by culture contain the monocytes, special substances are adopted to activate the NKT cells, and then the NKT cells are returned to the patient. This method is time consuming and costly and difficult to popularize clinically. Another approach to NKT cell therapy is in vivo activation, i.e. by directly administering NKT activators to the patient. The method is simple and convenient to operate, low in cost and high in clinical application potential.
It was demonstrated that NKT activation is mainly achieved by recognition of glycolipid antigens (e.g. α -galactosylceramide). However, these glycolipid antigens are poorly water soluble and inconvenient for clinical use. In addition, even after the glycolipid antigens are dissolved by adding a latent solvent and the like, in vivo experiments show that the NKT cells can be disabled by injecting the water-soluble antigen molecules into the human body for many times.
Disclosure of Invention
In order to solve the above problems, the present invention provides a glycolipid antigen injection, which comprises glycolipid antigen, solubilizer and injection solvent, wherein the weight-volume ratio of the glycolipid antigen to the solubilizer to the injection solvent is 1mg: 10-1000 mg:0.1 to 20ml;
the glycolipid antigen is alpha-galactosyl ceramide and/or beta-galactosyl ceramide.
Further, the weight volume ratio of the glycolipid antigen, the solubilizer and the injection solvent is 1mg: 50-500 mg:1 to 10ml.
Further, the weight volume ratio of the glycolipid antigen, the solubilizer and the injection solvent is 1mg: 50-250 mg: 1-2 ml.
Further, the weight volume ratio of the glycolipid antigen, the solubilizer and the injection solvent is 1mg:200mg:2ml of the solution.
Further, the solubilizer is selected from one or more of phospholipid, bile salt, polyethylene glycol lithium dodecahydroxy stearate, poloxamer 188, polyoxyethylene castor oil and alpha-tocopherol succinic acid polyethylene glycol ester.
Still further, the solubilizing agent is selected from a plurality of phospholipids, bile salts, lithium macrogoldodecahydroxystearate, poloxamer 188, cremophor, polyethylene glycol alpha-tocopheryl succinate.
Still further, the solubilizer is a combination of any one of bile salt, polyethylene glycol lithium dodecahydroxystearate, poloxamer 188, polyoxyethylene castor oil and alpha-tocopherol polyethylene succinate and phospholipid; the concentration of phospholipids in the combination is between 20 and 50%, preferably 50%.
Still further, the solubilizing agent is a combination of a phospholipid and a bile salt.
Further, the phospholipid is one or more of soybean lecithin, egg yolk lecithin and hydrogenated phospholipid; the bile salt is one or more of sodium deoxycholate, potassium deoxycholate, sodium glycocholate and potassium glycocholate.
Further, the injection solvent is any one of water for injection, sodium chloride injection, glucose injection and glucose sodium chloride injection, and water for injection is preferred.
The invention also provides a preparation method of the injection, which comprises the following steps:
(1) Weighing the raw materials according to the proportion;
(2) Dissolving glycolipid antigen and solubilizer with organic solvent, removing organic solvent under reduced pressure, adding injection solvent for redissolution, adsorbing with active carbon, filtering, bottling, and sterilizing to obtain glycolipid antigen injection.
Further, the organic solvent in the step 2) is chloroform or a mixture of chloroform and 1:3, mixing chloroform and absolute ethyl alcohol; the sterilization temperature is 110 ℃, and the time is 30min.
Further, freeze-drying the injection in the step 2) to prepare a freeze-dried powder injection; the freeze drying procedure was: prefreezing at-40 deg.C for 4h, vacuum drying at-40 deg.C for 24h, and vacuum drying at 20 deg.C for 8h.
The invention finally provides the application of the injection in preparing a medicament for preventing and/or treating malignant tumors and virus infection and regulating immune function.
The glycolipid antigen injection of the invention prepares glycolipid antigens (such as alpha-galactosyl ceramide) into nano micelles by using high molecular auxiliary materials, which not only can realize the solubilization of the antigens, but also avoids the problem of NKT failure caused by multiple administrations. The glycolipid antigen injection has simple preparation method and is easy to popularize and apply.
Obviously, many modifications, substitutions, and variations are possible in light of the above teachings of the invention, without departing from the basic technical spirit of the invention, as defined by the following claims.
The present invention will be described in further detail with reference to the following examples. This should not be understood as limiting the scope of the above-described subject matter of the present invention to the following examples. All the technologies realized based on the above contents of the present invention belong to the scope of the present invention.
Detailed Description
The raw materials and equipment used in the embodiment of the present invention are known products and commercially available products.
Example 1 preparation of alpha-galactosylceramide injection (A1) of the invention
Weighing 2mg of alpha-galactosylceramide injection, 200mg of soybean lecithin and 200mg of sodium glycocholate, placing the mixture into a round-bottom flask, adding a chloroform/absolute ethyl alcohol (1, 3, v/v) mixed solution for dissolving, removing an organic solvent by decompressing a rotary evaporator, adding 4mL of water for injection for complete dissolution, adding activated carbon for adsorption, filtering, filling, and carrying out high-pressure moist heat sterilization (110 ℃,30 min) to obtain the alpha-galactosylceramide injection. The particle size of the injection is 16 + -3 nm as determined by a laser particle sizer.
Example 2 preparation of alpha-galactosyl ceramide injection (A2) of the present invention
Weighing 2mg of alpha-galactosyl ceramide injection and 500mg of polyethylene glycol lithium dodecahydroxy stearate, placing the alpha-galactosyl ceramide injection into a round-bottom flask, adding chloroform for dissolving, removing an organic solvent through a rotary evaporator, adding 4mL of injection water for complete dissolution, adsorbing by activated carbon, filtering, filling, and carrying out high-pressure moist-heat sterilization (110 ℃,30 min) to obtain the alpha-galactosyl ceramide injection. The particle size of the injection is 22 + -5 nm as measured by a laser particle size analyzer.
Example 3 preparation of alpha-galactosylceramide injection (A3) of the invention
Weighing 2mg of alpha-galactosyl ceramide injection, 100mg of polyethylene glycol lithium dodecahydroxy stearate and 100mg of polyoxyethylene castor oil, placing the alpha-galactosyl ceramide injection in a round-bottom flask, adding chloroform for dissolving, decompressing by using a rotary evaporator to remove an organic solvent, adding 2mL of injection water for complete dissolution, adding activated carbon for adsorption, filtering, filling, and sterilizing by high-pressure moist heat (110 ℃ for 30 min) to obtain the alpha-galactosyl ceramide injection. The particle size of the injection is 40 +/-7 nm by the measurement of a laser particle size analyzer.
Example 4 preparation of alpha-galactosylceramide injection (A4) of the invention
Weighing 2mg of alpha-galactosyl ceramide injection, 20mg of polyethylene glycol lithium dodecahydroxy stearate and 80mg of soybean lecithin, placing the mixture in a round-bottom flask, adding chloroform for dissolving, removing an organic solvent through a rotary evaporator, adding 4mL of water for injection for demoulding, performing ultrasonic treatment through a probe until the mixture becomes a liquid with opalescence, adding activated carbon for adsorption, filtering, filling, and performing high-pressure moist heat sterilization (110 ℃,30 min) to obtain the alpha-galactosyl ceramide injection. The particle size of the injection is 146 +/-10 nm determined by a laser particle size analyzer.
Example 5 preparation of beta-galactosylceramide injection (A5) of the invention
Weighing 2mg of beta-galactosyl ceramide injection, 50mg of polyethylene glycol lithium dodecahydroxy stearate and 200mg of soybean lecithin, placing the mixture in a round-bottom flask, adding chloroform for dissolving, removing an organic solvent through a rotary evaporator, adding 4mL of water for injection for demoulding, performing ultrasonic treatment through a probe until the mixture becomes a liquid with opalescence, adding activated carbon for adsorption, filtering, filling, and performing high-pressure moist-heat sterilization (110 ℃,30 min) to obtain the beta-galactosyl ceramide injection. The particle size of the injection is 126 + -8 nm as measured by a laser particle size analyzer.
Example 6 preparation of beta-galactosylceramide lyophilized powder for injection (A6) of the invention
And (3) taking the alpha-galactosyl ceramide injection prepared in the example 1, and freeze-drying the alpha-galactosyl ceramide injection for 4 hours at the temperature of minus 40 ℃, then carrying out vacuum-pumping drying for 24 hours at the temperature of minus 40 ℃, adjusting the temperature to 20 ℃, and keeping vacuum drying for 8 hours) to obtain the freeze-dried powder injection.
The advantageous effects of the present invention are further illustrated by the following test examples
Test example 1, the alpha-galactosyl ceramide injection of the invention stimulates NKT cells to produce IFN-gamma by multiple administration
40C 57BL/6 mice were divided into three groups of 8 animals, and A1-A5, an α -galactosylceramide solution (dissolved in 1% DMSO-containing PBS) and physiological saline were administered to each group of animals by tail vein injection. (2 microgram per each) were injected three times every 2 weeks. IFN-gamma was measured in the serum of the animals at 24h after each injection, and the specific results are shown in Table 1.
TABLE 1 multiple activation of NKT by alpha-galactosylceramide to produce IFN-gamma (pg/mL)
As can be seen from table 1: the alpha-galactosyl ceramide injection prepared by the invention can not cause the failure of NKT even after multiple times of administration, but the alpha-galactosyl ceramide solution can activate the NKT to generate a large amount of IFN-gamma except the first administration, and can cause the failure of the NKT after multiple times of administration, thereby being incapable of effectively generating the IFN-gamma. This result further demonstrates the necessity of preparing α -galactosylceramide as a nano injection (rather than as a simple solution).
Comparative example 1 preparation of alpha-galactosyl ceramide injection
2mg of alpha-galactosylceramide injection, 5mg of soybean lecithin and 5mg of sodium glycocholate are weighed, placed in a round-bottomed flask, dissolved by adding a chloroform/absolute ethanol (1, 3, v/v) mixture, the organic solvent is removed by a rotary evaporator, and 4mL of water for injection is added. The drug is not completely dissolved.
Comparative example 2 preparation of alpha-galactosyl ceramide injection
Weighing 2mg of alpha-galactosyl ceramide injection and 10mg of lithium polyethylene glycol dodecahydroxy stearate, placing the alpha-galactosyl ceramide injection and the lithium polyethylene glycol dodecahydroxy stearate in a round-bottom flask, adding chloroform to dissolve the alpha-galactosyl ceramide injection and the lithium polyethylene glycol dodecahydroxy stearate, removing an organic solvent through a rotary evaporator, and adding 4mL of water for injection. The drug is not completely dissolved.
Comparative example 3 preparation of beta-galactosyl ceramide injection
Weighing 2mg of beta-galactosylceramide injection, 5mg of soybean lecithin and 5mg of sodium glycocholate, placing the mixture in a round-bottomed flask, adding a chloroform/absolute ethanol (1, 3, v/v) mixture for dissolution, removing an organic solvent by a rotary evaporator, and adding 4mL of water for injection. The drug is not completely dissolved.
Comparative example 4 preparation of beta-galactosylceramide injection
Weighing 2mg of beta-galactosyl ceramide injection and 10mg of polyethylene glycol lithium dodecahydroxystearate, placing the mixture into a round-bottom flask, adding chloroform to dissolve the mixture, removing an organic solvent through a rotary evaporator, and adding 4mL of water for injection. The drug is not completely dissolved.
From comparative examples 1 to 4, it can be seen that: the mass ratio of glycolipid antigen to solubilizing agent is higher than 1:10, the mixture of them is not easily dissolved in water for injection, and the quality of the pharmaceutical preparation is not good.
In conclusion, the glycolipid antigen injection prepared by the invention not only solves the problem of water insolubility, but also can avoid the problem of NKT failure caused by multiple times of administration, so that the application of the glycolipid antigen in immunotherapy is improved.
Claims (12)
1. A glycolipid antigen injection, which is characterized in that: the components of the composition comprise glycolipid antigens, a solubilizer and an injection solvent; the weight volume ratio of the glycolipid antigen, the solubilizer and the injection solvent is 1mg:50 to 250mg:1 to 2ml;
the solubilizer is selected from one or more of phospholipid, bile salt, polyethylene glycol lithium dodecahydroxystearate, poloxamer 188, polyoxyethylene castor oil and alpha-tocopherol succinic acid polyethylene glycol ester;
the phospholipid is one or more of soybean lecithin, egg yolk lecithin and hydrogenated phospholipid; the cholate is one or more of sodium deoxycholate, potassium deoxycholate, sodium glycocholate and potassium glycocholate;
the glycolipid antigen is alpha-galactosyl ceramide and/or beta-galactosyl ceramide;
the preparation method of the glycolipid antigen injection comprises the following steps:
a. weighing the raw materials according to the proportion;
b. dissolving glycolipid antigen and solubilizer with organic solvent, removing organic solvent under reduced pressure, adding injection solvent for redissolution, adsorbing with active carbon, filtering, bottling, and sterilizing to obtain glycolipid antigen injection.
2. The injection according to claim 1, characterized in that: the weight-volume ratio of the glycolipid antigen to the solubilizer to the injection solvent is 1mg:200mg:2ml of the solution.
3. The injection according to claim 1, characterized in that: the solubilizer is selected from a plurality of phospholipids, bile salts, polyethylene glycol lithium dodecahydroxystearate, poloxamer 188, polyoxyethylene castor oil and alpha-tocopherol succinic acid polyethylene glycol ester.
4. An injection according to claim 3, characterized in that: the solubilizer is the combination of any one of bile salt, polyethylene glycol lithium dodecahydroxystearate, poloxamer 188, polyoxyethylene castor oil and alpha-tocopherol succinic acid polyethylene glycol ester and phospholipid; the concentration of the phospholipid in the composition is 20 to 50 percent.
5. The injection according to claim 4, characterized in that: the concentration of phospholipides in the combination is 50%.
6. The injection according to claim 4, characterized in that: the solubilizer is a combination of phospholipid and bile salt.
7. The injection according to claim 6, characterized in that: the cholate is one or more of sodium deoxycholate, potassium deoxycholate, sodium glycocholate and potassium glycocholate.
8. The injection according to any one of claims 1 to 7, wherein: the injection solvent is any one of water for injection, sodium chloride injection, glucose injection and glucose and sodium chloride injection.
9. The method for producing an injection according to any one of claims 1 to 8, wherein: the method comprises the following steps:
(1) Weighing the raw materials according to the proportion in the preceding claim;
(2) Dissolving glycolipid antigen and solubilizer in organic solvent, removing organic solvent under reduced pressure, adding injection solvent for redissolution, adsorbing with active carbon, filtering, bottling, and sterilizing to obtain glycolipid antigen injection.
10. The method of claim 9, wherein: and 2) the organic solvent is chloroform or a mixture of chloroform and organic solvent in a volume ratio of 1:3, mixing chloroform and absolute ethyl alcohol; the sterilization temperature is 110 ℃, and the time is 30min.
11. The method of manufacturing according to claim 10, wherein: step 2), freeze-drying the injection to prepare a freeze-dried powder injection; the freeze drying procedure was: prefreezing at-40 deg.C for 4 hr, vacuum drying at-40 deg.C for 24 hr, and vacuum drying at 20 deg.C for 8 hr.
12. Use of the injection according to any one of claims 1 to 8 for the preparation of a medicament for the prevention and/or treatment of malignant tumors, viral infections, and for the regulation of immune function.
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