WO2020258785A1 - 一种乳剂注射液的预灌封注射制剂及其制备方法 - Google Patents

一种乳剂注射液的预灌封注射制剂及其制备方法 Download PDF

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Publication number
WO2020258785A1
WO2020258785A1 PCT/CN2019/127779 CN2019127779W WO2020258785A1 WO 2020258785 A1 WO2020258785 A1 WO 2020258785A1 CN 2019127779 W CN2019127779 W CN 2019127779W WO 2020258785 A1 WO2020258785 A1 WO 2020258785A1
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Prior art keywords
injection
emulsion
prefilled
preparation
filled
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PCT/CN2019/127779
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English (en)
French (fr)
Inventor
蔡文坚
岳峰
蓝镜东
曾少群
钟棱
方志锋
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广东嘉博制药有限公司
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Publication of WO2020258785A1 publication Critical patent/WO2020258785A1/zh

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/045—Hydroxy compounds, e.g. alcohols; Salts thereof, e.g. alcoholates
    • A61K31/05—Phenols
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/222—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin with compounds having aromatic groups, e.g. dipivefrine, ibopamine
    • 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
    • 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
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M5/00—Devices for bringing media into the body in a subcutaneous, intra-vascular or intramuscular way; Accessories therefor, e.g. filling or cleaning devices, arm-rests
    • A61M5/178—Syringes
    • A61M5/31—Details
    • A61M2005/3117—Means preventing contamination of the medicament compartment of a syringe
    • A61M2005/3121—Means preventing contamination of the medicament compartment of a syringe via the proximal end of a syringe, i.e. syringe end opposite to needle cannula mounting end

Definitions

  • the invention relates to the technical field of medicine preparation, in particular to a prefilled injection preparation of emulsion injection and a preparation method thereof.
  • the prefilled preparation is a new dosage form of injection that has appeared in recent years, that is, the drug is directly filled in the syringe, so that the syringe has the function of a packaging container, and it is injected directly when used. It has the advantages of more accurate dosage, convenient use and no cross-contamination.
  • the sealing structure at the end of the injection barrel of the prefilled syringe is used as a barrier to ensure the sterility of the drug liquid inside, and the sealing of the structure is particularly important. If the sealing effect of this part is not good, the prefilled injection cannot be sealed well, resulting in the injection cannot be stored for a long time; and at present, there is no public application of prefilling technology to emulsion injections.
  • the stability of the emulsion is also a major problem for prefilled preparations.
  • the sealing structure at the end of the prefilled syringe barrel serves as a barrier to ensure the sterility of the drug liquid inside, and the tightness of the structure is particularly important. If the sealing effect of this part is not good, the pre-filled injection cannot be sealed well, resulting in that the injection cannot be stored for a long time and the sealing effect also affects the stability of the emulsion injection.
  • the present invention provides a prefilled injection preparation of emulsion injection with good sealing performance, stable injection, accurate dosage and low cost, and a preparation method thereof.
  • the specific technical solutions are as follows:
  • a prefilled injection preparation for emulsion injection comprises a prefilled syringe and an injection filled therein, and the barrel of the prefilled syringe is in the shape of a boss,
  • the front end of the injection barrel is provided with an injection nozzle, the injection nozzle is in the form of a conical necking, the sealing cap is detachably connected with the injection nozzle, and the piston is liquid-tightly assembled inside the injection barrel,
  • the push rod is detachably connected to the piston, and further includes a sleeve provided on the inner surface of the rear end of the syringe barrel, and the inner surface of the sleeve is flat with the inner surface of the syringe barrel with which it is threaded.
  • paraffin is filled between the sleeve and the push rod, and a volume scale is provided on the outer surface of the syringe;
  • the injection is an emulsion injection, and the emulsion injection includes emulsion raw materials and injection Use water.
  • the emulsion injection of the present invention adopts the prefilling technology to prefill and seal the emulsion injection in a sealed container, which can well solve the problem of poor sealing effect at the tail of the existing syringe barrel and can reduce secondary pollution
  • the design structure is simple and reasonable, the connection and sealing are reliable, and the emulsion injection formula of the present invention has good stability.
  • the push rod is composed of two parts with a cylindrical and cross-shaped cross section, the push rod is cylindrical near the end of the piston, and the length of the cylindrical part of the push rod is the same as the length of the sleeve,
  • the rear end surface of the push rod with a cross-shaped cross section is provided with a pressing disc.
  • a sealing sheet is provided inside the sealing cap, one side of the sealing sheet is a flat structure, and the other side is a convex structure close to the injection nozzle.
  • a sealing ring is provided on the outer surface of the piston, and the design number of the sealing ring is three.
  • an elliptical ring-shaped armrest is provided in the vertical direction on the outer periphery of the rear end of the injection barrel, and the side of the armrest facing the injection nozzle is provided with a protrusion.
  • the piston, sealing sheet and sealing ring are all made of chlorinated butyl rubber.
  • the emulsion injection comprises the following mass percentage of raw materials: active drug 0.1%-10%, a mixture of medium-chain triglycerides, long-chain triglycerides or long-chain triglycerides 10%-20% %, phospholipid mixture 1% to 5%, glycerin 1% to 5%, pH adjuster 0.05% to 0.1%, and the balance of water for injection.
  • active drug 0.1%-10%
  • the weight-volume ratio of medium-chain triglycerides to long-chain triglycerides is 4:1 to 1:4.
  • the phospholipid mixture includes the following components in weight percentage: phosphatidylcholine 75%-85%, phosphatidylethanolamine 12%-18%, lysophosphatidylethanolamine 0.5%-2%, sphingomyelin 0.5%-2 %, phosphatidylinositol 0.5%-1.5%, synthetic lecithin PC 0.2-1.5%, phosphatidylglycerol PG 0.2-1.5%, and phosphatidylserine PS 0.1-1.5%.
  • phosphatidylcholine 75%-85% phosphatidylethanolamine 12%-18%
  • lysophosphatidylethanolamine 0.5%-2% lysophosphatidylethanolamine 0.5%-2%
  • sphingomyelin 0.5%-2 % phosphatidylinositol 0.5%-1.5%
  • synthetic lecithin PC 0.2-1.5% phosphatidylglycerol PG 0.2-1.5%
  • the active drug is flurbiprofen axetil or propofol.
  • the pH adjusting agent is one or two of sodium dihydrogen phosphate, citric acid, and sodium hydroxide.
  • the synthetic phospholipid PCs are dioleoyl lecithin DOPC, dimyristoyl lecithin DMPC, distearoyl phosphatidylcholine DSPC, dierucyl lecithin DEPC, dipalmitoyl lecithin DPPC, hydrogenated One of soybean lecithin HSPC;
  • the phosphatidylglycerol PG is one of dioleoylphosphatidylglycerol DOPG, dipalmitoylphosphatidylglycerol DPPG, egg yolk phosphatidylglycerol EPG, and distearoylphosphatidylglycerol DSPG ;
  • Phosphatidylserine PS is dipalmitoylphosphatidylserine DPPS.
  • the invention also provides a preparation method of a prefilled injection preparation of emulsion injection, which is characterized in that it comprises the following preparation steps:
  • step 2) Mix the solution obtained in step 1) with glycerin, oil for injection, and aqueous solution for injection at 20°C to 40°C, and adjust the pH to 8-9 with a pH regulator, and then pass through a homogenizer to form colostrum;
  • step 2) The colostrum obtained in step 2) is continuously homogenized for 5 to 7 times under a pressure of 500 kg/cm 2 to 600 kg/cm 2 to obtain an emulsion;
  • step 4) Fill the emulsion injection obtained in step 3) into the prefilled syringe, and then sterilize it at 115°C for 30 min.
  • the prefilled injection preparation of emulsion injection includes a prefilled sealed container and the emulsion injection filled therein, and the prefilled sealed container includes a syringe, a piston, a push rod, a sealing cap, and a sleeve
  • the inner surface of the sleeve is flush with the inner surface of the syringe barrel fitted with its thread, and paraffin is filled between the sleeve and the push rod.
  • the syringe barrel is provided with a volume scale scale.
  • the emulsion injection includes emulsion raw materials and water for injection.
  • the emulsion injection of the present invention adopts the prefilling technology to prefill and seal the emulsion injection in a sealed container, which can reduce secondary pollution.
  • the design structure is simple and reasonable, the connection and sealing are reliable, and the formulation of the emulsion injection of the present invention Good stability.
  • the present invention improves the stability of injections, improves the efficacy of preparations, and ensures the safety of medicines.
  • Fig. 1 is a schematic cross-sectional view of a prefilled syringe according to an embodiment of the present invention
  • Fig. 2 is a schematic structural diagram of a prefilled syringe provided by a specific embodiment of the present invention
  • Fig. 3 is a schematic structural diagram of a sealing cap of a prefilled syringe provided by a specific embodiment of the present invention
  • FIG. 4 is a schematic diagram of the push rod structure of a prefilled syringe provided by the specific embodiment of the present invention.
  • FIG. 5 is a schematic diagram of the structure of the sealing sheet of a prefilled syringe provided by the specific embodiment of the present invention.
  • Fig. 6 is a schematic structural diagram of a prefilled syringe piston and a sealing ring provided by a specific embodiment of the present invention.
  • Figures 1-2 exemplarily show a prefilled injection formulation of an emulsion injection provided by the present invention. As shown in Figures 1-2, it includes a prefilled syringe 10 and an emulsion injection 20 filled in the syringe.
  • the syringe 10 includes a syringe 101, a piston 102, a push rod 103, and a sealing cap 104.
  • the syringe 101 is made of polymer synthetic resin.
  • the body of the syringe 101 is in the shape of a boss.
  • An injection nozzle 1011 is provided at the front end, the injection nozzle 1011 is in the form of a conical necking, the sealing cap 104 is detachably connected with the injection nozzle 1011, and the piston 104 is liquid-tightly assembled on the injection barrel 101
  • the push rod 103 is detachably connected to the piston 104, and further includes a sleeve 30 disposed on the inner surface of the rear end of the syringe 101, and the inner surface of the sleeve 30 is threadedly engaged with it
  • the inner surface of the injection barrel 101 is flush, paraffin 40 is filled between the sleeve 30 and the push rod 103, and a volume scale is provided on the outer surface of the injection barrel 101.
  • the working process of the present invention the sleeve 30 and the inner surface of the rear end of the injection barrel 101 are detachably connected together by threads, and paraffin 40 is filled between the sleeve 30 and the push rod 103, and During the process, hold the sleeve 30, rotate the push rod 103 to separate the paraffin 40 between them, and push the push disc 1031, according to the volume set on the outer surface of the syringe 101 Use a graduated ruler to observe the quantitative injection of liquid medicine. After the sleeve 30 and the push rod 103 are rotated, the paraffin wax between them has clear traces of opening to prevent the product from being used again.
  • the front end of the piston 102 has a shape corresponding to the inner surface of the front end of the injection barrel 101, and the part of the sleeve 30 protruding from the injection barrel 101 can limit the feed movement of the push rod.
  • the pushing disc 1031 is close to the surface of the injection cylinder 101 and contacts the sleeve 30, preventing the push rod 103 from continuing to move forward.
  • FIG. 3 exemplarily shows a structural schematic diagram of the sealing cap of a prefilled syringe provided by the present invention.
  • a spiral groove is formed inside the sealing cap 104, which can be spirally connected to the front end of the syringe 101
  • the protruding part is threaded, and the outer surface of the sealing cap 104 is machined with mesh-shaped notches to increase contact friction.
  • the push rod 103 is composed of two parts with a cylindrical cross section and a cross section.
  • the end of the push rod 103 near the piston 102 is cylindrical, and the length of the cylindrical part of the push rod 103 is the same as that of the sleeve.
  • the cylinder 30 has the same length.
  • the rear end of the push rod 103 with a cross-shaped cross section is provided with a pressing disc 1031.
  • the end of the push rod 103 close to the piston 102 is designed to be cylindrical in order to facilitate the rotation and separation of the Paraffin 40.
  • a sealing ring 60 is provided on the outer surface of the piston 102, and the number of the sealing rings 60 is three to prevent the injection liquid from permeating out of the outer surface of the piston 102, and at the same time prevent the injection 20 and the paraffin wax. 40 contacts, increase the sealing of the device.
  • an elliptical ring-shaped armrest 1012 is provided in the vertical direction on the outer periphery of the rear end of the injection barrel 101, and the side of the armrest facing the injection nozzle is provided with a protrusion.
  • the protrusion is provided to increase friction and make operation easier .
  • the injection barrel 101 is made of a transparent material, preferably a transparent polymer synthetic resin, which can be PP, PE, PS, PA, PC, PVC, ABS, PET and other synthetic resins.
  • a transparent polymer synthetic resin which can be PP, PE, PS, PA, PC, PVC, ABS, PET and other synthetic resins.
  • the emulsion injection of this embodiment includes the following raw materials in mass volume fraction: flurbiprofen axetil 1%, medium-chain triglycerides 5%, long-chain triglycerides 5%, phospholipid mixture 2.5%, glycerol 2.25% , Disodium hydrogen phosphate 0.05% and the remainder of water for injection.
  • the phospholipid mixture includes the following components in weight percentage: phosphatidylcholine 80%, phosphatidylethanolamine 14%, lysophosphatidylethanolamine 1%, sphingomyelin 1%, phosphatidylinositol 1%, dioleoyl lecithin 1 %, dioleoylphosphatidylglycerol DOPG 1%, dipalmitoylphosphatidylserine DPPS 1%.
  • the preparation method of a prefilled injection preparation of emulsion injection of the present invention includes the following steps:
  • step 2) Stir and mix the solution obtained in step 1), glycerin, and the aqueous solution for injection at 20°C to 40°C, and adjust the pH to 8 with sodium dihydrogen phosphate, and then pass through a homogenizer to form colostrum;
  • step 2) The colostrum obtained in step 2) is homogenized continuously for 5 times under high pressure (holding pressure 500kg/cm 2 ⁇ 600kg/cm 2 );
  • step 4) Potting the obtained emulsion obtained in step 3) into the above-mentioned sealed container, and then sterilizing it at 115° C. for 30 min.
  • Example 1 As an example of the pre-filled injection preparation of the emulsion injection of the present invention, the difference from Example 1 is only that the emulsion injection is different;
  • the emulsion injection of this embodiment includes the following materials in mass and volume fractions: 0.1% of propofol, 16% of medium-chain triglycerides, 4% of long-chain triglycerides, 1% of phospholipid mixture, 1% of glycerol, hydrogen 0.1% sodium oxide and the remainder of water for injection.
  • the phospholipid mixture includes the following components by weight percentage: phosphatidylcholine 75%, phosphatidylethanolamine 15%, lysophosphatidylethanolamine 2%, sphingomyelin 2%, phosphatidylinositol 1.5%, hydrogenated soy lecithin HSPC1. 5%, dipalmitoylphosphatidylglycerol DPPG 1.5%, dipalmitoylphosphatidylserine DPPS 1.5%.
  • step 2) Mix the solution obtained in step 1) with glycerin and the aqueous solution for injection at 20°C to 40°C, and adjust the pH to 9 with sodium hydroxide, and then pass through a homogenizer to form colostrum;
  • step 2) The colostrum obtained in step 2) is homogenized continuously for 5 times under high pressure (holding pressure 500kg/cm 2 ⁇ 600kg/cm 2 );
  • step 4) Fill the emulsion obtained in step 3) into the above-mentioned sealed container, and then sterilize it at 115° C. for 30 min.
  • Example 1 As an example of the pre-filled injection preparation of the emulsion injection of the present invention, the difference from Example 1 is only that the emulsion injection is different;
  • the emulsion injection of this embodiment includes the following raw materials in mass volume fraction: flurbiprofen axetil 2%, long-chain triglycerides 10%, phospholipid mixture 3%, glycerol 3%, disodium hydrogen phosphate 0.04%, citric acid 0.02% citric acid and the balance water for injection.
  • the phospholipid mixture includes the following components in weight percentage: phosphatidylcholine 78%, phosphatidylethanolamine 18%, lysophosphatidylethanolamine 1.5%, sphingomyelin 0.5%, phosphatidylinositol 0.5%, distearoylphosphatidyl Choline DSPC 0.5%, egg yolk phosphatidylglycerol EPG 0.5%, dipalmitoyl phosphatidylserine DPPS 0.5%.
  • step 2) Mix the solution obtained in step 1) with sodium dihydrogen phosphate, glycerin, and an aqueous solution for injection at 20°C to 40°C, and adjust the pH to 8 with citric acid, and then pass through a homogenizer to form colostrum;
  • step 2) The colostrum obtained in step 2) is homogenized continuously for 7 times under high pressure (holding pressure 500kg/cm 2 ⁇ 600kg/cm 2 );
  • step 4) Put the emulsion injection obtained in step 3) into the above-mentioned sealed container, and then sterilize it at 115°C for 30 minutes.
  • Example 1 As an example of the pre-filled injection preparation of the emulsion injection of the present invention, the difference from Example 1 is only that the emulsion injection is different;
  • the emulsion injection of this embodiment includes the following raw materials in mass and volume fractions: propofol 6%, medium-chain triglycerides 3%, long-chain triglycerides 12%, phospholipid mixture 4%, glycerol 2.5%, phosphoric acid Disodium hydrogen 0.08% and the balance water for injection.
  • the lecithin includes the following components in weight percentage: phosphatidylcholine 80%, phosphatidylethanolamine 18%, lysophosphatidylethanolamine 0.5%, sphingomyelin 0.5%, phosphatidylinositol 0.5%, dierucyl lecithin DEPC 0.2 %, Distearoylphosphatidylglycerol DSPG 0.2%, dipalmitoylphosphatidylserine DPPS 0.1%.
  • step 2) Stir and mix the solution obtained in step 1), glycerin, and aqueous solution for injection at 20°C to 40°C, and adjust the pH to 8.5 with sodium dihydrogen phosphate, and then pass through a homogenizer to form colostrum;
  • step 2) The colostrum obtained in step 2) is homogenized continuously for 7 times under high pressure (holding pressure 500kg/cm 2 ⁇ 600kg/cm 2 );
  • step 4) Put the emulsion injection obtained in step 3) into the above-mentioned sealed container, and then sterilize it at 115°C for 30 minutes.
  • Example 1 As an example of the injection preparation of the emulsion injection of the present invention, the difference from Example 1 is only in the preparation method;
  • the emulsion injection of this embodiment includes the following raw materials in mass volume fraction: flurbiprofen axetil 10%, long-chain triglycerides 20%, phospholipid mixture 5%, glycerol 5%, sodium hydroxide 0.08% and the balance Of water for injection;
  • the phospholipid mixture includes the following components by weight percentage: phosphatidylcholine 85%, phosphatidylethanolamine 12%, lysophosphatidylethanolamine 0.5%, sphingomyelin 0.5%, phosphatidylinositol 0.5%, dioleoyl lecithin DOPC. .5%, dioleoylphosphatidylglycerol DOPG 0.5%, dipalmitoylphosphatidylserine DPPS 0.5%.
  • step 2) Stir and mix the solution obtained in step 1), glycerin, and the aqueous solution for injection at 20°C-40°C, and adjust the pH to 8.5 with sodium hydroxide, and then pass through a homogenizer to form colostrum;
  • step 2) The colostrum obtained in step 2) is homogenized continuously for 7 times under high pressure (holding pressure 500kg/cm 2 ⁇ 600kg/cm 2 );
  • step 4) Fill the emulsion obtained in step 3) into the above-mentioned sealed container, and then sterilize it at 115° C. for 30 min.
  • Example 1 The only difference between this comparative example and Example 1 is that the prefilled syringe used is a commonly used prefilled syringe on the market.
  • Example 1 The difference between this comparative example and Example 1 is only that the phospholipid mixture in the emulsion injection is ordinary lecithin on the market.
  • Example 1 The difference between this comparative example and Example 1 is only that the content of the phospholipid mixture in the emulsion injection is 0.6%.
  • Example 1 The difference between this comparative example and Example 1 is only that the content of the phospholipid mixture in the emulsion injection is 5.5%.
  • Example 1 The difference between this comparative example and Example 1 is only that the phospholipid component in the emulsion injection is phosphatidylcholine.
  • Example 1 The only difference between this comparative example and Example 1 is that the phospholipid component in the emulsion injection is phosphatidylethanolamine.
  • Example 1 The only difference between this comparative example and Example 1 is that the phospholipid components in the emulsion injection are 85% phosphatidylethanolamine and 15% phosphatidylethanolamine.
  • the content of the phospholipid mixture of Comparative Examples 3 to 4 is outside the scope of the present invention.
  • the phospholipid mixture is less than 1%, its stability is not good.
  • the content of the phospholipid mixture increases, its stability increases.
  • the content of the phospholipid mixture is greater than 5%, its stability tends to be stable and slightly decreases. Therefore, the content of the phospholipid mixture of the present invention is 1 to 5%.
  • the phospholipid mixture of Comparative Examples 5-7 only contains phosphatidylethanolamine and phosphatidylethanolamine, but lacks the less content of lysophosphatidylethanolamine, sphingomyelin, phosphatidylinositol, dioleoyl lecithin DOPC, two Oleoylphosphatidylglycerol DOPG, dipalmitoylphosphatidylserine DPPS, but from the results, it can be seen that its stability is significantly lower than that of Example 1, indicating that even the low content of lysophosphatidylethanolamine, sphingomyelin, phosphatidyl Inositol, dioleoyl lecithin DOPC, dioleoyl phosphatidyl glycerol DOPG, dipalmitoyl phosphatidyl serine DPPS are also indispensable. It is compounded with phosphatidylethanolamine and

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Abstract

一种乳剂注射液的预灌封注射制剂及其制备方法，其中，乳剂注射液的预灌封注射制剂包括预灌封注射器（10）和灌封于其中的乳剂注射液（20），预灌封注射器（10）包括注射筒（101）、活塞（102）、推杆（103）、密封帽（104）、套筒（30），套筒（30）内表面与其螺纹配合的注射筒（101）内表面平齐，在套筒（30）与推杆（103）之间填充有石蜡（40），注射筒（101）上设有容量刻度标尺，乳剂注射液（20）包括乳剂原料和注射用水。该乳剂注射液（20）采用预灌封技术，把乳剂注射液（20）预灌封在密封容器中，能很好的解决现有的注射器注射筒尾部的密封效果不好的问题，且可减少二次污染。该乳剂注射液的预灌封注射制剂结构简单、合理，连接密封可靠，且乳剂注射液配方稳定性好。

Description

一种乳剂注射液的预灌封注射制剂及其制备方法 技术领域
本发明涉及药品制备技术领域，尤其涉及一种乳剂注射液的预灌封注射制剂及其制备方法。
背景技术
预灌封制剂是近年来出现的注射剂新剂型，即将药物直接灌装在注射器内，使注射器兼具了包装容器的功能，使用时直接注射。其拥有用药剂量更准确、使用方便、无交叉污染的优点。但是预灌封注射器注射筒尾部的密封结构作为内装药液无菌保证屏障，该结构的密封性就显得尤为重要。如果这部分的密封效果不好，就不能对预灌封的注射液进行很好地密封，导致注射液不能够长时间保存；且目前，还尚未有公开将预灌封技术应用到乳剂注射剂的研究，也没有公开相应的制备工艺和产品。另一方面，乳剂的稳定性也是预灌封制剂的一大问题，同时预灌封注射器注射筒尾部的密封结构作为内装药液无菌保证屏障，该结构的密封性就显得尤为重要。如果这部分的密封效果不好，就不能对预灌封的注射液进行很好地密封，导致注射液不能够长时间保存且密封性同样影响乳剂注射液的稳定性。
发明内容
本发明为解决现有的技术缺陷，提供了一种密封性好、注射液稳定、药量准确、成本低廉的一种乳剂注射液的预灌封注射制剂及其制备方法。其具体的技术方案如下：
一种乳剂注射液的预灌封注射制剂，所述乳剂注射液的预灌封注射制剂包括预灌封注射器和灌封于其中的注射液，所述预灌封注射器筒身呈凸台状，所述注射筒前端设置有注射嘴，所述注射嘴呈锥状缩颈的形式，所述密封帽可拆卸的与所述注射嘴连接，所述活塞液密的装配在所述注射筒内部，所述推杆与所述活塞可拆卸连接，还包括套筒，所述套筒设置在所述注射筒后端内表面处， 所述套筒内表面与其螺纹配合的所述注射筒内表面平齐，在所述套筒与所述推杆之间填充有石蜡，所述注射筒外表面上设有容量刻度标尺；所述注射液为乳剂注射液，所述乳剂注射液包括乳剂原料和注射用水。通过在注射筒尾部设计套筒，在套筒与推杆之间填充有石蜡，能很好的解决现有的注射器注射筒尾部的密封效果不好的问题，注射筒外表面上设置的容量刻度标尺能够直观的观察计量使用的药液量，这种设计结构简单、合理，连接密封可靠。本发明的乳剂注射液采用预灌封技术，把乳剂注射液预灌封在密封容器中，能很好的解决现有的注射器注射筒尾部的密封效果不好的问题，且可减少二次污染，这种设计结构简单、合理，连接密封可靠，且本发明的乳剂注射液配方稳定性好。
优选地，所述推杆由截面为圆柱形和十字形的两部分组成，所述推杆靠近所述活塞端为圆柱状，所述推杆圆柱状部分的长度与所述套筒长度相同，所述推杆截面为十字形的后端面设置有推压圆盘。
优选地，在所述密封帽内部设置有密封片，所述密封片一面为平面结构，另一面靠近所述注射嘴的为凸起结构。
优选地，在所述活塞外表面设置有密封圈，所述密封圈设计数量有三个。
优选地，在所述注射筒后端外周向垂直方向设置有椭圆环状的扶手，所述扶手朝向所述注射嘴的一面设置有凸起。
优选地，所述活塞、密封片、密封圈均由氯化丁基橡胶制成。
优选地，所述乳剂注射液包括以下质量百分比的原料：活性药物0.1％～10％、中链甘油三酸酯、长链甘油三酸酯组成的混合物或长链甘油三酸酯10％～20％、磷脂类混合物1％～5％、甘油1％～5％、pH调节剂0.05％～0.1％和余量的注射用水。其中，中链甘油三酸酯与长链甘油三酸酯的重量体积比为4∶1～1：4。
优选地，所述磷脂类混合物包括以下重量百分比的成分：磷脂酰胆碱75％-85％、磷脂酰乙醇胺12％-18％、溶血磷脂酰乙醇胺0.5％-2％、鞘磷脂0.5％-2％、磷脂酰肌醇0.5％-1.5％、合成卵磷脂PC类0.2～1.5％、磷脂酰甘油PG 类0.2～1.5％和磷脂酰丝氨酸PS类0.1～1.5％。
优选地，所述活性药物为氟比洛芬酯或丙泊酚。
优选地，所述pH调节剂为磷酸二氢钠、枸橼酸、氢氧化钠中的一种或两种。
优选地，所述合成磷脂PC类为二油酰基卵磷脂DOPC、二肉豆蔻酰基卵磷脂DMPC、二硬脂酰基磷脂酰胆碱DSPC、二芥酰基卵磷脂DEPC、二棕榈酰基卵磷脂DPPC、氢化大豆卵磷脂HSPC中的一种；所述磷脂酰甘油PG类为二油酰磷脂酰甘油DOPG、二棕榈酰磷脂酰甘油DPPG、蛋黄磷脂酰甘油EPG、二硬脂酰磷脂酰甘油DSPG中一种；磷脂酰丝氨酸PS类为二棕榈酰基磷脂酰丝氨酸DPPS。
本发明还提供了一种乳剂注射液的预灌封注射制剂的制备方法，其特征在于，包括以下制备步骤：
1)将上述配比的活性药物、中链甘油三酸酯、长链甘油三酸酯组成的混合物或长链甘油三酸酯、磷脂类混合物在40℃～75℃下高速搅拌混合形成溶液；
2)将步骤1)得到的溶液和甘油、注射用油、注射用水溶液在20℃～40℃下搅拌混合，并用pH调节剂调节PH为8～9，然后经过均质机形成初乳；
3)将步骤2)得到的初乳在压力为500kg/cm 2～600kg/cm 2下连续均质5～7次得到乳剂；
4)将步骤3)得到的乳剂注射液灌封到所述的预灌封注射器中，再在115℃下灭菌30min。
本发明的有益效果：乳剂注射液的预灌封注射制剂包括预灌封密封容器和灌封于其中的乳剂注射液，预灌封密封容器包括注射筒、活塞、推杆、密封帽、套筒，套筒内表面与其螺纹配合的注射筒内表面平齐，在套筒与推杆之间填充有石蜡，注射筒上设有容量刻度标尺，乳剂注射液包括乳剂原料和注射用水。本发明的乳剂注射液采用预灌封技术，把乳剂注射液预灌封在密封容器中，可减少二次污染，这种设计结构简单、合理，连接密封可靠，且本发明的乳剂注射液配方稳定性好。
2、通过在注射筒尾部设计套筒，在套筒与推杆之间填充有石蜡，能很好的 解决现有的注射器注射筒尾部的密封效果不好的问题，注射筒外表面上设置的容量刻度标尺能够直观的观察计量使用的药液量，这种设计结构简单、合理，连接密封可靠。
3、本发明提高了注射剂的稳定性，提高了制剂的药效，保证了药品的安全。
附图说明
图1是本发明具体实施方式提供的一种预灌封注射器的剖视结构示意图；
图2是本发明具体实施方式提供的一种预灌封注射器的结构示意图；
图3是本发明具体实施方式提供的一种预灌封注射器的密封帽结构示意图；
图4是本发明具体实施方式提供的一种预灌封注射器的推杆结构示意图；
图5是本发明具体实施方式提供的一种预灌封注射器的密封片结构示意图；
图6是本发明具体实施方式提供的一种预灌封注射器活塞和密封圈配合的结构示意图。
图中：
10、注射器；101、注射筒；1011、注射嘴；1012、扶手；102、活塞；103、推杆；1031、推压圆盘；104、密封帽；20、注射液；30、套筒；40、石蜡；50、密封片；60、密封圈。
具体实施方式
下面结合附图对本发明作进一步地详细的说明，这些附图均为简化的示意图，仅以示意方式说明本发明的基本结构，本具体实施的方向以图1方向为标准。
实施例1
图1-2实例性的示出了本发明提供的一种乳剂注射液的预灌封注射制剂，如图1～2所示，包括预灌封注射器10和注射器内填充的乳剂注射液20，所述注射器10包括注射筒101、活塞102、推杆103、密封帽104，所述注射筒101由高分子合成树脂制成，所述注射筒101筒身呈凸台状，所述注射筒101前端设置 有注射嘴1011，所述注射嘴1011呈锥状缩颈的形式，所述密封帽104可拆卸的与所述注射嘴1011连接，所述活塞104液密的装配在所述注射筒101内部，所述推杆103与所述活塞104可拆卸连接，还包括套筒30，所述套筒30设置在所述注射筒101后端内表面处，所述套筒30内表面与其螺纹配合的所述注射筒101内表面平齐，在所述套筒30与所述推杆103之间填充有石蜡40，所述注射筒101外表面上设有容量刻度标尺。
本发明的工作过程：所述套筒30与所述注射筒101后端内表面通过螺纹可拆卸的连接在一起，在所述套筒30与所述推杆103之间填充有石蜡40，使用过程中，握住所述套筒30，旋转所述推杆103，使它们之间的所述石蜡40分离，推进所述推压圆盘1031，根据所述注射筒101外表面上设置的容量刻度标尺，观察定量注射药液，所述套筒30与所述推杆103之间发生转动之后，它们之间的石蜡具有清晰的打开痕迹，防止产品的二次使用。所述活塞102前端为与所述注射筒101前端内表面相对应的形状，所述套筒30突出所述注射筒101的部分可以对所述推杆进给运动形成限位，当所述活塞102运动到所述注射筒101前端内表面时，所述推压圆盘1031靠近所述注射筒101表面与所述套筒30接触，阻止所述推杆103继续向前运动。
图3实例性的示出了本发明提供的一种预灌封注射器的密封帽结构示意图，在所述密封帽104内部形成有螺旋状的凹槽，其能够与所述注射筒101前端螺旋状突出部分螺纹配合，所述密封帽104外表面加工有网状的刻痕，用以增大接触摩擦。
优选地，所述推杆103由截面为圆柱形和十字形的两部分组成，所述推杆103靠近所述活塞102端为圆柱状，所述推杆103圆柱状的部分长度与所述套筒30长度相同，所述推杆103截面为十字形的后端面设置有推压圆盘1031，所述推杆103靠近所述活塞102端设计成圆柱状是为了在使用时便于旋转分离所述石蜡40。
优选地，在所述活塞102外表面设置有密封圈60，所述密封圈60设计数量有三个，防止注射液从所述活塞102外表面渗透出去，同时防止所述注射液20与所述石蜡40接触，增加装置的密封性。
优选地，在所述注射筒101后端外周向垂直方向设置有椭圆环状的扶手1012，所述扶手朝向注射嘴的一面设置有凸起，设置凸起是为了增大摩擦力，更加容易操作。
优选地，所述的注射筒101由透明材料制备，优选透明高分子合成树脂，可以是PP、PE、PS、PA、PC、PVC、ABS、PET等合成树脂。
优选地，所述活塞102、所述密封片50、所述密封圈60均由氯化丁基橡胶制成，因为注射液一般在pH＝4.5左右的水溶液中可稳定保存，使用普通橡胶制备的活塞长期暴露于这种酸性条件下容易变形，而选择氯化丁基橡胶制备的活塞不容易发生变形，所存储的注射液可长期稳定保存。
本实施例的乳剂注射液包括以下质量体积分数的原料：氟比洛芬酯1％、中链甘油三酸酯5％、长链甘油三酸酯5％、磷脂类混合物2.5％、甘油2.25％、磷酸氢二钠0.05％和余量的注射用水。
所述磷脂类混合物包括以下重量百分比的成分：磷脂酰胆碱80％、磷脂酰乙醇胺14％、溶血磷脂酰乙醇胺1％、鞘磷脂1％、磷脂酰肌醇1％、二油酰基卵磷脂1％、二油酰磷脂酰甘油DOPG 1％、二棕榈酰基磷脂酰丝氨酸DPPS1％。
本发明的一种乳剂注射液的预灌封注射制剂的制备方法，包括以下步骤：
1)将上述配比的氟比洛芬酯、中链甘油三酸酯、长链甘油三酸酯、磷脂酰胆碱、磷脂酰乙醇胺、溶血磷脂酰乙醇胺、鞘磷脂，磷脂酰肌醇、二油酰基卵磷脂、二油酰磷脂酰甘油DOPG、二棕榈酰基磷脂酰丝氨酸DPPS混合在40℃～75℃高速搅拌形成溶液；
2)将步骤1)得到的溶液、甘油、注射用水溶液在20℃～40℃下搅拌混合，并用磷酸二氢钠调节PH为8，然后经过均质机形成初乳；
3)将步骤2)得到的初乳在高压下(保持压力500kg/cm 2～600kg/cm 2)连续均质5次；
4)将步骤3)得到的将所得的乳剂灌封到上述的密封容器中，再在115℃下灭菌30min。
实施例2
作为本发明乳剂注射液的预灌封注射制剂的一种实施例，与实施例1不同之处仅在于，其乳剂注射液的不同；
本实施例的乳剂注射液包括以下质量体积分数的原料：丙泊酚0.1％、中链甘油三酸酯16％、长链甘油三酸酯4％、磷脂类混合物1％、甘油1％、氢氧化钠0.1％和余量的注射用水。
所述磷脂类混合物包括以下重量百分比的成分：磷脂酰胆碱75％、磷脂酰乙醇胺15％、溶血磷脂酰乙醇胺2％、鞘磷脂2％、磷脂酰肌醇1.5％、氢化大豆卵磷脂HSPC1.5％、二棕榈酰磷脂酰甘油DPPG 1.5％、二棕榈酰基磷脂酰丝氨酸DPPS 1.5％。
本实施例的乳剂注射液的预灌封注射制剂的制备方法，包括以下步骤：
1)将上述配比的丙泊酚、中链甘油三酸酯、长链甘油三酸酯、磷脂酰胆碱、磷脂酰乙醇胺、溶血磷脂酰乙醇胺、鞘磷脂、磷脂酰肌醇、氢化大豆卵磷脂HSPC、二棕榈酰磷脂酰甘油DPPG、二棕榈酰基磷脂酰丝氨酸DPPS混合在40℃～75℃高速搅拌形成溶液；
2)将步骤1)得到的溶液和甘油、注射用水溶液在20℃～40℃下搅拌混合，并用氢氧化钠调节PH为9，然后经过均质机形成初乳；
3)将步骤2)得到的初乳在高压下(保持压力500kg/cm 2～600kg/cm 2)连续均质5次；
4)将步骤3)所得的乳剂灌封到上述的密封容器中，再在115℃下灭菌30min。
实施例3
作为本发明乳剂注射液的预灌封注射制剂的一种实施例，与实施例1不同之处仅在于，其乳剂注射液的不同；
本实施例的乳剂注射液包括以下质量体积分数的原料：氟比洛芬酯2％、长链甘油三酸酯10％、磷脂类混合物3％、甘油3％、磷酸氢二钠0.04％、枸橼酸0.02％和余量的注射用水。
所述磷脂类混合物包括以下重量百分比的成分：磷脂酰胆碱78％、磷脂酰乙醇胺18％、溶血磷脂酰乙醇胺1.5％、鞘磷脂0.5％、磷脂酰肌醇0.5％、二硬脂酰基磷脂酰胆碱DSPC0.5％、蛋黄磷脂酰甘油EPG 0.5％、二棕榈酰基磷脂酰丝氨酸DPPS 0.5％。
本实施例的乳剂注射液的预灌封注射制剂的制备方法，包括以下步骤：
1)将上述配比的氟比洛芬酯、长链甘油三酸酯、磷脂酰胆碱、磷脂酰乙醇胺、溶血磷脂酰乙醇胺、鞘磷脂、磷脂酰肌醇、二硬脂酰基磷脂酰胆碱DSPC、蛋黄磷脂酰甘油EPG、二棕榈酰基磷脂酰丝氨酸DPPS混合在40℃～75℃高速搅拌形成溶液；
2)将步骤1)得到的溶液和磷酸二氢钠、甘油、注射用水溶液在20℃～40℃下搅拌混合，并用枸橼酸调节PH为8，然后经过均质机形成初乳；
3)将步骤2)得到的初乳在高压下(保持压力500kg/cm 2～600kg/cm 2)连续均质7次；
4)将步骤3)所得的乳剂注射液到上述的密封容器中，再在115℃下灭菌30min。
实施例4
作为本发明乳剂注射液的预灌封注射制剂的一种实施例，与实施例1不同之处仅在于，其乳剂注射液的不同；
本实施例的乳剂注射液包括以下质量体积分数的原料：丙泊酚6％、中链甘油三酸酯3％、长链甘油三酸酯12％、磷脂类混合物4％、甘油2.5％、磷酸氢二钠0.08％和余量的注射用水。
所述卵磷脂包括以下重量百分比的成分：磷脂酰胆碱80％、磷脂酰乙醇胺18％、溶血磷脂酰乙醇胺0.5％、鞘磷脂0.5％、磷脂酰肌醇0.5％、二芥酰基卵磷脂DEPC 0.2％、二硬脂酰磷脂酰甘油DSPG 0.2％、二棕榈酰基磷脂酰丝氨酸DPPS 0.1％。
本实施例的乳剂注射液的预灌封注射制剂的制备方法，包括以下步骤：
1)将上述配比的丙泊酚、中链甘油三酸酯、长链甘油三酸酯、磷脂酰胆碱、 磷脂酰乙醇胺、溶血磷脂酰乙醇胺、鞘磷脂、磷脂酰肌醇、二芥酰基卵磷脂DEPC、二硬脂酰磷脂酰甘油DSPG、二棕榈酰基磷脂酰丝氨酸DPPS混合在40℃～75℃高速搅拌形成溶液；
2)将步骤1)得到的溶液、甘油、注射用水溶液在20℃～40℃下搅拌混合，并用磷酸二氢钠调节PH为8.5，然后经过均质机形成初乳；
3)将步骤2)得到的初乳在高压下(保持压力500kg/cm 2～600kg/cm 2)连续均质7次；
4)将步骤3)再将所得的乳剂注射液到上述的密封容器中，再在115℃下灭菌30min。
实施例5
作为本发明乳剂注射液的注射制剂的一种实施例，与实施例1不同之处仅在于，其制备方法的不同；
本实施例的乳剂注射液包括以下质量体积分数的原料：氟比洛芬酯10％、长链甘油三酸酯20％、磷脂类混合物5％、甘油5％、氢氧化钠0.08％和余量的注射用水；
所述磷脂类混合物包括以下重量百分比的成分：磷脂酰胆碱85％、磷脂酰乙醇胺12％、溶血磷脂酰乙醇胺0.5％、鞘磷脂0.5％，磷脂酰肌醇0.5％、二油酰基卵磷脂DOPC0.5％、二油酰磷脂酰甘油DOPG 0.5％、二棕榈酰基磷脂酰丝氨酸DPPS0.5％。
本实施例的乳剂注射液的预充式制剂，包括以下步骤：
1)将上述配比的氟比洛芬酯、长链甘油三酸酯、磷脂酰胆碱、磷脂酰乙醇胺、溶血磷脂酰乙醇胺、鞘磷脂，磷脂酰肌醇、二油酰基卵磷脂DOPC、二油酰磷脂酰甘油DOPG、二棕榈酰基磷脂酰丝氨酸DPPS混合在40℃～75℃高速搅拌形成溶液；
2)将步骤1)得到的溶液、甘油、注射用水溶液在20℃～40℃下搅拌混合，并用氢氧化钠调节PH为8.5，然后经过均质机形成初乳；
3)将步骤2)得到的初乳在高压下(保持压力500kg/cm 2～600kg/cm 2)连续均 质7次；
4)将步骤3)所得的乳剂灌封到上述的密封容器中，再在115℃下灭菌30min。
对比例1
本对比例与实施例1的区别仅在于，所使用的预灌封注射器为市面上常用的预灌封注射器。
对比例2
本对比例与实施例1的区别仅在于，乳剂注射液中的磷脂类混合物为市面上普通的卵磷脂。
对比例3
本对比例与实施例1的区别仅在于，所述的乳剂注射液中的磷脂类混合物的含量为0.6％。
对比例4
本对比例与实施例1的区别仅在于，所述的乳剂注射液中的磷脂类混合物的含量为5.5％。
对比例5
本对比例与实施例1的区别仅在于，所述乳剂注射液中的磷脂类成分为磷脂酰胆碱。
对比例6
本对比例与实施例1的区别仅在于，所述乳剂注射液中的磷脂类成分为磷脂酰乙醇胺。
对比例7
本对比例与实施例1的区别仅在于，所述乳剂注射液中的磷脂类成分为磷脂酰乙醇胺85％、磷脂酰乙醇胺15％。
实施例6
对实施例1至5以及对比例1制备的乳剂注射液按照《中国药典为2015年版》关于密封性实验的指导原则，进行密封隔氧性试验。样品放入恒温恒湿箱中，温度40℃相对湿度25％的条件下，分别于0、1、2、3和6个月测定，结果见表1：
表1本发明乳剂注射液密封性测试
Figure PCTCN2019127779-appb-000001
从表1可看出，加速6月本发明实施例1～5的甲氧基苯胺值、粒径和有关 物质相对于实施例1变化不明显。说明本发明预灌封制剂密封性更好。测定甲氧基苯胺值，可以间接了解上述原辅料在生产、储存及制剂过程中的氧化情况，从其中的变化值也可知，其隔氧性佳。
实施例7
将实施例1～5以及对比例1、2制备的注射液在冷藏避光的条件下保存10个月，于第0、1、2、3、6、8、10个月取样，进行检测，考察其在储存期间的Zeta电位。测试结果见表3。
表3稳定性测试
Figure PCTCN2019127779-appb-000002
从表3可看出，本发明实施例1～5相对于对比例1～2制备的乳剂注射液具有更好的稳定性，保存10个月后，依然稳定性佳，对比例1的密封性进一步影 响乳剂注射液的稳定性，可见，本发明的密封性、稳定性佳。
对比例3～4的磷脂类混合物的含量在本发明范围之外，当其磷脂类混合物小于1％时，其稳定性不佳，随着磷脂类混合物的含量增加，其稳定性增加，当磷脂类混合物的含量大于5％时，其稳定性趋于平稳，且略微下降，因此，本发明的磷脂类混合物含量为1～5％。
对比例5～7的磷脂类混合物相对于实施例1只含有磷脂酰乙醇胺、磷脂酰乙醇胺，缺少了含量少的溶血磷脂酰乙醇胺、鞘磷脂，磷脂酰肌醇、二油酰基卵磷脂DOPC、二油酰磷脂酰甘油DOPG、二棕榈酰基磷脂酰丝氨酸DPPS，但从结果可知，其稳定性相对于实施例1有比较明显的下降，表明，即使含量少的溶血磷脂酰乙醇胺、鞘磷脂，磷脂酰肌醇、二油酰基卵磷脂DOPC、二油酰磷脂酰甘油DOPG、二棕榈酰基磷脂酰丝氨酸DPPS也是比不可少，其与磷脂酰乙醇胺、磷脂酰乙醇胺复配，能够具有显著提高乳剂注射液稳定性的作用。
以上所述仅为本发明的较佳实施例而已，并不用以限制本发明，凡在本发明的精神和原则之内，所做的任何修改、等同替换、改进等，均应包含在本发明保护的范围之内。

Claims (10)

  1. 一种乳剂注射液的预灌封注射制剂，其特征在于，所述乳剂注射液的预灌封注射制剂包括预灌封注射器和灌封于其中的注射液，所述预灌封注射器筒身呈凸台状，所述注射筒前端设置有注射嘴，所述注射嘴呈锥状缩颈的形式，所述密封帽可拆卸的与所述注射嘴连接，所述活塞液密的装配在所述注射筒内部，所述推杆与所述活塞可拆卸连接，其特征在于，还包括套筒，所述套筒设置在所述注射筒后端内表面处，所述套筒内表面与其螺纹配合的所述注射筒内表面平齐，在所述套筒与所述推杆之间填充有石蜡，所述注射筒外表面上设有容量刻度标尺；所述注射液为乳剂注射液，所述乳剂注射液包括乳剂原料和注射用水。
  2. 根据权利要求1所述的预灌封注射制剂，其特征在于：所述推杆由截面为圆柱形和十字形的两部分组成，所述推杆靠近所述活塞端为圆柱状，所述推杆圆柱状部分的长度与所述套筒长度相同，所述推杆截面为十字形的后端面设置有推压圆盘。
  3. 根据权利要求1所述的预灌封注射制剂，其特征在于：在所述密封帽内部设置有密封片，所述密封片一面为平面结构，另一面靠近所述注射嘴的为凸起结构。
  4. 根据权利要求1所述的预灌封注射制剂，其特征在于：在所述活塞外表面设置有密封圈，所述密封圈设计数量有三个，优选地，所述活塞、密封片、密封圈均由氯化丁基橡胶制成。
  5. 根据权利要求1所述的乳剂注射液的预灌封注射制剂，其特征在于，所述乳剂注射液包括以下质量百分比的原料：活性药物0.1％～10％、中链甘油三酸酯、长链甘油三酸酯组成的混合物或长链甘油三酸酯10％～20％、磷脂类混合物1％～5％、甘油1％～5％、pH调节剂0.05％～0.1％和余量的注射用水。
  6. 根据权利要求5所述的乳剂注射液的预灌封注射制剂，其特征在于，所述活性药物为氟比洛芬酯或丙泊酚。
  7. 根据权利要求5所述的乳剂注射液的预灌封注射制剂，其特征在于，所述pH调节剂为磷酸二氢钠、枸橼酸、氢氧化钠中的一种或两种。
  8. 根据权利要求5所述的乳剂注射液的预灌封注射制剂，其特征在于，所述磷脂类混合物包括以下重量百分比的成分：磷脂酰胆碱75％-85％、磷脂酰乙醇胺12％-18％、溶血磷脂酰乙醇胺0.5％-2％、鞘磷脂0.5％-2％、磷脂酰肌醇0.5％-1.5％、合成卵磷脂PC类0.2～1.5％、磷脂酰甘油PG类0.2～1.5％和磷脂酰丝氨酸PS类0.1～1.5％。
  9. 根据权利要求8所述的所述的乳剂注射液的预灌封注射制剂，其特征在于，所述合成磷脂PC类为二油酰基卵磷脂DOPC、二肉豆蔻酰基卵磷脂DMPC、二硬脂酰基磷脂酰胆碱DSPC、二芥酰基卵磷脂DEPC、二棕榈酰基卵磷脂DPPC、氢化大豆卵磷脂HSPC中的一种；所述磷脂酰甘油PG类为二油酰磷脂酰甘油DOPG、二棕榈酰磷脂酰甘油DPPG、蛋黄磷脂酰甘油EPG、二硬脂酰磷脂酰甘油DSPG中一种；磷脂酰丝氨酸PS类为二棕榈酰基磷脂酰丝氨酸DPPS。
  10. 一种如权利要求5～9所述的乳剂注射液的预灌封注射制剂的制备方法，其特征在于，包括以下制备步骤：
    1)将上述配比的活性药物、中链甘油三酸酯、长链甘油三酸酯组成的混合物或长链甘油三酸酯、磷脂类混合物在40℃～75℃下高速搅拌混合形成溶液；
    2)将步骤1)得到的溶液和甘油、注射用水溶液在20℃～40℃下搅拌混合，并用pH调节剂调节pH为8～9，然后经过均质机形成初乳；
    3)将步骤2)得到的初乳在压力为500kg/cm 2～600kg/cm 2下连续均质5～7次得到乳剂；
    4)将步骤3)得到的乳剂注射液灌封到所述的预灌封注射器中，再在115℃下灭菌30min。
PCT/CN2019/127779 2019-06-28 2019-12-24 一种乳剂注射液的预灌封注射制剂及其制备方法 WO2020258785A1 (zh)

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