CN114796110A - Insoluble drug concentrated solution without ethanol and micelle solution prepared from insoluble drug concentrated solution - Google Patents

Insoluble drug concentrated solution without ethanol and micelle solution prepared from insoluble drug concentrated solution Download PDF

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Publication number
CN114796110A
CN114796110A CN202110117255.6A CN202110117255A CN114796110A CN 114796110 A CN114796110 A CN 114796110A CN 202110117255 A CN202110117255 A CN 202110117255A CN 114796110 A CN114796110 A CN 114796110A
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weight percentage
phospholipid
cosolvent
emulsifier
propylene glycol
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吴翠栓
程晓波
张丹
侯继祥
赵博册
张强
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Beijing Deli Furui Medical Science & Technology Co ltd
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Beijing Deli Furui Medical Science & Technology Co ltd
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Priority to CN202110117255.6A priority Critical patent/CN114796110A/en
Priority to PCT/CN2021/137169 priority patent/WO2022160970A1/en
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    • 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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    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
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    • 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
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    • 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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Abstract

The invention relates to an ethanol-free insoluble drug concentrate and a micellar solution prepared from the same. The invention belongs to the field of pharmaceutical preparations. Specifically, the invention relates to an ethanol-free insoluble drug concentrate and a preparation method thereof, and also relates to a micellar solution prepared from the concentrate.

Description

Insoluble drug concentrated solution without ethanol and micelle solution prepared from insoluble drug concentrated solution
Technical Field
The invention belongs to the field of pharmaceutical preparations. Specifically, the invention relates to an ethanol-free insoluble drug concentrate and a preparation method thereof, and also relates to a micellar solution prepared from the concentrate.
Background
According to statistics, more than 40% of the drugs sold in the market at present belong to the insoluble drugs, and the insoluble drugs in the development stage account for 70%. The administration of poorly soluble drugs, particularly the administration of poorly soluble drugs by injection, has been one of the difficulties and hot spots in the research of the field of pharmaceutical preparations. The main reason is that many poorly soluble drugs cannot be prepared into injections due to the solubility problem, and the injections have an irreplaceable effect clinically, so that increasing the solubility of the poorly soluble drugs and further realizing injection administration of the poorly soluble drugs become one of the most active research directions in the field of pharmacy.
In recent years, researchers have developed many methods to increase the solubility of poorly soluble drugs, including making prodrugs, adjusting pH, using co-solvents, using solubilizing aids, making emulsions or liposomes, inclusion techniques, micellar solubilization, nanosuspension techniques, and the like. Among them, the cosolvent is widely used, and ethanol is used as the cosolvent.
Ethanol is widely used in injections as an important cosolvent. For example, as an antitumor drug, docetaxel injection contains 13% anhydrous ethanol; as adrenocortical hormone drugs, hydrocortisone injection contains 50% ethanol, hydrocortisone acetate injection (alcohol type) contains 50% ethanol; as cardiovascular and cerebrovascular medicines, the deacetyl hairy flower glycoside injection contains 10% ethanol, the digitoxin injection contains 10% (V/V) ethanol, the nimodipine injection contains 20% (V/V) ethanol, the glycerin nitrate injection, the diazepam injection, the pyritinol hydrochloride injection and the shuxuening injection also use 95% ethanol as auxiliary materials; as antibacterial drugs, azithromycin injection, azithromycin sodium chloride injection, amphotericin B liposome for injection and voriconazole for injection also contain ethanol; as immunosuppressive drugs, each milliliter of tacrolimus injection contains 638mg of ethanol, and the auxiliary materials of the cyclosporine injection also comprise ethanol; as the medicine for respiratory system, the potassium dehydroandrographolide succinate injection contains ethanol; as a gynecological agent, prostaglandin E2 injection also contains ethanol.
In addition, ethanol is also widely used in preparations for oral administration of poorly soluble drugs. For example, Huoxiang Zhengqi liquid contains 40% -50% of ethanol; the ethanol content of the ten drops of water is 60-70%; the compound radix Glycyrrhizae oral liquid contains radix Glycyrrhizae fluid extract and compound Camphora tincture; the syrup for treating common cold and cough contains Glycyrrhrizae radix fluid extract and pericarpium Citri Junoris tincture; the cyclosporin oral solution and the levocarnitine oral solution both contain a small amount of ethanol; the digoxin oral solution contains 9 to 11 percent of ethanol; the ergocryptine caffeine oral liquid contains 5.8% (v/v) ethanol. In addition, the following drugs also all contain ethanol: ketorolac tromethamine tablet/capsule, nitroglycerin aerosol, salbutamol aerosol, clenbuterol hydrochloride aerosol, musk pain-relieving aerosol (ethanol content is 47-57%), chest widening aerosol (ethanol content is 27% (ml/g) -42% (ml/g)), isosorbide dinitrate aerosol (containing 90% ethanol), bone pain tincture (ethanol content is 45-55%), swelling and pain relieving tincture (ethanol content is 47-57%), wound-removing swelling-relieving tincture (ethanol content is 50-60%), burn tincture (ethanol content is 70-75%), muscle pain-relieving tincture (ethanol content is 50-60%), compound camphor tincture (ethanol content is 52-60%), belladonna tincture (ethanol content is 60-70%), ginger tincture (ethanol content is 80-88% -polygala tenuifolia (ethanol content is 50-58%), (ethanol content is 50-58%)), Iodine tincture (containing 45-55% of ethanol (ml/ml)), belladonna fluid extract (ethanol content is 52-66%), Zhejiang fritillaria fluid extract (ethanol content is 50-70%), ginger fluid extract (ethanol content is 72-80%), polygala fluid extract (ethanol content is 38-48%), angelica fluid extract (ethanol content is 45-50%), liquorice fluid extract (ethanol content is 20-25%), rhubarb fluid extract (ethanol content is 40-50%), motherwort fluid extract (ethanol content is 16-20%), turmeric acne-eliminating liniment (ethanol content is 35-60%), Guyouling liniment (ethanol content is 20-25%), musk Shuhuo liniment (ethanol content is 50-58%), musk pain-relieving liniment (ethanol content is 47-57%), ringworm (ethanol content is not less than 60%), ketoprofen liniment (ethanol content is 65-75%), Shutongan film coating agent (ethanol content is 42-52%), bonesetting water (ethanol content is 56-66%), glycerol alcohol solution (containing 2% (V/V) ethanol), compound chlorhexidine acetate spray and the like.
However, ethanol-containing preparations, particularly injections, in the prescription often cause adverse effects after administration, for example, strong vascular irritation, pain at the injection site when injected into a blood vessel, and phlebitis caused by repeated injections; in addition, ethanol has influence on nervous system, which causes muscle incoordination, slow response, inattention, decreased self-control ability, hypomnesis, and intelligence deterioration; ethanol also causes damage to the liver and irritation to the stomach. The ethanol-containing preparation in the prescription can not be used by patients allergic to ethanol, so that the medicine use of the part of patients is limited. In addition, when the preparation containing ethanol is combined with cephalosporins or nitroimidazoles, disulfiram-like adverse reactions are possibly caused, and chest pain, myocardial infarction, acute heart failure, dyspnea, acute liver injury, convulsion and even death are possibly induced. Therefore, it is important to remove ethanol from the prescription of poorly soluble drugs.
There is still a great need for ethanol-free poorly soluble pharmaceutical compositions, in particular for injection, with good stability.
The invention aims to provide an ethanol-free insoluble drug concentrated solution, so that the side effects caused by ethanol are avoided, and a safer choice is provided for clinical application of insoluble drugs.
The inventor surprisingly found through a great deal of experimental research that clinically applicable dose of the slightly soluble drug can be prepared into a stable composition by using a specific compound emulsifier and co-emulsifier, the composition can realize good dissolution of the slightly soluble drug, is a concentrate, is a uniform and transparent solution, and the preparation process is extremely simple. The composition can be diluted into micelle solution by using aqueous solvent before use, and the formed micelle solution is directly used for administration to patients, is convenient to use and has excellent stability. The aqueous vehicle may be an aqueous vehicle suitable for injection (e.g., water for injection, 5% glucose injection, 0.9% sodium chloride injection, etc.) or an aqueous vehicle suitable for oral administration (e.g., purified water, etc.). Moreover, the micellar solution obtained by diluting the composition of the invention fully meets the requirements of intravenous injection, and can be administered by intravenous injection.
Therefore, the concentrated solution of the invention not only has excellent stability, but also contains less types of excipients, has simple preparation process and is suitable for various difficultly soluble medicines. The micelle solution obtained by diluting the concentrated solution of the invention can smoothly realize the administration of insoluble drugs, particularly the injection administration, and meets the clinical requirements which are not met at present.
Brief description of the invention
The invention aims to provide an ethanol-free insoluble drug concentrated solution and a simple, environment-friendly and easily industrialized method for preparing the concentrated solution. It is another object of the present invention to provide a micelle solution which can smoothly achieve administration of a poorly soluble drug, particularly administration by injection.
In a first aspect, the present invention provides an ethanol-free poorly soluble drug concentrate, characterized in that the concentrate comprises a poorly soluble drug and a carrier that facilitates micelle formation, the carrier consisting of a complex emulsifier and a co-solvent, wherein the complex emulsifier consists of a phospholipid and a non-phospholipid emulsifier, the co-solvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and mixtures thereof, more preferably from propylene glycol, PEG200, PEG300, PEG400 and mixtures thereof, and the concentrate does not contain oil.
The phospholipid is preferably selected from soybean phospholipid, egg yolk lecithin and their mixture, more preferably egg yolk lecithin.
The non-phospholipid emulsifier is preferably selected from the group consisting of polyoxyethylene castor oil (e.g. polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil), polyoxyethylene hydrogenated castor oil (e.g. polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil), polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbates (e.g. polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80) and mixtures thereof. More preferably, the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, neat polyoxyethylene 35 castor oil, polyethylene glycol 15-hydroxystearate, polysorbate 80, and mixtures thereof.
In one embodiment of this aspect, in the concentrate of the present invention, when the weight of the poorly soluble drug, the complex emulsifier, and the co-solvent is taken to total 100% by weight, the weight percentage of the poorly soluble drug is 0.1% to 20%, preferably 0.5% to 15%, for example, 0.5%, 1%, 1.5%, 2%, 5%, 6%, 10%, 15%; the weight percentage of the phospholipid is 0.1-20%, preferably 0.5-10%, such as 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10%; the weight percentage of the non-phospholipid emulsifier is 20-80%, preferably 30-70%, such as 30%, 35%, 40%, 43%, 46%, 48%, 50%, 70%; the balance of cosolvent.
The concentrated solution of the present invention may consist of only the poorly soluble drug and a carrier for helping to form micelles, the carrier consisting of a complex emulsifier and a co-solvent, wherein the complex emulsifier consists of a phospholipid and a non-phospholipid emulsifier, the co-solvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and mixtures thereof, preferably from propylene glycol, PEG200, PEG300, PEG400 and mixtures thereof, and the concentrated solution does not contain oil.
Alternatively, the concentrate of the present invention may further contain a pH adjuster and/or an antioxidant. The pH regulator can be one or more selected from citric acid, citrate (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetate (such as sodium acetate), phosphoric acid, and phosphate (such as sodium monohydrogen phosphate, sodium dihydrogen phosphate, or sodium phosphate). The antioxidant may be one or more selected from alpha-tocopherol succinate (α -tocopherol succinate), ascorbyl palmitate (ascorbyl palmitate), Butylated Hydroxyanisole (BHA), and Butylated Hydroxytoluene (BHT).
When the concentrate of the present invention contains oil, the concentrate is allowed to stratify upon standing. Thus, the concentrate of the present invention is free of oil. The "oil" is, for example: vegetable oils such as soybean oil, corn oil, coconut oil, safflower oil, perilla oil, olive oil, castor oil, sunflower seed oil, cottonseed oil, tea oil, etc.; animal oils such as fish oil, egg oil, lanolin, etc.; mineral oils such as liquid paraffin, etc.; natural or synthetic triglycerides, such as Medium Chain Triglycerides (MCT), Long Chain Triglycerides (LCT), structural oils, and the like; and other known greases.
In a second aspect, the present invention provides a method for preparing said ethanol-free poorly soluble pharmaceutical concentrate, characterized in that said method comprises the steps of: mixing the insoluble medicine, phospholipid, non-phospholipid emulsifier and cosolvent in any order, stirring, filtering, packaging, and sealing.
In a third aspect, the present invention provides a micellar solution obtained by diluting the ethanol-free poorly soluble drug concentrate described above with an aqueous vehicle. The obtained micelle solution has uniform and transparent appearance and can be used for injection administration.
In a fourth aspect, the present invention provides the use of the ethanol-free poorly soluble drug concentrate described above for the preparation of a micellar solution. The micellar solution is particularly useful for intravenous injection.
Brief description of the drawings
FIG. 1 is a microscopic observation of representative HE stained sections of rabbit ears from rabbits given a 5% glucose injection.
FIG. 2 is a microscopic observation of representative HE stained sections of rabbit ears from rabbits given a commercial nimodipine injection.
Fig. 3 is a microscopic observation of a representative HE stained section of rabbit ears from rabbits administered with nimodipine injection of the present invention.
Detailed Description
Detailed description of the preferred embodiments
Embodiment 1. a poorly soluble drug concentrate free of ethanol, comprising a poorly soluble drug and a carrier that facilitates micelle formation, wherein:
the carrier consists of a composite emulsifier and a cosolvent,
the compound emulsifier is composed of phospholipid and non-phospholipid emulsifier, and the phospholipid is selected from soybean phospholipid, egg yolk lecithin and the mixture thereof,
the cosolvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and their mixture, preferably selected from propylene glycol, PEG200, PEG300, PEG400 and their mixture,
and the concentrate is oil free.
Embodiment 2. the concentrate of embodiment 1 wherein the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene castor oil (e.g., polyoxyethylene 35 castor oil, neat polyoxyethylene 35 castor oil), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil), polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbates (e.g., polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, particularly polysorbate 80), and mixtures thereof.
Embodiment 3. the concentrate of embodiment 2 wherein the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, neat polyoxyethylene 35 castor oil, polyethylene glycol 15-hydroxystearate, polysorbate 80, and mixtures thereof.
Embodiment 4. the concentrate of any of embodiments 1-3, wherein the co-solvent is selected from the group consisting of propylene glycol, PEG300, PEG400, and mixtures thereof.
Embodiment 5. the concentrate according to any one of embodiments 1 to 4, wherein the weight percentage of the poorly soluble drug is 0.1 to 20%, preferably 0.5 to 15%, when the weight of the poorly soluble drug, the complex emulsifier, and the co-solvent is taken to total 100% by weight; the weight percentage of the phospholipid is 0.1-20%, preferably 0.5-10%; the weight percentage of the non-phospholipid emulsifier is 20-80%, preferably 30-70%; the balance of cosolvent.
Embodiment 6. the composition according to any one of embodiments 1 to 5, wherein the poorly soluble drug is selected from celecoxib (celecoxib), valdecoxib (valdecoxib), etoricoxib (etoricoxib), ibuprofen (ibuprofen), dexibuprofen (dexibuprofen), propofol (propofol), flurbiprofen axetil, alprostadil (alprostadil), clevidipine butyrate (clevidipine butyrate), dexamethasone palmitate (demethoxyne palmate), felodipine (felodipine), nimodipine (modipidil), nifedipine (nifedipine), nitrendipine (nitrendipine), cyclosporine (cyclosporine), tacrolimus (tacrolimus), levosimendan (vosimethidol), itraconazole (voconazole), voriconazole (voconazole 10), troconazole (vofluconazole 10), troconazole (vofluconazole), troconazole (troconazole), troconazole (voconazole) or the like, Clopidogrel (clopidol), paclitaxel (paclitaxel), docetaxel (docetaxel), cabazitaxel (cabazitaxel), etoposide (etoposide), teniposide (teniposide), hydroxycamptothecin (hydroxycamptothecin), irinotecan (irinotecan), ubenimex (ubenimex), cisplatin (cilastatin), carboplatin (carboplatin), capecitabine (capecitabine), oxaliplatin (oxaliplatin), gefitinib (gefitinib), doxorubicin (doxorubicin), vinblastine (vinblastine), vincristine (vinristine), vinpocetine (vinpoccetine), digoxin (vindesine), piroxicam (piroxicam), spironolactone (spironolactone), valprovalproic acid (valacic), vitamin (moxetacin), vitamin (vitamin A), vitamin A, vitamin E (vitamin A); preferably, the poorly soluble drug is selected from the group consisting of celecoxib, ibuprofen, dexibuprofen, propofol, flurbiprofen axetil, alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, cabazitaxel, etoposide, teniposide and etoricoxib; most preferably, the poorly soluble drug is selected from the group consisting of nimodipine, posaconazole, docetaxel, clopidogrel, levosimendan, tacrolimus, cyclosporine, paclitaxel, ibuprofen, coenzyme Q10, cabazitaxel, celecoxib, and etoricoxib.
Embodiment 7. the concentrate of any of embodiments 1-6, further comprising a pH adjuster, an antioxidant, or both.
Embodiment 8. the composition according to any one of embodiments 1 to 6, wherein:
the insoluble drug is nimodipine, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of nimodipine is 1%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 46%, and the weight percentage of propylene glycol is 51%;
or
The insoluble drug is posaconazole, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is PEG300, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of posaconazole is 1%, the weight percentage of egg yolk lecithin is 3%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 50%, and the weight percentage of PEG300 is 46%;
or
The indissolvable drug is docetaxel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the indissolvable drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of docetaxel is 1%, the weight percentage of egg yolk lecithin is 3%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 48% and the weight percentage of propylene glycol is 48%;
or
The slightly soluble drug is clopidogrel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the slightly soluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of clopidogrel is 15%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 43% and the weight percentage of propylene glycol is 40%;
or
The insoluble drug is levosimendan, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of levosimendan is 0.5%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 50%, and the weight percentage of propylene glycol is 47.5%;
or
The insoluble drug is tacrolimus, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the tacrolimus is 1.5%, the weight percentage of the egg yolk lecithin is 2%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 46%, and the weight percentage of the propylene glycol is 50.5%;
or
The insoluble drug is cyclosporine, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the cyclosporine is 10%, the weight percentage of the egg yolk lecithin is 2%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 43% and the weight percentage of the propylene glycol is 45%;
or
The insoluble drug is paclitaxel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the paclitaxel is 1%, the weight percentage of the egg yolk lecithin is 2%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 46%, and the weight percentage of the propylene glycol is 51%;
or
The indissolvable drug is ibuprofen, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is PEG300, and when the weight of the indissolvable drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the ibuprofen is 10%, the weight percentage of the egg yolk lecithin is 2%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 40%, and the weight percentage of the PEG300 is 48%;
or
The poorly soluble drug is coenzyme Q10, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the poorly soluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the coenzyme Q10 is 5%, the weight percentage of the egg yolk lecithin is 10%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 30% and the weight percentage of the propylene glycol is 55%;
the slightly soluble drug is cabazitaxel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is tween80, the cosolvent is propylene glycol, and when the weight of the slightly soluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of cabazitaxel is 1%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of tween80 is 46%, and the weight percentage of propylene glycol is 51%;
the insoluble drug is celecoxib, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the celecoxib is 6%, the weight percentage of the egg yolk lecithin is 0.5%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 70%, and the weight percentage of the propylene glycol is 23.5%;
or
The insoluble drug is etoricoxib, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the etoricoxib is 5%, the weight percentage of the egg yolk lecithin is 5%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 35%, and the weight percentage of the propylene glycol is 55%.
Embodiment 9 use of a concentrate according to any one of embodiments 1 to 8 in the preparation of a micellar solution for intravenous injection, in particular intravenous drip.
Embodiment 10. a method of making a concentrate of any of embodiments 1 to 8, the method comprising the steps of: mixing the insoluble medicine, phospholipid, non-phospholipid emulsifier and cosolvent in any order, stirring, filtering, packaging, and sealing.
Embodiment 11. a micelle solution obtained by diluting the concentrated solution described in any one of embodiments 1 to 8 with an aqueous vehicle.
Embodiment 12 the micellar solution of embodiment 11, wherein the aqueous vehicle is water for injection, 5% dextrose injection or 0.9% sodium chloride injection.
Embodiment 13. the micellar solution according to embodiment 12 for use in intravenous injection, in particular intravenous drip.
Compositions of the invention and methods of making the same
The inventors have surprisingly found that poorly soluble drugs such as nimodipine can be prepared as ethanol-free stable compositions using a complex emulsifier consisting of a phospholipid and a non-phospholipid emulsifier and a specific co-solvent, which is a concentrate that is diluted with an aqueous vehicle to form a micellar solution just prior to use. When diluted with an aqueous vehicle suitable for injection, such as water for injection, 5% dextrose injection, or 0.9% sodium chloride injection, the resulting micellar solution can be used directly for administration by injection, such as intravenous injection.
Accordingly, in a first aspect, the present invention provides an ethanol-free poorly soluble drug concentrate, characterized in that the concentrate comprises a poorly soluble drug and a carrier that facilitates micelle formation, wherein the carrier consists of a complex emulsifier consisting of a phospholipid and a non-phospholipid emulsifier, and a co-solvent selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and mixtures thereof, preferably from propylene glycol, PEG200, PEG300 or PEG400, and the concentrate is free of oil.
The phospholipid is preferably selected from soybean phospholipid, egg yolk lecithin and their mixture, more preferably egg yolk lecithin.
The non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene castor oil (e.g., polyoxyethylene 35 castor oil, pure polyoxyethylene 35 castor oil), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil), polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbate (e.g., polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, especially polysorbate 80) and mixtures thereof. Preferably, the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, neat polyoxyethylene 35 castor oil, polyethylene glycol 15-hydroxystearate, polysorbate 80, and mixtures thereof.
When the concentrate of the present invention contains oil, the concentrate is allowed to stand for stratification. Thus, the composition of the present invention is free of oil. The "oil" is, for example: vegetable oils such as soybean oil, corn oil, coconut oil, safflower oil, perilla oil, olive oil, castor oil, sunflower seed oil, cotton seed oil, tea oil, etc.; animal oils such as fish oil, egg oil, lanolin, etc.; mineral oils such as liquid paraffin, etc.; natural or synthetic triglycerides, such as Medium Chain Triglycerides (MCT), Long Chain Triglycerides (LCT), structural oils, and the like; and other known greases.
In a preferred embodiment of this aspect, in the concentrated solution of the present invention, when the weight of the poorly soluble drug, the complex emulsifier, and the co-solvent is taken as 100 wt%, the weight percentage of the poorly soluble drug is 0.1% to 20%, preferably 0.5% to 15%, such as 0.5%, 1%, 1.5%, 2%, 5%, 6%, 10%, 15%; the weight percentage of the phospholipid is 0.1-20%, preferably 0.5-10%, such as 0.5%, 1%, 1.5%, 2%, 3%, 4%, 5%, 10%; the weight percentage of the non-phospholipid emulsifier is 20-80%, preferably 30-70%, such as 30%, 35%, 40%, 43%, 46%, 48%, 50%, 70%; the balance of cosolvent.
The concentrated solution of the invention is a uniform and transparent solution and has good physical and chemical stability. For example, when the solution is placed at room temperature for 12 months or at 40 ℃ for 30 days, the concentrated solution in the embodiment 5 of the invention is always a transparent and uniform solution, no delamination or drug precipitation is observed, the content of the insoluble drug and related substances and the like are not obviously changed, and the requirements of the drug quality control standard are met.
The concentrate of the invention may be diluted with an aqueous vehicle to form a micellar solution. The aqueous vehicle may be an aqueous vehicle suitable for injection (e.g., water for injection, 5% glucose injection, 0.9% sodium chloride injection, etc.) or an aqueous vehicle suitable for oral administration (e.g., purified water, etc.). After dilution with an aqueous vehicle suitable for injection, such as 5% dextrose injection, the concentrate of the present invention forms a micellar solution that meets the requirements of intravenous injection and even intravenous drip injection, and thus, the micellar solution can be directly used for subcutaneous injection, intradermal injection, intraperitoneal injection, intravenous injection, including intravenous bolus injection and intravenous drip.
Upon dilution of the concentrate of the invention with an aqueous vehicle, a clear solution results which is neither cloudy nor present with any precipitate. Upon preliminary examination, it is estimated that micelles having a particle size of about 10nm or less are formed in the solution, and thus the formed solution is referred to as "micellar solution".
The concentrated solution of the invention not only has good stability per se, but also the micellar solution obtained by dilution of the concentrated solution has good stability. For example, the solution formed by diluting the concentrated solution of the present invention with a 5% glucose injection is left at room temperature for 24 hours, and no drug precipitation or separation occurs.
The "poorly soluble drug" of the present invention is a known drug that can be used in the field of medicine, and has low solubility in water relative to the effective dose thereof. More specifically, the "poorly soluble drug" of the present invention refers to a drug having a solubility of "slightly soluble" (solute 1g (ml) is soluble in 100 to less than 1000ml of a solvent), "very slightly soluble" (solute 1g (ml) is soluble in 1000 to less than 10000ml of a solvent), or "hardly soluble or insoluble" (solute 1g (ml) is not completely soluble in 10000ml of a solvent) which is described in "general examples" of the chinese pharmacopoeia.
Examples of poorly soluble drugs according to the present invention include, but are not limited to: celecoxib, valdecoxib, etoricoxib, ibuprofen, dexibuprofen, propofol, flurbiprofen axetil, alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, miconazole, ketoconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, cabazitaxel, etoposide, teniposide, hydroxycamptothecin, irinotecan, ubenimexminstil, cisplatin, carboplatin, capecitabine, oxaliplatin, gefitinib, doxorubicin, vinblastine, vinpocetine, vindesine, piroxicam, spironolactone, valproic acid, tamoxifen, azithromycin, vitamin A, vitamin D, Vitamin E, vitamin K, fenofibrate, indomethacin and Reidesciclovir. Preferably, the poorly soluble drug is selected from the group consisting of celecoxib, ibuprofen, dexibuprofen, propofol, flurbiprofen axetil, alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, cabazitaxel, etoposide, teniposide and etoricoxib. Most preferably, the poorly soluble drug is selected from the group consisting of nimodipine, posaconazole, docetaxel, clopidogrel, levosimendan, tacrolimus, cyclosporine, paclitaxel, ibuprofen, coenzyme Q10, cabazitaxel, celecoxib, and etoricoxib.
The inventor screens the emulsifying agent used in the concentrated solution of the invention, and the phospholipid emulsifying agent considers soybean lecithin, yolk lecithin and hydrogenated soybean lecithin; non-phospholipid emulsifiers polyoxyethylene 40 hydrogenated castor oil (e.g. kolliphor RH40), polyoxyethylene 35 castor oil (e.g. kolliphor EL), polyethylene glycol 15-hydroxystearate (e.g. kolliphor HS15), vitamin E polyethylene glycol succinate (TPGS), polysorbate 80 (e.g. tween 80) were investigated. Experimental results show that the stability of the solution obtained by diluting the concentrated solution prepared by using the single phospholipid emulsifier or the non-phospholipid emulsifier is poor, and the concentrated solution can be layered about 1 hour after the solution is formed; only when the phospholipid and the non-phospholipid emulsifier are used in combination, the obtained concentrated solution is stable and uniform, and the obtained solution has good stability after being diluted, thereby meeting all requirements of intravenous injection preparations.
The inventor also screens the cosolvent, and the cosolvent comprises propylene glycol, glycerol, PEG200, PEG300, PEG400 and the like, can form a uniform and transparent concentrated solution in the form of a solution, and the concentrated solution has good physical and chemical stability. However, the concentrates prepared with glycerol are more viscous than several other co-solvents.
The most preferred concentrates of the present invention are those having the components and proportions given in example 5 of the present application.
The ethanol-free poorly soluble drug concentrate of the present invention described above may consist of only a poorly soluble drug and a carrier that facilitates micelle formation, the carrier consisting of a complex emulsifier and a co-solvent, wherein the complex emulsifier consists of a phospholipid and a non-phospholipid emulsifier, the co-solvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and mixtures thereof, preferably from propylene glycol, PEG200, PEG300, PEG400 and mixtures thereof, and the concentrate does not contain oil.
Alternatively, the ethanol-free poorly soluble pharmaceutical concentrate of the present invention described above may also contain other components, such as a pH adjuster and/or an antioxidant. The pH regulator can be one or more selected from citric acid, citrate (such as sodium citrate), maleic acid, tartaric acid, hydrochloric acid, sodium hydroxide, acetic acid, acetate (such as sodium acetate), phosphoric acid, and phosphate (such as sodium monohydrogen phosphate, sodium dihydrogen phosphate, or sodium phosphate). The antioxidant can be selected from one or more of alpha-tocopherol succinate, ascorbyl palmitate, Butylated Hydroxyanisole (BHA) and Butylated Hydroxytoluene (BHT).
In a second aspect, the present invention provides a method for preparing said ethanol-free poorly soluble pharmaceutical concentrate, characterized in that said method comprises the steps of: mixing the insoluble medicine, phospholipid, non-phospholipid emulsifier and cosolvent in any order, stirring, filtering, packaging, and sealing.
The inventors found that the process for preparing the concentrate of the present invention is very simple, and the order of addition of the individual components, the stirring time, etc. do not affect the quality of the concentrate as long as the poorly soluble drug is ensured to be dissolved.
The invention adopts a very simple prescription process to prepare the ethanol-free insoluble drug concentrated solution with good stability, and the micellar solution which can be directly used for intravenous injection administration can be obtained by diluting the ethanol-free insoluble drug concentrated solution with an aqueous solvent. Compared with the prior art, the concentrated solution has the advantages of simplified formula and simple preparation process, and can be obtained by simple mixing, stirring, filtering and packaging. A homogenizer, a microfluidizer and a complex liquid preparation system are not needed; the process can be realized by common enterprises. Moreover, the physical and chemical stability of the concentrated solution is obviously improved; the storage and transportation do not need a cold chain, thereby greatly reducing the cost of production, transportation, storage and use and providing great convenience for clinical medication.
In a third aspect, the present invention provides a micellar solution obtained by diluting the ethanol-free poorly soluble drug concentrate described above with an aqueous vehicle. The obtained micelle solution has uniform and transparent appearance and can be used for injection administration.
The micellar solution is homogeneous and transparent, neither turbid nor any precipitate present. Upon preliminary examination, it is estimated that micelles having a particle size of about 10nm or less are formed in the solution, and thus the formed solution is referred to as "micellar solution", which is close to a true solution. The micellar solution may be stable for at least 24 hours at room temperature.
The micellar solution avoids the side effects associated with ethanol due to the absence of ethanol, e.g., a substantially reduced vascular irritation compared to a corresponding injection solution comprising ethanol.
The micellar solution can be administered to a patient to treat a disease that is treatable by a poorly soluble drug contained therein. For example, the nimodipine-containing concentrate and micellar solution can be used for improving blood circulation in the recovery period of acute cerebrovascular disease, treating cerebral vasospasm after subarachnoid hemorrhage of various reasons and ischemic neurological disorder hypertension, migraine and the like caused by the cerebral vasospasm, treating vascular dementia, sudden deafness and the like; the celecoxib-containing concentrates and micellar solutions are useful in the treatment of acute pain and inflammatory diseases such as osteoarthritis and rheumatoid arthritis; concentrates and micellar solutions comprising paclitaxel or docetaxel can be used to treat cancer, for example, solid tumors such as breast cancer, ovarian cancer, head and neck cancer, lung cancer (including non-small cell lung cancer and small cell lung cancer), pancreatic cancer, gastric cancer, melanoma, soft tissue sarcoma; the concentrate and micellar solution containing ibuprofen or dexibuprofen are useful for the treatment of pain, such as headache, arthralgia, migraine, toothache, myalgia, neuralgia, dysmenorrhea. The poorly soluble drugs and their uses described herein are known in the art and the prior art literature describing the use of these poorly soluble drugs is considered part of the present application.
In a fourth aspect, the present invention provides the use of the ethanol-free poorly soluble drug concentrate described above for the preparation of a micellar solution. The micellar solutions are particularly useful for intravenous injection, such as intravenous bolus injection and intravenous drip.
In the present disclosure, the inventors have studied in detail the major factors affecting the formation, physical and chemical stability, and physical stability of the micelle solution obtained after dilution of an ethanol-free poorly soluble drug concentrate using a variety of drugs such as nimodipine as a model of poorly soluble drugs, and have obtained the concentrate of the present invention. The concentrated solution can be widely applied to insoluble drugs, realizes the injection administration of the insoluble drugs, and provides new treatment possibility for clinical application.
Definition of
In the context of the present application, the terms "poorly soluble drug concentrate free of ethanol", "composition of the invention", "concentrate of the invention" and the like are used interchangeably and refer to a composition as described herein comprising the poorly soluble drug and the micelle-forming facilitating carrier, except where the context indicates otherwise.
The term "vehicle which facilitates micelle formation" as used herein refers to a pharmaceutically acceptable vehicle which facilitates formation of a micellar solution upon dilution of the concentrate of the invention with an aqueous vehicle.
The term "consisting of … …" as used herein means that no material other than the listed components is included in significant amounts. For example, in the concentrate of the present invention, the carrier that contributes to micelle formation is composed of the complex emulsifier and the co-solvent, which means that no significant amount of other substances that contribute to micelle formation are included in addition to the complex emulsifier and co-solvent defined herein.
The term "ethanol" as used herein refers to the formula CH 3 CH 2 A substance of OH.
The term "medium chain triglycerides" as used herein refers to non-volatile vegetable oils extracted from the hard dried endosperm of coconut or the dried endosperm of oil coconut, which is a mixture of saturated fatty acid triglycerides. Medium chain triglycerides are commercially available, for example from Liaoning emerging pharmaceuticals, IOI Oleo GmbH, Germany, and the like.
The term "polyoxyethylated castor oil" as used herein refers to a material obtained by reacting varying amounts of ethylene oxide and castor oil. Examples of polyoxyethylated castor oils include, but are not limited to, polyoxyethylated 35 castor oil, pure polyoxyethylated 35 castor oil.
The term "polyoxyethylene 35 castor oil" as used herein refers to a material obtained by reacting 1mol of glyceryl ricinoleate with 35mol of ethylene oxide, which contains, in addition to polyoxyethylene glyceryl triricinoleate, small amounts of polyethylene glycol ricinoleate and free ethylene glycol. Polyoxyethylene 35 castor oil is commercially available, for example under the tradenames kolliphor EL and kolliphor ELP from BASF or the like.
The term "pure polyoxyethylene 35 castor oil" as used herein refers to purified polyoxyethylene glycerol triricinoleate, substantially free of polyethylene glycol ricinoleate and free ethylene glycol.
The term "polyoxyethylene hydrogenated castor oil" as used herein refers to a material obtained by reacting varying amounts of ethylene oxide with hydrogenated castor oil. Examples of polyoxyethylene hydrogenated castor oil include, but are not limited to, polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil.
The term "polyoxyethylene 40 hydrogenated castor oil" as used herein means a material obtained by reacting one mole of glycerol trihydroxystearic acid with 40 to 45 moles of ethylene oxide, which contains a small amount of polyethylene glycol trihydroxystearic acid, free polyethylene glycol, in addition to polyoxyethylene glycerol trihydroxystearate. Polyoxyethylene 40 hydrogenated castor oil is commercially available, for example from BASF or the like under the tradename kolliphor RH 40.
The term "polyoxyethylene 60 hydrogenated castor oil" as used herein means a substance obtained by reacting one mole of glycerol trihydroxystearic acid with 60 moles of ethylene oxide, which contains a small amount of polyethylene glycol trihydroxystearic acid, free polyethylene glycol, in addition to polyoxyethylene glycerol trihydroxystearate.
The term "polyethylene glycol 15-hydroxystearate" as used herein is commercially available, for example under the trade name kolliphor HS15 or Solutol HS-15 from BASF or Sigma-Aldrich.
The term "vitamin E polyethylene glycol succinate (TPGS)" as used herein is a water-soluble derivative of vitamin E resulting from the reaction of the carboxyl group of vitamin E succinate with the hydroxyl group of polyethylene glycol, which is commercially available, for example under the trade name Tocofersolan (TPGS) from BASF.
The term "polysorbate" as used herein refers to a series of partial fatty acid esters of polyoxyethylene sorbitan copolymerized in a ratio of about 20.5 or 4 moles of ethylene oxide per mole of sorbitol. Examples of polysorbates include, but are not limited to, for example, polysorbates 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, particularly polysorbate 80. Polysorbates are commercially available, for example, under the trade names tween 20, tween 40, tween80, and the like, commercially available from tokyo wil pharmaceutical products ltd.
The terms "about," "approximately," "left-right," as used herein, mean that the numerical values given thereafter can be expanded by up to 20%. For example, "about 100" means 80% to 120%.
Examples
The following examples are intended to illustrate the invention, but in no way limit the scope thereof as defined by the appended claims.
Unless otherwise stated, high performance liquid chromatography was performed using Shimadzu LC-20AT, the temperature units given are degrees Celsius, and temperature manipulations not stated were performed AT ambient temperature. The meanings of abbreviations used in the examples are shown in Table 1.
TABLE 1 abbreviations
Abbreviations Means of Source
ELP Polyoxyethylene 35 castor oil kolliphor EL BASF
EPC Egg yolk lecithin EPC 80 Lipoid
SPC Soybean lecithin Mandarin organism of Jiangsu
HSPC Hydrogenated soybean lecithin Lipoid
RH40 Polyoxyethylene 40 hydrogenated castor oil kolliphor RH40 BASF
HS15 15-Hydroxystearic acid polyethylene glycol ester kolliphor HS15 BASF
Tween 80 Tween80 Nanjing weier pharmaceutical industry
TPGS Polyethylene glycol 1000 vitamin E succinate BASF
MCT Medium chain triglycerides Liaoning emerging pharmaceutical industry
LCT Soybean oil Liaoning emerging pharmaceutical industry
Example 1: screening of Single emulsifiers
TABLE 2 formulation containing a single emulsifier
Components Prescription 1 Prescription 2 Prescription 3 Prescription 4 Prescription 5 Prescription 6 Prescription 7 Prescription 8
Nimodipine 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g 0.1g
HS15 4.6g -- -- -- -- -- -- --
Tween80 -- 4.6g -- -- -- -- -- --
ELP -- -- 4.6g -- -- -- -- --
TPGS -- -- -- 4.6g -- -- -- --
RH40 -- -- -- -- 4.6g -- -- --
EPC -- -- -- -- -- 4.6g -- --
SPC -- -- -- -- -- -- 4.6g --
HSPC -- -- -- -- -- -- -- 4.6g
Propylene glycol 5.3g 5.3g 5.3g 5.3g 5.3g 5.3g 5.3g 5.3g
Total of 10g 10g 10g 10g 10g 10g 10g 10g
The process comprises the following steps: the prescribed amounts of each component were added to a 20ml vial and magnetically stirred until all components were completely dissolved.
The nimodipine concentrated solution obtained by the formulas 1 to 5 is a light yellow clear transparent solution, the nimodipine concentrated solution obtained by the formulas 6 to 8 is a turbid solution, and EPC, SPC and HSPC are insoluble in the system, so that the solution cannot be obtained, and the investigation after dilution is not performed any more.
1ml of the concentrated solution prepared according to the prescription 1-5 is diluted with 100ml of 5% glucose injection. After standing at 25 ℃, the solution was observed to form and the stability of the resulting solution was examined.
The results of the experiment are shown in table 3.
TABLE 3 appearance of nimodipine concentrates prepared with a single emulsifier, dilution to form a solution and stability of the solution formed after dilution
Figure BDA0002920822000000171
The above experimental data show that concentrate in the form of clear solution cannot be prepared using phospholipid emulsifiers EPC, SPC or HSPC alone. Although nimodipine concentrates prepared by using the non-phospholipid emulsifier HS15, Tween80, ELP, TPGS or RH40 alone are all transparent solutions, and form clear and transparent solutions after being diluted by 5% glucose injection according to the volume ratio of 1:100, the solution obtained after dilution has the phenomenon of drug precipitation after being placed at 25 ℃ for about 1 hour, which indicates that the diluted solution is unstable and cannot meet the requirements of clinical administration, especially injection administration.
Example 2: screening of Complex emulsifiers
TABLE 4 formulation containing Complex emulsifiers
Components Prescription 9 Prescription 10 Prescription 11
Nimodipine 0.1g 0.1g 0.1g
HS15 4.6g 4.6g 4.6g
EPC 0.2
SPC 0.2g
HSPC 0.2g
Propylene glycol 5.1g 5.1g 5.1g
Total of 10g 10g 10g
The process comprises the following steps: the prescribed amounts of each component were added to a 20ml vial and magnetically stirred until all components were completely dissolved.
The nimodipine concentrates obtained from recipes 9-10 were all clear and transparent pale yellow solutions and no delamination was observed after 12 months of storage at 25 ℃.
The nimodipine concentrated solution obtained by the formula 11 is a turbid solution, and HSPC is insoluble in a system and cannot form a solution, so the investigation after dilution is not performed any more.
1ml of the concentrated solution obtained by the prescription 9-10 is diluted by 100ml of 5% glucose injection to form a clear and transparent solution. This was left at 25 ℃ and the stability of the resulting solution after dilution was observed. The results showed that no precipitate was visible after 24h at 25 ℃.
The results of the experiment are shown in Table 5.
TABLE 5 stability of the solution formed after dilution of nimodipine concentrate prepared with complex emulsifiers
Figure BDA0002920822000000181
The above experimental results show that nimodipine concentrate in the form of transparent solution cannot be prepared by using the composite emulsifier consisting of HS15 and HSPC, but nimodipine concentrate prepared by using the composite emulsifier consisting of HS15, EPC and SPC, respectively, is a uniform and transparent solution, and it is observed that no delamination occurs after the concentrates are left at 25 ℃ for 12 months. The concentrates of formulas 9 and 10 were diluted with 5% dextrose injection at a volume ratio of 1:100, both forming clear and transparent solutions. As shown in Table 5, when these solutions were left at 25 ℃ for 24 hours, no precipitate was observed, and the requirement for intravenous administration was satisfied.
Thus, a formulation comprising a phospholipid and a non-phospholipid complex emulsifier should be used, and the phospholipid should not be HSPC, since not all phospholipid emulsifiers are capable of producing a clear and transparent solution.
Example 3: screening of oils
The inventors have investigated various pharmaceutically acceptable oils and the specific experimental design is as follows:
TABLE 6 formulations containing different oils
Figure BDA0002920822000000191
The process comprises the following steps: the prescribed amounts of each component were added to a 20ml vial and magnetically stirred until all components were completely dissolved.
The appearance of nimodipine concentrates prepared according to formulas 12-21 was observed. The results of the experiment are shown in Table 7.
TABLE 7 stability of nimodipine concentrates prepared with formulations 12-21
Figure BDA0002920822000000201
As can be seen from the experimental results in Table 7, the concentrated solutions of formulas 12-21 are turbid liquids, and are layered after being placed at room temperature for about 1h, and are not stable systems, so the stability of the diluted solutions is not examined.
The above experimental results show that the concentrate cannot contain oils, and that other oils of similar nature, except MCT, LCT, olive oil, fish oil, corn oil, structured oil, castor oil, sunflower seed oil, cottonseed oil, tea oil, which were examined in formulas 12-21, should not be included in the formula of the present invention.
Example 4: screening of Co-solvents
The inventor researches a plurality of medicinal non-ethanol cosolvents, and the specific experimental design is as follows:
TABLE 8 formulations containing different Co-solvents
Components Prescription 22 Prescription 23 Prescription 24 Prescription 25 Prescription 26
Nimodipine 0.1g 0.1g 0.1g 0.1g 0.1g
HS15 4.6g 4.6g 4.6g 4.6g 4.6g
EPC 0.3g 0.3g 0.3g 0.3g 0.3g
Propylene glycol 1.6g -- -- -- --
PEG200 -- 1.6g -- -- --
PEG300 -- -- 1.6g -- --
PEG400 -- -- -- 1.6g --
Glycerol 1.6g
Total of 10g 10g 10g 10g 10g
The process comprises the following steps: the prescribed amounts of each component were added to a 20ml vial and magnetically stirred until all components were completely dissolved.
The appearance of nimodipine concentrates prepared according to recipes 22-26 was observed.
Nimodipine concentrate prepared according to the prescription 22-26 is diluted 100 times with 5% glucose injection in a volume ratio of 1: 100. After 24 hours at 25 ℃, the solution was observed to form and the stability of the resulting solution was examined. The results of the experiment are shown in Table 9.
TABLE 9-appearance of nimodipine concentrates prepared with formulations 22-26, dilution to form a solution, and stability of the solution resulting from dilution
Figure BDA0002920822000000211
As can be seen from the results of the experiments in Table 9, the concentrates prepared with the co-solvents examined were all pale yellow clear transparent solutions, and the concentrates of formulas 22-25 were very fluid, in contrast to the concentrate of formula 26, which was more viscous and less fluid than the concentrate of formulas 22-25. The solutions obtained after dilution with these concentrates all have good stability and no precipitate is found after standing at 25 ℃ for 24 hours.
Example 5: preparation of insoluble pharmaceutical composition without ethanol (total amount of insoluble drug, compound emulsifier, and cosolvent is 100%)
Concentrate 1
Components Weight percent Dosage of
Nimodipine 1％ 0.1g
HS15 46％ 4.6g
EPC 2％ 0.2g
Propylene glycol 51％ 5.1g
In total 100％ 10g
The process comprises the following steps:
the recipe amount of EPC and nimodipine were weighed into a 20ml vial, the recipe amount of propylene glycol was added and stirred in a water bath at 60 ℃ for 1min at 2000 rpm. To this was added the prescribed amount of HS15 and stirred in a water bath at 60 ℃ at 2000rpm for 5min to obtain a uniform transparent solution.
Concentrate 2
Components Weight percent Dosage of
Posaconazole 1％ 0.1g
HS15 50％ 5.0g
EPC 3％ 0.3g
PEG300 46％ 4.6g
In total 100％ 10g
The process comprises the following steps:
the recipe amounts of EPC, posaconazole, PEG300, HS15 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous and transparent solution.
Concentrate 3
Components Weight percent Amount of the composition
Docetaxel 1％ 0.1g
HS15 48％ 4.8g
EPC 3％ 0.3g
Propylene glycol 48％ 4.8g
In total 100％ 10g
The process comprises the following steps:
the recipe amount of EPC and docetaxel was weighed into a 20ml vial, the recipe amount of propylene glycol was added, and stirred in a water bath at 60 ℃ for 10min at 2000 rpm. To this was added HS15 in the prescribed amount and stirred at 2000rpm in a water bath at 60 ℃ for 5min to obtain a uniform transparent solution.
Concentrate 4
Components Weight percent Dosage of
Clopidogrel 15％ 1.5g
HS15 43％ 4.3g
EPC 2％ 0.2g
Propylene glycol 40％ 4.0g
In total 100％ 10g
The process comprises the following steps:
EPC, clopidogrel, propylene glycol and HS15 in the prescribed amounts are weighed and placed in a 20ml vial, and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a uniform and transparent solution.
Concentrate 5
Components Weight percent Dosage of
Levosimendan 0.5％ 0.05g
HS15 50％ 5.0g
EPC 2％ 0.2g
Propylene glycol 47.5％ 4.75g
In total 100％ 10g
The process comprises the following steps:
the prescribed amounts of EPC, levosimendan, propylene glycol, HS15 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous transparent solution.
Concentrate 6
Components Weight percent Dosage of
Tacrolimus 1.5％ 0.15g
HS15 46％ 4.6g
EPC 2％ 0.2g
Propylene glycol 50.5％ 5.05g
In total 100％ 10g
The process comprises the following steps:
the recipe amounts of EPC, tacrolimus, propylene glycol, HS15 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous transparent solution.
Concentrated solution 7
Components Weight percent Dosage of
Cyclosporin 10％ 1.0g
HS15 43％ 4.3g
EPC 2％ 0.2g
Propylene glycol 45％ 4.5g
In total 100％ 10g
The process comprises the following steps:
the recipe amounts of EPC, cyclosporin, propylene glycol, HS15 were weighed into a 20ml vial and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a uniform and transparent solution.
Concentrate 8
Components Weight percent Amount of the composition
Paclitaxel 1％ 0.1g
HS15 46％ 4.6g
EPC 2％ 0.2g
Propylene glycol 51％ 5.1g
In total 100％ 10g
The process comprises the following steps:
the recipe amounts of EPC, paclitaxel, propylene glycol, HS15 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous transparent solution.
Concentrate 9
Components Weight percent Dosage of
Ibuprofen 10％ 1.0g
HS15 40％ 4.0g
EPC 2％ 0.2g
PEG300 48％ 4.8g
In total 100％ 10g
The process comprises the following steps:
the prescribed amounts of EPC, ibuprofen, PEG300, HS15 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous transparent solution.
Concentrated solution 10
Components Weight percent Dosage of
Coenzyme Q10 5％ 0.5g
HS15 30％ 3.0g
EPC 10％ 1.0g
Propylene glycol 55％ 5.5g
In total 100％ 10g
The process comprises the following steps:
the prescribed amounts of EPC, coenzyme Q10, propylene glycol, HS15 were weighed into 20ml vials and stirred at 2000rpm in a water bath at 60 ℃ for 15min to obtain a homogeneous transparent solution.
Concentrated solution 11
Components Weight percent Dosage of
Cabazitaxel 1％ 0.1g
Tween80 46％ 4.6g
EPC 2％ 0.2g
Propylene glycol 51％ 5.1g
In total 100％ 10g
The process comprises the following steps:
the recipe amounts of EPC, cabazitaxel, propylene glycol, Tween80 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous, transparent solution.
Concentrate 12
Components Weight percent Amount of the composition
Celecoxib 6％ 0.6g
HS15 70％ 7.0g
EPC 0.5％ 0.05g
Propylene glycol 23.5％ 2.35g
In total 100％ 10g
The process comprises the following steps:
the recipe amounts of EPC, celecoxib, propylene glycol, HS15 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous transparent solution.
Concentrated solution 13
Components Weight percent Dosage of
Etoricoxib 5％ 0.5g
HS15 35％ 3.5g
EPC 5％ 0.5g
Propylene glycol 55％ 5.5g
In total 100％ 10g
The process comprises the following steps:
the prescribed amount of EPC, etoricoxib, propylene glycol, HS15 were weighed into a 20ml vial and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous transparent solution.
Concentrated solution 14
Components Weight percent Dosage of
Nimodipine 1％ 0.1g
ELP 46％ 4.6g
EPC 2％ 0.2g
Propylene glycol 51％ 5.1g
In total 100％ 10g
The process comprises the following steps:
the recipe amount of EPC and nimodipine were weighed into a 20ml vial, the recipe amount of propylene glycol was added and stirred in a water bath at 60 ℃ for 1min at 2000 rpm. Then, a prescribed amount of ELP was added thereto, and the mixture was stirred in a water bath at 60 ℃ at 2000rpm for 5min to obtain a uniform transparent solution.
Concentrated solution 15
Components Weight percent Dosage of
Posaconazole 1％ 0.1g
RH40 50％ 5.0g
EPC 3％ 0.3g
PEG300 46％ 4.6g
In total 100％ 10g
The process comprises the following steps:
the recipe amounts of EPC, posaconazole, PEG300, and RH40 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous and transparent solution.
Concentrate 16
Components Weight percent Dosage of
Docetaxel 1％ 0.1g
Tween80 48％ 4.8g
EPC 3％ 0.3g
Propylene glycol 48％ 4.8g
In total 100％ 10g
The process comprises the following steps:
the recipe amount of EPC and docetaxel was weighed into a 20ml vial, the recipe amount of propylene glycol was added, and stirred in a water bath at 60 ℃ for 10min at 2000 rpm. A prescribed amount of Tween80 was further added thereto, and the mixture was stirred in a water bath at 60 ℃ at 2000rpm for 5 minutes to obtain a uniform transparent solution.
Concentrated solution 17
Components Weight percent Dosage of
Clopidogrel 15％ 1.5g
ELP 43％ 4.3g
EPC 2％ 0.2g
Propylene glycol 40％ 4.0g
In total 100％ 10g
The process comprises the following steps:
EPC, clopidogrel, propylene glycol and ELP in the prescribed amounts are weighed and placed in a 20ml vial, and stirred for 15min at 2000rpm in a water bath at 60 ℃ to obtain a uniform and transparent solution.
Concentrate 18
Components Weight percent Dosage of
Levosimendan 0.5％ 0.05g
HS15 25％ 2.5g
Tween80 25％ 2.5g
EPC 2％ 0.2g
Propylene glycol 47.5％ 4.75g
In total 100％ 10g
The process comprises the following steps:
the prescribed amounts of EPC, levosimendan, propylene glycol, HS15, Tween80 were weighed into a 20ml vial and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a uniform transparent solution.
Concentrated solution 19
Components Weight percent Dosage of
Tacrolimus 1.5％ 0.15g
ELP 46％ 4.6g
EPC 2％ 0.2g
Propylene glycol 50.5％ 5.05g
In total 100％ 10g
The process comprises the following steps:
the recipe amounts of EPC, tacrolimus, propylene glycol, ELP were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous transparent solution.
Concentrated solution 20
Components Weight percent Dosage of
Levosimendan 0.5％ 0.05g
Tween80 50％ 5.0g
EPC 2％ 0.2g
Propylene glycol 47.5％ 4.75g
In total 100％ 10g
The process comprises the following steps:
the prescribed amounts of EPC, levosimendan, propylene glycol, Tween80 were weighed into 20ml vials and stirred in a water bath at 60 ℃ for 15min at 2000rpm to obtain a homogeneous transparent solution.
Example 6: stability study of the concentrates of the invention
According to the guidelines of stability tests of crude drugs and pharmaceutical preparations in 9001 of the general rules of the four parts of the book of Chinese pharmacopoeia 2015, the concentrated solution 1 in example 5 is placed at the temperature of 25 +/-2 ℃ and the relative humidity of 60 +/-5%, and samples are taken at the end of months 0, 3, 6 and 12 to examine corresponding indexes.
1. Sample information: concentrate 1 of example 5, run No. 20190615
2. Stability test conditions:
Figure BDA0002920822000000281
3. analytical method
(1) Traits
The checking method comprises the following steps: visual inspection was carried out.
(2) Related substances
The detection method comprises the following steps: HPLC method
The experimental conditions are as follows:
a chromatographic column: c18 column (type: AgiLent EcLipse XDB-C18, length 25cm, inner diameter 4.6mm, filler particle size 5.0 μm)
Column temperature: at room temperature
A detector: UV detector (235 nm wavelength)
Mobile phase: methanol-acetonitrile-water (35:38:27)
Flow rate: 1.0mL/min
Sample injection volume: 20 μ L
Operating time: 25min
The system adaptability is as follows: the degree of separation of the nimodipine peak from the impurity I (2, 6-dimethyl-4- (3-nitrophenyl) -3, 5-pyridinedicarboxylic acid 2-methoxyethyl ester isopropyl ester) peak in the system-adapted solution chromatography should be greater than 3.0.
Specific experimental operations:
taking the placed concentrated solution 1 at each specified time point, precisely weighing, adding methanol for dissolving, and quantitatively diluting to prepare a solution containing about 0.2mg of nimodipine in each 1mL as a test solution; a proper amount of nimodipine standard substance is precisely measured and diluted into a solution containing about 2 mu g of nimodipine in every 1mL by using methanol, and the solution is used as a control solution. And taking a proper amount of the nimodipine standard substance and the impurity I standard substance, adding methanol for dissolving and diluting to prepare a mixed solution containing about 200 mu g of nimodipine and 1 mu g of impurity I in every 1mL, and taking the mixed solution as a system adaptive solution. Measured by high performance liquid chromatography under the conditions as described above. And (4) avoiding light. The chromatogram was recorded to 3 times the retention time of the main component peak. In the system adaptability solution chromatogram, the separation degree of the nimodipine peak and the impurity I peak is more than 3.0.
Precisely measuring 20 μ L of each of the sample solution and the reference solution, respectively injecting into a liquid chromatograph, and recording chromatogram. In the chromatogram of the sample solution, an impurity peak (a minimum peak area of 3000Counts) is present except a blank solvent peak, and the content of the impurity is calculated according to a 1% self-contrast method added with a correction factor, and the impurity limit is shown in the following table.
Figure BDA0002920822000000291
(3) Content and related substances
The detection method comprises the following steps: HPLC method
The experimental conditions are as follows:
a chromatographic column: c18 column (type: AgiLent EcLipse XDB-C18, length 25cm, inner diameter 4.6mm, filler particle size 5.0 μm)
Column temperature: at room temperature
A detector: UV detector (235 nm wavelength)
Mobile phase: methanol-acetonitrile-water (35:38:27)
Flow rate: 1.0mL/min
Sample introduction volume: 10 μ L
Operating time: for 10min
The system adaptability is as follows: the number of theoretical plates is not less than 8000 according to the calculation of the main peak of nimodipine, the separation degree of nimodipine and adjacent impurity peaks meets the requirement, and the relative standard deviation of repeated sample injection is not more than 2.0 percent.
Specific experimental operations:
under the chromatographic conditions, the relative standard deviation of the retention time of the main peak of repeated injection is not more than 2.0 percent.
10 mu L of the system applicability solution under the related substance item is taken and injected into a liquid chromatograph, and the separation degree of nimodipine and impurity I peak is more than 3.0. Taking 1 part of the concentrated solution, precisely weighing, dissolving with methanol, and diluting into a solution containing about 2mg of nimodipine per 1mL, as a test solution; taking a nimodipine standard substance, precisely weighing, adding methanol to dissolve and dilute the nimodipine standard substance into a solution containing about 20 mu g of nimodipine in every 1mL, and taking the solution as a control solution. Precisely measuring 10 μ L of sample solution or reference solution, injecting into liquid chromatograph, and recording chromatogram. Calculated as peak area by external standard method.
4. Results of the experiment
TABLE 10 long-term stability test (25 ℃ C. + -2 ℃ C., RH 60% + -5%) of concentrate 1 of example 5 (batch No.: 20190615)
Figure BDA0002920822000000301
"-" indicates no detection of the substance, RRT indicates relative retention time
The above experiment results show that the concentrated solution 1 in example 5 is placed for 12 months at the temperature of 25 ℃ +/-2 ℃ and the relative humidity of 60% +/-5%, and all indexes meet the requirements, and the physical stability and the chemical stability are good.
The inventors also examined the stability of the concentrates 2 to 13 of example 5 at 40 ℃. + -. 2 ℃ and 60%. + -. 5% relative humidity for 0, 5, 10 and 30 days as the index of the content of poorly soluble drug, and the results are shown in Table 11.
TABLE 11-results of stability examination of concentrates 2 to 13 of example 5
Preparation Day 0 5 days 10 days 30 days
Concentrate 2 100％ 98.2％ 99.1％ 96.8％
Concentrate 3 100％ 98.2％ 97.6％ 96.7％
Concentrate 4 100％ 99.5％ 97.3％ 98.1％
Concentrate 5 100％ 99.6％ 98.1％ 96.2％
Concentrate 6 100％ 100.1％ 98.9.7％ 97.7％
Concentrated solution 7 100％ 100.1％ 99.7％ 98.5％
Concentrate 8 100％ 100.1％ 98.4％ 96.9％
Concentrate 9 100％ 99.8％ 98.5％ 98.1％
Concentrated solution 10 100％ 99.5％ 97.6％ 97.0％
Concentrated solution 11 100％ 100.2％ 98.5％ 97.3％
Concentrate 12 100％ 100.2％ 101.7％ 99.5％
Concentrated solution 13 100％ 98.6％ 98.7％ 97.2％
From the above results, it can be seen that the concentrated solutions 2-13 of example 5, when placed at 40 ℃. + -. 2 ℃ and RH 60%. + -. 5% for 30 days, all have poorly soluble drug content maintained in the range of 90% -110%, and have good chemical stability.
In addition, the concentrated solutions 2-13 sampled on days 0, 5, 10, 30 were diluted with 5% glucose injection at a volume ratio of 1:100, and all formed stable micellar solutions for at least 24 hours.
Example 7: irritation test of the micellar solution of the present invention
1. Experimental methods
1.1 dosing regimens and test indices
The daily dose of the commercially available nimodipine injection for human administration is 10mg, which is calculated as the average body weight of 60kg for human, and 0.47mg/kg for rabbit. The nimodipine injection, the commercially available nimodipine injection and the 5% glucose injection are respectively administrated to rabbits by ear edge intravenous drip, and are administrated for 1 time every day and 7 days continuously. Visual observation was performed before each day and 48 hours after the last dose. After the last visual examination, the animals were euthanized, rabbit ears at the injection site and in the vicinity were clipped, hematoxylin-eosin staining (HE staining for short) was performed, the sections were observed under an optical microscope to determine the presence or absence of pathological changes such as vasodilation, congestion, bleeding, thrombosis, hyperplasia of the vessel wall, infiltration of inflammatory cells, degenerative necrosis of endothelial cells, edema of peripheral tissues, and each animal was scored according to the "blood vessel dissection scoring criteria" shown in table 12.
TABLE 12 vascular dissection scoring criteria
Vascular irritation response Scoring
No obvious reaction 0
Mild hyperemia 1
Mild and moderate congestion and swelling 2
Severe congestion, swelling, ear drop 3
Mild-moderate congestion, swelling, and mild-moderate necrosis 4
Mild, moderate congestion, swelling, and moderate-severe extensive necrosis 5
The scores of the animals in the same group were averaged, and the stimulation level was determined according to the following criteria.
Group mean score Stimulation level
0～0.4 Is free of
0.5～1.4 Very slight
1.5～2.4 Mild degree of
2.5～3.4 Of moderate degree
3.5～4.4 Severe degree
4.5 and above Extremely severe degree
1.2 materials of the experiment
1.2.1 test article
Name: nimodipine concentrate of the invention (concentrate 1 of example 5, batch No. DME-0092020121701, diluted with 5% dextrose injection to a nimodipine concentration of 0.2mg/ml)
Concentration: 0.2mg/ml
The characteristics are as follows: clear, transparent, pale yellow oil solution
The manufacturer: beijing Delifurui medicine science and technology limited
1.2.2 commercial controls
Name: nimodipine injection (trade name: nimodipine, containing 23.7% (v/v) ethanol), specification: 50ml, 10 mg. It is diluted with 5% glucose injection to nimodipine concentration of 0.2mg/ml before administration
Batch number: BXJC7A1
The characteristics are as follows: slightly yellow clear liquid
The validity period is as follows: 2024.01.28
The manufacturer: bayer pharmaceutical and health promotion Co Ltd
1.2.3 negative controls
Name: 5% glucose injection
Batch number: SD20091515
The manufacturer: shandonghua pharmaceutical Co., Ltd
1.3 Experimental animals
Variety: rabbit
Grade: SPF stage
Quantity: 18 pieces of
Weight: 2 to 3kg
The source is as follows: beijing Jinmuyang laboratory animal cultivation Limited liability company
1.4 dose and group
Administration dose: 0.47mg nimodipine/kg
Grouping: rabbits were randomly divided into 3 groups of 6 rabbits each. Three groups were administered to a commercially available nimodipine injection (group a), a nimodipine injection of the present invention (group B), and a 5% glucose injection (group C), respectively. See table 13 for details.
TABLE 13 rabbit vascular irritation test design
Figure BDA0002920822000000331
The administration mode comprises the following steps: intravenous drip of the ear using a syringe pump.
2. Results of the experiment
2.1 visual observation of results
During the experiment, the rabbits in each group had good general conditions of drinking water, behavior, body temperature, respiration, hair, mouth, nose, eyes, feces and the like, and were not abnormal. No obvious abnormalities were seen in all animals ears prior to dosing.
2.2 injection site Observation and Scoring results
Sections prepared with HE staining as described in section 1.1 were observed with an optical microscope. The results are as follows:
no local irritation such as congestion, red swelling, degeneration, necrosis, etc. was observed in the ear of group C animals. Under the hyposcope, the epidermis is complete, and the intact hair follicle and sebaceous gland structures can be seen; under the high power microscope, the stroma is composed mainly of collagen fibers and fibroblasts, between which small capillaries are visible. The results demonstrate that the 5% glucose injection drop administration is substantially non-irritating to rabbit ears. Representative HE staining (100 x and 400 x) results for group C rabbits are shown in fig. 1.
The ears of the animals in group A were engorged, swollen, necrotic and blackened. Under the hyposcope, severe edema of the whole ear, vasodilatation and severe local bleeding were observed, and the epidermis was seen as a distinct suppurative necrotic focus. Under high power, local connective tissue fibrocyte hyperplasia was observed with scattered small amounts of inflammatory cells; large infiltration of inflammatory cells such as neutrophils, lymphocytes and macrophages can be seen in necrotic lesions in the epidermal area; the interstitial bleeding is severe and is distributed diffusely with a large number of red blood cells. The results demonstrate that the injection of nimodipine injection droplets containing ethanol on the market causes severe irritation to rabbit ears, resulting in severe edema, inducing inflammation and causing large area skin necrosis. Representative HE staining (20 x and 400 x) results for group a rabbits are shown in figure 2.
The animals in group B were well defined by intact ears with only minor mild hyperemia and swelling. The rabbit ears are observed under a light microscope, mild loose edema can be seen, and other obvious abnormalities are not seen. The result proves that the nimodipine injection has small irritation, and the irritation is obviously improved compared with the commercially available nimodipine injection. Representative HE staining (20X and 200X) results for group B rabbits are shown in FIG. 3.
The results of each group's irritation scores are shown in Table 14, based on the detailed scoring criteria of 1.1.
TABLE 14 vascular irritation score
Group of Mean score Stimulation level
A 5±0.2 Severe severity of disease
B 2±0.3 Mild degree of
C 0 Is free of
The experimental results show that the nimodipine injection has significantly less irritation to blood vessels than the commercially available nimodipine injection, and has very obvious advantages.
All patent and non-patent documents cited herein are incorporated by reference in their entirety as if each were individually set forth in its entirety.
While specific embodiments and examples are provided herein to illustrate the invention, this is not to be construed as limiting the scope of the invention. Based on the disclosure, it will be apparent to those skilled in the art that other modifications and equivalents can be made without departing from the spirit of the invention, and these modifications and equivalents are within the scope of the invention.

Claims (13)

1. An ethanol-free poorly soluble drug concentrate comprising a poorly soluble drug and a carrier that facilitates micelle formation, wherein:
the carrier consists of a composite emulsifier and a cosolvent,
the compound emulsifier is composed of phospholipid and non-phospholipid emulsifier, and the phospholipid is selected from soybean phospholipid, egg yolk lecithin and the mixture thereof,
the cosolvent is selected from propylene glycol, glycerol, PEG200, PEG300, PEG400 and their mixture, preferably selected from propylene glycol, PEG200, PEG300, PEG400 and their mixture,
and the concentrate is oil free.
2. The concentrate of claim 1 wherein the non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene castor oil (e.g., polyoxyethylene 35 castor oil, neat polyoxyethylene 35 castor oil), polyoxyethylene hydrogenated castor oil (e.g., polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 60 hydrogenated castor oil), polyethylene glycol 15-hydroxystearate, vitamin E polyethylene glycol 1000 succinate (TPGS), polysorbates (e.g., polysorbate 20, 21, 40, 60, 61, 65, 80, 81, 85, 120, particularly polysorbate 80), and mixtures thereof.
3. The concentrate of claim 2 wherein said non-phospholipid emulsifier is selected from the group consisting of polyoxyethylene 40 hydrogenated castor oil, polyoxyethylene 35 castor oil, neat polyoxyethylene 35 castor oil, polyethylene glycol 15-hydroxystearate, polysorbate 80, and mixtures thereof.
4. The concentrate of any one of claims 1 to 3 wherein the co-solvent is selected from the group consisting of propylene glycol, PEG300, PEG400 and mixtures thereof.
5. The concentrate according to any one of claims 1 to 4, wherein the weight percentage of the poorly soluble drug is 0.1% to 20%, preferably 0.5% to 15%, when the weight of the poorly soluble drug, the complex emulsifier, and the co-solvent is taken to total 100% by weight; the weight percentage of the phospholipid is 0.1-20%, preferably 0.5-10%; the weight percentage of the non-phospholipid emulsifier is 20-80%, preferably 30-70%; the balance of cosolvent.
6. The composition of any one of claims 1 to 5, wherein the poorly soluble drug is selected from the group consisting of celecoxib, valdecoxib, etoricoxib, ibuprofen, dexibuprofen, propofol, flurbiprofen, alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, miconazole, ketoconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, cabazitaxel, etoposide, teniposide, hydroxycamptothecin, irinotecan, ubenimex, cisplatin, carboplatin, capecitabine, oxaliplatin, gefitinib, doxorubicin, vinblastine, vincristine, vindesine, and valdecoxib, Piroxicam, spironolactone, valproic acid, tamoxifen, azithromycin, vitamin A, vitamin D, vitamin E, vitamin K, fenofibrate, indomethacin, and Reidesvir; preferably, the poorly soluble drug is selected from the group consisting of celecoxib, ibuprofen, dexibuprofen, propofol, flurbiprofen axetil, alprostadil, clevidipine butyrate, dexamethasone palmitate, felodipine, nimodipine, nifedipine, nitrendipine, cyclosporine, tacrolimus, levosimendan, adefovir dipivoxil, erythromycin, roxithromycin, posaconazole, itraconazole, voriconazole, progesterone, coenzyme Q10, clopidogrel, paclitaxel, docetaxel, cabazitaxel, etoposide, teniposide and etoricoxib; most preferably, the poorly soluble drug is selected from the group consisting of nimodipine, posaconazole, docetaxel, clopidogrel, levosimendan, tacrolimus, cyclosporine, paclitaxel, ibuprofen, coenzyme Q10, cabazitaxel, celecoxib, and etoricoxib.
7. The concentrate of any of claims 1 thru 6 further comprising a pH adjuster, an antioxidant, or both.
8. The composition according to any one of claims 1 to 6, wherein:
the insoluble drug is nimodipine, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of nimodipine is 1%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 46%, and the weight percentage of propylene glycol is 51%;
or
The insoluble drug is posaconazole, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is PEG300, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of posaconazole is 1%, the weight percentage of egg yolk lecithin is 3%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 50%, and the weight percentage of PEG300 is 46%;
or
The indissolvable drug is docetaxel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the indissolvable drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of docetaxel is 1%, the weight percentage of egg yolk lecithin is 3%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 48% and the weight percentage of propylene glycol is 48%;
or
The slightly soluble drug is clopidogrel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the slightly soluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of clopidogrel is 15%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 43% and the weight percentage of propylene glycol is 40%;
or
The insoluble drug is levosimendan, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of levosimendan is 0.5%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of 15-hydroxystearic acid polyethylene glycol ester is 50%, and the weight percentage of propylene glycol is 47.5%;
or
The insoluble drug is tacrolimus, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the tacrolimus is 1.5%, the weight percentage of the egg yolk lecithin is 2%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 46%, and the weight percentage of the propylene glycol is 50.5%;
or
The insoluble drug is cyclosporine, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the cyclosporine is 10%, the weight percentage of the egg yolk lecithin is 2%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 43% and the weight percentage of the propylene glycol is 45%;
or
The insoluble drug is paclitaxel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the paclitaxel is 1%, the weight percentage of the egg yolk lecithin is 2%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 46%, and the weight percentage of the propylene glycol is 51%;
or
The indissolvable drug is ibuprofen, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is PEG300, and when the weight of the indissolvable drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the ibuprofen is 10%, the weight percentage of the egg yolk lecithin is 2%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 40%, and the weight percentage of the PEG300 is 48%;
or
The poorly soluble drug is coenzyme Q10, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the poorly soluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the coenzyme Q10 is 5%, the weight percentage of the egg yolk lecithin is 10%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 30% and the weight percentage of the propylene glycol is 55%;
the slightly soluble drug is cabazitaxel, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is tween80, the cosolvent is propylene glycol, and when the weight of the slightly soluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of cabazitaxel is 1%, the weight percentage of egg yolk lecithin is 2%, the weight percentage of tween80 is 46%, and the weight percentage of propylene glycol is 51%;
the insoluble drug is celecoxib, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the celecoxib is 6%, the weight percentage of the egg yolk lecithin is 0.5%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 70%, and the weight percentage of the propylene glycol is 23.5%;
or
The insoluble drug is etoricoxib, the phospholipid is egg yolk lecithin, the non-phospholipid emulsifier is 15-hydroxystearic acid polyethylene glycol ester, the cosolvent is propylene glycol, and when the weight of the insoluble drug, the composite emulsifier and the cosolvent is 100 wt%, the weight percentage of the etoricoxib is 5%, the weight percentage of the egg yolk lecithin is 5%, the weight percentage of the 15-hydroxystearic acid polyethylene glycol ester is 35%, and the weight percentage of the propylene glycol is 55%.
9. Use of a concentrate according to any one of claims 1 to 8 for the preparation of a micellar solution for intravenous injection, in particular intravenous drip.
10. A method of preparing a concentrate according to any of claims 1 to 8, the method comprising the steps of: mixing the insoluble medicine, phospholipid, non-phospholipid emulsifier and cosolvent in any order, stirring, filtering, packaging, and sealing.
11. A micellar solution obtained by diluting the concentrate of any one of claims 1 to 8 with an aqueous vehicle.
12. The micellar solution of claim 11, wherein the aqueous vehicle is water for injection, 5% dextrose injection, or 0.9% sodium chloride injection.
13. The micellar solution according to claim 12, for use in intravenous injection, in particular intravenous drip.
CN202110117255.6A 2021-01-28 2021-01-28 Insoluble drug concentrated solution without ethanol and micelle solution prepared from insoluble drug concentrated solution Pending CN114796110A (en)

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