CN101829053B - Preparation method of gossypol acetate intravenous injection fatty emulsion - Google Patents
Preparation method of gossypol acetate intravenous injection fatty emulsion Download PDFInfo
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- CN101829053B CN101829053B CN2010101640257A CN201010164025A CN101829053B CN 101829053 B CN101829053 B CN 101829053B CN 2010101640257 A CN2010101640257 A CN 2010101640257A CN 201010164025 A CN201010164025 A CN 201010164025A CN 101829053 B CN101829053 B CN 101829053B
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Abstract
The invention discloses a preparation method of gossypol acetate intravenous injection fatty emulsion. In the method, gossypol acetate is used as an active constituent, ethyl oleate or middle-chain fatty acid triglyceride is used as an oil phase, soya bean lecithin is used as a surface active agent, absolute ethyl alcohol or PEG (Polyethylene Glycol) 400 is used as a cosurfactant, and sterilized water for injection is used as a water phase. The method comprises the following steps of: (1) dissolving the gossypol acetate in diethyl ether and then mixing with the oil phase, the surface active agent and the cosurfactant; decompressing and evaporating to remove the diethyl ether and preserving at a constant temperature for later use; (2) heating the sterilized water for injection and preserving at a constant temperature for later use; (3) mixing liquids obtained in the steps (1) and (2) at a constant temperature of 60 or 70 DEG C and stirring until a transparent and homogeneous solution is formed; making the volume constant and then repeatedly homogenizing by using a homogenizer; and filtering by using a millipore filter membrane. Proved by researches, the gossypol acetate intravenous injection fatty emulsion prepared by using the method has good slow release and targeting effects and good stability.
Description
Technical field
The present invention relates to a kind of method for preparing of gossypol acetate pharmaceutical preparation, particularly a kind of method for preparing of gossypol acetate intravenous injection fatty emulsion.
Background technology
Gossypol (gossypol) is called gossypol again, is a kind of xanchromatic phenolic compound.In the natural organs such as seed, leaf, stem and root that are present in Malvaceae cotton Cotton Gossypii.Under the room temperature, gossypol is yellow crystal, is soluble in organic solvents such as ethanol, ether, acetone, chloroform; Also be dissolved in oils and fats; But water insoluble, hexane and lower boiling petroleum ether, wherein most of organic solvent is bigger to human toxicity, is not suitable as pharmaceutical carrier.
Gossypol is known by people as the male contraception medicine.In recent years, its antitumor action day by day also comes into one's own, and it has widely lethal effect such as hysteromyoma, carcinoma of prostate, colon cancer, pulmonary carcinoma, hepatocarcinoma, laryngeal carcinoma, tumor of head and neck, glioma etc. to tumor cell.
Gossypol has advantages such as the source is abundant, cost is low, and can bring into play synergistic therapeutic actions with chemotherapy, radiotherapy etc. as a kind of broad-spectrum anti-cancer drug.China produces cotton big country, and the gossypol source is abundant, and the research and development of strengthening gossypol tumor preparation will have good economic and social benefit.
The gossypol preparation of listing has only the gossypol acetate administer orally preparation at present, makes oral male contraceptive agent or is used to treat gynaecopathia, comprises menorrhagia or imbalance, endometriosis etc.But because gossypol and gossypol acetate are water insoluble, its oral formulations bioavailability is low, to GI irritation property loss of appetite, feel sick, gastrointestinal reaction such as vomiting, and " peak valley " phenomenon occurs and cause hypokalemia easily.
Chinese patent 200510022777.9 (applicant: Shenyang Pharmaceutical University; Publication number CN1827117; Open day on 09 06th, 2006; The Granted publication date: on December 16th, 2009) disclose a kind of oral gossypol acetate slow releasing preparation and the gossypol acetate tablet is added slow-release material form slow releasing preparation and avoid " peak valley " phenomenon occurring, be used for solving " peak valley " phenomenon.But slow releasing preparation its drug loading after adding numerous slow-release auxiliary material is limited and still can't avoid it to the gastrointestinal stimulation.And that gossypol acetate is used to treat the dosage of tumor is higher relatively; U.S. Pat 5385936 (the date of application: July 12 nineteen ninety; Open day: January 31 nineteen ninety-five) disclosed gossypol acetate was used for the tumor treatment method and shows, the human dosage that gossypol acetate is used to treat tumor is 40-100mg/ days.In the one of which clinical trial phase part tumor dose is reached 70mg/ days still to no effect.It is thus clear that the gossypol acetate UD is at least 40-60mg, could reduces patient's administration number of times and obtain curative effect preferably.And above-mentioned preparation can't be realized the administration of targeting property.
Ejection preparation helps improving drug bioavailability usually; Help better bringing into play the therapeutical effect of medicine; But because the gossypol acetate water solublity is relatively poor; Be difficult to process stable ejection preparation, inventor of the present invention finds that gossypol sodium also is difficult to reach ideal drug loading and stability in injection solvent commonly used utilizing water-soluble gossypol sodium to prepare in the process of injection.
Lipomul is a kind of pharmaceutical dosage form that can significantly improve drug solubility, drug loading and the pharmaceutics characteristic tool that improves poorly water soluble drugs is had very great help, at present the domestic lipomul of having studied several drugs.But, need carry out a large amount of screening experiment to prescription and could obtain best pharmaceutical carrier and proportioning because different pharmaceutical as obtaining stable lipomul, is that the kind of pharmaceutical carrier and the requirement of consumption exist than big-difference to adjuvant.And need be optimized the effect that relates to the stability that just can reach expection and slow release, target administration to preparation technology.At present, in the prior art not about the report of the method for preparing of the lipomul of gossypol.
Summary of the invention
To above-mentioned prior art, the invention provides a kind of method that is used to prepare gossypol acetate intravenous injection fatty emulsion.
The present invention realizes through following technical scheme:
A kind of method for preparing of gossypol acetate intravenous injection fatty emulsion; Be to be active component with the gossypol acetate; Ethyl oleate or medium-chain fatty acid triglyceride are oil phase, and soybean lecithin is a surfactant, and dehydrated alcohol or PEG400 are cosurfactant; Sterilized water for injection is a water, and its preparation process is following:
(1) gossypol acetate is dissolved in ether, mixes with oil phase, surfactant, cosurfactant then, mixing temperature is 60 or 70 ℃; Stir speed (S.S.) is 1600-1800rpm; Mixing time is 1-2 hour, and reduction vaporization removes ether, and 60 or 70 ℃ of constant temperature are preserved subsequent use;
(2) with the sterilized water for injection heating, 60 or 70 ℃ of constant temperature are preserved subsequent use;
(3) 60 or 70 ℃ of constant temperature are down with (1), (2) gained liquid mixing; Stir speed (S.S.) is 2000-2400rpm; Mixing time is 1 hour, and the solution to forming transparent homogeneous is settled to 1000ml with sterilized water for injection; Use homogenizer homogenize 5-6 time repeatedly under 40-60Mpa then, with 0.45 μ m filtering with microporous membrane.
Said medium-chain fatty acid is meant the fatty acid of C8～C10.
For explaining conveniently, and avoid in the present lipomul pertinent literature " oil phase " speech being used the misunderstanding that causes lack of standardization, in this description further part, step (1) gained liquid is called the oil phase medicinal liquid, step (2) gained liquid is called water liquid.
The gossypol acetate intravenous injection fatty emulsion that method for preparing of the present invention obtains shows after deliberation; Be oil phase, be surfactant, be cosurfactant, be the drug loading that water can significantly improve gossypol acetate with the sterilized water for injection with ethyl oleate or medium-chain fatty acid (C8-C10) triglyceride, but mixing temperature, mixing speed, mixing time and homogenization pressure and homogenize number of times all there are appreciable impact to stability of formulation and emulsion droplet granularity, slow release effect and targeting property with dehydrated alcohol or PEG400 with bean lecithin or Tween 80.Showing for kinetics and tissue distribution through comprehensive preparation process research and body giving drugs into nose, is 60 or 70 ℃ at oil phase medicinal liquid mixing temperature, and stir speed (S.S.) is 1600-1800rpm; Mixing time is 1-2 hour, and oil phase medicinal liquid and water liquid mixing temperature are 60 or 70 ℃, and stir speed (S.S.) is 2000-2400rpm; Mixing time is 1 hour; Homogenization pressure is 40-60Mpa, when the homogenize number of times is 5-6 time, can remain on 70-150nm with 0.45 μ m filtering with microporous membrane gained injection emulsion droplet mean diameter.The gained injection has good slow release and targeting effect, and has good stable property.This method for preparing technology is simple, is beneficial to suitability for industrialized production.Prepare the gossypol acetate injection with this method and possess outstanding substantive distinguishing features and obvious improvement.
Description of drawings
Curve when Fig. 1 is the medicine behind the gossypol acetate intravenous injection fatty emulsion rat single tail vein injection;
Fig. 2 is the tissue content behind the gossypol acetate intravenous injection fatty emulsion tumor-bearing mice single tail vein injection.
The specific embodiment
Below in conjunction with embodiment the present invention is further described:
The preparation of embodiment 1 gossypol acetate intravenous injection fatty emulsion
Prescription:
Gossypol acetate 40g
Ethyl oleate 207g
Soybean lecithin 35g
Dehydrated alcohol 18g
Sterile water for injection is to 1000ml
Preparation:
The recipe quantity gossypol acetate is dissolved in ether, under 60 ℃ of waters bath with thermostatic control, adds ethyl oleate, soybean lecithin, dehydrated alcohol then, stir while adding; Mixing speed is 1600rpm, stirs 2 hours, and reduction vaporization removes ether; As the oil phase medicinal liquid, 60 ℃ of waters bath with thermostatic control are preserved subsequent use;
With an amount of sterilized water for injection, 60 ℃ of waters bath with thermostatic control are preserved as water liquid;
Under 60 ℃ of constant temperature, oil phase liquid is slowly splashed into water liquid; Stir while adding, mixing speed is 2200rpm, stirs 1 hour to the solution that forms transparent homogeneous; Be settled to 1000ml with sterilized water for injection; Use under homogenizer (NS10012k high pressure homogenizer, the Italian Niro Soavi S.p.A. company) 60Mpa homogenize repeatedly 5 times then, 0.45 μ m filtering with microporous membrane.Be distributed into 1000 parts, sterilization is preserved.
Gained sample, emulsion droplet mean diameter are 104nm, and envelop rate is 87.2%.
The preparation of embodiment 2 gossypol acetate intravenous injection fatty emulsions
Prescription:
Gossypol acetate 60g
Ethyl oleate 220g
Soybean lecithin 43g
PEG400?35g
Sterile water for injection is to 1000ml
Preparation:
The recipe quantity gossypol acetate is dissolved in ether, under 70 ℃ of waters bath with thermostatic control, adds ethyl oleate, soybean lecithin, PEG400 then, stir while adding; Mixing speed is 1700rpm, stirs 1.5 hours, and reduction vaporization removes ether; As oil phase liquid, 70 ℃ of waters bath with thermostatic control are preserved subsequent use;
70 ℃ of waters bath with thermostatic control of an amount of sterilized water for injection are preserved as water liquid;
Under 70 ℃ of constant temperature, oil phase liquid is slowly splashed into water liquid; Stir while adding, mixing speed is 2000rpm, stirs 1 hour to the solution that forms transparent homogeneous; Be settled to 1000ml with sterilized water for injection; Use under homogenizer (NS10012k high pressure homogenizer, the Italian Niro Soavi S.p.A. company) 60Mpa homogenize repeatedly 6 times then, 0.45 μ m filtering with microporous membrane.Be distributed into 1000 parts, sterilization is preserved.
Gained sample, emulsion droplet mean diameter are 142nm, and envelop rate is 93.6%.
The preparation of embodiment 3 gossypol acetate intravenous injection fatty emulsions
Prescription:
Gossypol acetate 80g
Medium-chain fatty acid (C8-C10) triglyceride 297g
Soybean lecithin 36g
PEG400?29g
Sterile water for injection is to 1000ml
Preparation:
The recipe quantity gossypol acetate is dissolved in ether; Under 70 ℃ of waters bath with thermostatic control, add medium-chain fatty acid (C8-C10) triglyceride, soybean lecithin, PEG400 then, stir while adding, mixing speed is 1800rpm; Stirred 2 hours; Reduction vaporization removes ether, and as oil phase liquid, 70 ℃ of waters bath with thermostatic control are preserved subsequent use;
70 ℃ of waters bath with thermostatic control of an amount of sterilized water for injection are preserved as water liquid;
Under 70 ℃ of constant temperature, oil phase liquid is slowly splashed into water liquid; Stir while adding, mixing speed is 2400rpm, stirs 1 hour to the solution that forms transparent homogeneous; Be settled to 1000ml with sterilized water for injection; Use under homogenizer (NS10012k high pressure homogenizer, the Italian Niro Soavi S.p.A. company) 40Mpa homogenize repeatedly 6 times then, 0.45 μ m filtering with microporous membrane.Be distributed into 1000 parts, sterilization is preserved.
Gained sample, emulsion droplet mean diameter are 93nm, and envelop rate is 97.4%.
Embodiment 4 gossypol acetate intravenous injection fatty emulsions are tested in pharmacokinetics in rats
12 of Wister rats; 180-240g; At one night of fasting before male and female half and half experiment, be divided into 2 groups at random, 6 every group; Experimental group single tail vein injection gives embodiment 1 made intravenous injection fatty emulsion (with the administration of gossypol acetate 40mg/kg body weight), and matched group is processed suspension per os gastric infusion (with the administration of gossypol acetate 40mg/kg body weight) with the carboxymethyl cellulose of gossypol acetate suspendible and 0.25%.
Give to want back the 0th, 30,60 minute and the 2nd, 8,16,24 hour respectively blood sampling measure gossypol acetate content in the blood plasma, curve chart when drawing medicine, the result sees Fig. 1.The visible intravenous injection fatty emulsion of curve chart has significant slow release characteristics during from medicine, and bioavailability is significantly higher than oral administration.
Embodiment 5 gossypol acetate intravenous injection fatty emulsions are in the intravital tissue distribution experiment of tumor-bearing mice
Lotus Lewis lung cancer C-57 model mice is buied by Shaanxi academy of traditional Chinese medicine Experimental Animal Center, and the C-57 mice is provided by The Fourth Military Medical University's Experimental Animal Center, age in 4-6 week, and body weight 15-25g, totally 60, male.The tumor of model is cut, ground and to process cell homogenates, it is subcutaneous to be inoculated in C-57 experiment mice right fore root veutro, every inoculation 2.0 * 10
7Individual tumor cell, cumulative volume 0.20ml.Lump is grown up after 2 weeks, is used for experiment.
Tumor-bearing mice is divided into 2 groups at random; Every group 30; Experimental group single tail vein injection gives embodiment 2 made intravenous injection fatty emulsions (with the administration of gossypol acetate 40mg/kg body weight), and matched group is suspended in 0.25% carboxymethyl cellulose with gossypol acetate and processes suspension per os gastric infusion (with the administration of gossypol acetate 40mg/kg body weight).After the administration 1,2,8,12,16,24 hour every group put to death 5 mices, take out the tumor tissues and the heart, liver, spleen, lung, kidney, brain is measured its tissue content.Calculate its relative amount according to the concentration of organizing Chinese medicine and tissue weight, the result sees Fig. 2.
Be significantly higher than the oral administration preparation by gossypol acetate content in the tumor tissues after the visible gossypol acetate intravenous injection agent administration of tissue distribution figure.Gossypol acetate intravenous injection fatty emulsion has certain targeting property to tumor tissues.
The stability experiment of embodiment 6 gossypol intravenous injection fatty emulsions
Embodiment 1-3 gained intravenous injection fatty emulsion is carried out stability experiment.
(1) strong illumination test: gossypol intravenous injection fatty emulsion is observed after placing 5 days and 10 days respectively under the 4000lx illumination, and the result finds, and compares before the placement, and injection still keeps clear, does not see the profit layering.
(2) high humility test: gossypol intravenous injection fatty emulsion is placed in the airtight vessel respectively at 25%, 75% and 92.5% relative humidity condition held, investigates stable after 5 days and 10 days.With place before compare, intravenous injection still keeps clear, does not see the profit layering.
(3) hot test: gossypol intravenous injection fatty emulsion is placed in the airtight vessel and places respectively under 40,60,80 ℃ of conditions, investigate stable after 5 days and 10 days.With place before compare, still keep clear, do not see the profit layering.
(4) accelerated test: with the centrifugal 10min of gossypol intravenous injection fatty emulsion 4000rpm, still keep clear, do not see the profit layering.
(5) the room temperature investigation that keeps sample: gossypol intravenous injection fatty emulsion was placed respectively 1,2,3,6,12,24 month under 25 ℃ of temperature, relative humidity 75% condition, still kept clear, do not see that profit layering and medicine separate out.
Embodiment 7 preparation temperatures are to the influence research of gossypol intravenous injection fatty emulsion
Prescription according to embodiment 1-3; The preparation gossypol acetate intravenous injection fatty emulsion; Three kinds of prescription preparation temperatures all are set at 40 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃ five kinds of temperature, and other conditions are constant, and oil phase medicinal liquid and water liquid are mixed to the solution that forms transparent homogeneous; Be settled to 1000ml with sterilized water for injection, observe lipomul surface oil droplet and Emulsion wall built-up situation.And further high pressure homogenize is processed lipomul.The result shows, under 40 ℃ of conditions, oil phase medicinal liquid and water liquid is mixed to the solution that forms transparent homogeneous, is settled to 1000ml with sterilized water for injection, and there is oil droplet on the Emulsion surface and has wall cling phenomenon; Under 80 ℃, the 90 ℃ conditions oil phase medicinal liquid and water liquid are mixed to the solution that forms transparent homogeneous; Be settled to 1000ml with sterilized water for injection; Emulsion no oil droplet in surface and wall cling phenomenon; But the emulsion droplet particle diameter of lipomul differs greatly behind the high pressure homogenize, drug releasing rate is produced exert an influence than great fluctuation process and to tissue distribution.Under 60 ℃, 70 ℃ conditions, oil phase medicinal liquid and water liquid are mixed to the solution that forms transparent homogeneous, are settled to 1000ml with sterilized water for injection, Emulsion no oil droplet in surface and wall cling phenomenon, the emulsion droplet particle diameter difference of lipomul all is no more than 20nm behind the high pressure homogenize.
Embodiment 8 preparation pressure are to the influence research of gossypol intravenous injection fatty emulsion
According to the prescription of embodiment 1 and 3, the preparation gossypol acetate intravenous injection fatty emulsion, two kinds of prescription preparation homogenization pressures are all set 20Mpa, 40Mpa, 60Mpa, four kinds of pressure of 90Mpa.Other conditions are constant.After accomplishing, preparation carries out the experiment of tumor-bearing mice tissue distribution.
Lotus Lewis lung cancer C-57 model mice is buied by Shaanxi academy of traditional Chinese medicine Experimental Animal Center, and the C-57 mice is provided by The Fourth Military Medical University's Experimental Animal Center, and body weight 15-20g is totally 48, male.The tumor of model is cut, ground and to process cell homogenates, it is subcutaneous to be inoculated in C-57 experiment mice right fore root veutro, every inoculation 2.0 * 10
7Individual tumor cell, cumulative volume 0.20ml.Lump is grown up after 2 weeks, is used for experiment.
Tumor-bearing mice is divided into 8 groups at random; Every group 6; The single tail vein injection gives prescription according to embodiment 1 and 3 at 20Mpa, 40Mpa, 60Mpa, four kinds of made intravenous injection fatty emulsions of homogenization pressure of 90Mpa (with the administration of gossypol acetate 40mg/kg body weight) respectively; Put to death mice in 24 hours after the administration, take out tumor tissues and measure its tissue content.Calculate its relative amount according to the concentration of organizing Chinese medicine and tumor tissues weight, the result sees table 1.
The influence (μ g/g, mean+SD) that table 1 homogenization pressure distributes at tumor tissues to gossypol intravenous injection fatty emulsion
aCompare p＜0.05 with the preparation that 20Mpa prepares down;
aCompare p＜0.05 with the preparation that 90Mpa prepares down.
It is higher that the result shows that the gossypol intravenous injection fatty emulsion of homogenization pressure 40Mpa and 60Mpa preparation distributes at tumor tissues, and compare with 90Mpa with 20Mpa that there were significant differences.
The influence of embodiment 9 even matter number of times
According to the prescription of embodiment 1 and 2, the preparation gossypol acetate intravenous injection fatty emulsion, the even matter time number average of two kinds of prescription preparations is set 5 times, 6 times, 8 times, 10 times four kinds of even matter number of times.Other conditions are constant.After accomplishing, preparation measures its emulsion droplet particle diameter.The result sees table 2.
The even matter number of times of table 2 is to the influence (nm, mean+SD) of gossypol intravenous injection fatty emulsion emulsion droplet particle diameter
The result shows that the emulsion droplet particle diameter all differed greatly when even matter number of times surpassed 8 times.
Claims (2)
1. the method for preparing of a gossypol acetate intravenous injection fatty emulsion; It is characterized in that: be to be active component with the gossypol acetate; Ethyl oleate or medium-chain fatty acid triglyceride are oil phase, and soybean lecithin is a surfactant, and dehydrated alcohol or PEG400 are cosurfactant; Sterilized water for injection is a water, and its preparation process is following:
(1) 40～80g gossypol acetate is dissolved in ether; Mix with 200～300g oil phase, 30～50g surfactant, 10～40g cosurfactant then; Mixing temperature is 60 ℃ or 70 ℃, and stir speed (S.S.) is 1600-1800rpm, and mixing time is 1-2 hour; Reduction vaporization removes ether, and 60 ℃ or 70 ℃ of constant temperature are preserved subsequent use;
(2) with sterilized water for injection heating, 60 ℃ or 70 ℃ of constant temperature are preserved subsequent use;
(3) 60 or 70 ℃ of constant temperature are down with (1), (2) gained liquid mixing; Stir speed (S.S.) is 2000-2400rpm, and mixing time is 1 hour, to the solution that forms transparent homogeneous; Be settled to 1000ml with sterilized water for injection; Use homogenizer homogenize 5-6 time repeatedly under 40-60Mpa then,, promptly get the gossypol acetate intravenous injection fatty emulsion of mean diameter at 70～150nm with 0.45 μ m filtering with microporous membrane.
2. the gossypol acetate intravenous injection fatty emulsion that adopts the method for preparing of the described a kind of gossypol acetate intravenous injection fatty emulsion of claim 1 to prepare.
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Effective date of registration: 20230411 Address after: 13S, Shuguang Building, No. 012 Keji South 12th Road, Gaoxin District, Yuehai Street, Nanshan District, Shenzhen, Guangdong Province, 518000 Patentee after: Shenzhen Carbon Cloud Intelligent Peptide Pharmaceutical Technology Co.,Ltd. Address before: 250014 No. 44 West Wenhua Road, Lixia District, Shandong, Ji'nan Patentee before: SHANDONG University |