CN102552142B - Liposome preparing method suitable for industrial production - Google Patents
Liposome preparing method suitable for industrial production Download PDFInfo
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Abstract
The invention aims at providing a liposome preparing method suitable for industrial production. The liposome preparing method provided by the invention comprises the following steps of: dissolving a fat-soluble chemical constituent in an organic solvent and a carrier in an aqueous phase, dropwise adding a carrier solution to the organic solvent under the condition of water-bath magnetic force stirring, reducing the pressure to remove the organic solvent and water content, decreasing grain sizes under the action of additional applied force after redissolving by using a hydration medium, adding a freeze-drying protective agent for freeze drying to obtain liposome powder, and redissolving to obtain a liposome solution before use. According to the liposome preparing method, the liposome is prepared by using a pressure reduction carrier free-drying technology so that the stability of the liposome can be substantially increased; and the preparing method facilitates the large-scale production, thereby a new thinking for the industrial production of the liposome is provided.
Description
Technical field
The technology of the present invention field relates to design and the preparation of novel pharmaceutical formulation, and a kind of method for preparing lipidosome of suitable suitability for industrialized production is provided.
Background technology
Liposome has slow release, targeting, raising medicine stability and improves advantages such as pharmacokinetic properties, is one of focus of nearly 20 years domestic and international novel drug-supplying system research fields.Because liposome when being delivered to tumor vessel, can entering tumor tissues by capillary tube epithelial tissue gap, thereby reach certain tumor tissues targeting.The passive target effect of liposome drug-loading system distributes because it has changed in the body of medicine, thus can when improving curative effect, reduce toxicity, as the good carrier that improves the medicine drug loading.By the application of liposome, good solution the low problem of insoluble drug dissolubility, played the reduction toxic reaction, eliminate the effect of side reaction, higher targeting distribution character is arranged.So liposome as novel transmission system, is occupying an important position aspect the research and development of injection cancer therapy drug.Yet the listing product of external Liposomal formulation is still very few so far; At home, except the substrate of indivedual external preparation, liposome research is in laboratory stage substantially.Main cause is: (1) liposome turbid liquor is easily assembled at lay up period, fusion and drug leakage, and especially the seepage of water soluble drug is more remarkable; Simultaneously, the easy oxidation of natural phospholipid, hydrolysis are difficult to satisfy the requirement of pharmaceutical preparation stability; (2) preparation technology of Liposomal formulation is complicated, is difficult for enlarging producing.Method for preparing lipidosome commonly used has film dispersion method and alcohol injection, the former is difficult to enlarge production, the latter has serious dissolvent residual problem, and the liquid towards liposome carries out lyophilization can alleviate storage stability to a certain extent, but complex process, cost height.
Summary of the invention
The invention provides a kind of novel preparation method of Injectable liposomal, its preparation technology can degerming remove thermal source, need not special installation, be beneficial to amplification, production time is short, be easy to suitability for industrialized production more, improved the stability of medicine and adjuvant, for extensive patients provides the injection freeze-dried lipidosome preparation of safety and stability more.
The present invention prepares by following equipment:
The three neck round-bottomed flasks that rhombohedral rotor is housed are positioned in the magnetic agitation water-bath.Three mouths of three neck round-bottomed flasks are connected with respectively as lower device: the left side mouth is vacuum orifice 1; The centre is charge door 2, is connected with charging hopper when reinforced, seals with plug during preparation; The right side is discharging opening 3, seals with plug during preparation.Equipment drawing is seen Fig. 1.
Preparation technology is as follows:
1, carrier is dissolved in water for injection, and medicine, matrix material and stabilizing agent are dissolved in organic solvent, adds the activated carbon filtration depyrogenation respectively;
2, at 20-70 ℃, under the condition of magnetic agitation, the water for injection that is dissolved with carrier material is joined in the organic solvent that is dissolved with medicine and matrix material gradually;
3, at 20-70 ℃, under the condition of magnetic agitation, organic solvent and water for injection are removed in 2 decompressions, add the aquation medium aquation that contains emulsifying agent then, particle diameter by the solution after the applied external force reduction aquation through 0.22 μ m membrane filtration degerming, obtains uniform liposome solutions;
4, add freeze drying protectant with 3, remove moisture through lyophilization, obtain dry 7-ethyl-10-hydroxycamptothecine lipidosome freeze-dried injection, be recovered to liposome, drug administration by injection after the aquation jolting before using.
Wherein, carrier is selected from sodium chloride, glucide, as: one or more in glucose, sucrose, mannitol, the sorbitol etc.
Matrix material is phospholipid, is selected from one or more mixture in sphingomyelin, phosphatidylcholine, Phosphatidylserine, the cuorin.
Stabilizing agent is selected from butylated hydroxyarisol, 2,6-di-t-butyl hydroxy-methylbenzene, nitrogen, alpha-tocopherol, one or more mixture in α-tocopheryl acetate, the dilauryl thiodipropionate etc.
Emulsifying agent is selected from poloxamer, one or more mixture in polyoxyethylene hydrogenated Oleum Ricini, Tweens, the spans etc.
Freeze drying protectant is glucide, as: one or more in lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran, the polyvinylpyrrolidone (PVP) etc.
Preparation method of the present invention is for can all being suitable for the medicine that film dispersion method prepares liposome.
Description of drawings:
Fig. 1 is the equipment drawing of preparation of the present invention.
The specific embodiment:
It below is the instantiation that is prepared as of lipidosome freeze-dried injection.
Embodiment one:
1) the 1kg glucose transporter is dissolved in 2L water for injection, and 10g7-ethyl-10-hydroxycamptothecine, 200g soybean lecithin and 0.01 μ moL/mL alpha-tocopherol are dissolved in 20L ethanol, add 1% activated carbon filtration depyrogenation respectively;
2) at 20 ℃, under the condition of magnetic agitation, the water for injection that is dissolved with carrier material is joined in the organic solvent that is dissolved with medicine and matrix material gradually;
3) at 20 ℃, under the condition of magnetic agitation, with 2) reduce pressure and remove organic solvent and water for injection, add the sodium hydroxide-phosphate buffer solution 10L aquation that contains the 1g poloxamer then, particle diameter by the solution after the ultrasonic wave concussion reduction aquation, through 0.22 μ m membrane filtration degerming, obtain uniform liposome solutions;
4) with 3) add 500g mannitol, after lyophilization, remove moisture, obtain dry 7-ethyl-10-hydroxycamptothecine lipidosome freeze-dried injection, be recovered to liposome, drug administration by injection after the aquation jolting before using.
Embodiment two:
1) 2kg sodium chloride carrier is dissolved in 4L water for injection, and 20g paclitaxel, 300g sphingomyelin and 0.02 μ moL/mL butylated hydroxyarisol are dissolved in 20L ethanol, add 1% activated carbon filtration depyrogenation respectively;
2) at 30 ℃, under the condition of magnetic agitation, the water for injection that is dissolved with carrier material is joined in the organic solvent that is dissolved with medicine and matrix material gradually;
3) at 30 ℃, under the condition of magnetic agitation, with 2) reduce pressure and remove organic solvent and water for injection, add the acetic acid-acetate buffer solution 10L aquation that contains the 3g polyoxyethylene hydrogenated Oleum Ricini then, particle diameter by the solution after the hand concussion reduction aquation, through 0.22 μ m membrane filtration degerming, obtain uniform liposome solutions;
4) with 3) add 400g sucrose, after lyophilization, remove moisture, obtain dry Paclitaxel liposome lyophilized injectable powder, be recovered to liposome, drug administration by injection after the aquation jolting before using.
Embodiment three:
1) 3kg mannitol carrier is dissolved in 4L water for injection, 30g Docetaxel, 100g cuorin and 0.03 μ moL/mL 2, and 6-di-t-butyl hydroxy-methylbenzene is dissolved in 20L ethanol, adds 1% activated carbon filtration depyrogenation respectively;
2) at 50 ℃, under the condition of magnetic agitation, the water for injection that is dissolved with carrier material is joined in the organic solvent that is dissolved with medicine and matrix material gradually;
3) at 50 ℃, under the condition of magnetic agitation, with 2) reduce pressure and remove organic solvent and water for injection, add the hydrochloric acid solution aquation 10L that contains the 5g Tween 80 then, particle diameter by the solution after the magnetic agitation reduction aquation through 0.22 μ m membrane filtration degerming, obtains uniform liposome solutions;
4) with 3) add the 300g lactose, after lyophilization, remove moisture, obtain dry Docetaxel lipidosome freeze-dried injection, be recovered to liposome, drug administration by injection after the aquation jolting before using.
Embodiment four:
1) 5kg sorbitol carrier is dissolved in 6L water for injection, and 40g ftorafur, 400g soybean lecithin are dissolved in 20L ethanol, adds 1% activated carbon filtration depyrogenation respectively, and logical nitrogen is preserved;
2) at 60 ℃, under the condition of magnetic agitation, the water for injection that is dissolved with carrier material is joined in the organic solvent that is dissolved with medicine and matrix material gradually;
3) at 60 ℃, under the condition of magnetic agitation, with 2) reduce pressure and remove organic solvent and water for injection, add the citric acid solution 10L aquation that contains the 7g polysorbas20 then, particle diameter by the solution after the ultrasonic reduction aquation of popping one's head in, through 0.22 μ m membrane filtration degerming, obtain uniform liposome solutions;
4) with 3) add the 200g dextran, after lyophilization, remove moisture, obtain dry ftorafur lipidosome freeze-dried injection, be recovered to liposome, drug administration by injection after the aquation jolting before using.
Embodiment five:
1) 7kg sucrose carrier is dissolved in 10L water for injection, and 17g 5-fluorouracil, 500g soybean lecithin and 0.04 μ moL/mL dilauryl thiodipropionate are dissolved in 20L ethanol, add 1% activated carbon filtration depyrogenation respectively;
2) at 70 ℃, under the condition of magnetic agitation, the water for injection that is dissolved with carrier material is joined in the organic solvent that is dissolved with medicine and matrix material gradually;
3) at 70 ℃, under the condition of magnetic agitation, with 2) reduce pressure and remove organic solvent and water for injection, add the carbonic acid-carbonate buffer solution 10L aquation that contains the 8g span 20 then, particle diameter by the solution after the dispersing emulsification machine reduction aquation, through 0.22 μ m membrane filtration degerming, obtain uniform liposome solutions;
4) with 3) add the 100g trehalose, after lyophilization, remove moisture, obtain dry 5-fluorouracil lipidosome freeze-dried injection, be recovered to liposome, drug administration by injection after the aquation jolting before using.
The various kinds of drug lipidosome freeze-dried injection that makes by above-described embodiment method is appointed and is got wherein qualified six parts, measures envelop rate, drug loading, particle diameter, bacterioscopy, and heat source check, all conformance with standard.
Overcome the Liposomal formulation poor stability that commonsense method prepares by above-mentioned concrete enforcement example gained lipidosome freeze-dried injection, be difficult to realize industrial shortcoming, and proved technology simple possible of the present invention that product safety is effective, steady quality.
The protection authority of the present patent application is not limited in this; and the present invention also can other form embody under the condition that does not deviate from its basic feature; therefore we think that the present invention has embodiment and implements example generally speaking is illustrative rather than restrictive; protection domain is determined according to claims rather than according to above-mentioned explanation, so all implication and the variations in the equivalency range thereof in claim all should be included in the scope of the invention.
Compare with common technology thin film-freeze drying technology
1 applied film-freeze drying technology prepares liposome, and aquation forms the process need 30min of liposome; Application technology prepares liposome, and carrier dissolves back formation liposome rapidly rapidly during aquation, and hydration process only needs 5min.
2 thin film-freeze drying technology is the most commonly used at laboratory, but because can't in tun, realize forming the thin film of homogeneous, so the difficult commercial production that realizes can only expand the scale of production by the quantity that increases Rotary Evaporators.Decompressed vector-freeze drying technology of the present invention enlarges when producing in the carrier surface film forming, only needs to increase the carrier amount and gets final product, and production equipment is not had specific (special) requirements.
3 decompressed vectors-freeze drying technology and thin film-freeze drying technology productivity ratio the results are shown in Table 1.
Table 1
| ? | Total inventory/kg | Total output/kg | Yield/% |
| Decompressed vector-freeze drying technology | 2.00 | 1.82 | 91 |
| Thin film-freeze drying technology | 2.00 | 1.66 | 83 |
4 see Table 2 with the particle diameter comparing data after the liposome aquation of identical prescription (except carrier) thin film-freeze drying technology and decompressed vector of the present invention-freeze drying technology preparation:
Table 2
| ? | Thin film-freeze drying technology | Decompressed vector-lyophilizing |
| Particle size/nm | 267.00 | 236.00 |
| Particle size/nm(after 8h) | 268.00 | 238.00 |
5 six months stability (20-25 ℃) of the liposome comparing datas with identical prescription (except carrier) thin film-freeze drying technology and decompressed vector of the present invention-freeze drying technology preparation see Table 3:
Table 3
| ? | Time(month) | Appearance | pH | entrapment efficiency(%) | Particle size(nm) |
| Decompressed vector-lyophilizing | Initial | Uniform， dry | 3.22 | ﹥85 | 238.00 |
| ? | 1 | Uniform， dry | 3.22 | ﹥85 | 245.00 |
| ? | 3 | Uniform， dry | 3.20 | ﹥85 | 249.00 |
| ? | 6 | Uniform， dry | 3.14 | ﹥85 | 261.00 |
| ? | Initial | Uniform， dry | ? | ﹥80 | 263.00 |
| Thin film- |
1 | Uniform， dry | ? | ﹥80 | 271.00 |
| ? | 3 | Uniform， dry | ? | ﹥80 | 275.00 |
| ? | 6 | Uniform， dry | ? | ﹥80 | 280.00 |
Introduce the research process of this preparation method below
Single factor of preparation technology is investigated experiment
(1) choice of Solvent
Select methanol respectively, ethanol, acetonitrile, ethyl acetate, chloroform dissolved substance and matrix material.Final dissolving dehydrated alcohol is as the solvent of medicine and matrix material.
(2) investigation of mixing speed
Investigated mixing speed 10,30 respectively, during 50,70,90,110,130,150,170,200 rpm, final excellent mixing speed of selecting is 170rpm, and preparation time is suitable, and when preventing that material from splashing, the carrier suspendible is also more abundant.
(3) investigation of preparation temperature
Investigated following liposome preparation temperature respectively: room temperature (20 ℃-25 ℃), 30 ℃, 40 ℃, 50 ℃, 60 ℃, 70 ℃.When preparation temperature was lower than 40 ℃, the speed of absolute ethanol volatilizes was slower, and preparation time is longer.Preparation temperature is 50 ℃, 60 ℃, in the time of 70 ℃, measure envelop rate according to method under the entrapment efficiency determination item, and the results are shown in Table 4.Consider higher entrapment and suitable preparation time, finally select 50 ℃ as preparation temperature.
The envelop rate of the different preparation temperatures of table 4
| The preparation temperature(℃) | 50 | 60 | 70 |
| EE (%) | 85.32 | 70.69 | 59.47 |
(4) selection of aquation mode
Respectively at ultrasonic 10min; Magnetic agitation 10min; Hand 10min every jolting twice in 30 seconds, crosses under the condition of dispersing emulsification machine 10min, crosses the filter membrane of 0.8 μ m with the aquation WATER AS FLOW MEDIUMization, according to method mensuration envelop rate under the entrapment efficiency determination item, the results are shown in Table 5.The final magnetic agitation method of selecting, the liposome encapsulation of using after this method is recombinated is higher, and application conditions is simple, more is applicable to clinical.
The envelop rate of the different aquation conditions of table 5
| The reconstituted method | Ultrasonator | magnetic stirring | Shake by hand |
| EE (%) | 68.51 | 81.72 | 80.42 |
(5) investigation of hydration time
Use aquation WATER AS FLOW MEDIUMization 5,10,15 respectively, cross the filter membrane of 0.8 μ m behind the 20min, measure envelop rate according to method under the entrapment efficiency determination item, the results are shown in Table 6.The final 5min that selects is as the optimum reorganization time of liposome, and the liposome encapsulation that makes is all greater than 80%.
The envelop rate of the different hydration times of table 6
| The reconstituted time(min) | 5 | 10 | 15 | 20 |
| EE (%) | 82.59 | 82.36 | 76.15 | 74.12 |
(6) investigation of hydration temperature
Get an amount of liposome powder, respectively (20 ℃-25 ℃), 35 ℃, 45 ℃, 55 ℃, 65 ℃, 75 ℃, 85 ℃ of following aquation media are recombinated, and cross the filter membrane of 0.8 μ m, and measuring the reorganization temperature according to method under the entrapment efficiency determination item is that the 45-65 ℃ of envelop rate under the condition is all greater than 80%.So when clinical use, recommending the serviceability temperature scope is 20-70 ℃, 55 ℃ of conduct reorganization of final selection temperature in this research, the liposome quality after the reorganization is higher.
Claims (1)
1. the method for preparing lipidosome of a suitable suitability for industrialized production is characterized in that decompressed vector is prepared liposome technology to combine with freeze drying technology, and its concrete steps are:
(1) carrier is dissolved in water for injection, and 7-ethyl-10-hydroxycamptothecine, matrix material and stabilizing agent are dissolved in organic solvent, adds the activated carbon filtration depyrogenation respectively;
(2) at 20-70 ℃, under the condition of magnetic agitation, the water for injection that is dissolved with carrier material is joined in the organic solvent that is dissolved with medicine and matrix material gradually;
(3) at 20-70 ℃, under the condition of magnetic agitation, organic solvent and water for injection are removed in (2) decompression, add the aquation medium aquation that contains emulsifying agent then, particle diameter by the solution after the applied external force reduction aquation, through 0.22 μ m membrane filtration degerming, obtain uniform liposome solutions;
(4) (3) are added freeze drying protectant, remove moisture through lyophilization, obtain dry lipidosome freeze-dried injection, be recovered to liposome, drug administration by injection after the aquation jolting before using;
Described carrier is one or more in sodium chloride, glucose, sucrose, mannitol, the sorbitol;
Described matrix material is one or more mixture in sphingomyelin, phosphatidylcholine, Phosphatidylserine, the cuorin;
Described stabilizing agent is one or more mixture in anhydrous sodium sulfite, Vc, nitrogen, dibenzylatiooluene, alpha-tocopherol, α-tocopheryl acetate, the hydroquinone;
Described emulsifying agent is poloxamer, one or more mixture in polyoxyethylene hydrogenated Oleum Ricini, Tweens, the spans;
Described freeze drying protectant is one or more in lactose, mannitol, sorbitol, xylitol, sucrose, trehalose, dextran, the polyvinylpyrrolidone;
Described applied external force is hand concussion, and ultrasonic washing unit is ultrasonic, and it is ultrasonic to pop one's head in, and magnetic agitation is crossed dispersing emulsification machine.
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| CN103622924B (en) * | 2013-12-10 | 2016-06-15 | 沈阳药科大学 | A kind of docetaxel liposome and preparation method thereof |
| CN106214641A (en) * | 2016-08-22 | 2016-12-14 | 沈阳鑫泰格尔医药科技开发有限公司 | A kind of liposome being applicable to water soluble drug and preparation method thereof |
| CN113397978A (en) * | 2021-07-16 | 2021-09-17 | 江西科技师范大学 | System for preparing and purifying nanoliposome |
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| 中心复合效应面设计法优化7-乙基-10-羟基喜树碱(SN-38) 前体脂质体处方;叶田田等;《沈阳药科大学学报》;20111031;第28卷(第10期);第776页第2.1栏至第2.2栏，第778页第3栏 * |
| 叶田田等.中心复合效应面设计法优化7-乙基-10-羟基喜树碱(SN-38) 前体脂质体处方.《沈阳药科大学学报》.2011,第28卷(第10期),第776页第2.1栏至第2.2栏，第778页第3栏. |
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Effective date of registration: 20181123 Address after: 110016 No. 103, cultural road, Shenhe District, Shenyang, Liaoning Co-patentee after: Shenyang Junhong Pharmaceutical Technology Co., Ltd. Patentee after: Shenyang Pharmaceutical University Address before: 110013 No. 103 Cultural Road, Shenhe District, Shenyang City, Liaoning Province Patentee before: Shenyang Pharmaceutical University |