CN104706574A - Dexamethasone palmitate fat emulsion concentrated solution, preparation method and application thereof - Google Patents
Dexamethasone palmitate fat emulsion concentrated solution, preparation method and application thereof Download PDFInfo
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Abstract
A dexamethasone palmitate fat emulsion concentrated solution, a preparation method and an application thereof belong to the field of pharmacology and pharmaceutics. According to the invention, the defect that a traditional fat emulsion preparation technology is complex and the product has poor stability is overcome. The preparation technology provided by the invention is simple; the general physical stirring process is only needed; and no homogenization technology is required. A product prepared in the invention can be sterilized through a 0.22-micron microfiltration membrane. During the process of forming a dexamethasone palmitate fat emulsion system by encountering water, the product can be spontaneously emulsified only when slightly oscillated without homogenization treatment. Under optimized conditions, average particle size is about 0.2 micron after emulsification, and the narrow particle size distribution fully embodies injection fat emulsion characteristics. The product has good fluidity, will not be retained on the wall, is single-phase, transparent and clear in appearance, can undergo clarification detection and will not cause preparation stratification after multigelation. The product provided by the invention is used in treating rheumatoid arthritis.
Description
Technical field
The invention belongs to materia medica and pharmaceutical art, relate to Limethason fat milk concentrated solution, Preparation Method And The Use.
Background technology
Limethason (Dexamethasone Palmitate) introduces cetylate active component dexamethasone the 21st, and the non-specific steroidal anti-inflammatory drugs of one of the fat-solubility obtained, for the treatment of chronic rheumatic arthritis.The Limethason injection used clinically, a kind ofly be soft substrate with fatty oil and the lipid microsphere disperse system encapsulated by immobilized artificial membrane, be dissolved in fatty oil at this system Chinese medicine, being wrapped in immobilized artificial membrane by phospholipid emulsification, to be encapsulated in particle diameter be in the milk-globule of 0.2 μm.After administration, Limethason lipid microsphere can rapidly by the macrophage of inflammation part or leukocyte engulf, under Esterified Enzyme effect, Limethason takes off ester and forms dexamethasone, play antiinflammatory action (Guo Junhua, Huang Feng, Zhangjiang woods, Deng, (2012) Chinese rheumatology magazine 16:393-397).
Lipomul, also known as lipid microsphere, there is certain targeting, the concentration of non-target area medicine can be reduced, its mean diameter about 0.2 μm, blood capillary can not be blocked, as pharmaceutical carrier, there is obvious lymphsystem and monocytes/macrophages system (MPS) targeting, can assemble at the tissue (as tumor, inflammation district) with leaky blood vessel, namely strengthen through with retention effect (enhanced permeability and retention effect, thus there is natural passive target effect EPR).Electron Microscopy shows, and fat milk drug delivery system enters active inflammatory cell (as huge phagocyte, neutrophilic granulocyte), vascular endothelial cell, tumor cell (as: MM46 cell, Kupffer ' s cell) by endocytosis; Flow Cytometry display fat milk drug delivery system also can be absorbed by active T lymphocyte.Fat milk drug delivery system, due to its superior safety, stability and biocompatibility, is a kind of desirable pharmaceutical carrier.
Fat emulsion formulation preparation process comprises colostrum preparation, the large process of homogenizing two, and containing a large amount of water in system.As injection preparation, medicine prison system has high requirement to safety, extremely tight at the control overflow of the selection of adjuvant and particle diameter, as national Specification mean diameter must not cross 0.4 μm, 90% particle diameter aggregate-value must not be greater than 0.6 μm (1 μm equals 1000 nanometers).Therefore, in colostrum preparation, homogenization, need strictly to control parameters such as shear rate, temperature, homogenization pressure and cycle-indexes, take time and effort, considerably increase production cost.This is due to directly will suitable (Hiroko Shibata, et al. (2009) Int. J. Pharm. 378:167-176 under composition condition; Dirk L. Teagarden, et al.(1996) Adv. Drug. Deliv. Rev. 20:155-164) after the mixing of materials such as phospholipid, oil, water, oil-water separation phenomenon can be there is, only have these materials, through special homogenizer process, as high pressure homogenizer, could form the emulsion of stable uniform, in homogenizing process, material is subject to dither, hole, shearing, and the coordinative role such as impact, finally broken up or be refined as the insoluble phase granule in liquid.
Limethason injection is the same with usual fat emulsion formulation, there is the deficiency of poor stability and complicated process of preparation: those skilled in the art understand, the fat emulsion formulations such as Limethason injection, be rendered as opaque milkiness liquid in outward appearance, can not clarity detection be carried out; Easily there is the phenomenons such as profit layering, cohesion, flocculation in product stock process; Preparation technology relates to colostrum preparation, high pressure homogenize, and technique is unstable, and temperature, emulsification times and production equipment all have an impact to product quality, and cause newborn grain uneven; Further, existing fat milk needs Special Equipment under high pressure sterilizing.
A desirable Limethason preparation is the characteristic that can keep lipid microsphere, has that preparation stability is high, appearance transparent is limpid, technique is simple, without the need to special installation simultaneously, can be degerming by microporous filter membrane mode, to reduce production cost.
Summary of the invention
The present inventor is through deep research and performing creative labour, obtain a kind of Limethason fat milk concentrated solution, the present inventor is surprised to find, Limethason fat milk concentrated solution of the present invention, after mixing with water, without homogenizing means, stable emulsion can be formed, can effectively overcome Oil-water separation phenomenon.And the preparation lamination that product of the present invention can effectively overcome the density contrast between different auxiliary material and bring, obtains single-phase, transparent, stable thus, meeting after water can the Limethason fat milk concentrated solution of spontaneous emulsification.Thus provide following invention:
One aspect of the present invention relates to a kind of Limethason fat milk concentrated solution, and it comprises the Limethason as principal agent, and oil for injection, cosolvent, low hlb surfactant and high hlb surfactant.
Limethason fat milk concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(4) or multinomial:
(1) in described injection grease separation soybean oil, safflower oil, olive oil, fish oil and medium chain fatty acid ester any one or multiple; Preferably, described oil for injection is soybean oil and/or medium chain fatty acid ester; Particularly, described medium chain fatty acid ester is medium chain length fatty acid triglyceride and/or Medium chain fatty acid propylene glycol ester;
(2) described cosolvent be selected from propylene glycol, glycerol and PEG400 one or more; Preferably, described cosolvent comprises propylene glycol, alternatively, also comprise be selected from glycerol and PEG400 one or more; Particularly, described propylene glycol is 1,2-PD;
(3) described low hlb surfactant is the surfactant of 4≤HLB≤9; Particularly, it is selected from one or more in phospholipid, polyglycerol acrylate, span 20, sorbester p18, sorbester p17 and polyglycereol-6-dioleate; Preferably, described low hlb surfactant comprises phospholipid, alternatively, its also comprise be selected from polyglycerol acrylate and sorbester p17 one or more; Particularly, described phospholipid is soybean lecithin and/or Ovum Gallus domesticus Flavus lecithin; Preferably, be soybean lecithin;
(4) described high hlb surfactant is the non-ionic surface active agent of HLB >=12; Particularly, it is selected from one or more in polysorbas20, Tween 80, tocopherol polyethyleneglycol succinate, polyoxyethylene ether (35) Oleum Ricini, polyoxyethylene ether (40) castor oil hydrogenated, Gelucire 44/14, Polyethylene Glycol caprylic/capric glyceride, polyethyleneglycol-12-hydroxy stearin; Preferably, described high hlb surfactant comprises polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini, and alternatively, it also comprises Tween 80 and/or tocopherol polyethyleneglycol succinate.
The present invention relates to a kind of Limethason fat milk concentrated solution, it comprises:
Principal agent: Limethason,
Oil for injection: soybean oil,
Cosolvent: 1,2-PD,
Low hlb surfactant: phospholipid, and
High hlb surfactant: polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini;
Alternatively, described oil for injection also comprises medium chain length fatty acid triglyceride;
Alternatively, described low hlb surfactant also comprises polyglycerol acrylate;
Alternatively, described high hlb surfactant also comprises Tween 80.
Limethason fat milk concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(5) or multinomial:
(1) content of described Limethason is 0.5-10%(w/w); Be preferably 1-5%(w/w);
(2) content of described oil for injection is 45-85%(w/w); Be preferably 45-70%(w/w);
(3) content of described cosolvent is 5-30%(w/w); Be preferably 7-21%(w/w);
(4) content of described low hlb surfactant is 7.5%-17%(w/w);
(5) content of described high hlb surfactant is 8%-23%(w/w).
Limethason fat milk concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(9) or multinomial:
(1) content of described Limethason is 1-5%(w/w), be preferably 2-4%(w/w);
(2) content of described soybean oil is 5-60%, is preferably 5-50%;
(3) content of described medium chain length fatty acid triglyceride is 0%-80%, is preferably 0%-65%;
(4) content of described 1,2-PD is 5%-15%, is preferably 7%-10%;
(5) content of described phospholipid is 5%-15%, is preferably 7%-12%;
(6) content of described polyglycerol acrylate is 0-8%, is preferably 0-5%;
(7) content of described polyethyleneglycol-12-hydroxy stearin is 0-20%, is preferably 0-15%;
(8) content of described polyoxyethylene ether (35) Oleum Ricini is 0-20%, is preferably 0-15%;
(9) content of described Tween 80 is 0-15%, is preferably 0-10%.
Limethason fat milk concentrated solution according to any one of the present invention, is characterized in that any one in the item of following (1)-(7) or multinomial:
(1) the not moisture or water content of described Limethason fat milk concentrated solution is lower than 1%;
(2) described Limethason fat milk concentrated solution is not containing saccharide;
(3) the unambiguous essence of described Limethason fat milk concentrated solution;
(4) described Limethason fat milk concentrated solution its preparation method does not comprise removing or falls low-moisture step (such as rotary evaporation, spraying dry or lyophilization);
(5) alternatively, described Limethason fat milk concentrated solution also comprises antioxidant; Particularly, described antioxidant be selected from oleic acid, enuatrol, vitamin E and vitamin A any one or multiple;
(6) described Limethason fat milk concentrated solution is transparent, single phase soln;
(7) described Limethason fat milk concentrated solution adopts 0.22 μm of microporous filter membrane mode degerming.
Limethason fat milk concentrated solution according to any one of the present invention, its component and content are as below 1)-4) shown in group any one group:
1）
Limethason 2-4 gram
Soybean oil 5-30 grams
MCT Oil (Crodamol GTCC) 30-65 grams
1,2-PD 6-12 grams
Soybean lecithin (Epikuron 170, Degussa) 7-12 grams
Polyglycerol acrylate 0-5 gram
Tween 80 4-10 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 6-15 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin E 0-3 gram;
2）
Limethason 2-4 gram
Soybean oil 20-45 grams
Miglyol 812 (Miglyol 812, SASOL) 20-45 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 grams
Polyglycerol acrylate 0-5 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 5-15 grams
Tween 80 3-8 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin E 0-3 gram;
3）
Limethason 2-4 gram
Soybean oil 35-50 grams
Miglyol 812 (Miglyol 812, SASOL) 0 – 15 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 grams
Polyglycerol acrylate 0-3 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 5-15 grams
Tween 80 2-10 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin E 0-3 gram;
4）
Limethason 2-4 gram
Soybean oil 25-45 gram
Miglyol 812 (Miglyol 812, SASOL) 5-45 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 gram
Refining polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, BASF) 5-15 gram
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin E 0-3 gram.
Limethason fat milk concentrated solution according to any one of the present invention, its component and content are as shown in any a group in (1) below-(4) group:
（1）
Limethason 4 grams
Soybean oil 5 grams
MCT Oil (Crodamol GTCC) 63 grams
1,2-PD 8 grams
Soybean lecithin (Epikuron 170, Degussa) 7. 5 grams
Tween 80 4 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 8.2 grams
Vitamin E 0.3 gram;
（2）
Limethason 3 grams
Soybean oil 29.5 grams
Miglyol 812 (Miglyol 812, SASOL) 29.5 grams
1,2-PD 7.5 grams
Soybean lecithin (Epikuron 170, Degussa) 11 grams
Polyglycerol acrylate 4 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 11 grams
Tween 80 4 grams
Vitamin E 0.3 gram
Oleic acid 0.2 gram;
（3）
Limethason 3 grams
Soybean oil 50 grams
1,2-PD 9 grams
Soybean lecithin (Epikuron 170, Degussa) 12 grams
Polyglycerol acrylate 2.6 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 13 grams
Tween 80 10 grams
Vitamin E 0.35 gram
Oleic acid 0.05 gram;
（4）
Limethason 2.5 grams
Soybean oil 30.5 grams
Miglyol 812 (Miglyol 812, SASOL) 30.5 grams
1,2-PD 9 grams
Soybean lecithin (Epikuron 170, Degussa) 12 grams
Refining polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, BASF) 15 grams
Vitamin E 0.3 gram
Enuatrol 0.2 gram.
It should be noted that; above-mentioned 1) unit of gram-4) in group or (1)-(4) group represents the ratio between each component, if be revised as other unit of weight, includes but not limited to; such as kilogram and milligram etc., also all within protection scope of the present invention.
Another aspect of the invention relates to a kind of injection Limethason fat milk, and its Limethason fat milk concentrated solution according to any one of the present invention adds water or aqueous solution self emulsifying obtains; Particularly, described injection Limethason fat milk mean diameter is 0.05-0.7 μm; Be preferably 0.1-0.4 μm; More preferably, be 0.17-0.23 μm.
After Limethason fat milk concentrated solution of the present invention meets water dilution, can spontaneous emulsification be the Limethason fat milk meeting injection requirement.
Another aspect of the invention relates to the preparation method of the Limethason fat milk concentrated solution according to any one of the present invention, comprises the steps:
1) at 20-45 DEG C, low hlb surfactant is added oil, under 2000-20000rpm condition, be stirred to and form transparent clear solution;
2) under 20-75 DEG C of condition, Limethason is added step 1) product, and under 200-2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20-45 DEG C of condition, cosolvent, high hlb surfactant and optional antioxidant are added step 2) product, and under 200-800rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition Limethason fat milk concentrated solution.
About step 1) or step 2) or step 3) in the oil, low hlb surfactant, high hlb surfactant and the cosolvent that use, wherein moisture will lower than 1%, or do not have free water.
Product in step 3), without removing or low-moisture step (such as rotary evaporation, spraying dry or lyophilization) is fallen, water content is lower than 1%(by weight percentage).
Another aspect of the invention relates to Limethason fat milk concentrated solution according to any one of the present invention or the application of injection Limethason fat milk of the present invention in rheumatoid arthritis clinical treatment.
The explanation of the part term that the present invention relates to:
Fat milk, refers to also known as lipid microsphere, and after emulsion or the emulsifying of fat milk concentrated solution, the one of formation is soft substrate with fatty oil and is encapsulated by immobilized artificial membrane, and mean diameter is the microparticulate system of about 0.2 μm.
In the present invention, for the percentage ratio of the content of each component, if not otherwise specified, the percentage by weight (w/w) accounting for pharmaceutical composition gross weight is all referred to.
The beneficial effect of the invention
Good product mobility of the present invention, not wall built-up, outward appearance is single-phase, transparent, limpid shape, can accept clarity and detect, after multigelation, preparation lamination can not occur; Product of the present invention is met water and is formed in Limethason fat milk plant process, without the need to homogenizing process, only need slight oscillatory can spontaneous emulsification, during Clinical practice after the dilution of the aqueous solution such as normal saline or glucose solution also slight oscillatory, can spontaneous emulsification be the fat milk system meeting injection requirement, under optimum condition, after emulsifying, mean diameter is at about 0.2 μm, and particle size distribution is narrow and small fully demonstrates injection fat milk characteristic.
Preparation technology of the present invention is simple, only needs General Physics whipping process, does not need homogenization, do not need dewatering process, Limethason fat milk concentrated solution prepared by the present invention, can be degerming by 0.22 μm of microporous filter membrane.The present invention has that preparation technology is simple, low production cost, is easy to the advantage of transporting, storing, has application prospect.
Detailed description of the invention
Below in conjunction with embodiment, embodiment of the present invention are described in detail, but it will be understood to those of skill in the art that the following example only for illustration of the present invention, and should not be considered as limiting scope of the present invention.Unreceipted actual conditions person in embodiment, the condition of conveniently conditioned disjunction manufacturer suggestion is carried out.Agents useful for same or the unreceipted production firm person of instrument, being can by the conventional products of commercial acquisition.
Embodiment 1: the preparation of Limethason fat milk concentrated solution sample 1
Its constituent is as follows:
Limethason 4 grams
Soybean oil 5 grams
MCT Oil (Crodamol GTCC) 63 grams
1,2-PD 8 grams
Soybean lecithin (Epikuron 170, Degussa) 7. 5 grams
Tween 80 4 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 8.2 grams
Vitamin E 0.3 gram
This Limethason fat milk concentrated solution preparation method is as follows:
1) at 20 DEG C, the soybean lecithin of above-mentioned weight is added in medium chain length fatty acid triglyceride and soybean oil, under 20000rpm condition, be stirred to and form transparent clear solution;
2) under 20 DEG C of conditions, the Limethason of above-mentioned weight is added step 1) product, and under 200rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20 DEG C of conditions, by 1 of above-mentioned weight, 2-propylene glycol, Tween 80, polyethyleneglycol-12-hydroxy stearin and vitamin E add step 2) product, and under 200rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition Limethason fat milk concentrated solution.
Embodiment 2: the preparation of Limethason fat milk concentrated solution sample 2
Its constituent is as follows:
Limethason 3 grams
Soybean oil 29.5 grams
Miglyol 812 (Miglyol 812, SASOL) 29.5 grams
1,2-PD 7.5 grams
Soybean lecithin (Epikuron 170, Degussa) 11 grams
Polyglycerol acrylate 4 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 11 grams
Tween 80 4 grams
Vitamin E 0.3 gram
Oleic acid 0.2 gram
This Limethason fat milk concentrated solution preparation method is as follows:
1) at 45 DEG C, the soybean lecithin of above-mentioned weight, polyglycerol acrylate are added in Miglyol 812 and soybean oil, under 2000rpm condition, be stirred to and form transparent clear solution;
2) under 65 DEG C of conditions, the Limethason of above-mentioned weight is added step 1) product, and under 1000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 30 DEG C of conditions, by 1 of above-mentioned weight, 2-propylene glycol, Tween 80, polyethyleneglycol-12-hydroxy stearin, oleic acid and vitamin E add step 2) product, and under 800rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition Limethason fat milk concentrated solution.
Embodiment 3: the preparation of Limethason fat milk concentrated solution sample 3
Its constituent is as follows:
Limethason 3 grams
Soybean oil 50 grams
1,2-PD 9 grams
Soybean lecithin (Epikuron 170, Degussa) 12 grams
Polyglycerol acrylate 2.6 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 13 grams
Tween 80 10 grams
Vitamin E 0.35 gram
Oleic acid 0.05 gram
This Limethason fat milk concentrated solution preparation method is as follows:
1) at 30 DEG C, the soybean lecithin of above-mentioned weight, polyglycerol acrylate are added soybean oil, under 10000rpm condition, be stirred to and form transparent clear solution;
2) under 75 DEG C of conditions, the Limethason of above-mentioned weight is added step 1) product, and under 1000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 45 DEG C of conditions, by 1 of above-mentioned weight, 2-propylene glycol, Tween 80, polyethyleneglycol-12-hydroxy stearin, oleic acid, and vitamin E adds step 2) product, and under 500rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition Limethason fat milk concentrated solution.
Embodiment 4: the preparation of Limethason fat milk concentrated solution sample 4
Its constituent is as follows:
Limethason 2.5 grams
Soybean oil 30.5 grams
Miglyol 812 (Miglyol 812, SASOL) 30.5 grams
1,2-PD 9 grams
Soybean lecithin (Epikuron 170, Degussa) 12 grams
Refining polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, BASF) 15 grams
Vitamin E 0.3 gram
Enuatrol 0.2 gram
This Limethason fat milk concentrated solution preparation method is as follows:
1) at 25 DEG C, the soybean lecithin of above-mentioned weight is added in Miglyol 812 and soybean oil, under 8000rpm condition, be stirred to and form transparent clear solution;
2) under 60 DEG C of conditions, the Limethason of above-mentioned weight is added step 1) product, and under 2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 25 DEG C of conditions, by 1 of above-mentioned weight, 2-propylene glycol, polyoxyethylene ether (35) Oleum Ricini, and enuatrol, vitamin E add step 2) product, and under 500rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition Limethason fat milk concentrated solution.
Embodiment 5: spectrodensitometry is tested
With Hitachi U-2001 ultraviolet-uisible spectrophotometer, at ambient temperature, 600nm place measures optical density.Wherein Limethason fat milk concentrated solution is the sample 1-4 according to embodiment 1-4 preparation process gained, selects commercially available prod LIMETHASON in contrast.
Result is as shown in table 1.
Table 1: the optical density value of different sample solution
| Sample | 1 | 2 | 3 | 4 | LIMETHASON? |
| Optical density | 0.003 | 0.006 | 0.001 | -0.002 | 2.214 |
Optical density represents the permeability of light, and numerical value is lower, shows that sample is more clarified homogeneous, and from result, product appearance of the present invention is homogeneous, limpid, transparent.
embodiment 6: stability test
Sample 1-4 prepared by embodiment 1-4, reference substance is commercially available prod LIMETHASON.
Experimental technique: by different sample after-20 DEG C of freeze overnight, is positioned over 20 DEG C and naturally thaws, and multigelation like this 6 times, observe sample appearance under environmental condition, result of the test is in table 2.
Table 2: different sample is after freeze thawing, and sample appearance changes
| Sample | Cosmetic variation |
| 1 | Outward appearance is clarified, not stratified, not wall built-up, good fluidity |
| 2 | Outward appearance is clarified, not stratified, not wall built-up, good fluidity |
| 3 | Outward appearance is clarified, not stratified, not wall built-up, good fluidity |
| 4 | Outward appearance is clarified, not stratified, not wall built-up, good fluidity |
| LIMETHASON? | Oil-water stratification, wall built-up is serious |
From table 2, sample 1-4 all has fabulous stability, and through multigelation, outward appearance still can keep transparent homogeneous phase, not wall built-up, not stratified, has good mobility.
embodiment 7: particle size determination
Sample 1-4 prepared by embodiment of the present invention 1-4, adopt Mastersizer 2000 Particle Size Analyzer to detect particle diameter, sample adds the normal saline of 10 times of volumes, measures after slight oscillatory spontaneous emulsification.
Table 3: particle size distribution after different sample emulsifying
Note: d(0.1) represent that the cumulative particle sizes distribution number of sample is the particle diameter of 10% correspondence, d(0.5), d(0.9), d(1) the rest may be inferred.
Its particle size distribution is as shown in table 3, and the particle size distribution of four embodiments is between 0.1-0.8 μm, and mean diameter 0.2 μm, fully demonstrates fat milk feature.The d(0.9 of four embodiment products) be all less than 0.6 μm, meet injection fat milk Particle size requirements.
Although the specific embodiment of the present invention has obtained detailed description, it will be understood to those of skill in the art that.According to disclosed all instructions, can carry out various amendment and replacement to those details, these change all within protection scope of the present invention.Four corner of the present invention is provided by claims and any equivalent thereof.
Claims (10)
1. a Limethason fat milk concentrated solution, it comprises the Limethason as principal agent, and oil for injection, cosolvent, low hlb surfactant and high hlb surfactant.
2. Limethason fat milk concentrated solution according to claim 1, is characterized in that any one in the item of following (1)-(4) or multinomial:
(1) in described injection grease separation soybean oil, safflower oil, olive oil, fish oil and medium chain fatty acid ester any one or multiple; Preferably, described oil for injection is soybean oil and/or medium chain fatty acid ester; Particularly, described medium chain fatty acid ester is medium chain length fatty acid triglyceride and/or Medium chain fatty acid propylene glycol ester; Preferably, described medium chain fatty acid ester is medium chain length fatty acid triglyceride;
(2) described cosolvent be selected from propylene glycol, glycerol and PEG400 one or more; Preferably, described cosolvent comprises propylene glycol, alternatively, also comprise be selected from glycerol and PEG400 one or more; Particularly, described propylene glycol is 1,2-PD;
(3) described low hlb surfactant is the surfactant of 4≤HLB≤9; Particularly, it is selected from one or more in phospholipid, polyglycerol acrylate, span 20, sorbester p18, sorbester p17 and polyglycereol-6-dioleate; Preferably, described low hlb surfactant comprises phospholipid, alternatively, its also comprise be selected from polyglycerol acrylate and sorbester p17 one or more; Particularly, described phospholipid is soybean lecithin and/or Ovum Gallus domesticus Flavus lecithin; Preferably, be soybean lecithin;
(4) described high hlb surfactant is the non-ionic surface active agent of HLB >=12; Particularly, it is selected from one or more in polysorbas20, Tween 80, tocopherol polyethyleneglycol succinate, polyoxyethylene ether (35) Oleum Ricini, polyoxyethylene ether (40) castor oil hydrogenated, Gelucire 44/14, Polyethylene Glycol caprylic/capric glyceride, polyethyleneglycol-12-hydroxy stearin; Preferably, described high hlb surfactant comprises polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini, and alternatively, it also comprises Tween 80 and/or tocopherol polyethyleneglycol succinate.
3. a Limethason fat milk concentrated solution, it comprises:
Principal agent: Limethason,
Oil for injection: soybean oil,
Cosolvent: 1,2-PD,
Low hlb surfactant: phospholipid, and
High hlb surfactant: polyethyleneglycol-12-hydroxy stearin and/or polyoxyethylene ether (35) Oleum Ricini;
Alternatively, described oil for injection also comprises medium chain length fatty acid triglyceride;
Alternatively, described low hlb surfactant also comprises polyglycerol acrylate;
Alternatively, described high hlb surfactant also comprises Tween 80.
4. Limethason fat milk concentrated solution according to any one of claim 1 to 3, is characterized in that any one in the item of following (1)-(5) or multinomial:
(1) content of described Limethason is 0.5-10%(w/w); Be preferably 1-5%(w/w);
(2) content of described oil for injection is 45-85%(w/w); Be preferably 45-70%(w/w);
(3) content of described cosolvent is 5-30%(w/w); Be preferably 7-21%(w/w);
(4) content of described low hlb surfactant is 7.5%-17%(w/w);
(5) content of described high hlb surfactant is 8%-23%(w/w).
5. the Limethason fat milk concentrated solution described according to claim 3 or 4, is characterized in that any one in the item of following (1)-(9) or multinomial:
(1) content of described Limethason is 1-5%(w/w), be preferably 2-4%(w/w);
(2) content of described soybean oil is 5-60%, is preferably 5-50%;
(3) content of described medium chain length fatty acid triglyceride is 0%-80%, is preferably 0%-65%;
(4) content of described 1,2-PD is 5%-15%, is preferably 7%-10%;
(5) content of described phospholipid is 5%-15%, is preferably 7%-12%;
(6) content of described polyglycerol acrylate is 0-8%, is preferably 0-5%;
(7) content of described polyethyleneglycol-12-hydroxy stearin is 0-20%, is preferably 0-15%;
(8) content of described polyoxyethylene ether (35) Oleum Ricini is 0-20%, is preferably 0-15%;
(9) content of described Tween 80 is 0-15%, is preferably 0-10%.
6. Limethason fat milk concentrated solution according to any one of claim 1 to 5, is characterized in that any one in the item of following (1)-(7) or multinomial:
(1) the not moisture or water content of described Limethason fat milk concentrated solution is lower than 1%;
(2) described Limethason fat milk concentrated solution is not containing saccharide;
(3) the unambiguous essence of described Limethason fat milk concentrated solution;
(4) described Limethason fat milk concentrated solution its preparation method does not comprise removing or falls low-moisture step (such as rotary evaporation, spraying dry or lyophilization);
(5) alternatively, described Limethason fat milk concentrated solution also comprises antioxidant; Particularly, described antioxidant be selected from oleic acid, enuatrol, vitamin E and vitamin A any one or multiple;
(6) described Limethason fat milk concentrated solution is transparent, single phase soln;
(7) described Limethason fat milk concentrated solution adopts 0.22 μm of microporous filter membrane mode degerming.
7. a Limethason fat milk concentrated solution, its component and content are as below 1)-4) shown in group any one group:
1）
Limethason 2-4 gram
Soybean oil 5-30 grams
MCT Oil (Crodamol GTCC) 30-65 grams
1,2-PD 6-12 grams
Soybean lecithin (Epikuron 170, Degussa) 7-12 grams
Polyglycerol acrylate 0-5 gram
Tween 80 4-10 grams
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 6-15 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin E 0-3 gram;
2）
Limethason 2-4 gram
Soybean oil 20-45 grams
Miglyol 812 (Miglyol 812, SASOL) 20-45 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 grams
Polyglycerol acrylate 0-5 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 5-15 grams
Tween 80 3-8 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin E 0-3 gram;
3）
Limethason 2-4 gram
Soybean oil 35-50 grams
Miglyol 812 (Miglyol 812, SASOL) 0 – 15 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 grams
Polyglycerol acrylate 0-3 gram
Polyethyleneglycol-12-hydroxy stearin (Solutol HS 15, BASF) 5-15 grams
Tween 80 2-10 grams
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin E 0-3 gram;
4）
Limethason 2-4 gram
Soybean oil 25-45 gram
Miglyol 812 (Miglyol 812, SASOL) 5-45 grams
1,2-PD 6-14 grams
Soybean lecithin (Epikuron 170, Degussa) 7-13 gram
Refining polyoxyethylene ether (35) Oleum Ricini (Cremophor ELP, BASF) 5-15 gram
Oleic acid 0-3 gram
Enuatrol 0-3 gram
Vitamin E 0-3 gram.
8. an injection Limethason fat milk, its Limethason fat milk concentrated solution according to any one of the present invention adds water or aqueous solution self emulsifying obtains; Particularly, described injection Limethason fat milk mean diameter is 0.05-0.7 μm; Be preferably 0.1-0.4 μm; More preferably, be 0.17-0.23 μm.
9. the preparation method of the Limethason fat milk concentrated solution described in claim 1 to 7 kind of any one, comprises the steps:
1) at 20-45 DEG C, low hlb surfactant is added oil for injection, under 2000-20000rpm condition, be stirred to and form transparent clear solution;
2) under 20-45 DEG C of condition, Limethason is added step 1) product, and under 200-2000rpm stirring condition Keep agitation, until the transparent limpid shape of whole system;
3) under 20-45 DEG C of condition, cosolvent, high hlb surfactant and optional antioxidant are added step 2) product, and under 200-800rpm stirring condition Keep agitation, until form homogeneous preparations that is single-phase, transparent clear, after 0.22 μm of microporous filter membrane is degerming, final acquisition Limethason fat milk concentrated solution.
10. the Limethason fat milk concentrated solution according to any one of claim 1 to 7 or the application of injection Limethason fat milk according to claim 8 in rheumatoid arthritis clinical treatment.
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| CN112156072A (en) * | 2020-10-13 | 2021-01-01 | 西安力邦制药有限公司 | Medicine-carrying fat emulsion preparation for accelerating medicine absorption and lipid metabolism |
| CN115463084A (en) * | 2021-06-10 | 2022-12-13 | 北京泰德制药股份有限公司 | Compound oil solution preparation for long-acting analgesia and preparation method thereof |
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| CN1596899A (en) * | 2004-07-28 | 2005-03-23 | 沈阳药科大学 | Dexamehasone palmitate freeze-dried emulsion and its preparation method |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN106727308A (en) * | 2016-12-14 | 2017-05-31 | 广东药科大学 | A kind of dexamethasone lipid emulsion droplet ocular fluid and preparation method thereof |
| CN112156072A (en) * | 2020-10-13 | 2021-01-01 | 西安力邦制药有限公司 | Medicine-carrying fat emulsion preparation for accelerating medicine absorption and lipid metabolism |
| CN115463084A (en) * | 2021-06-10 | 2022-12-13 | 北京泰德制药股份有限公司 | Compound oil solution preparation for long-acting analgesia and preparation method thereof |
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