CN103349644A - Lansoprazole complex micelle medicine composition for injection and preparation method thereof - Google Patents
Lansoprazole complex micelle medicine composition for injection and preparation method thereof Download PDFInfo
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Abstract
The invention discloses a lansoprazole complex micelle medicine composition for injection. The lansoprazole complex micelle medicine composition comprises lansoprazole, phospholipid, bile acid, amino acid and alkaline matters. Furthermore, the invention discloses a preparation method of medicine composition solution and an injection preparation prepared from the medicine composition. An experiment of an applicant confirms that the medicine composition disclosed by the invention overcomes the problem that the lansoprazole is difficultly dissolved in water; and the obtained medicine composition has good stability and is more suitable for clinical use and industrial production.
Description
Technical field
The invention discloses a kind of Lansoprazole for injecting composite micelle pharmaceutical composition, comprise lansoprazole, phospholipid, bile acid, lactose, aminoacid, alkaline matter, further the invention discloses the preparation method of described pharmaceutical composition and based on the ejection preparation of this pharmaceutical composition, belong to pharmaceutical field.
Background technology
Lansoprazole Lansprazole another name: Takepron, TAKEPRON, the military field drug company listing of O-GAST1992 Japan is a kind of new proton pump inhibitor after omeprazole (Omeprazole).Both structural similarities; be benzimidizole derivatives; the medicine of novel gastric acid secretion inhibiting; gastric acid secretion inhibiting forcefully; and the not impact of the various initiating agents of irriate gastric acid secretion; helicobacter pylori also there is inhibitory action, has good action at aspects such as protection and promotion gastric mucosa ulcer healing, reduction ulcer recurrence rates.The disease that is used for sour parasecretion is such as peptic ulcer, reflux esophagitis and Zollinger-Ellison syndrome.
Proton pump inhibitor is to treat at present the state-of-the-art class medicine of peptic ulcer.It presses down the main mechanism of acid: human body is positioned at the H on the parietal cell secretory duct under receptor and second message,second messenger's effect
+-ATP enzyme decomposes ATP and obtains energy. pass through H
+/ K
+Transporting mechanism is with H in the endochylema
+Pump into gastral cavity, form gastric acid with Cl one again.Wherein proton pump is the important step in the gastric acid secretion process. the activity that suppresses H LATP enzyme is the gastric acid secretion that is caused by any stimulation capable of blocking.Lansoprazole (lansoprazole, LPZ) is the representative drugs in the proton pump inhibitor, compares with omeprazole, has introduced trifluoro ethoxy in its structure, and lipotropy increases, and can more promptly see through parietal cell performance drug effect.Contain sulfinyl in the LPZ structure, to wet, heat is responsive, reduces bad stability with pH.LPZ belongs to low solubility, high infiltration class medicine, and dissolution rate is the rate-limiting step that affects its absorption.
Lansoprazole is the extremely white tasteless crystalline powder of palm fibre of white, and melting point is at about 166 ℃.Lansoprazole is soluble in dimethyl formamide; Be dissolved in methanol; Be slightly soluble in ethanol; Be slightly soluble in ethyl acetate, dichloromethane and acetonitrile; Be slightly soluble in ether; Be dissolved in hardly normal hexane and water.Lansoprazole can stably be exposed to light and reach two months.In water, reduce degradation rate with pH value and increase, the degradation half life of material was when pH5 about 0.5 hour in the time of 25 ℃, pH value 7 about 18 hours.The lansoprazole of listing only has the oral formulations such as conventional tablet and capsule at present, but lansoprazole is insoluble in water, and oral absorption is poor, and bioavailability is low.
Exploitation to the lansoprazole injection never rests, and for example, Chinese patent application 200410036486 discloses lansoprazole can be for the freeze-dried composition of injection, comprises lansoprazole, auxiliary, cosolvent, stabilizing agent basic amino acid, water; Chinese patent application 201110281552.0 discloses a kind of Lansoprazole freeze-dried injection, is made by lansoprazole, solubilizing agent sodium hydroxide and stabilizing agent tromethane; Chinese patent application 201210115887 discloses Lansoprazole medicine composition of a kind of injection and preparation method thereof, its compositions contain lansoprazole, poloxamer,, lactose etc., but the pH of above-mentioned injection is up to about 11, be strong alkali solution after water-soluble, when clinical use, owing to its strong and stimulating, can't use clinically.And above-mentioned lyophilized injectable powder is stable and solubility is all relatively poor, can't satisfy the requirement of 24 months shelf lifes of listing product.
In order to ensure the effectiveness of lansoprazole medication, safety and stability, people have further carried out the developmental research of Lansoprazole liposome preparation, for example Chinese patent application 201010612336.5, Chinese patent application 201110152524.9 and Chinese patent application disclose a kind of by lansoprazole, the phospholipid raw material, antioxidant, immobilized artificial membrane molecular state diluent, liposome medicine carrying body dispersant, excipient, surfactant, ethanol, phosphate buffer and water are made, it is numerous and diverse because ingredient is many, production cost is increased, and increased the risk of medication, more make the difficult quality control of product.
Because lansoprazole is insoluble in water, be dissolved in the high pH value solution, pH value so need to add microfilter, has increased cost and risk being lower than 10.50-10.55 meeting crystallization.And high pH value not only can affect its stability, and increases the zest of clinical application, can't ensure the safety of medication.Therefore, be badly in need of the novel formulation of the convenient and safe lansoprazole of a kind of good stability of research and medication.
Summary of the invention
For addressing the above problem, the invention provides a kind of more approaching neutrality of pH value and pH value made behind lyophilized powder and the injection and change littlely, solubility is good, Lansoprazole medicine composition of stay-in-grade injection and preparation method thereof.Further, the present invention also provides a kind of newtype drug commercial assembly packaging, this packing is formed by medicine organic facies packing and the water packaged combination of independent packaging, wherein organic facies is comprised of lansoprazole, phospholipid, bile acid and water-soluble polyol, water is made by nonacid aminoacid, alkaline matter and water for injection, during use organic facies and water is mixed rear injection use.This novel package has further solved the requirement of lansoprazole pharmaceutical preparation long-time stability, and makes its medication safer convenient.
In the lansoprazole preparation research, the pleasantly surprised discovery of applicant can obtain the pharmaceutical preparation of more approaching neutrality (pH value 8-10) to wherein adding nonacid aminoacid in the aminoacid and alkaline matter (sodium hydroxide, potassium hydroxide or the mixture of the two) for the preparation of lansoprazole pharmaceutical preparation on traditional phospholipid, bile acid basis, more can significantly improve its dissolubility, stability in aqueous solution.And this scheme preparation method is simple, does not need to use centrifugal, ultrasonic etc. can't be applied to the large technology of producing of industry, has reduced production cost, is suitable for industrial mass production; Adopt the resulting solution particle diameter of this scheme less than 50nm, mean diameter is not higher than 25nm, is starkly lower than the product that prior art can provide; The solution that this scheme provides adopts as required normal saline, glucose etc. to be diluted to desired concn when clinical practice and gets final product, the convenient use.
Based on above-mentioned discovery, the invention discloses a kind of Lansoprazole medicine composition, this pharmaceutical composition contains lansoprazole, phospholipid, bile acid, nonacid aminoacid, alkaline matter; Be prepared into injection after mentioned component can being dissolved in water for injection, also can in mentioned component, add the lyophilizing excipient and prepare pharmaceutical aqueous solution with the water for injection dissolving, be prepared into lyophilized injectable powder after its lyophilizing again.Wherein said nonacid aminoacid can be one or more the mixture in glycine, alanine, valine, phenylalanine, serine, glutamine, lysine, arginine, the histidine; Described alkaline matter is sodium hydroxide, potassium hydroxide or the mixture of the two;
Further, the invention discloses preparation method and the purposes of this pharmaceutical composition in the preparation medicine of described Lansoprazole medicine composition.
Pharmaceutical composition of the present invention, the mass ratio of lansoprazole wherein, phospholipid, bile acid, nonacid aminoacid, alkaline matter can be 1: 1-100: 1-150: 1-50: 0.1-1; Preferably, the mass ratio of lansoprazole, phospholipid, bile acid, aminoacid, alkaline matter is 1: 3-10: 4-20: 1-30: 0.1-0.5.
The nonacid aminoacid that the present invention is used, be selected from glycine, alanine, valine, phenylalanine, serine, glutamine, lysine, arginine, histidine, preferably the mixture of one or more in glycine, alanine, valine, the serine.
The used alkaline matter of the present invention can be sodium hydroxide, potassium hydroxide or the mixture of the two, but its use amount needs strict control, purpose is to make the aqueous phase solution of pharmaceutical composition of the present invention keep alkalescence, if it also is to use that those skilled in the art adopt other can make aqueous solution keep weakly alkaline material, it comprises within the scope of the invention, it is the wide material sources of considering the two that the present invention uses sodium hydroxide, potassium hydroxide, preparation is simple, usually in pharmacy, use, can be applicable to large-scale production.
The used phospholipid of the present invention is selected from soybean phospholipid, egg yolk lecithin, the Semen sojae atricolor sphingomyelins, the egg yolk sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, two Petiolus Trachycarpi phosphatidylcholines, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINE, the distearyl phosphatidylcholine, two Petiolus Trachycarpi PGs, two Petiolus Trachycarpi Phosphatidylserine, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, DMPEA, dilinoleoylphosphatidylcholine, dilinoleic acid glyceride phosphatidylcholine, dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE, the mixture of one or more of dilinoleic acid glyceride phosphatidyl glycerol, preferred soybean phospholipid, egg yolk lecithin, the Semen sojae atricolor sphingomyelins, the egg yolk sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, the mixture of one or more in the phosphatidylinositols, most preferably soybean phospholipid, egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE.
The used bile acid of the present invention is selected from free bile acid, conjugated bile acid or its mixture, free cholic acid comprises cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid etc., is preferably cholic acid, deoxycholic acid, chenodeoxycholic acid, Hyodeoxycholic Acid; Conjugated bile acid is that carboxyl in the above-mentioned free bile acid and glycine (H2NCH2COOH) or taurine (H2NCH2CH2S03H) or other contain the product after amino in the amino chemical compound forms amido link, is preferably glycocholic acid, sweet ammonia deoxycholic acid, sweet ammonia chenodeoxycholic acid, sweet ammonia ursodesoxycholic acid, taurocholic acid, taurodeoxycholic acid, Taurochenodeoxycholic Acid, tauroursodeoxycholic acid;
On the basis of further investigation medicinal composition solution character of the present invention, the applicant further finds by add the dissolubility that water miscible medicinal polyhydric alcohol can improve the present composition in the present composition.The used polyhydric alcohol of the present invention is water-soluble polyol, and as long as especially micromolecular water-soluble polyol can be medicinal, includes but not limited to propylene glycol, glycerol, ethylene glycol, Polyethylene Glycol, preferred propylene glycol.Described Polyethylene Glycol can be present available any water miscible Polyethylene Glycol pharmaceutically, includes but not limited to PEG200, PEG400, PEG600, PEG800 etc., preferred PEG400.
When adding water-soluble polyol, the amount of adding can be regulated according to the needs of actual preparation, common its quality take the 0.1-10 of lansoprazole consumption doubly for preferably.
On the basis of the above, in conjunction with the needs of preparation, can also add common pharmaceutic adjuvant in the medicinal composition solution of the present invention as waiting a regulator, lyophilization excipient etc.
Described grade is opened regulator and is included but not limited to 0.9% sodium chloride solution, 5% glucose solution, preferably adopts 0.9% sodium chloride solution.
Described excipient can be selected from but be not limited to is in mannitol, sorbitol, sodium chloride, gelatin hydrolysate, the polyvinylpyrrolidone etc. one or more, is preferably mannitol.
Medicinal composition solution of the present invention can be prepared as by the formulation method of routine the lansoprazole injection, includes but not limited to injection, freeze-dried powder, in conjunction with needs clinical and that use, is preferably the lansoprazole injection.
Pharmaceutical composition of the present invention can be prepared as the lansoprazole injection through techniques such as simple filtration sterilizations, the more approaching neutrality of its pH value (8-10), it is the more acceptant alkalescence of human body, can not cause stimulation during clinical use, improved clinical safety in utilization, therefore, prepared injection has the excellent specific property of medicinal composition solution, the convenient use.
To those skilled in the art, solution being prepared as freeze-dried powder is a kind of common preparation process.By in medicinal composition solution of the present invention, adding the lyophilizing excipient, such as mannitol, lactose, sorbitol, sodium chloride, gelatin hydrolysate, polyvinylpyrrolidone (preferred mannitol, lactose, sorbitol) etc. the mixture of one or more in can be prepared as pharmaceutical composition of the present invention freeze-dried powder under suitable lyophilisation condition, the consumption of lyophilizing usefulness excipient without limits, as long as conveniently medicine is prepared into lyophilized formulations, generally speaking, with respect to 1 weight portion lansoprazole, lyophilizing is 1-100 part with the consumption of excipient, preferred 1-50 weight portion.
The invention provides the preparation method of Lansoprazole medicine composition, comprise lansoprazole, phospholipid, bile acid joined in the organic solvent and dissolve, remove the backward water that contains nonacid aminoacid, alkaline matter that wherein adds of organic solvent and be prepared into pharmaceutical composition micellar solution.
In one embodiment of the invention, provide a kind of preparation method of lansoprazole injection, comprised the steps:
1. lansoprazole, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution.Organic solvent is removed in distilling under reduced pressure, obtains organic facies; Perhaps will remove mixture behind the organic solvent and add in the water-soluble polyol and dissolve, as organic facies;
2. mixings that the nonacid base acid of ammonia, alkaline matter and/or other adjuvant be added to the water dissolved, as water;
3. with above-mentioned organic facies and water mix homogeneously, make the lansoprazole injection according to the conventional preparation method of injection.
In another embodiment of the present invention, provide a kind of preparation method of Lansoprazole freeze-dried powder pin, comprised the steps:
1. lansoprazole, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, organic solvent is removed in distilling under reduced pressure, as organic facies; Perhaps will remove mixture behind the organic solvent and add in the water-soluble polyol and dissolve, as organic facies;
2. with mixing that is added to the water such as freeze-dried excipient, nonacid aminoacid and alkaline matters, dissolving is as water;
3. with organic facies and the water mix homogeneously of above-mentioned steps, make freeze-dried powder according to the preparation method of conventional lyophilized formulations.
In another embodiment of the present invention, provide a kind of preparation method of lansoprazole commercial packing, comprised the steps:
1. lansoprazole, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, organic solvent is removed in distilling under reduced pressure, adds water-soluble polyol as organic facies;
2. nonacid aminoacid, alkaline matter are dissolved in the water, obtain water;
3. above-mentioned organic facies and water are made organic facies concentrated solution for injection and water injection according to the preparation method of regular injection liquid respectively and pack respectively, then the organic facies of independent packaging is packed mutually and water packaged combination packing forms commercial packing.
In above-mentioned preparation method, described organic solvent general reference can be dissolved the organic solvent of lansoprazole, phospholipid, bile acid, includes but not limited to one or more the mixture in ethanol, ethyl acetate, ether, the acetone.Lansoprazole, phospholipid, bile acid can join in the organic solvent with random order, also can add other adjuvants in this step.
In above-mentioned preparation method, the order that water adds adjuvant is not restricted. and can be according to the needs of preparation to wherein adding suitable adjuvant when the preparation water, to those skilled in the art, it is apparent selecting suitable adjuvant for different specifications, the different conditions such as dosage form.
Lansoprazole can be widely used in treatment such as peptic ulcer, reflux esophagitis and Zollinger-Ellison syndrome disease, therefore obvious, the application provides the purposes of Lansoprazole medicine composition solution of the present invention in the lansoprazole medicine of the above-mentioned disease of preparation treatment.
Applicant's experiment confirm, with respect to solubilizing systems of the prior art, common micelle types such as phospholipid-bile acid mixed micelle, albumen-phospholipid micellar system, HS15-phospholipid micellar system, pharmaceutical composition of the present invention joins the solution that forms in phospholipid, the bile acid by employing with nonacid aminoacid, alkaline matter and has significant synergism, solubilization to lansoprazole is more obvious, stability also significantly strengthens, and the gained injection can reach better drug loading and drug level.
The specific embodiment:
The below will illustrate by embodiment and realize technical scheme of the present invention that these embodiments do not consist of further restriction to the present invention.Those skilled in the art are equal to replacement or corresponding improvement according to existing knowledge to the present invention, belong to scope of the present invention.In the following example, the applicant provides the method that medicinal composition solution of the present invention is prepared into ejection preparation (injection, freeze-dried powder), an example of only using as pharmaceutical composition of the present invention does not limit medicinal composition solution of the present invention and only is used for this purposes.
Embodiment 1
The preparation method step is as follows:
(1) injection: lansoprazole, soybean phospholipid, chenodeoxy cholic acid are dissolved in the 1L ethyl acetate, are stirred to mix homogeneously to fully dissolving, the reclaim under reduced pressure ethyl acetate obtains organic facies.With alanine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, adding 0.3% injection activated carbon to above-mentioned micellar solution stirred 30 minutes, after decarburization is filtered, 0.22um microporous filter membrane carries out fine straining, minute be filled to cillin bottle or peace is cutd open bottle, namely get lansoprazole injection of the present invention, gained injection concentration is 10mg/ml, drug loading is 10%, and the drug microparticles mean diameter is 24nm.
(2) lyophilized injectable powder: lansoprazole, soybean phospholipid, chenodeoxy cholic acid are dissolved in the 1L ethyl acetate, are stirred to mix homogeneously to fully dissolving, the reclaim under reduced pressure ethyl acetate obtains organic facies.With alanine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, add lactose to above-mentioned micellar solution, add 0.3% injection activated carbon and stirred 30 minutes, decarburization after the 0.22um microporous filter membrane carries out fine straining, is adopted following freeze-dry process after filtering:
Pre-freeze: products temperature drops to-45 ℃, is incubated and namely can carries out sublimation drying after 3 hours;
Sublimation drying: the sublimation drying temperature is controlled at below-12 ℃:
Dry again: the drying stage maximum temperature is controlled at 35 ℃ again, and loss on drying should be up to specification;
Behind dry the end, the intrinsic pressure plug of case, outlet lock aluminium lid, the qualified rear packing of product inspection and get final product.
(3) organic facies, water assembly packaging: lansoprazole, soybean phospholipid, chenodeoxy cholic acid are dissolved in the 600ml ethylene glycol, are stirred to mix homogeneously to fully dissolving, as organic facies.Alanine, sodium hydroxide are joined stirring and dissolving in the water (1L), as water.Add 0.3% injection activated carbon to organic facies and aqueous phase respectively and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, minute was filled to cillin bottle, and packing namely gets lansoprazole commercial packing of the present invention respectively.
Embodiment 2
Preparation method:
(1) injection; Lansoprazole, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 1L dehydrated alcohol, are stirred to abundant dissolving, decompression recycling ethanol adds propylene glycol, obtains organic facies.With glycine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, aforementioned pharmaceutical compositions solution is added 0.3% injection activated carbon to be stirred 30 minutes, after decarburization is filtered, 0.22um microporous filter membrane carries out fine straining, minute be filled to cillin bottle or peace is cutd open bottle, namely get lansoprazole injection of the present invention, gained injection concentration is 5mg/ml, and the drug microparticles mean diameter is 15nm.
(2) lyophilized injectable powder: with lansoprazole,, phosphatidylcholine, sweet ammonia deoxycholic acid be dissolved in the 1L dehydrated alcohol, is stirred to mix homogeneously to fully dissolving, decompression recycling ethanol obtains organic facies.With alanine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, add mannitol to above-mentioned micellar solution, stirred 30 minutes to wherein adding 0.3% injection activated carbon again, after decarburization is filtered, 0.22um after microporous filter membrane carries out fine straining, adopt following freeze-dry process:
Pre-freeze: products temperature drops to-45 ℃, is incubated and namely can carries out sublimation drying after 3 hours;
Sublimation drying: the sublimation drying temperature is controlled at below-12 ℃;
Dry again: the drying stage maximum temperature is controlled at 35 ℃ again, and loss on drying should be up to specification;
Behind dry the end, the intrinsic pressure plug of case, outlet lock aluminium lid, the qualified rear packing of product inspection and get final product.
(3) organic facies/water assembly packaging: lansoprazole, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 2L ethanol, are heated to 50 ℃ of stirrings, to fully dissolving.Ethanol is removed in distilling under reduced pressure, then adds propylene glycol (800ml) mix homogeneously and obtains organic facies; The glycine potassium hydroxide is joined the middle mix homogeneously of water for injection (2L) as water.Add 0.3% injection activated carbon to organic facies and aqueous phase respectively and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, minute was filled to peace to cut open bottle, and packing namely gets lansoprazole commercial packing of the present invention respectively.
Embodiment 3
Preparation method:
(1) injection: lansoprazole, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 1L acetone, are stirred to abundant dissolving, reclaim under reduced pressure acetone adds PEG400, obtains organic facies.With valine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, aforementioned pharmaceutical compositions solution is added 0.3% injection activated carbon stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, minute be filled to cillin bottle or peace is cutd open bottle, namely get lansoprazole injection of the present invention.Gained injection concentration is 5mg/ml, and the drug microparticles mean diameter is 22nm.
(2) lyophilized injectable powder: lansoprazole, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 1L acetone, are stirred to mix homogeneously to fully dissolving, reclaim under reduced pressure acetone obtains organic facies.With valine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, add sorbitol to above-mentioned micellar solution, again to wherein aforementioned pharmaceutical compositions solution being added lactose, adding 0.3% injection activated carbon stirred 30 minutes, after decarburization is filtered, 0.22um after microporous filter membrane carries out fine straining, adopt following freeze-dry process:
Pre-freeze: products temperature drops to-45 ℃, is incubated and namely can carries out sublimation drying after 3 hours;
Sublimation drying: the sublimation drying temperature is controlled at below-12 ℃;
Dry again: the drying stage maximum temperature is controlled at 35 ℃ again, and loss on drying should be up to specification;
Behind dry the end, the intrinsic pressure plug of case, outlet lock aluminium lid, the qualified rear packing of product inspection and get final product.
(3) organic facies/water assembly packaging: lansoprazole, phosphatidylcholine, sweet ammonia deoxycholic acid are dissolved in the 1L PEG400 (PEG400), are heated to 50 ℃ of stirrings, to fully dissolving, as organic facies; Valine, potassium hydroxide are joined in the water for injection mix homogeneously as water.Add 0.3% injection activated carbon to organic facies and aqueous phase respectively and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, minute was filled to cillin bottle, and packing namely gets lansoprazole commercial packing of the present invention respectively.
Embodiment 4
Preparation method:
(1) injection: lansoprazole, egg yolk sphingomyelins, deoxycholic acid are dissolved in the 1L acetone, are stirred to abundant dissolving, reclaim under reduced pressure acetone obtains organic facies.With serine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, aforementioned pharmaceutical compositions solution is added 0.3% injection activated carbon stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, divide to be filled to pacify and cut open bottle, namely get lansoprazole injection of the present invention.Gained injection concentration is 5mg/ml, and the drug microparticles mean diameter is 20nm.
(2) lyophilized injectable powder: lansoprazole, egg yolk sphingomyelins, deoxycholic acid are dissolved in the 1L acetone, are stirred to mix homogeneously to fully dissolving, reclaim under reduced pressure acetone obtains organic facies.With serine, the sodium hydroxide stirring and dissolving that is added to the water, as water.Organic facies is joined the aqueous phase mix homogeneously obtain micellar solution, in above-mentioned micellar solution, add mannitol, stirred 30 minutes to wherein adding 0.3% injection activated carbon again, after decarburization is filtered, 0.22um after microporous filter membrane carries out fine straining, adopt following freeze-dry process:
Pre-freeze: products temperature drops to-45 ℃, is incubated and namely can carries out sublimation drying after 3 hours;
Sublimation drying: the sublimation drying temperature is controlled at below-12 ℃;
Dry again: the drying stage maximum temperature is controlled at 35 ℃ again, and loss on drying should be up to specification;
Behind dry the end, the intrinsic pressure plug of case, outlet lock aluminium lid, the qualified rear packing of product inspection and get final product.
(3) organic facies/water assembly packaging: lansoprazole, egg yolk sphingomyelins, deoxycholic acid are dissolved in the 1L glycerol, are heated to 60 ℃ of stirrings, to fully dissolving, as organic facies; Serine, potassium hydroxide are joined in the water for injection mix homogeneously as water.Add 0.3% injection activated carbon to organic facies and aqueous phase respectively and stirred 30 minutes, after decarburization was filtered, the 0.22um microporous filter membrane carried out fine straining, minute was filled to peace to cut open bottle, and packing namely gets lansoprazole commercial packing of the present invention respectively.
The comparative example 1
According to the content of Chinese patent application 201110152524 embodiment 1, the applicant has prepared following injection.
Make by patent application 201110152524 embodiment 1 preparation method.
The comparative example 2
Prescription and method according to embodiment 1 among the Chinese patent application 201210115887.X prepare Lansoprazole freeze-dried injection.The pH value of this lyophilized injectable powder is 10.8.
Embodiment 1～4 preparation micellar solution clarity determination methods
According to " Chinese Pharmacopoeia version (two ones) in 2010 " appendix IX B method, just embodiment 1-4 preparation injection or the freeze-dried powder of embodiment 1-27 preparation placed respectively the turbid glass tubing of using of ratio of pairing with the turbidity standard of equivalent after with 5ml water for injection jolting dissolving, after turbidity standard prepares 5 minutes, vertical with placing under the umbrella canopy lamp in the darkroom, illumination is 1000Lx, from the horizontal direction observation and comparison, the clarification of the solution of preparation is not deeper than turbidity standard No. 1.
Test one: room temperature stability is observed
Get the micellar solution of embodiment 1 preparation and at room temperature preserved six months, detect the variations such as its physicochemical property, be recorded as following form
Table 1 (I) embodiment 1 room temperature reserved sample observing result
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance | Clarification | Clarification | Clarification | Clarification | Clarification |
| Content | 100 | 99.94 | 99.92 | 99.88 | 99.81 |
(II) embodiment 2 room temperature reserved sample observing results
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Outward appearance | Clarification | Clarification | Clarification | Clarification | Clarification |
| Content | 100 | 99.98 | 99.93 | 99.90 | 99.86 |
By above-mentioned data as seen, the every detection index of injection of the present invention does not almost change in the room temperature storage process, steady quality.Simultaneously can find to add the stability that water-soluble polyol can increase micellar solution lansoprazole of the present invention.
In long-term put procedure, the micellar solution clarification, visualization is without opalescence.According to " Chinese Pharmacopoeia version (two ones) in 2010 " appendix IX B method, the solution of preparation is placed respectively the turbid glass tubing of using of ratio of pairing with the turbidity standard of equivalent, after turbidity standard prepares 5 minutes, vertical with placing under the umbrella canopy lamp in the darkroom, illumination is 1000Lx, observe, compare from horizontal direction, the solution clarification of preparation is not deeper than turbidity standard No. 1.
Test two: particle diameter detects and clarity observation
Get the injection of embodiment of the invention 1-4 and comparative example 1 the lansoprazole injection, carry out particle diameter and clarity detects, acquired results such as following table 2.
Get respectively the injection of embodiment 1-4 and comparative example 1 liposome, at room temperature placed six months, observe its clarity, result such as following table 3.
Table 2 particle diameter testing result
| Sample number | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | The comparative example 1 |
| Maximum particle diameter (nm) | 43 | 35 | 48 | 43 | 335 |
| Minimum grain size (nm) | 4 | 10 | 5 | 8 | 105 |
| Mean diameter (nm) | 24.1 | 15.0 | 22.1 | 20.3 | 213.0 |
Table 3 clarity observed result
| Time (moon) | 0 | 1 | 2 | 3 | 6 |
| Embodiment 1 | Clarification | Clarification | Clarification | Clarification | Clarification |
| Embodiment 2 | Clarification | Clarification | Clarification | Clarification | Clarification |
| Contrast 1 | Clarification | Clarification | Clarification | Muddy | Muddy |
Can be found out by the above results, micellar solution of the present invention and comparative example's 1 micellar solution particle diameter all is starkly lower than other technologies scheme of the prior art, technical solution of the present invention is better than simple phospholipid, cholic acid system in the situation that does not add polyhydric alcohol, add after the polyhydric alcohol, the present invention program's obvious technical effects is better than simple phospholipid, cholate micellar system.The injection of comparative example's 1 gained contains ethanol, be unfavorable for injection, and particle diameter is obviously greater than technical scheme of the present invention, and stability also significantly is lower than technical solution of the present invention.
Test three, pH value, redissolution test
The Lansoprazole freeze-dried injection that embodiment of the invention 1-4 is prepared carries out lyophilizing front and back pH value and the investigation of redissolution situation, and compares (comparative example 2) with CN201210115887.X embodiment 1 product, the results are shown in lower tabulation 4.
Table 4pH value, the situation measurement result of redissolving
| ? | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 | The comparative example 2 |
| PH value before the lyophilizing | 8.54 | 8.87 | 9.33 | 9.52 | 11.18 |
| PH value after redissolving | 8.28 | 8.66 | 9.08 | 9.24 | 11.07 |
| The redissolution time (second) | 30 | 20 | 30 | 25 | 420 |
| The redissolution situation | Clarification | Clarification | Clarification | Clarification | Clarification |
| Particulate matter | Qualified | Qualified | Qualified | Qualified | Qualified |
The freeze-dried powder that above-mentioned several redissolution are qualified carries out influence factor's test, respectively (25 ℃ of 60 ℃, high humidity, humidity 90% ± 5%), high light (4500lx ± 500lx) placed 20 days, respectively at sampling calibrating in the 20th day, result and comparison in 0 day, investigate the stability of sample, the results are shown in such as following table 5.
Table 5: study on the stability result
As can be seen from the above results, lansoprazole injection of the present invention is brought into play significant synergism by nonacid aminoacid and phospholipid bile acid, alkaline matter, thereby has the technique effect that significantly is better than the prior art scheme.Particularly, pH value acid was lower than prior art after the Lansoprazole for injecting of the present invention's preparation redissolved, neutrality closer to human body, and pH value changes before than lyophilizing very little, redissolution speed is fast, and the redissolution situation is good, particulate matter is qualified, good stability, and pH descends before than lyophilizing much after redissolving by the standby Lansoprazole for injecting of other patent systems, and the pH value of lansoprazole is higher in the prior art, is unfavorable for clinical use, and high alkalinity causes the unstable of packaging material cillin bottle easily, has caused certain risk for the safety stable and medication of lansoprazole.And the stability of prior art products has larger gap than the sample of the present invention's preparation.
Can find out also from above-mentioned data that simultaneously lansoprazole micellar solution can be disperseed more evenly when micellar solution of the present invention adds polyhydric alcohol (embodiment 2), mean diameter further reduces.
Claims (14)
1. Lansoprazole for injecting pharmaceutical composition, this pharmaceutical composition contains lansoprazole, phospholipid, bile acid, nonacid aminoacid, alkaline matter, wherein nonacid aminoacid is selected from one or more the mixture in glycine, alanine, valine, phenylalanine, serine, glutamine, lysine, arginine, the histidine, and alkaline matter is sodium hydroxide, potassium hydroxide or the mixture of the two.
2. according to claim 1 pharmaceutical composition, the mass ratio of lansoprazole, phospholipid, bile acid, nonacid aminoacid, alkaline matter is 1: 1-100: 1-150: 1-50: 0.1-1.
3. according to claim 2 composite micelle pharmaceutical composition, the mass ratio of lansoprazole, phospholipid, bile acid, nonacid aminoacid, alkaline matter is 1: 3-10: 4-20: 1-30: 0.1-0.5.
4. the pharmaceutical composition of any one in 3 according to claim 1, wherein nonacid aminoacid is selected from one or more the mixture in glycine, alanine, valine, the serine.
5. the pharmaceutical composition of any one in 3 according to claim 1, wherein phospholipid is selected from soybean phospholipid, egg yolk lecithin, the Semen sojae atricolor sphingomyelins, the egg yolk sphingomyelins, hydrogenated soya phosphatide, the hydrogenation egg yolk lecithin, phosphatidylcholine, PHOSPHATIDYL ETHANOLAMINE, Phosphatidylserine, phosphatidyl glycerol, phosphatidylinositols, two Petiolus Trachycarpi phosphatidylcholines, two Petiolus Trachycarpi PHOSPHATIDYL ETHANOLAMINE, the distearyl phosphatidylcholine, two Petiolus Trachycarpi PGs, two Petiolus Trachycarpi Phosphatidylserine, dimyristoyl phosphatidyl choline, GLYCEROL,DIMYRISTOYL PHOSPHATIDYL, DMPEA, dilinoleoylphosphatidylcholine, dilinoleic acid glyceride phosphatidylcholine, dilinoleic acid glyceride PHOSPHATIDYL ETHANOLAMINE, the mixture of one or more of dilinoleic acid glyceride phosphatidyl glycerol.
6. the pharmaceutical composition of any one in 3 according to claim 1; wherein bile acid is selected from free bile acid, conjugated bile acid or the mixture of the two; wherein free bile acid is cholic acid, lithocholic acid, deoxycholic acid, chenodeoxycholic acid, ursodesoxycholic acid, Hyodeoxycholic Acid or its mixture, and conjugated bile acid is carboxyl and the product behind the formation of the amino in glycine or the taurine amido link or the mixture of these products in the above-mentioned free bile acid.
7. the pharmaceutical composition of any one in 6 according to claim 1, said composition further contains water-soluble polyol, and this water-soluble polyol is selected from a kind of or its multiple mixture in propylene glycol, glycerol, ethylene glycol, the Polyethylene Glycol.
8. according to claim 7 pharmaceutical composition, wherein water-soluble polyol is PEG400.
9. the pharmaceutical composition of any one in 7 according to claim 1, said composition is lyophilized injectable powder, and further contains the lyophilizing excipient that is selected from mannitol, lactose, sorbitol, sodium chloride, gelatin hydrolysate, polyvinylpyrrolidone.
10. the commercial assembly packaging of a lansoprazole medicine, this packing is formed by the organic facies packing and the water packaged combination that contain lansoprazole of independent packaging, the described organic facies of lansoprazole that contains is by lansoprazole, phospholipid, bile acid and water-soluble polyol form, water is by nonacid aminoacid, alkaline matter and water for injection are made, wherein water-soluble polyol is selected from propylene glycol, glycerol, ethylene glycol, a kind of or its multiple mixture in the Polyethylene Glycol, nonacid aminoacid is selected from glycine, alanine, valine, phenylalanine, serine, glutamine, lysine, arginine, the mixture of one or more in the histidine, alkaline matter are sodium hydroxide, potassium hydroxide or the mixture of the two.
11. the preparation method of the described Lansoprazole medicine composition of any one comprises the steps: among the claim 1-8
1. lansoprazole, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, remove organic solvent, as organic facies; Perhaps will remove to add in the water-soluble polyol in the mixture behind the organic solvent and dissolve, as organic facies;
2. nonacid aminoacid and alkaline matter are added to the water, mix, dissolving is rear as water;
3. with above-mentioned two step gained organic faciess and water mix homogeneously, make the lansoprazole injection.
12. the preparation method of the described Lansoprazole medicine composition of claim 9 comprises the steps:
1. lansoprazole, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, remove organic solvent, as organic facies; Perhaps will remove to add in the water-soluble polyol in the mixture behind the organic solvent and dissolve, as organic facies;
2. nonacid aminoacid, alkaline matter and freeze-dried excipient are added to the water, mix, dissolving is as water;
3. with organic facies and the water mix homogeneously of above-mentioned steps, according to a conventional method lyophilization is prepared into into freeze-dried powder.
13. the preparation method of the lansoprazole medicine commercial packing of claim 10 comprises the steps:
1. lansoprazole, phospholipid, bile acid are dissolved in the organic solvent and stir, form settled solution, organic solvent is removed in distilling under reduced pressure, adds water-soluble polyol as organic facies;
2. nonacid aminoacid, alkaline matter are dissolved in the water, obtain water;
3. above-mentioned organic facies and water are made organic facies concentrated solution for injection and water injection according to the preparation method of regular injection liquid respectively and pack respectively, then with organic facies packing and the commercial packing of water packaged combination packing composition of independent packaging.
14. the purposes of the described Lansoprazole medicine composition of any one in the medicine of preparation treatment peptic ulcer, reflux esophagitis and Zollinger-Ellison syndrome disease in 10 according to claim 1.
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| Publication number | Priority date | Publication date | Assignee | Title |
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| CN112294762A (en) * | 2020-10-23 | 2021-02-02 | 南京科默生物医药有限公司 | Micelle, antifungal composition, and preparation method and application thereof |
| CN113058074A (en) * | 2020-01-02 | 2021-07-02 | 华利源(上海)生物医药科技有限公司 | Temperature-sensitive filler composition |
| CN114010522A (en) * | 2021-12-22 | 2022-02-08 | 郑州大学 | A kind of lipoic acid mixed micelle and its preparation method and application |
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| CN102600088A (en) * | 2012-04-19 | 2012-07-25 | 湖北济生医药有限公司 | Injection lansoprazole medicine composition and preparation method thereof |
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| CN102600088A (en) * | 2012-04-19 | 2012-07-25 | 湖北济生医药有限公司 | Injection lansoprazole medicine composition and preparation method thereof |
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Cited By (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN113058074A (en) * | 2020-01-02 | 2021-07-02 | 华利源(上海)生物医药科技有限公司 | Temperature-sensitive filler composition |
| CN113058074B (en) * | 2020-01-02 | 2022-04-29 | 华利源(上海)生物医药科技有限公司 | Temperature-sensitive filler composition |
| CN112294762A (en) * | 2020-10-23 | 2021-02-02 | 南京科默生物医药有限公司 | Micelle, antifungal composition, and preparation method and application thereof |
| CN112294762B (en) * | 2020-10-23 | 2022-10-28 | 南京科默生物医药有限公司 | Micelle, antifungal composition, and preparation method and application thereof |
| CN114010522A (en) * | 2021-12-22 | 2022-02-08 | 郑州大学 | A kind of lipoic acid mixed micelle and its preparation method and application |
| CN114010522B (en) * | 2021-12-22 | 2023-10-13 | 郑州大学 | A lipoic acid mixed micelle and its preparation method and application |
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