CN1969876B - Lyophilized injection of lentinan and preparation process thereof - Google Patents
Lyophilized injection of lentinan and preparation process thereof Download PDFInfo
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- CN1969876B CN1969876B CN2005100221448A CN200510022144A CN1969876B CN 1969876 B CN1969876 B CN 1969876B CN 2005100221448 A CN2005100221448 A CN 2005100221448A CN 200510022144 A CN200510022144 A CN 200510022144A CN 1969876 B CN1969876 B CN 1969876B
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Abstract
The invention discloses a freeze dried of mushroom polysaccharide, which comprises the following steps: adopting neutral amino acid as rack agent; blending evenly; reducing the density of sodium hydroxide; filtering; adjusting pH value.
Description
Technical field
The present invention relates to a kind of freeze dried lentinan holoside powder injecta, belong to drug world.
Background technology
Lentinan is a kind of active substance with obvious anticancer effect of separating in the Lentinus Edodes, be found first in Japan in 1969, Japan at first produced and lentinan is prepared into outside the injectable powder country of sale in 1986, the clinical cancer in digestive system such as gastric cancer, rectal cancer that are mainly used in, its main route of administration is intravenous drip or injects, China began the lentinan of import Japan aginomoto in 1988, and was applied to clinical.Since nineteen eighty-two, institute of antibiotics, Sichuan, Henan Medicine Industrial Inst., successively extract lentinan from the Lentinus Edodes liquid that submerged fermentation is cultivated, " Lentinula edodes mycelium polysaccharide " by name, the lentinan that difference is extracted from sporophore.Kaifeng pharmaceutical factory produced lentinan film in 1986.Ministry of Public Health approval Meifeng Pharmaceutical Factory Fuzhou City's test manufacture in the same year " Lentinula edodes mycelium polysaccharide sheet " and " lentinan intramuscular dose ", all effective to chronic persistent hepatitis, part hepatitis B patient surface antigen is turned out cloudy; And combined with chemotherapy Drug therapy advanced esophageal cancer, gastric cancer also have better curative effect.What at present mainly be that Nanjing Zhenzhong Biological Engineering Co., Ltd produces on the market is the lentinan for injection of raw material with the lentinan.
Report lentinan injection is also arranged at present, it is to adopt single mannitol to make caffolding agent, existing production is adopted and is transferred pH to filter after the neutrality, the dissolving of employing high-concentration sodium hydroxide, cause lentinan loss and decomposition easily, occur phenomenons such as suspendible is inhomogeneous in the aqueous solution of preparation, cause safety in utilization to reduce.
Summary of the invention
Technical scheme of the present invention has provided a kind of lentinan lyophilized injectable powder, and another technical scheme of the present invention has provided the preparation method of this lyophilized injectable powder.
Technical scheme of the present invention is a kind of antineoplastic lentinan lyophilized preparation, it is characterized in that being is raw material with following weight proportion medicine: 0.8～1.20 part of lentinan, 80～200 parts of freeze-dried excipient freeze-dried excipients.
Preferred drug ratio is: 1.15 parts of lentinan, 100～160 parts of freeze-dried excipients.
More preferably, it is that lentinan and freeze-dried excipient by following weight proportion is prepared from:
1 part of lentinan, 130 parts of freeze-dried excipients.
Described freeze-dried excipient can be a kind of in glycine, alanine, serine or the proline, or the mixture of they and mannitol, and preferred freeze-dried excipient is a glycine.Weight proportion is in the mixture of neutral amino acid and mannitol: 120～150 parts of neutral amino acids, 0～30 part in mannitol.Preferably, described neutral amino acid is: glycine.
Further, freeze dried lentinan holoside powder injecta of the present invention is that lentinan and freeze-dried excipient by following weight proportion is prepared from:
0.8～1.20 part of lentinan, 80～200 parts of freeze-dried excipients, freeze-dried excipient is 120～150 parts of glycine, 0～30 part in mannitol by weight.
Further, it is that lentinan and freeze-dried excipient by the following weight proportioning is prepared from:
1.15 parts of lentinan, 150 parts of glycine.
The present invention also provides the preparation method of this lentinan lyophilized preparation, and it comprises the steps:
A, the lentinan that takes by weighing the following weight proportioning and freeze-dried excipient: 0.8～1.20 part, 80～200 parts of freeze-dried excipients;
B, get lentinan, with the alkali liquor dissolving, add freeze-dried excipient, mix, filter, regulating pH with hydrochloric acid is that the bottle of packing into is divided in 6.5～8.0 backs, after the lyophilizing, seals.
Preferred drug ratio is to get 1.15 parts of lentinan, with the alkali liquor dissolving, mixes stirring for 150 parts with a kind of freeze-dried excipient again, filters.Transferring pH with hydrochloric acid is that the bottle of packing into is divided in 6.5～8.0 backs, after the lyophilizing, seals.Described antineoplastic freeze dried lentinan holoside powder injecta is characterized in that freeze-dried excipient can be the mixture of institute's neutral amino acid or neutral amino acid and mannitol; Wherein, described neutral amino acid is one or more in glycine, alanine, serine or the proline, and freeze-dried excipient is a glycine preferably.
The described alkali liquor of step b is the sodium hydroxide of 0.1～1 molar concentration.
Lentinan is a biological response modifier, and it is by the immune stimulatory cell maturation, differentiation and propagation, improve host's organism balance, reach recovery and improve the reactivity of host cell lymphokine, hormone and other physiologically active factor, owing to be indirect action, so toxic and side effects is little.The toxicity of lentinan generally has dizziness, reversibility such as uncomfortable in chest reaction, and a few patients has flush.The intravenous drip lentinan is prone to anaphylactic shock.The present invention compares with current technology, before pH is being transferred in employing on the technology, filter and to reduce the lentinan loss of active ingredients, lentinan dissolves under alkali condition, the solution state that is complete and homogeneous filters easily, adjust pH again after the filtration, more reasonable, and former process using elder generation adjust pH, lentinan has been separated out and has been suspension, and it is bigger to refilter then loss.The inventor adopts the NaOH solution of lower concentration simultaneously, more helps reducing in the production process because the degradation reaction that caustic alkali causes.Because lentinan easily decomposes so adopt neutral amino acid in the excipient substance of the present invention under acid and the alkali condition, because the hydrotropy effect and the pH regulator effect of amino acids, overcome former process using mannitol, the phenomenon of the inhomogeneous solution that lyophilizing caffolding agents such as dextran occur in aqueous solution, obtain homodisperse solution, its toxicity is reduced.Simultaneously adopt small amount of mannitol or do not adopt mannitol, make assay more accurate because of it, more convenient.The examine stability result shows that solution is more stable.
Main with local, that whole body group medicine is relevant specific safety test explanations such as anaphylaxis (local, whole body and photosensitive toxicity), haemolysis and part (blood vessel reason, skin, mucosa, flesh etc.) zest, lentinan agent man of the present invention exempts from quiet notes 0.4mg/kg, observes blood vessel non-stimulated for three days on end.Intramuscular injection 0.1mg/ only observes non-stimulated to muscle behind 48h.The hemolytic test shows that erythrocyte is insoluble.Guinea pig intraperitoneal injection is subjected to reagent thing 0.5ml, the next day once, totally 3 sensitization.Preparation in the 14th day serum in injection back carries out the intradermal injection passive sensitization to Cavia porcellus first, excites after 48 hours.Result of the test shows that the reaction of lentinan for injection models of passive skin irritability is negative.Systemic allergy test (ASA) initiatively: guinea pig intraperitoneal injection is tried thing 0.5ml, the next day once, totally 3 sensitization.Injection first gave intravenous injection in back the 14th day, 21 days and excited by reagent 2ml, and result of the test shows that initiatively systemic anaphylaxis is negative for lentinan for injection.
Lentinan freeze-dried powder of the present invention adopts neutral amino acid to make caffolding agent, solution is more even, clinical use is safer, by reducing naoh concentration, filter the back and regulate pH value, can reduce the lentinan loss, reduce because the hydrolysis that soda acid causes provides a kind of effective and safe drug to select for clinical.
Obviously, according to foregoing of the present invention,,, can also make modification, replacement or the change of other various ways not breaking away under the above-mentioned basic fundamental thought of the present invention prerequisite according to the ordinary skill knowledge and the customary means of this area.
The specific embodiment of form is described in further detail foregoing of the present invention again by the following examples.But this should be interpreted as that the scope of the above-mentioned theme of the present invention only limits to following example.All technology that realizes based on foregoing of the present invention all belong to scope of the present invention.
Specific implementation method
Embodiment 1 lentinan freeze-dried powder adjuvant screening test of the present invention
Get 5 of 200ml volumetric flasks, add Lentinus Edodes polysaccharide raw material 115mg respectively, add the sodium hydroxide solution of 3ml 1 molar concentration, allow its natural swelling, stirring and dissolving adds a small amount of water for injection dilution, stirs evenly, add glycine, alanine, serine, proline, mannitol 14.0g successively, filter, filtrate is neutralized to pH7.2 with hydrochloric acid, adds injection water to 200 milliliter again, carry out the solution uniformity and detect result such as table 1.
Table 1 solution uniformity testing result
| Excipient | Glycine | Alanine | Serine | Proline | Mannitol |
| PH test paper color development inspection technique | Colour developing evenly | Colour developing evenly | Colour developing evenly | Colour developing evenly | It is inhomogeneous to develop the color, and soaks into layering |
| The microscopic observation method | Be uniformly dispersed | Be uniformly dispersed | Be uniformly dispersed | Be uniformly dispersed | Disperse inhomogeneous |
| The result | Homogeneous solution | Homogeneous solution | Homogeneous solution | Homogeneous solution | Non-homogeneous solution |
Experimental result shows that the aminoacid of selecting for use contrasts with respect to the simple caffolding agent of doing with mannitol, and lentinan disperses more even in aqueous solution.Owing to disperse uniformly, use safer clinically.
The ratio of adjuvant screening test of embodiment 2 lentinan freeze-dried powders of the present invention
Get 7 of 200ml volumetric flasks, add Lentinus Edodes polysaccharide raw material 115mg respectively, add the sodium hydroxide solution of 3ml 1 molar concentration, allow its natural swelling, stirring and dissolving adds a small amount of water for injection dilution, stir evenly, add glycine, 10.0g, in 7 volumetric flasks, add mannitol 0g, 2g, 5g, 10g, 15,30g, 40g successively, mixing, filter, filtrate is neutralized to pH7.2 with hydrochloric acid, adds injection water to 200 milliliter again, carry out the solution uniformity and detect result such as table 2.
Table 2 solution uniformity testing result
| Glycine: mannitol | ?100∶0 | ?100∶2 | ?100∶5 | ?100∶10 | ?100∶15 | ?100∶30 | ?100∶40 |
| PH test paper color development inspection technique | Evenly | Evenly | Evenly | Soak into slightly | Soak into slightly | Obviously layering | Obviously layering |
| The microscopic observation method | Evenly | Evenly | Evenly | Evenly | Evenly | Inhomogeneous | Inhomogeneous |
| The result | Evenly | Evenly | Evenly | Evenly | Equal | Inhomogeneous | Inhomogeneous |
Experimental result shows that it is good to select for use aminoacid to make caffolding agent separately, and just consumption is big slightly, but and after mannitol share, both can improve the form of lyophilized formulations, can reduce the whole consumption of excipient again.
Embodiment 3 lentinan freeze-dried powder major ingredient of the present invention and supplementary product compatibility screening tests
Get this product 115mg respectively,, add right amount of auxiliary materials, add the injection water to 150ml with 0.25mol/L sodium hydroxide 50ml dissolving, regulate pH to 7.0～7.5, be diluted to 200ml with sterilized water for injection, aseptic filtration, packing (2ml/ bottle), lyophilization, result of the test sees Table 3.
Determining of table 3 supplementary product consumption
Result of the test shows, and is best when every injection adjuvant (glycine) consumption is the 150mg outward appearance, i.e. principal agent: adjuvant is 1.15: 150, promptly 1: 130.
The preparation of embodiment 4 lentinan freeze-dried powders of the present invention
Get lentinan raw material 1.10 gram, add 0.25mol/L sodium hydroxide solution 500ml, allow its natural swelling, stirring and dissolving, add a small amount of water for injection dilution, stir evenly, add alanine 100g, stir, filter, filtrate is neutralized to pH6.8～7.2 with hydrochloric acid, adds injection water to 2000 milliliter again, filters and surveys content, packing, the 2ml/ bottle carries out lyophilization, outlet seals, gland, lid is rolled in leak detection, labels.
The preparation of embodiment 5 lentinan freeze-dried powders of the present invention
Get lentinan raw material 1.15 gram, add 0.25mol/L sodium hydroxide solution 500ml, allow its natural swelling, stirring and dissolving, add a small amount of water for injection dilution, stir evenly, add serine 120g, stir, filter, filtrate is neutralized to pH6.8～7.2 with hydrochloric acid, adds injection water to 2000 milliliter again, filters and surveys content, packing, the 2ml/ bottle carries out lyophilization, outlet seals, gland, lid is rolled in leak detection, labels.
The preparation of embodiment 6 lentinan freeze-dried powders of the present invention
Get lentinan raw material 1.05 gram, add the sodium hydroxide solution of 30ml 1 molar concentration, allow its natural swelling, stirring and dissolving, add a small amount of water for injection dilution, stir evenly, add glycine 120g, stir, filter, filtrate is neutralized to pH6.8～7.2 with hydrochloric acid, adds injection water to 2000 milliliter again, filters and surveys content, packing, the 2ml/ bottle carries out lyophilization, outlet seals, gland, lid is rolled in leak detection, labels.
The preparation of embodiment 7 lentinan freeze-dried powders of the present invention
Get lentinan raw material 1.08 gram, add the sodium hydroxide solution of 30ml 1 molar concentration, allow its natural swelling, stirring and dissolving, add a small amount of water for injection dilution, stir evenly, add glycine and mannitol mixture (100: 15) 150g, stir, filter, filtrate is neutralized to pH6.8～7.2 with hydrochloric acid, adds injection water to 2000 milliliter again, filters and surveys content, packing, the 2ml/ bottle carries out lyophilization, outlet seals, gland, lid is rolled in leak detection, labels.
Below prove beneficial effect of the present invention by physicochemical property and toxicological experiment.
Test example 1 lentinan freeze-dried powder physical and chemical experiment of the present invention and toxicological experiment
Get lentinan raw material 1.15 grams, add 0.25mol/L sodium hydroxide solution 500ml, allow its natural swelling, stirring and dissolving, add a small amount of water for injection dilution, stir evenly, add glycine and mannitol mixture (100: 5) 140g, stir, filter, filtrate is neutralized to pH6.8～7.2 with hydrochloric acid, adds injection water to 2000 milliliter again, filters
Stability test: product is after high temperature (40 ℃, 60 ℃, 80 ℃), high humidity (RH92.5%, RH75%, 25 ℃) and illumination influence factors such as (4500lx) test, and appearance character, clarity, pH value, content and sterility test all meet the requirements.3 months investigation result of product accelerated test of the present invention (40 ℃ of RH75%), appearance character, clarity, pH value, content, impurity and sterility test all meet the requirements.
Product of the present invention keeps sample in room temperature and investigates the 0th, 1,3,6,12,18,24 month, and every project all meets the requirements through regularly taking a sample to check.
Toxicological experiment proves, adopt the lentinan lyophilized formulations of this method preparation, specification 1mg is diluted to 2ml/ with normal saline and props up, in injection is subjected to reagent thing 2ml/kg to the rabbit auricular vein, observed in continuous 3 days, the vascular stimulation implementations, the result shows, after the rabbit injection is subjected to the reagent thing, do not have obvious struggle phenomenon, reaction of animals gentleness, auricular vein blood vessel and surrounding tissue do not have obvious red and swollen phenomenon.Histopathologic examination, pick up the ears epidermis, dermal tissue structure of administration one is intact, does not see degeneration, necrosis, disappearance and hyperkeratosis, and auricular vein does not have obvious expansion, does not see thrombosis; Give the injection of rabbit quadriceps femoris and be subjected to reagent thing 1ml, behind 48h, observation muscular irritation test situation, result show that the muscular tissue of lentinan for injection injection site does not have any difference with contrast position muscular tissue, and the order of reaction is 0;
Hemolytic experiment: from the rabbit heart extracting blood, make into and add normal saline behind the defibrinated blood and be made into 2% red cell suspension, add test liquid, and do the positive, negative control, and observing after 1 hour, the result shows the positive, the whole haemolysis of control tube, the erythrocyte that is tried thing and negative control pipe all sinks, supernatant liquid achromatism and clarity, not coagulation of R-RBC.
Passive anaphylaxis test (PCA): guinea pig intraperitoneal injection is subjected to reagent thing 0.5ml, the next day once, totally 3 sensitization.Preparation in the 14th day serum in injection back carries out the intradermal injection passive sensitization to Cavia porcellus first, excites after 48 hours.Result of the test shows that the reaction of lentinan for injection models of passive skin irritability is negative.
Systemic allergy test (ASA) initiatively: guinea pig intraperitoneal injection is tried thing 0.5ml, the next day once, totally 3 sensitization.Injection first gave intravenous injection in back the 14th day, 21 days and excited by reagent 2ml, and result of the test shows that initiatively systemic anaphylaxis is negative for lentinan for injection.
Lentinan freeze-dried powder of the present invention adopts neutral amino acid to make caffolding agent, solution is more even, clinical use is safer, by reducing naoh concentration, filter the back and regulate pH value, can reduce the lentinan loss, reduce because the hydrolysis that soda acid causes provides a kind of effective and safe drug to select for clinical.
Claims (3)
1. freeze dried lentinan holoside powder injecta, it is characterized in that: it is to be prepared from by the lentinan of following weight proportion and freeze-dried excipient glycine: 1.15 parts of lentinan, 150 parts of glycine.
2. method for preparing the described freeze dried lentinan holoside powder injecta of claim 1, it comprises the steps:
A, the lentinan that takes by weighing the following weight proportioning and freeze-dried excipient glycine: 1.15 parts of lentinan, 150 parts of glycine;
B, get lentinan, with the alkali liquor dissolving, add the freeze-dried excipient glycine, mix, filter, regulating pH with hydrochloric acid is that the bottle of packing into is divided in 6.5～8.0 backs, after the lyophilizing, seals.
3. according to the preparation method of the described freeze dried lentinan holoside powder injecta of claim 2, it is characterized in that: the described alkali liquor of step b is the sodium hydroxide of 0.1～1 molar concentration.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1288729A (en) * | 2000-07-19 | 2001-03-28 | 南京振中生物工程有限公司 | Freeze dried lentinan holoside powder injecta and its preparation |
| CN1939334A (en) * | 2005-09-28 | 2007-04-04 | 北京赛生药业有限公司 | Freeze-drying powder for injecting lentinan and its content determination |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1288729A (en) * | 2000-07-19 | 2001-03-28 | 南京振中生物工程有限公司 | Freeze dried lentinan holoside powder injecta and its preparation |
| CN1939334A (en) * | 2005-09-28 | 2007-04-04 | 北京赛生药业有限公司 | Freeze-drying powder for injecting lentinan and its content determination |
Non-Patent Citations (2)
| Title |
|---|
| 侯惠民 主编.药用辅料应用技术（第二版）.中国医药科技出版社,2002,284-285. * |
| 毕殿洲 主编.药剂学（第四版）.人民卫生出版社,1999,241-242. * |
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