CN102988423B - Compound ossotide liposome injection - Google Patents
Compound ossotide liposome injection Download PDFInfo
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- CN102988423B CN102988423B CN201210559121.0A CN201210559121A CN102988423B CN 102988423 B CN102988423 B CN 102988423B CN 201210559121 A CN201210559121 A CN 201210559121A CN 102988423 B CN102988423 B CN 102988423B
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- liposome
- bone peptide
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicinal Preparation (AREA)
Abstract
The invention discloses a compound ossotide liposome injection and a preparation method thereof. The liposome injection is prepared from compound ossotide, cholesterol, yolk phosphatidylinositol, Tween 60, trehalose and mannitol. The liposome injection has excellent preparation stability, the liposome cannot crack due to fusion, ice crystal and the like in the freezing process, and excellent encapsulation efficiency of the liposome can be maintained after being stored for a long time; the solubility of compound ossotide can be improved, the quality of a preparation product can be improved, the toxic and side effects can be reduced, the maintenance period of medicament in systemic circulation can be increased, the bioavailability of the medicament can be improved, and the curative effect can be remarkably improved; and the preparation method is simple, and is suitable for industrial production.
Description
Technical field
The present invention relates to a kind of injection and method for making thereof of complex bone peptide, be specifically related to a kind of lipidosome injection and method for making thereof of complex bone peptide, belong to medical technical field.
Background technology
Complex bone peptide is a kind of Chinese medicine extract, and specifically take the health pig of 3 parts of quality or the Scorpio of fetal bovine limb bone and a mass ratio is raw material, extracts the thick product obtaining.Complex bone peptide is rich in the long factor of multiple bone, main component: polypeptide, aminoacid, organic calcium, phosphorus, inorganic calcium, inorganic salt, trace element etc., each composition has stronger mutual coordinative role, can promote knitting, regulate bone metabolism, balance osteogenesis, has stronger mutual coordinative role, and without gastrointestinal reaction and addiction, releasing osteoporosis patient's misery safely and effectively.Be used for the treatment of clinically the diseases such as rheumatism, rheumatoid arthritis, hyperosteogeny, fracture.Polypeptide drug molecular weight is larger, and molecule is easily assembled, and fat-soluble poor, the difficult biomembrane that sees through, conventionally can only drug administration by injection.
The complex bone peptide dosage form of listing is mainly injection and aseptic freeze-dried powder pin at present., the complex bone peptide injection that common process is prepared, physics and chemistry stable in properties is poor, and long-term storage drug quality can decline but also can generate some impurity, brings toxic and side effects, has left hidden danger to clinical use.Freeze-dried powder fabrication cycle is long, and expense is high, price.
Patent documentation CN1579541A discloses a kind of complex bone peptide injection and preparation method, through extraction complex bone peptide its, complex bone peptide and a certain proportion of excipient are made to preparation, this preparation method is the preparation method of traditional aseptic freeze-dried injectable powder, preparation process is complicated, and the bioavailability of somewhat expensive and medicine is not high.And the main component of complex bone peptide solution is micromolecule polypeptide class material, in preservation process, very easily causes that polymerization forms macromole, thereby affect biological activity and the drug safety of this product.Patent documentation CN1830485A discloses a kind of anti-inflammation analgesia medicine compound bone peptide injection and preparation method thereof.It,, through extracting, in lucifuge, makes injection in nitrogen filled protection situation by complex bone peptide extracting solution.But complex bone peptide is easily assembled in liquid, generate macromolecular substances, affect bioavailability, also strengthened the insecurity of medication.Patent documentation CN100998607A discloses a kind of injecta containing compound bone peptide and sodium chloride and preparation method thereof.It is comprised of complex bone peptide solution, sodium chloride, water for injection.But the complex bone peptide for injection bioavailability that this conventional preparation method is made is low, and complex bone peptide is macromole, easily assembles, and increased the insecurity of medicine.Patent documentation CN101156872A discloses a kind of compound recipe bone-peptide preparation and preparation method thereof.Its preparation comprises injection with small volume and lyophilized injectable powder.But the preparation that this conventional method is produced, causes the disqualification rate of medicine to increase to some extent, increase the risk of human body.Patent documentation CN1903358A discloses a kind of oral administered compound bone peptide drug regimen and preparation method thereof, this kind of method adopts cyclodextrin bag and technology to increase dissolubility and the stability of complex bone peptide, but this medicine is polypeptide class biomolecule, in body, digestive enzyme can decompose medicine, affect the absorption of medicine, reduce bioavailability.
In pharmaceutical carrier induction system, the research of the submicrons such as microemulsion, microsphere, nanoparticle, liposome, pharmacosomes has become very active field in novel pharmaceutical formulation research.Drug encapsulation can be changed in these submicrons to medicine distribution in vivo, increase medicine in the abundance of target organ, thereby improve curative effect, alleviate toxic and side effects.
In targeting drug delivery system, the research of liposome is comparatively extensive, and liposome has good targeting and biocompatibility in vivo.
As a kind of new medicinal preparation, Liposomal formulation has the following advantages: (1) has slow releasing function: active component slowly discharges, and delays renal excretion and metabolism, thereby extends action time, improves mass effect; (2) reduce drug toxicity; (3) increase the dissolubility of medicine, improve the quality of the pharmaceutical preparations; (4) there is targeting: the contained medicine of liposome maintains high concentration in liver, spleen reticuloendothelial system internal organs part, thereby plays the effect of medicine organ targeting; (5) there is the protective effect to active pharmaceutical ingredient.
Liposome (Liposome) is dispersed in water discovery while carrying out electron microscopic observation by British scholar Bangham and Standlish by phospholipid at first.Phospholipid is dispersed in water self-assembling formation multilamellar vesicle, every layer of equal bilayer of lipid not; Between vesicle central authorities and each layer, by water, separated, bilayer thickness is about 4nm.Afterwards, this bimolecular folliculus with similar biofilm structure was called to liposome.Liposome can be divided into multilamelar liposome and courage and insight liposome.Unilamelar liposome is divided into again small unilamellar vesicle and large unilamellar vesicle.Small unilamellar vesicle is spherical, and size is generally 20-50 nanometer; Large unilamellar vesicle is of a size of micron number magnitude.
The people such as Britain Lai Men in 1971 start liposome for pharmaceutical carrier, Main Function mechanism is that drug powder or solution are wrapped in the water that liposome bilayer lipid membrane seals or are embedded in liposome bilayer lipid membrane, this microgranule has class cellularity, enter principal agent in human body and by reticuloendothelial system phagocytic, activated the autoimmune function of body, and the interior distribution of the body that changes encapsulated medicine, make the drug main will be liver, spleen, in the histoorgan such as lung and bone marrow, put aside, thereby improve the therapeutic index of medicine, reduce the toxicity of therapeutic dose and the reduction medicine of medicine.
In recent years, continuous progress along with biotechnology, liposome preparation technology gradual perfection, liposome mechanism of action is further illustrated, in addition liposome is applicable to vivo degradation, avirulence and non-immunogenicity, particularly great number tested data proof liposome can improve Drug therapy index, reduces drug toxicity and reduce drug side effect as pharmaceutical carrier, and reduces the advantages such as drug dose.
Summary of the invention
In order to form colory complex bone peptide lipidosome injection, thereby importantly find, can good compatible with complex bone peptide it well be sealed and non-leakage filmogen, and find the excipient composition that can make liposome form stable injectable agent.
To achieve these goals, large quantity research and realization that the inventor carries out, find the complex bone peptide of specified weight proportioning, cholesterol, PI, polysorbate60, trehalose and mannitol can be made complex bone peptide lipidosome injection, wherein, envelop rate as the complex bone peptide of active constituents of medicine is high, liposome particle diameter is little and be evenly distributed, compare with complex bone peptide injection of the prior art, the retention time significant prolongation of the active constituents of medicine of preparation of the present invention in body circulation, the biocompatibility of medicine is high, bioavailability obviously improves, curative effect obviously improves.
On the one hand, the invention provides a kind of complex bone peptide lipidosome injection, it is mainly made by the composition of following weight proportion:
Preferably, the weight ratio between cholesterol and PI is between 1:2-1:4.
Further preferably, complex bone peptide lipidosome injection of the present invention is mainly made by the composition of following weight proportion:
Further preferably, the weight ratio between cholesterol and PI is between 1:2-1:3.
Again further preferably, complex bone peptide lipidosome injection according to the present invention is made by the medicine and the excipient composition that comprise following weight proportion:
Again further preferably, the weight ratio between cholesterol and PI is 1:2.
As one of specific embodiment of the present invention, complex bone peptide lipidosome injection of the present invention can also add the mannitol of 10 parts to be prepared into freeze-dried powder.
As the phospholipid that is used to form liposome, can use natural phospholipid and synthetic phospholipid.In the present invention, as the complex bone peptide of active constituents of medicine, its water solublity is good, fat-soluble poor.For the feature of complex bone peptide, the inventor finds that by research PI is particularly suitable for as basic phospholipid filmogen.
PI (PI) is as a kind of natural phospholipid, and its content is very high, easily obtains, cheap.The phase transition temperature of PI is higher, is easy to form stable liposome membrane.
In complex bone peptide lipidosome injection of the present invention, for the complex bone peptide of 3 weight portions, the consumption of PI is 8-80 weight portion.If the consumption of PI, lower than 8 weight portions, cannot form stable liposome; Otherwise, if the consumption of the consumption of PI higher than 80 weight portions, the envelop rate as the complex bone peptide of active constituents of medicine declines, the quality of injection and curative effect reduce.
In complex bone peptide lipidosome injection of the present invention, cholesterol is for regulating the membrane stability of liposome.
The inventor finds through research, when cholesterol and PI weight ratio are 1:2-1:4, can form stable complex bone peptide liposome.When cholesterol and PI weight ratio are during lower than 1:2, membrane stability reduces, and complex bone peptide is easy to seepage; When cholesterol and PI weight ratio are during higher than 1:4, complex bone peptide liposome membrane mobility is too high, and the complex bone peptide being wrapped in liposome is easy to discharge.In addition, research finds, when cholesterol and PI weight ratio are 1:2-1:4, formed liposome toxicity is low.
Research shows, the stability of liposome and bioavailability have close corresponding relation.Stability is higher, and bioavailability is higher.Therefore, the stability of complex bone peptide lipidosome injection of the present invention is high, is to cause one of factor that drug bioavailability is high.
On the other hand, the inventor studies discovery, in complex bone peptide lipidosome injection of the present invention, for the complex bone peptide of 3 weight portions, the consumption of PI is 8-80 weight portion, cholesterol is 4-20 weight portion, and cholesterol and PI weight ratio be while being 1:2-1:4, and the envelop rate of formed complex bone peptide lipidosome injection is high.
In complex bone peptide lipidosome injection of the present invention, with Tween-60, further improve the stability of liposome membrane.Tween-60 (polysorbate-60) is a kind of non-ionic surface active agent, when for PI duplicature, can improve the chemical energy between this duplicature, thereby improve the chemical stability of liposome in waterborne liquid, and then improve the stability of complex bone peptide lipidosome injection.
In complex bone peptide lipidosome injection of the present invention, for the complex bone peptide of 3 weight portions, the consumption of Tween-60 is 1-60 weight portion.If the consumption of Tween-60 is lower than 1 weight portion, because its consumption is too low, cause the stability improvement of complex bone peptide lipidosome injection inadequate, otherwise, if the consumption of Tween-60 is higher than 60 weight portions, too high for its consumption and cause liposome membrane to be easy to reveal.
Research is found, when using the complex bone peptide, PI, cholesterol, Ovum Gallus domesticus Flavus lecithin of above-mentioned specified quantitative and Tween-60, can obtain colory complex bone peptide liposome, its envelop rate and stability are all very high, toxicity is low, and bioavailability is high.
In complex bone peptide lipidosome injection of the present invention, use trehalose and mannitol as excipient, be further used for forming stable injection.
Trehalose be by two glucose molecules with α, α, 1; the nonreducing sugar that 1-glycosidic bond forms; self property is highly stable, and its most obvious character is under anhydrous condition, to have the biomembranous ability of protection, even if make liposome also keep complete form in the situation that of dehydration.
In complex bone peptide lipidosome injection of the present invention, trehalose can effectively be protected form and the stability of liposome particles, further improves the stability of lipidosome injection.
Mannitol is being pharmaceutically good diuretic, reduces the diluent of intracranial pressure, intraocular pressure and treatment kidney medicine, dehydrant, sugar succedaneum, the excipient that is also used as tablet and solid, liquid, especially can support for lyophilized injectable powder provide good molding.
Complex bone peptide lipidosome injection of the present invention, the specification of its complex bone peptide can be 30mg, 2ml:30mg or 5ml:75mg.
On the other hand, the present invention also provides a kind of preparation method of complex bone peptide lipidosome injection, specifically comprises and is prepared as follows step:
(1) cholesterol, PI and polysorbate60 are dissolved in buffer salt solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under aseptic condition, in the liposome of solution state, add complex bone peptide, under constantly stirring, add trehalose;
(4) 0.45 μ m filtering with microporous membranes, fill, sterilizing, obtains.
On the other hand, the present invention also provides a kind of preparation method of complex bone peptide liposome freeze-drying powder injection injection, specifically comprises and is prepared as follows step:
(1) cholesterol, PI and polysorbate60 are dissolved in buffer salt solution, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under aseptic condition, in the liposome of solution state, add complex bone peptide, under constantly stirring, add trehalose and mannitol;
(4) 0.45 μ m filtering with microporous membranes, fill, lyophilization, obtains.
Preparation method described above, wherein said buffer salt solution is selected from a kind of in phosphate buffered solution, citrate buffer solution, carbonate buffer solution, borate buffer solution, is preferably pH and is 6.8 phosphate buffered solution.
Preparation method described above, wherein the temperature of the solution state liposome described in step (3) is 35 ℃.
Preparation method described above, wherein described in step (4), cryodesiccated concrete mode is, and pre-freeze temperature is-20 ~-65 ℃, and the pre-freeze time is 2 ~ 24 hours, and the distillation time is 12 ~ 48 hours, then baking temperature is 0 ~ 35 ℃, then be 2 ~ 12 hours drying time; Sterilising conditions is 121 ℃, 30min.The challenge of preparing liposome is how to make liposome membrane to form the high vesicle of envelop rate of suitable size, appropriate configuration material, and these materials do not spill at formation liposome.
The inventor, by selecting suitable material composition, adopting suitable preparation technology, has obtained colory complex bone peptide lipidosome injection, and liposome particle diameter is little, and particle size distribution is even, and envelop rate is high, and stability is high.
Lipidosome injection of the present invention has reduced toxic and side effects, improved formulation products quality, had good preparation stability, in refrigerating process, liposome can not break because of dehydration, fusion, ice crystal etc., after long term storage, liposome keeps good envelop rate equally.
The complex bone peptide lipidosome injection making by the inventive method, has improved the dissolubility of complex bone peptide, has improved the quality of formulation products, reduced toxic and side effects, increased the retention time of medicine in body circulation, improved the bioavailability of medicine, curative effect obviously improves; And preparation method is simple, be suitable for industrialized great production.
Accompanying drawing explanation
Fig. 1 is the blood drug level-time graph of complex bone peptide lipidosome injection.
Wherein:
The specific embodiment
By concrete preferred embodiment, the present invention is further described below.These embodiment are only illustrative, and should not be construed as limitation of the present invention.
the preparation of embodiment 1 complex bone peptide lipidosome injection
Composition used and weight thereof are as follows:
Adopt following technique to prepare complex bone peptide lipidosome injection:
(1) 400g cholesterol, 800g PI and 100g polysorbate60 are dissolved in to 2000ml pH and, in 6.8 phosphate buffered saline, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under aseptic condition, in the liposome of 35 ℃ of solution states, add 300g complex bone peptide, under constantly stirring, add 500g trehalose;
(4) 0.45 μ m filtering with microporous membranes, fill, then, at 121 ℃ of sterilizing 30min, obtains complex bone peptide lipidosome injection.
the preparation of embodiment 2 complex bone peptide lipidosome injections
Composition used and weight thereof are as follows:
Adopt following technique to prepare complex bone peptide lipidosome injection:
(1) 500g cholesterol, 1000g PI and 500g polysorbate60 are dissolved in to 5000ml pH and, in 6.8 phosphate buffered saline, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under aseptic condition, in the liposome of 35 ℃ of solution states, add 750g complex bone peptide, under constantly stirring, add 1000g trehalose;
(4) 0.45 μ m filtering with microporous membranes, fill, then, at 121 ℃ of sterilizing 30min, obtains complex bone peptide lipidosome injection.
the preparation of embodiment 3 complex bone peptide liposome freeze-drying powder injection injections
Composition used and weight thereof are as follows:
Adopt following technique to prepare complex bone peptide liposome freeze-drying powder injection injection:
(1) 400g cholesterol, 800g PI and 100g polysorbate60 are dissolved in the phosphate buffered saline that the pH of 2000ml is 6.8, make blank liposome;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under aseptic condition, in the liposome of 35 ℃ of solution states, add 300g complex bone peptide, under constantly stirring, add 500g trehalose and 1000g mannitol;
(4) 0.45 μ m filtering with microporous membranes, fill, then carries out lyophilizing, and pre-freeze temperature is-45 ℃, and the pre-freeze time is 22 hours, and the distillation time is 40 hours, then baking temperature is 35 ℃.Be 12 hours drying time again, obtains complex bone peptide liposome freeze-drying powder injection injection.
the preparation of comparative example 1-3 complex bone peptide lipidosome injection
Adopt identical with embodiment 1 respectively production technology, the composition in comparative example 1-3 is as shown in Table 1 below made respectively to complex bone peptide lipidosome injection;
Composition used in table 1 comparative example 1-3
Wherein, "/" represents not use, and comparative example 3 is only simple lyophilization, there is no pre-freeze, distillation and dry process again.
the mensuration of test example 1 liposome particle diameter
Under room temperature condition, get the complex bone peptide lipidosome injection in embodiment 1-3 and comparative example 1-3, be placed in the sample cell of SubmicronParticle Sizer Model 370 particle diameter detectors, measure particle size distribution and mean diameter; With projection electron microscope, observe particle shape.The results are shown in following table 2.
Table 2 liposome particle diameter testing result
As known from Table 2, the liposome particle diameter that embodiment 1-3 makes is even, aobvious spherical, big or small homogeneous; The liposome particle diameter that comparative example 1-3 makes is inhomogeneous, and shape is indefinite, not of uniform size.
Particularly, even when adopting same production technology, in embodiment 1-3, the particle appearance of gained complex bone peptide liposome and mean diameter thereof are obviously better than the complex bone peptide liposome of gained in comparative example 1-3.When the composition beyond using the present invention's composition used is described, or when composition consumption is outside the composition amount ranges of the present invention's restriction, or be different from when of the present invention when the freeze-dry process of preparation method, the outward appearance of gained complex bone peptide liposome is inferior to the present invention, and mean diameter obviously goes out greatly a lot.
the mensuration of test example 2 envelop rates
Rotating speed high speed centrifugation by the complex bone peptide lipidosome injection of preparing in embodiment 1-3 and comparative example 1-3 with 5000r/min, centrifugal 20 minutes, get supernatant, with dissolve with methanol, HPLC method is surveyed complex bone peptide content, and computational envelope rate, the results are shown in following table 3.
Table 3 entrapment efficiency determination result
The envelop rate of the Liposomal formulation that as shown in Table 3, prepared by embodiment 1-3 is significantly higher than the envelop rate of the Liposomal formulation of comparative example 1-3.When the composition beyond using the present invention's composition used is described, or when composition consumption is outside the composition amount ranges of the present invention's restriction, or be different from when of the present invention when the freeze-dry process of preparation method, the liposome encapsulation of gained liposome is lower than the present invention.
test example 3 study on the stability
By embodiment of the present invention 1-3 and comparative example the 1-3 sample of preparing and the complex bone peptide injection freeze-dried powder (lot number: 20110224 that goes on the market, Nanjing Xinbai Pharmaceutical Co) be placed in respectively lower 6 months of the condition of 40 ℃ of high temperature, relative humidity 75%, carry out accelerated test investigation, experimental result is shown in following table 4.
Table 4 accelerated test result
As shown in Table 4, while accelerating June, the content of listing preparation and comparative example 1-3 reduces, and related substance raises; And sample property of the present invention, content and related substance variation are all not obvious, illustrate that product stability of the present invention is good.
test example 4 percolation ratio tests
Get sample prepared by test example 1-3 and comparative example 1-3, at ambient temperature, respectively at 0 day, 30 days, 60 days, 90 days and 180 days, make regular check on, measure envelop rate, with the dose comparison of sealing for 0 day, calculate percolation ratio, the results are shown in following table 5.
Table 5 percolation ratio result of the test
As shown in Table 5, during long term storage, the complex bone peptide lipidosome injection percolation ratio of preparing in embodiment of the present invention 1-3 changes little, and the injection percolation ratio of preparing in comparative example 1-3 increases gradually, liposome seepage is serious, and complex bone peptide lipidosome injection prepared by this explanation the present invention has higher stability.
the mensuration of test example 5 blood drug level
28 rats are divided into 6 groups at random, every group respectively drug administration by injection embodiment 1,2 and 3 and comparative example 1,2 and 3 in the injection of preparation, and commercially available complex bone peptide injection (lot number: 20110224, Nanjing Xinbai Pharmaceutical Co), injection volume is 30mg complex bone peptide.After administration, respectively at 0.5h, 1h, 2h, 4h, 6h, 10h, 15h, 20h and 30h, take a blood sample, blood sample after treatment, is measured blood drug level with HPLC-MS method.Complex bone peptide lipidosome injection and the blood drug level of commercially available complex bone peptide injection and the relation curve of time in drafting embodiment 1 and 3, in the complex bone peptide lipidosome injection of preparation, comparative example 1,2,3, prepared, be shown in accompanying drawing 1.
As shown in Figure 1, compare with commercially available complex bone peptide lipidosome injection with the complex bone peptide lipidosome injection of preparation in comparative example 1,2 and 3, in the embodiment of the present invention 1,2 and 3, the complex bone peptide lipidosome injection of preparation has the following advantages: release rate in vivo slows down, in body circulation, distribution time extends, reached improved slow release effect, bioavailability increases.
industrial applicibility
From the result of above-described embodiment and experimental example, complex bone peptide liposome of the present invention has good outward appearance, and granule is little, and particle diameter is even, envelop rate is high, and stability is high, and percolation ratio is low, the time of staying is in vivo long, and bioavailability is high, has good industrial application value.
Below through the specific embodiment and the embodiment the present invention is had been described in detail; but should understand; these explanations do not form any restriction to scope of the present invention; in the case of without departing from the spirit and scope of protection of the present invention; can carry out multiple modification, improvement and replacement to technical solutions and their implementation methods of the present invention, these are all because falling within the scope of protection of the present invention.
Each list of references of mentioning in the application or quoting, which is hereby incorporated by reference.
Claims (3)
1. a complex bone peptide lipidosome injection, is characterized in that being made by the composition of following weight proportion:
And the weight ratio between cholesterol and PI is 1:2;
Its preparation method comprises the steps:
(1) cholesterol, PI and polysorbate60 are dissolved in buffer salt solution, make blank liposome; Described buffer salt solution is that pH is 6.8 phosphate buffered solution;
(2) blank liposome of above-mentioned preparation is processed through flowing steam sterilization, then supersound process twice, each 15 minutes;
(3) under aseptic condition, in the liposome of solution state, add complex bone peptide, under constantly stirring, add trehalose and mannitol;
(4) 0.45 μ m filtering with microporous membranes, fill, sterilizing or lyophilization, obtain complex bone peptide lipidosome injection.
2. complex bone peptide lipidosome injection according to claim 1, the temperature that it is characterized in that the solution state liposome described in step (3) is 35 ℃.
3. complex bone peptide lipidosome injection according to claim 1, it is characterized in that the lyophilization step described in step (4) is: pre-freeze temperature is-20～-65 ℃, the pre-freeze time is 2～24 hours, the distillation time is 12～48 hours, baking temperature is 0～35 ℃ again, then be 2～12 hours drying time; Sterilising conditions is 121 ℃, 30min.
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| CN1830485A (en) * | 2005-03-08 | 2006-09-13 | 巴里莫尔制药（通化）有限公司 | Preparation method of anti-inflammation analgesia medicine compound bone peptide injection |
| CN100998607A (en) * | 2006-01-09 | 2007-07-18 | 王德农 | Injecta containing compound bone peptide and sodium chloride |
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