CN102698247B - Glutamine dipeptide and compound amino acid medicinal composition prepared with solvent crystallization method - Google Patents
Glutamine dipeptide and compound amino acid medicinal composition prepared with solvent crystallization method Download PDFInfo
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- CN102698247B CN102698247B CN 201210207713 CN201210207713A CN102698247B CN 102698247 B CN102698247 B CN 102698247B CN 201210207713 CN201210207713 CN 201210207713 CN 201210207713 A CN201210207713 A CN 201210207713A CN 102698247 B CN102698247 B CN 102698247B
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Abstract
The invention relates to a medicinal composition of glutamine dipeptide sterile powder for injection and a compound amino acid injection, prepared with a solvent crystallization method, in particular to a combined application package. The medicinal composition comprises glutamine dipeptide sterile powder for injection, water for injection and a compound amino acid injection. Due to the adoption of the combined application package disclosed by the invention, great convenience is brought to the requirement of clinical administration; great convenience is brought to purchase and dispensation of an administration unit, and cost is saved; the combined application package is made for emergent use, and plays a great role in ensuring the stability of every single medicament, and the clinical application quality and bioavailability of a medicament can be enhanced; and the composition disclosed by the invention has the effect of remarkably reducing liver damage.
Description
Technical field
The present invention relates to the pharmaceutical composition of a kind of alanyl glutamine and amino acid, be specifically related to a kind of Combination application packing of injection alanyl glutamine sterilized powder and Amino Acid Compound Injection of solvent crystallization preparation, belong to medical technical field.
Background technology
(L-Glutamine is essential amino acid in a kind of body Gln) to L-glutaminate, also is the maximum aminoacid of people's in-vivo content, has important function at protein, nucleic acid in synthesizing.The content of Gln in blood plasma up to 0.8 ~ 0.9 mM/liter, account for 20% of free amino acid total amount.Gln is the energy source of metabolically active cells such as intestinal epithelial cell, renal cells and immunologically competent cell; The nitrogenous source vehicle that is considered to body is transported nitrogenous source between each tissue in vivo, and critical functions such as noxious substance such as ammonia are removed in performance.
Alanyl glutamine discharges L-glutaminate through the dipeptidase effect in vivo rapid the decomposition, supplies with the synthetic or energy expenditure use of body material, and its bioavailability height does not have summation.
The injection alanyl glutamine is the aseptic freeze-dried powder of alanyl glutamine, is white or off-white color sterilized powder, is a kind of parenteral nutrition medicine, for the patient who accepts parenteral nutrition provides glutamine.Alanyl glutamine is by the development of German Fresenius company, and import in 1999 claims glutamine dipeptide again to China.
Alanyl glutamine generally is with compatible Freamine or contains amino acid whose transfusion and dissolve by 0.2g/ml and be called a volume before infusion, then with the carrier solution infusion.1 volume alanyl glutamine should mix (for example: the 20g/100ml alanyl glutamine should add 500ml carrier solution at least) with the carrier solution of at least 5 volumes.Dosage is decided according to catabolic degree and amino acid whose requirement.Supplying with amino acid whose maximal dose every day for parenteral nutrition is the 2g/kg body weight, and alanine and the glutamine amount supplied with by alanyl glutamine should count.The amount of amino acid of supplying with by alanyl glutamine should not surpass 20% of whole aminoacid quantity delivereds.
At present, it all is respectively from different manufacturer's buyings by medication unit that domestic compatibility about injection alanyl glutamine and Amino Acid Compound Injection is used, compatibility arrives together during clinical practice, like this because the difference of manufacturer causes the widely different of drug quality, compatibility is used and has been had a strong impact on final drug quality, has further influenced patient's treatment.
Patent documentation CN201223558Y discloses the double-chamber transfusion bag of a kind of splendid attire amino acid injection and alanyl glutamine injection, but alanyl glutamine exists with the form of solution, places unstablely for a long time, can produce degraded.People such as Zhou Xin research points out that alanyl glutamine adds Amino Acid Compound Injection and causes hepatic injury, and this also is the extensive use that is unfavorable for alanyl glutamine and aminoacid combination.
In order to overcome the insoluble technical problem that the combination of alanyl glutamine and amino acid exists in the prior art, the inventor has proposed a kind of new alanyl glutamine and pharmaceutical composition and the application packages thereof of amino acid.
Summary of the invention
One of purpose of the present invention provides a kind of new alanyl glutamine and the pharmaceutical composition of amino acid, comprises injection alanyl glutamine sterilized powder and the Amino Acid Compound Injection of solvent crystallization preparation.
One of purpose of the present invention provides a kind of injection alanyl glutamine sterilized powder of solvent crystallization preparation and the Combination application of Amino Acid Compound Injection to pack, and comprises injection alanyl glutamine sterilized powder and Amino Acid Compound Injection.
Further, also can comprise injection alanyl glutamine sterilized powder, water for injection and Amino Acid Compound Injection in this assembly packaging, the quality influence that has been caused by the mass discrepancy of producing when having avoided that compatibility is used together like this, improved the safety that the patient uses greatly, to the buying of medication unit with make up a prescription very big convenience also is provided, saved cost simultaneously.
Combination application packing provided by the invention, usage is added the Amino Acid Compound Injection mix homogeneously for earlier injection alanyl glutamine sterilized powder being dissolved fully with water for injection earlier, and intravenous drip gets final product.
The invention provides a kind of pharmaceutical composition that contains alanyl glutamine and amino acid, wherein alanyl glutamine is that injection alanyl glutamine sterilized powder, the amino acid that solvent crystallization prepares is compatible Freamine or contains amino acid whose transfusion.
Pharmaceutical composition of the present invention can also comprise water for injection, and wherein, packing specification is injection alanyl glutamine 10-20g, water for injection, Amino Acid Compound Injection 50-1000ml.
As the present invention's one preferred embodiment, packing specification of the present invention is injection alanyl glutamine sterilized powder 10g, water for injection 50ml and Amino Acid Compound Injection 250ml.
As the present invention's one preferred embodiment, packing specification of the present invention is injection alanyl glutamine sterilized powder 20g, water for injection 100ml and Amino Acid Compound Injection 500ml.
Injection alanyl glutamine provided by the invention is the sterilized powder of white or off-white color.Its preparation method is:
(1) in ten thousand grades of clean area proportioning room, alanyl glutamine is added 50% alcoholic solution heating for dissolving, be made into the solution of about 12-13%, the about 0.2%(w/v of adding dosing amount) medicinal carbon, stirring and adsorbing 30 minutes, coarse filtration is taken off charcoal, again through 0.22 μ m microporous filter membrane fine straining, filtrate places under the low temperature 0-4 ℃ condition and left standstill 20 hours, separate out mass crystallization, filter, drain, then with filter cake in 50 ℃ of drying under reduced pressure 4 hours, get the alanyl glutamine sterilized powder.
(2) at hundred grades of clean areas, the control relative humidity is lower than about 45%, carries out aseptic subpackagedly with automatic packer, jumps a queue, and rolls lid.
The sterilized water for injection of water for injection provided by the invention for making by the injection production technology.Its preparation method is: gets fresh water for injection fill, seals, and sterilization, namely.
Amino Acid Compound Injection provided by the invention is 18 kinds of sterile water solutions that crystalline amino acid is formulated, concrete component comprises tyrosine 0.11-0.35g, alanine 1.88-6.20g, leucine 3.79-12.50g, proline 1.0-3.3g, isoleucine 1.7-5.6g, glycine 3.24-10.70g, phenylalanine 2.83-9.35g, tryptophan 0.39-1.30g, valine 1.36-4.50g, methionine 1.06-3.50g, Aspartic Acid 1.15-3.80g, cysteine 0.44-1.00g, glutamic acid 1.97-6.50g, arginase 12 .63-7.90g, histidine 2-6g, lysine hydrochloride 3.33-12.40g, threonine 1.97-6.50g, serine 0.67-2.20g, disodium edetate 0.1-0.2g, sodium sulfite 1-2g, sorbitol 20-40g, water for injection 1000ml.
The preparation method of Amino Acid Compound Injection of the present invention is:
(1) about 60% water for injection of getting about full dose boils and adds an amount of sorbitol and make dissolving, adds about 0.15%(g/ml again) active carbon boiled 20 minutes, and return the filter 20 minutes after-filtration that decolour and go into rare filling of joining.
(2) filter feeds nitrogen after going into sorbitol liquid immediately in the dilute preparing tank, what add simultaneously about full dose 40% in addition again uses 0.15(g/ml) active carbon boils 20 minutes pretreated water for injection of absorption and the merging of sorbitol liquid, opens when cooling water makes amalgamation liquid be cooled to 60 ℃ to begin to feed intake.
(3) earlier the disodium edetate of an amount of mix homogeneously and the stabilizing agent of sodium sulfite are divided into halves, a copy of it stabilizing agent is dropped in the amalgamation liquid, by above-mentioned prescription order each aminoacid is dropped into one by one then and make dissolving, should control temperature during to tryptophan can drop into below 50 ℃ about, aminoacid feeds intake and finishes, and adds another part stabilizing agent and cystine.
(4) slowly adding to regulate pH value 5.8-6.2 with about 10% caustic lye of soda, add adding to the full amount of water for injection, add 0.15%(g/ml) active carbon stirs decolouring 20 minutes, circulating filtration 30 minutes.
(5) filter qualified to visible foreign matters after, fill is sealed, the sterilization, namely.
The invention provides a kind of method for preparing Amino Acid Compound Injection, step is: above-mentioned various amino acid sequences are added, and pH value is regulated in dissolving, carbon absorption, and fill is sealed, sterilization.
The invention provides the method that a kind of solvent crystallization prepares injection alanyl glutamine sterilized powder, the steps include: alanyl glutamine is dissolved in water, carbon absorption, decarburization, fine straining, crystallize, sucking filtration, drying, aseptic subpackaged, jump a queue, roll lid.
The present invention also provides a kind of injection alanyl glutamine sterilized powder of solvent crystallization preparation and the Combination application of Amino Acid Compound Injection to be packaged in the application for preparing in the treatment amino acids nutritional supplementation medicine, it is normal to have the metabolism of the human body protein of promotion, correct negative nitrogen balance, replenish protein, the effect of accelerating wound.
Alanyl glutamine and amino acid make up extensive use in the prior art, but both exist with liquid form, particularly the injection of alanyl glutamine duration of storage more be easy to generate decomposition, therefore remix use after, produce the side effect that is difficult to expect.
Pharmaceutical composition of the present invention dissolves injection alanyl glutamine sterilized powder earlier during use with water for injection, again with compatible Freamine or contain amino acid whose transfusion and mix intravenous drip.
More seriously, people such as Zhou Xin research points out that alanyl glutamine adds Amino Acid Compound Injection and causes hepatic injury, by studying for a long period of time of inventor, produce basic reason that liver decreases and also be quality owing to the injection of the injection of alanyl glutamine and amino acid and change and cause.
Therefore, because the dissolubility of partial amino-acid is relatively poor, the Amino Acid Compound Injection incompatibility is made aseptic powder injection, the inventor produced will easier generation degraded the alanyl glutamine injection make the independent preservation of sterilized powder, the comparative test by has hereinafter proved that product of the present invention has the side effect that unforeseeable reduction liver decreases.
The applicant has disclosed the injection alanyl glutamine sterilized powder that makes the preparation of a kind of lyophilization and the Combination application packing of Amino Acid Compound Injection in its priority document 201110267409.6, in follow-up research, the applicant finds to use the injection alanyl glutamine sterilized powder of solvent crystallization preparation and the Combination application packing of Amino Acid Compound Injection to have better stability and curative effect, possible reason is that solvent crystallization is than lyophilization, active component low temperature spontaneous nucleation, the crystal formation dissolubility is better, faster, more stable, the curative effect onset is faster; And the solvent crystallization preparation process is simple, has saved production cost greatly; The sterilized powder particle diameter that the while solvent crystallization makes is bigger, good fluidity, easier packing.
Benefit of the present invention:
(1) Combination application packing of the present invention greatly facilitates the needs of clinical application.
(2) Combination application of the present invention packing has been saved cost to the buying of medication unit with make up a prescription very big convenience also is provided.
(3) Combination application of the present invention packing matching while using is of great benefit to the stability of each drug alone, can improve clinical practice quality and the bioavailability of medicine.
(4) combination of the present invention has the benefit that reduces hepatic injury significantly.
The specific embodiment
Embodiment 1The preparation of assembly packaging medicine
Combination: injection alanyl glutamine sterilized powder 10g, water for injection 50ml and Amino Acid Compound Injection 250ml
Preparation process:
1, the preparation of injection alanyl glutamine
(1) in ten thousand grades of clean area proportioning room, the 1000g alanyl glutamine is added 50% alcoholic solution 8000ml heating for dissolving, be made into about 12.5% solution, the medicinal carbon that adds 16g, stirring and adsorbing 30 minutes, coarse filtration is taken off charcoal, again through 0.22 μ m microporous filter membrane fine straining, filtrate places under the low temperature 0-4 ℃ condition and left standstill 20 hours, separate out mass crystallization, filter, drain, then with filter cake in 50 ℃ of drying under reduced pressure 4 hours, get the alanyl glutamine sterilized powder.
(2) hundred grades of clean areas, under hundred grades of conditions, the control relative humidity is lower than 45%, carries out aseptic subpackagedly with automatic packer, and the 10g/ bottle is jumped a queue, and rolls lid.
2, the preparation of water for injection
Get fresh water for injection fill, 10ml/ props up, seal, and 121 ℃ of pressure sterilizings 20 minutes, namely.
3, the preparation of Amino Acid Compound Injection
(1) gets 60L water for injection and boil and add sorbitol 2000g and make dissolving, add the 90g active carbon again and boiled 20 minutes, return 20 minutes after-filtration of filter decolouring and go into rare filling of joining.
(2) filter feeds nitrogen after going into sorbitol liquid immediately in the dilute preparing tank, adds other 40L simultaneously again and begins to feed intake through boiling 20 minutes pretreated water for injection of absorption and the merging of sorbitol liquid with the 60g active carbon, opening when cooling water makes amalgamation liquid be cooled to 60 ℃.
(3) part that earlier the disodium edetate 10g of mix homogeneously and sodium sulfite 200g is divided into two, a copy of it is dropped in the amalgamation liquid, then in order with tyrosine 0.11g, alanine 1.88g, leucine 3.79g, proline 1.0g, isoleucine 1.7g, glycine 3.24g, phenylalanine 2.83g, tryptophan 0.39g, valine 1.36g, methionine 1.06g, Aspartic Acid 1.15g, cysteine 0.44g, glutamic acid 1.97g, arginase 12 .63g, histidine 2g, lysine hydrochloride 3.33g, threonine 1.97g, serine 0.67g, drop into one by one and make dissolving, should control temperature during to tryptophan and can drop into below 50 ℃, aminoacid feeds intake and finishes, and adds another part stabilizing agent and cystine.
(4) slowly add to regulate pH value 5.9 with 10% caustic lye of soda, add adding to the full amount of water for injection, add the 150g active carbon and stir decolouring 20 minutes, circulating filtration 30 minutes.
(5) filter qualified to visible foreign matters after, fill, the 250ml/ bottle seals, 121 ℃ of pressure sterilizings 20 minutes, namely.
Embodiment 2The preparation of assembly packaging medicine
Combination: injection alanyl glutamine powder 20g, water for injection 100ml and Amino Acid Compound Injection 500ml
Preparation process:
1, the preparation of injection alanyl glutamine
(1) in ten thousand grades of clean area proportioning room, the 2000g alanyl glutamine is added 50% alcoholic solution 16000ml heating for dissolving, be made into about 12.5% solution, the medicinal carbon that adds 32g, stirring and adsorbing 30 minutes, coarse filtration is taken off charcoal, again through 0.22 μ m microporous filter membrane fine straining, filtrate places under the low temperature 0-4 ℃ condition and left standstill 20 hours, separate out mass crystallization, filter, drain, then with filter cake in 50 ℃ of drying under reduced pressure 4 hours, get the alanyl glutamine sterilized powder.
(2) hundred grades of clean areas, under hundred grades of conditions, the control relative humidity is lower than 45%, carries out aseptic subpackagedly with automatic packer, and the 20g/ bottle is jumped a queue, and rolls lid.
2, the preparation of water for injection
Get fresh water for injection fill, 20ml/ props up, seal, and 121 ℃ of pressure sterilizings 20 minutes, namely.
3, the preparation of Amino Acid Compound Injection
(1) gets 60L water for injection and boil and add sorbitol 4000g and make dissolving, add the 90g active carbon again and boiled 20 minutes, return 20 minutes after-filtration of filter decolouring and go into rare filling of joining.
(2) filter feeds nitrogen after going into sorbitol liquid immediately in the dilute preparing tank, adds other 40L simultaneously again and begins to feed intake through boiling 20 minutes pretreated water for injection of absorption and the merging of sorbitol liquid with the 60g active carbon, opening when cooling water makes amalgamation liquid be cooled to 60 ℃.
(3) part that earlier the disodium edetate 20g of mix homogeneously and sodium sulfite 100g is divided into two, a copy of it is dropped in the amalgamation liquid, then in order with tyrosine 0.35g, alanine 6.20g, leucine 12.50g, proline 3 .3g, isoleucine 5.6g, glycine 10.70g, phenylalanine 9.35g, tryptophan 1.30g, valine 4.50g, methionine 3.50g, Aspartic Acid 3.80g, cysteine 1.00g, glutamic acid 6.50g, arginine 7.90g, histidine 6g, lysine hydrochloride 12.40g, threonine 6.50g, serine 2.20g, drop into one by one and make dissolving, should control temperature during to tryptophan and can drop into below 50 ℃, aminoacid feeds intake and finishes, and adds another part stabilizing agent and cystine.
(4) slowly add to regulate pH value 6.2 with 10% caustic lye of soda, add adding to the full amount of water for injection, add the 150g active carbon and stir decolouring 20 minutes, circulating filtration 30 minutes.
(5) filter qualified to visible foreign matters after, fill, the 500ml/ bottle seals, 121 ℃ of pressure sterilizings 20 minutes, namely.
Experimental example 3Stability test
A collection of and the embodiment of the invention 1 preparation sample compares by 201110267409.6 embodiment 1 preparation sample, and 40 ℃ of high temperature, following 6 months of relative humidity 75% ± 5% condition is carried out accelerated test and investigated, and the results are shown in Table 1.
Table 1 stability and measuring of dissolution velocity result
As shown in Table 1, the sample of 201110267409.6 embodiment, 1 preparation, dissolution velocity is significantly very slow, and related substance raises when accelerating June; And the sample dissolution speed of the embodiment of the invention 1 preparation is very fast, and it is less to accelerate after 6 months the related substance variation.Proved absolutely the superiority of the present invention aspect raising stability and dissolution velocity.
Experimental example 4The clinical application test
The be admitted to hospital patient of the pharmaceutical composition that uses alanyl glutamine and amino acid of 30 examples is investigated, and one group for using injection alanyl glutamine sterilized powder and Amino Acid Compound Injection (product of the embodiment of the invention 1) 10 examples (being called for short combination 1).One group is used the product (being called for short combination 2) from 201110267409.6 embodiment 1.One group for using alanyl glutamine injection and Amino Acid Compound Injection (with the isocyatic commercially available prod of the product of embodiments of the invention 1, Shandong Lukang Cisen Pharmaceutical Co., Ltd produces, lot number 20110701) 10 examples (being called for short combination 3), three groups of compositions medicines that use are same lot number, and be after the date of manufacture 6 months service time.Using the course for the treatment of is 3 days, respectively three groups of patient's liver functions is checked that 10 routine patient's average test results are as follows before and after using:
Table 2 liver function test result
By above result as can be seen, 10 routine patient's medications of using combination 3 alanyl glutamine injection and Amino Acid Compound Injection after 3 days liver function occur unusually, change bigger; And the every detection index variation of the 10 routine patients that use combination 1 injection alanyl glutamine sterilized powder and Amino Acid Compound Injection is very little, and abnormal phenomena does not appear in liver function, is better than making up 2.
Liver function recovery is normal after patient's drug withdrawal of combination 3, illustrate that combination 1 alanyl glutamine injection and Amino Acid Compound Injection can produce damage to patient's liver function, this is because make up alanyl glutamine injection in 3, be that form with solution exists, and alanyl glutamine poor stability in aqueous solution, be easy to degraded, its catabolite causes hepatocyte impaired; The form that makes up the aseptic freeze-dried powder of alanyl glutamine in 1 injection alanyl glutamine sterilized powder and the Amino Acid Compound Injection and be with solid exists, stablized by contrast a lot, so the abnormal liver function phenomenon do not occur.
Claims (1)
1. one kind is reduced the Combination application packing that contains alanyl glutamine and amino acid that liver decreases, and it is characterized in that alanyl glutamine is that injection alanyl glutamine sterilized powder, the amino acid that solvent crystallization prepares is compatible Freamine or contains amino acid whose transfusion; Wherein Amino Acid Compound Injection is 18 kinds of sterile water solutions that crystalline amino acid is formulated, and concrete component comprises tyrosine 0.11-0.35g, alanine 1.88-6.20g, leucine 3.79-12.50g, proline 1.0-3.3g, isoleucine 1.7-5.6g, glycine 3.24-10.70g, phenylalanine 2.83-9.35g, tryptophan 0.39-1.30g, valine 1.36-4.50g, methionine 1.06-3.50g, Aspartic Acid 1.15-3.80g, cysteine 0.44-1.00g, glutamic acid 1.97-6.50g, arginase 12 .63-7.90g, histidine 2-6g, lysine hydrochloride 3.33-12.40g, threonine 1.97-6.50g, serine 0.67-2.20g, disodium edetate 0.1-0.2g, sodium sulfite 1-2g, sorbitol 20-40g, water for injection 1000ml.
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