CN109966503A - A kind of ibuprofen suspension suspending agent and its application - Google Patents

A kind of ibuprofen suspension suspending agent and its application Download PDF

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Publication number
CN109966503A
CN109966503A CN201910052568.0A CN201910052568A CN109966503A CN 109966503 A CN109966503 A CN 109966503A CN 201910052568 A CN201910052568 A CN 201910052568A CN 109966503 A CN109966503 A CN 109966503A
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mrpc
albumen
seq
suspending agent
ibuprofen suspension
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章军
王秀敏
贺雪峰
刘承东
马薇薇
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XIAMEN CASAMOY TECHNOLOGY CO LTD
Xiamen University
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XIAMEN CASAMOY TECHNOLOGY CO LTD
Xiamen University
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/192Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/42Proteins; Polypeptides; Degradation products thereof; Derivatives thereof, e.g. albumin, gelatin or zein
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/10Dispersions; Emulsions
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/405Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from algae

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  • Animal Behavior & Ethology (AREA)
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  • Proteomics, Peptides & Aminoacids (AREA)
  • Pain & Pain Management (AREA)
  • Engineering & Computer Science (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Rheumatology (AREA)
  • Biotechnology (AREA)
  • Gastroenterology & Hepatology (AREA)
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  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Peptides Or Proteins (AREA)

Abstract

The invention discloses a kind of ibuprofen suspension suspending agent and its applications, and the amino acid sequence of the MrpC albumen is as shown in SEQ ID NO 01.MrpC albumen in the present invention is far longer than methylcellulose to the suspending ability of brufen, and is better than xanthan gum.

Description

A kind of ibuprofen suspension suspending agent and its application
Technical field
The invention belongs to suspending agent technical fields, and in particular to a kind of ibuprofen suspension suspending agent and its application.
Background technique
Ibuprofen suspension in the prior art is also used for for fever caused by children's common cold or influenza, headache Alleviate children mild to moderate pain such as headache, arthralgia, neuralgia, migraine, toothache, courbature, neuralgia.The brufen is mixed Every milliliter of 20mg of brufen containing main ingredient of suspension, auxiliary material are as follows: pregelatinized starch, xanthan gum, glycerol, sucrose, anhydrous citric acid, Sodium benzoate, Tween 80, edible pigment, edible essence, pure water, wherein the effect of xanthan gum is suspending agent.But the xanthan gum Suspending function and effect are still ideal not to the utmost.
Summary of the invention
The purpose of the present invention is to provide a kind of ibuprofen suspension suspending agents.
Another object of the present invention is to provide application of the MrpC albumen in suspending brufen.
A further object of the present invention is to provide a kind of ibuprofen suspension compositions.
Technical scheme is as follows:
A kind of ibuprofen suspension suspending agent, effective component include MrpC albumen, the amino acid sequence of the MrpC albumen As shown in SEQ ID NO 01.
In a preferred embodiment of the invention, effective component is the MrpC albumen.
It is further preferred that the nucleotide sequence of the MrpC albumen is as shown in SEQ ID NO 02.
Another technical solution of the invention is as follows:
Application of the MrpC albumen in suspending brufen, the amino acid sequence of the MrpC albumen such as 01 institute of SEQ ID NO Show.
In a preferred embodiment of the invention, the nucleotide sequence of the MrpC albumen such as 02 institute of SEQ ID NO Show.
Yet another aspect of the invention is as follows:
A kind of ibuprofen suspension composition, including it is brufen, pregelatinized starch, MrpC albumen, glycerol, sucrose, anhydrous Citric acid, sodium benzoate, Tween 80, edible pigment, edible essence and pure water, the wherein amino acid sequence of MrpC albumen such as SEQ Shown in ID NO 01.
In a preferred embodiment of the invention, the nucleotide sequence of the MrpC albumen such as 02 institute of SEQ ID NO Show.
The beneficial effects of the present invention are: the MrpC albumen in the present invention is far longer than methyl fibre to the suspending ability of brufen Dimension element, and it is better than xanthan gum.
Detailed description of the invention
Fig. 1 is the photo of frustule suspended state before and after replacement fresh culture in the embodiment of the present invention 1, wherein left side is Control group, right side are the situation after replacing fresh culture after stationary culture 6 days.
Fig. 2 is MrpC separation and purification of protein and MALDI-TOF-MS qualification figure in the embodiment of the present invention 1.
Fig. 3 is that the critical concentration that MrpC inhibits cell to sink in the embodiment of the present invention 1 detects figure, wherein 1.0 μ g/mL; 2.5μg/mL;3.15μg/mL;4.30μg/mL;5.45μg/mL;6.60μg/mL;7.75μg/mL;8.90μg/mL;9.115μg/ mL;10.155μg/mL;11.300μg/mL.
Fig. 4 is the MrpC content detection figure in the embodiment of the present invention 1 in different growing stage culture medium.
Fig. 5 is MrpC far ultraviolet circular dichroism figure in the embodiment of the present invention 1.
Fig. 6 is MrpC electron cryo-microscopy observation figure in the embodiment of the present invention 1.
Fig. 7 is the tem observation figure of MrpC in the embodiment of the present invention 1.
Fig. 8 is the influence that MrpC suspends to different cells in the embodiment of the present invention 1, wherein standing after 1: 8000g centrifugation;2: It is resuspended in new BG-11;3: being resuspended in 60 μ g/mL MrpC BG-11;A.Anabaena sp.PCC 7120; B.M.aeruginosa PPC 7820;C.Synechocystis sp.PCC6803;D.Chlore sp.;E.Nostoc fflagelliforme FACHB 838;F.Gloeobacter violaceus PCC 7421;G.Synechococcus sp.PCC 7942;H.E coli.BL21(DE3);I. pichia pastoris yeast GS 115..
Fig. 9 is MrpC in the embodiment of the present invention 1 to the suspension effect of variety classes powder, wherein A. starch;B. agar Sugar;C. fish meal;D. spirulina powder (Spirulina platensis).
Figure 10 is ibuprofen suspension sedimentation volume ratio figure in the embodiment of the present invention 1 and embodiment 3.
Figure 11 is that the SDS-PAGE of the secretory protein extracted in the embodiment of the present invention 2 is analyzed and anti-MrpC-IgG is special Property detection figure, wherein M:marker;1: the protein component of the M.aeruginosa PCC7806 secretion of extraction;2: long to algae is gone The western blotting of time culture is detected.
Figure 12 is M.aeruginosa PCC7806 secretory protein MALDI-TOF-MS peptide fingerprinting in the embodiment of the present invention 2 Spectrum.
Specific embodiment
Technical solution of the present invention is further explained and described below by way of specific embodiment combination attached drawing.
The discovery and identification of the suspending function of 1 MrpC albumen of embodiment
One, (the cell culture situation of prolonged culture medium and fresh culture is compareed such as Fig. 1 institute for the discovery of suspension albumen Show)
Frustule suspend the phenomenon that it is related with the secretion in its culture medium, next identify come suspending agents from A kind of protein MrpC of algae secretion.
Two, the separation identification of MrpC
The separation of secretory protein and Mass Spectrometric Identification in frustule, as shown in Figure 2
The critical concentration that MrpC inhibits cell to sink, as a result as shown in figure 3, display MrpC protein concentration is greater than 30ug/ ML can inhibit Microcystis aeruginosa Strains sinking
MrpC content detection in different growing stage culture medium, as a result as shown in figure 4, display laboratory cultures 60 days Left and right MrpC has just reached the concentration having an impact to cell settlement
Conclusion: MrpC is the factor of determination that frustule suspends
Three, the physicochemical property of suspension albumen MrpC
The sequencing and analyzing of 1.MrpC
The genome of M.aeruginosa PCC 7806 was completed in 2007 by Pasteur Institut (Frangeul, Quillardet etal.2008).MrpC gene order is obtained by genbank, full length gene 465bp rises Beginning codon is ATG (underscore), and terminator is TAG (underscore).The primary structure of protein is exactly in protein and peptide chain Amino acid residue puts in order, and is determined by putting in order for genetic code on gene.It is analyzed and is obtained using DNAman MrpC amino acid sequence overall length 154aa, it is consistent with document forecasting sequence.MrpC is exocytosis albumen, and N-terminal is believed comprising 33aa Number peptide (underscore), the 34th aa glutamine are modified to pyroglutamic acid (Zilliges, Kehr et al.2008).
MrpC gene order (SEQ ID NO 02):
The amino acid sequence (SEQ ID NO 01) of MrpC albumen:
2.MrpC albumen physicochemical property
MrpC sterling is white, soluble easily in water and PBS, does not dissolve in ethyl alcohol, methanol, acetone and other organic solvent.Heavy metallic salt: Silver nitrate, cadmium iodide, plumbi nitras, manganese sulfate, cobalt nitrate etc. can all be such that MrpC is denaturalized.
Using NDJ-1 rotational viscometer, the apparent viscosity of room temperature measuring 1mg/mL MrpC is under 30r/min revolving speed 6mPa.S.Viscosity more hour, since the limitation of instrument can not measure.When MrpC concentration reaches 30ug/mL, so that it may keep a variety of Frustule suspends, thus it is speculated that the viscosity of solution at this time is nearly close to water.
The MrpC that laboratory is extracted is 14Kda through SDS-PAGE measurement molecular weight.Zilliges Y etc. utilizes molecular sieve (body Product exclusion chromatography) measure under natural conditions MrpC molecular weight be 120kDa-170kDa.Most celloglobulins are due to its molecule shape The highly asymmetric property of shape, is not available ultracentrifugation.Ultracentrifugation is carried out to MrpC, is found when concentration is 1.2mg/mL MrpC can not be got off by centrifugation, and it is 168S that sedimentation coefficient is measured when being diluted to 60ug/mL, and to 1.2mg/mLMrpC ultrasound It is 68S that sedimentation coefficient is measured when (f=20kHz, I=10 ± 5%W) 60s, and MrpC is high polymer to initial guess under natural conditions.
3. circular dichroism (CD) measures MrpC secondary structure
The carbon atom of Amino Acids in Proteins is asymmetric carbon atom, has optical activity, when plane circularly polarized light passes through When these photoactive chromophores, photolytic activity center is not identical to the absorption of the left and right circularly polarized light in plane circularly polarized light, It generates and absorbs difference, due to the presence of this absorption difference, cause the difference of vibration of Polarization Vector, circularly polarized light becomes oval inclined Shake light, and here it is the circular dichroism of protein.Circular dichroism is a kind of quick, letter for studying protein conformation in weak solution Single, accurate method.
Fig. 5 show the circular dichroism of MrpC solution, and MrpC concentration is 0.1mg/mL, wave-length coverage 190-260nm.From As can be seen that MrpC is in 193am or so a posivtive spike in Fig. 5, there are weak peaks at the place 222nm or so, illustrate MrpC with alpha-helix Based on.It is calculated by curve fitting software CD Pro and obtains MrpC secondary structures through the Fitting Calculation are as follows: alpha-helix knot Structure accounts for 87.7%, β-corner structure and accounts for 12.3%.
4. electron cryo-microscopy observes MrpC
Electron cryo-microscopy technology be aqueous large biological molecule is carried out be rapidly frozen to liquid nitrogen or liquid helium temperature (freezing rate > 104 DEG C/s), make sample at or close to its physiological activity state, and be imaged under cryogenic using low electron dose, from And the three-dimensional structure of large biological molecule can be studied on high-resolution level.By MrpC albumen diluted concentration to 25-50 μ g/mL, fastly Albumen form is observed in Electronic Speculum after quickly cooling jelly.Electronic Speculum result such as Fig. 6 shows that the nanoscale that MrpC is diameter about 8.5nm is long linear Object, i.e. protein nano fiber.The arrangement of nanofiber does not find rule, and some multi beam nanofibers form cluster side by side, different empty Between the fiber filament that arranges it is parallel or criss-cross, to form network structure.
Directly MrpC (100ug/mL) is observed under transmission electron microscope after copper mesh natural drying.Fig. 7 shows that diameter is to receive Meter level and length are long linear up to several microns, these long threads form reticular structure in a crisscross manner, the size of mesh with The concentration of thread is related.The reticular structure observed is consistent with electron cryo-microscopy results presumption, but the fibre of common Electronic Speculum Dimension silk diameter is then greater than electron cryo-microscopy, it may be possible to which multiple fibre silk constitutes cluster.These results confirm that MrpC assembles in solution At nanoscale long fibre shape, and as MrpC concentration increase forms reticular structure.
Four, application potential of the MrpC albumen as Novel suspending dispersing agent
Just because of the Nanostructure Network being found above, it may infer that the suspension effect of MrpC albumen is non-specific 's.
Whether there is effect to the suspension of different cells for verifying MrpC, as a result, it has been found that can hinder with the concentration of 60 μ g/mL Only Anabaena sp.PCC 7120, M.aeruginosa PPC7820, Synechocystis sp.PCC 6803, Chlore Sp., Nostoc flagelliforme FACHB 838,7421 and of Gloeobacter violaceus PCC The sinking of the Cells of Blue-green Algae such as Synechococcus sp.PCC 7942, and MrpC is to E coli.DH5 α and Pichia pastoris GS 115 Generate the concentration (Fig. 8) that same effect then needs to be greater than 100 μ g/mL.Although MrpC has the function of inhibiting different cells, But the effect of the generation of Cells of Blue-green Algae to be become apparent from.
In addition, MrpC can also inhibit fish meal, spirulina powder (Spirulina platensis) and starch at 500 μ g/mL Deng sinking;Although MrpC the suspension of agarose is influenced it is smaller, agarose in water can imbibition specific gravity increase, Ke Nengxu Ability of the MrpC concentration much larger than 500 μ g/mL is wanted to inhibit its sinking (Fig. 9).Therefore, MrpC can not only inhibit different cells Sink, and certain powder can be inhibited to sink, the effect for illustrating that MrpC inhibits cell to sink is nonspecific.
The above result shows that MrpC albumen has nonspecific suspension function, alternative traditional chemical dispersant and stabilization Agent.
Five, investigation of the MrpC albumen to ibuprofen suspension suspending effect
Ibuprofen suspension is also used for alleviating children gently extremely for fever caused by children's common cold or influenza, headache Moderate pain such as headache, arthralgia, neuralgia, migraine, toothache, courbature, neuralgia.
Every milliliter of 20mg of brufen containing main ingredient.Auxiliary material are as follows: pregelatinized starch, xanthan gum, glycerol, sucrose, anhydrous Chinese holly Rafter acid, sodium benzoate, Tween 80, edible pigment, edible essence, pure water.Wherein the effect of xanthan gum is suspending agent.
The present invention substitutes the suspending function of xanthan gum using MrpC albumen, experiments have shown that can substitute, and suspension effect More preferably.By measuring suspension and the sedimentation volume ratio of original prescription suspension, the again properties such as dispersion, evaluation by MrpC suspending When MrpC is suspending agent, the quality stability (and being control with existing suspending agent) of preparation prescription, experimental data is proved MrpC is that suspending agent is better than existing suspending agent.
The height and sedimentation volume ratio that different time measures see the table below.
Ibuprofen suspension sedimentation volume ratio
According to data in table, with Hu/Ho (sedimentation volume ratio) for ordinate, the time is abscissa, draws the heavy of each prescription Curve is dropped, Figure 10 is seen, compares the suspending ability of three kinds of suspending agents.
Can significantly it be found out by Figure 10, MrpC is far longer than methylcellulose to the suspending ability of brufen, and Better than xanthan gum.Wherein suspending agent of the xanthan gum as commodity Merrill Lynch (brufen suspension oral solution), can be obtained by the test MrpC albumen can play brufen more excellent suspending performance.
The separating-purifying of 2 MrpC albumen of embodiment
1. the culture of frustule
Microcystic aeruginosa Microcystis aeruginosa PCC 7806 is inoculated in Fresh BG-11 by 1: 50 Culture medium, 28 DEG C of continuous light shaking table cultures.
2. ammonium sulfate salting-out process protein precipitation
(1) it takes incubation time to be greater than two months algae solution high speed centrifugations and goes algae;
(2) what is obtained goes algae culture to refilter once;
(3) it is quantitatively slowly added to be ground into fine-powdered and dry anhydrous ammonium sulfate in filtrate, and keeps stirring, magnetic can be used
Power stirring, until there is albumen precipitation precipitation;
(4) 12000g is centrifuged albumen precipitation, and supernatant continuously adds ammonium sulfate precipitated protein, obtains albumen in batches, and method is same
On, until the solubility of ammonium sulfate is 100% in solution.
(5) the PBS dissolution of albumen precipitation certain volume, then high speed centrifugation are primary, discard precipitated impurities, supernatant is
Protein solution.
Ammonium sulfate salting-out process precipitating removes the albumen in algae culture medium, is about the 5% of its solubility the amount of ammonium sulfate is added When obtained albumen precipitation to inhibiting algae to sink to the bottom significant effect, which is dissolved with PBS, -20 DEG C of preservations.Such as Figure 11 institute Show there was only a band by SDS-PAGE detection, illustrate to obtain protein purer;As shown in figure 12, it reflects through MALDI-TOF-MS Surely only have two peaks 1077.461m/z and 949.434m/z, the result score searched in matrix database is lower, but with It is found that M.aeruginosa PCC 7806 a secretory protein MrpC the peak MALDI-TOF-MS spectrum it is consistent, it was demonstrated that The extraction albumen is Mrp C.
3 MrpC of embodiment is applied to ibuprofen suspension
The composition of existing ibuprofen suspension: brufen 0.08g, Tween-80 40 μ L, xanthan gum 7mg, pre-paying Starch 0.16g, glycerol 0.4mL, sucrose 1.2g, citric acid 20mg, sodium benzoate 8mg, methylcellulose 0.02g, purified water add To 4mL.
Operation:
(1) brufen (crossing No. 6 sieves) is taken, Tween-80 and glycerol grinding is added, after grinding sufficiently, is added under stiring pre- Gelling starch, suspending agent (methylcellulose, xanthan gum), slowly plus water is ground, and citric acid, sodium benzoate, sucrose are added afterwards, mends Water is allowed to evenly dispersed, obtains the first ibuprofen suspension to 4mL.
(2) suspending agent (methylcellulose, xanthan in above-mentioned first ibuprofen suspension are replaced with MrpC protein solution Glue), the second ibuprofen suspension is made, concentration of the MrpC albumen in second ibuprofen suspension is 0.5mg/mL.
(3) sedimentation volume ratio of the first ibuprofen suspension and the second ibuprofen suspension, comparison MrpC albumen and biography are surveyed The suspending effect difference of system suspending agent.Can significantly it be found out by Figure 10, MrpC is far longer than the suspending ability of brufen Methylcellulose, and it is better than xanthan gum.Wherein suspending agent of the xanthan gum as commodity Merrill Lynch (brufen suspension oral solution) leads to Crossing the test can show that MrpC albumen can play brufen more excellent suspending performance.
The foregoing is only a preferred embodiment of the present invention, the range that the present invention that therefore, it cannot be limited according to is implemented, i.e., Equivalent changes and modifications made in accordance with the scope of the invention and the contents of the specification should still be within the scope of the present invention.
Sequence table
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Xiamen Casamoy Technology Co., Ltd.
<120>a kind of ibuprofen suspension suspending agent and its application
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Claims (7)

1. a kind of ibuprofen suspension suspending agent, it is characterised in that: its effective component includes MrpC albumen, the ammonia of the MrpC albumen Base acid sequence is as shown in SEQ ID NO 01.
2. a kind of ibuprofen suspension suspending agent as described in claim 1, it is characterised in that: its effective component is the MrpC Albumen.
3. a kind of ibuprofen suspension suspending agent as claimed in claim 1 or 2, it is characterised in that: the core of the MrpC albumen Nucleotide sequence is as shown in SEQ ID NO 02.
Application of the 4.MrpC albumen in suspending brufen, the amino acid sequence of the MrpC albumen is as shown in SEQ ID NO 01.
5. application as claimed in claim 4, it is characterised in that: the nucleotide sequence of the MrpC albumen such as SEQ ID NO 02 It is shown.
6. a kind of ibuprofen suspension composition, it is characterised in that: including brufen, pregelatinized starch, MrpC albumen, glycerol, Sucrose, anhydrous citric acid, sodium benzoate, Tween 80, edible pigment, edible essence and pure water, the wherein amino acid of MrpC albumen Sequence is as shown in SEQ ID NO 01.
7. ibuprofen suspension composition as claimed in claim 6, it is characterised in that: the nucleotide sequence of the MrpC albumen As shown in SEQ ID NO 02.
CN201910052568.0A 2019-01-18 2019-01-18 A kind of ibuprofen suspension suspending agent and its application Pending CN109966503A (en)

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Citations (4)

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Publication number Priority date Publication date Assignee Title
CN103156812A (en) * 2011-12-08 2013-06-19 杭州赛利药物研究所有限公司 Dextrorotation ibuprofen dried suspension and preparation method thereof
CN104475756A (en) * 2015-01-06 2015-04-01 厦门大学 Method for preparing nano silver through suspended protein MrpC
CN106606476A (en) * 2015-10-27 2017-05-03 康芝药业股份有限公司 Ibuprofen suspension drops and preparation method thereof
CN106727303A (en) * 2017-01-03 2017-05-31 天大药业(珠海)有限公司 Ibuprofen oral suspension and preparation method thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103156812A (en) * 2011-12-08 2013-06-19 杭州赛利药物研究所有限公司 Dextrorotation ibuprofen dried suspension and preparation method thereof
CN104475756A (en) * 2015-01-06 2015-04-01 厦门大学 Method for preparing nano silver through suspended protein MrpC
CN106606476A (en) * 2015-10-27 2017-05-03 康芝药业股份有限公司 Ibuprofen suspension drops and preparation method thereof
CN106727303A (en) * 2017-01-03 2017-05-31 天大药业(珠海)有限公司 Ibuprofen oral suspension and preparation method thereof

Non-Patent Citations (1)

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Title
AMODIO FUGGI,ET AL.: "NITRATE AND AMMONIUM ASSIMI LATION IN ALGAL CELLSUSPENSIONS AND RELATED pH VARIATIONS IN THE EXTERNAL MEDIUM, MONITORED BY ELECTRODES", 《PLANT SCIENCE LETTERS》 *

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