CN107261106A - Thymopeptide-5, chitosan inclusion compound of rifamycin isoniazid and preparation method thereof - Google Patents
Thymopeptide-5, chitosan inclusion compound of rifamycin isoniazid and preparation method thereof Download PDFInfo
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- CN107261106A CN107261106A CN201710388148.0A CN201710388148A CN107261106A CN 107261106 A CN107261106 A CN 107261106A CN 201710388148 A CN201710388148 A CN 201710388148A CN 107261106 A CN107261106 A CN 107261106A
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- rifamycin
- isoniazid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
- A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
- A61K38/08—Peptides having 5 to 11 amino acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/51—Nanocapsules; Nanoparticles
- A61K9/5107—Excipients; Inactive ingredients
- A61K9/513—Organic macromolecular compounds; Dendrimers
- A61K9/5161—Polysaccharides, e.g. alginate, chitosan, cellulose derivatives; Cyclodextrin
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Abstract
The present invention relates to a kind of thymopeptide-5, the chitosan inclusion compound of rifamycin isoniazid and preparation method thereof, the inclusion compound is the nano particle that Chitosan-coated thymopeptide-5 and rifamycin isoniazid heterocomplex are obtained.The present invention is included the medicine (thymopeptide-5, rifamycin isoniazid heterocomplex) of two kinds of different action target spots together by simple clathration, obtain thymopeptide-5, the chitosan inclusion compound of rifamycin isoniazid, it has the more preferable fungistatic effect of mixture than rifamycin and isoniazid to mycobacterium tuberculosis, inclusion compound after medicine-feeding part is sent to by specific administering mode to scatter, two or more drug molecules are respectively acting on respective target spot and played a role, and the dose of medicine is reduced while drug effect is ensured.
Description
Technical field
The present invention relates to medical synthesis technical field, and in particular to a kind of thymopeptide-5, the shell of rifamycin-isoniazid gather
Sugared inclusion compound and preparation method thereof.
Background technology
Tuberculosis is a kind of worldwide epidemic infectious diseases, and with fatal risk.To tuberculotherapy one
As shared using various medicaments, such as isoniazid, rifampin are applied in combination more than six months.Patient takes these medicines together
Or separately take, total dose is taken mode and brought inconvenience to patient than larger, and patient needs to have recorded several drugses
Take period.Therefore, it is favourable to patient to prepare the combination formulations of several drugses, and treatment tuberculosis is clinically there is no at present
Unitary agent.
The content of the invention
The technical problems to be solved by the invention are that there is provided a kind of thymus gland five for above shortcomings in the prior art
Peptide, chitosan inclusion compound of rifamycin-isoniazid and preparation method thereof.
In order to solve the above technical problems, the technical scheme that the present invention is provided is：
A kind of thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid are provided, the inclusion compound is Chitosan-coated
The nano particle that thymopeptide-5 and rifamycin-isoniazid heterocomplex are obtained.
By such scheme, the preparation method of the rifamycin-isoniazid heterocomplex is as follows：
1) He Cheng oxazines rifamycin：Rifamicina is dissolved in DMF, rifamicina is obtained
Solution, adds the concentrated sulfuric acid and rifamicina is acidified, be warming up to 35-50 DEG C after solution is changed into peony, be slowly added dropwise
Continue ring-closure reaction after N, N- dihydroxymethyl tert-butylamine, completion of dropping, reaction is cooled to room temperature after terminating, uses the glacial acetic acid aqueous solution
Sediment is separated out, sediment is filtered, washed, the dry get of Gan Dao oxazine rifamycin；
2) rifamycin-isoniazid heterozygosis medicine is synthesized：Step 1) Suo get oxazine rifamycins are dissolved in into absolute ethyl alcohol to obtain
Dao oxazine rifamycin solution, piperazine and isoniazid are then added into Suo Shu oxazine rifamycin solution, 55-60 DEG C is warming up to
Condensation reaction is carried out, post processing obtains good fortune mycin-isoniazid heterocomplex after reaction terminates.
By such scheme, step 1) the rifamicina solution concentration be 0.02-0.08g/mL.
By such scheme, step 1) concentrated sulfuric acid concentration is 98%, wherein sulfuric acid and rifamicina mol ratio are 1:
2。
By such scheme, step 2) Suo Shu oxazine rifamycins solution concentration is 0.03-0.08g/mL.
The present invention also provides above-mentioned thymopeptide-5, the preparation method of the chitosan inclusion compound of rifamycin-isoniazid, and it is walked
It is rapid as follows：Rifamycin-isoniazid heterocomplex is dissolved in NaOH solution, rifamycin-isoniazid solution is obtained, then by profit
Good fortune mycin-isoniazid solution is added in the NaOH solution of thymopeptide-5, is added the aqueous solution of sodium tripolyphosphate, is sufficiently mixed
Mixed liquor, is then slowly dropped in chitosan-acetic acid solution by mixed liquor, and 30min is stirred at room temperature, and adds lactose and is used as protection
Agent, thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid are obtained after carrying out freeze-drying 48h.
Preferably, the rifamycin-isoniazid solution concentration is 0.001-0.004g/mL.
Preferably, the concentration of the NaOH solution of the thymopeptide-5 is 0.01-0.02g/mL.
Preferably, the concentration of aqueous solution of the sodium tripolyphosphate is 0.001-0.004g/mL.
Preferably, the mass ratio of chitosan, rifamycin-isoniazid heterocomplex, thymopeptide-5 and sodium tripolyphosphate is
5-10：0.5-1.5：1.5-3：1-2.
Preferably, mixed liquor is slowly dropped to the concentration of chitosan in the reaction solution obtained in chitosan-acetic acid solution
For 1.5-6.0g/L.Test result indicates that, only in certain concentration range, i.e., chitosan concentration scope is in 1.5- in reaction solution
Chitosan nano particle can be formed during 6.0g/L.
Present invention additionally comprises the drug regimen comprising above-mentioned thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid
Thing.
And above-mentioned thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid are used to treat purposes lungy.
Thymopeptide-5 (thymopentin, TP5) is artificial synthesized pentapeptide, its amino acid sequence and structure with by 49
32~36 amino acids composition of the natural thymopoietin (thymopoietin, TP) of amino acid composition is identical, i.e. TP is biological
The active group Arg-Lys-Asp-Val-Tyr of function, is a kind of bidirectional immune regulator with the similar bioactivity of TP,
Existing clinic is widely used in the treatment of the diseases such as rheumatoid arthritis, malignant tumour, chronic hepatitis and severe infections, there is wide
Development prospect.
TP5 is degraded to amino acid by protease and aminopeptidase quickly in vivo.Current TP5 clinical practice preparations are injection
With, by carry out modifying for chemical structure, add enzyme inhibitor or change method of administration (such as nasal-cavity administration) can increase protease and
Aminopeptidase stability improves trap.Its structural formula is as follows：
Rifamycinoid antibiotics, is the class antibiotic produced by Mediterranean Streptothrix, it has broad-spectrum antibacterial action,
To the gram-positive bacteriums such as tubercle bacillus, Mycobacterium leprae, streptococcus, pneumococcus, particularly resistant Staphylococcus grape ball
The inhibitory action of bacterium is all very strong.Isoniazid is anti-mycobacterium tuberculosis medicine, and for pulmonary tuberculosis, cutaneous tuberculosis etc., earliest invention is in 1952
Year, its invention makes the change lungy treated and serve essence.By heterozygosis technology by rifamycin and isoniazid two
Person, which is combined together obtained rifamycin-isoniazid heterocomplex, has preferable drug activity.Structural formula is as follows：
Several different single target drugs are combined according to " HAART " or selection uses and acts on multiple molecular targets
Preferable curative effect is then had during target " Mutiple Targets " drug therapy complex disease.Method by being included in pharmacy, will have not
Drug molecule inclusion with target spot gets up to form Mutiple Targets medicine, because two drug molecules lack general character, so in vivo
All or part of architectural feature of original molecule can each be retained.Then by specific administering mode, the administration specified is reached
Position, inclusion compound scatter, and two or more drug molecules are respectively acting on respective target spot and played a role.According to this hair
Existing, the applicant prepares thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid.By to synthesized inclusion compound
Active testing, it is found that this inclusion compound has preferable antibacterial activity with respect to any of which component.
The beneficial effects of the present invention are：The present invention is by simple clathration by the medicine of two kinds of different action target spots
(thymopeptide-5, rifamycin-isoniazid heterocomplex) is included together, obtains thymopeptide-5, the shell of rifamycin-isoniazid gathers
Sugared inclusion compound, it has the more preferable fungistatic effect of mixture than rifamycin and isoniazid to mycobacterium tuberculosis, passes through spy
Fixed administering mode is sent to inclusion compound after medicine-feeding part and scatter, and two or more drug molecules are respectively acting on respective
Target spot and play a role, ensure drug effect while reduce medicine dose.
Brief description of the drawings
Fig. 1 be thymopeptide-5 (TP5), chitosan nano particle, the step 2 of embodiment 1) prepare rifamycin-isoniazid
Heterozygosis medicine and the step 3 of embodiment 1) prepare thymopeptide-5, the infrared light of the chitosan inclusion compound of rifamycin-isoniazid
Spectrogram.
Embodiment
To make those skilled in the art more fully understand technical scheme, the present invention is made below in conjunction with the accompanying drawings into
One step is described in detail.
Embodiment 1
Thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid are prepared, is comprised the following steps that：
1) He Cheng oxazines rifamycin：Load rifamycin-S-sodium salt 1.00g (0.0014mol) in there-necked flask, add
20mLN, dinethylformamide (DMF) is dissolved, and is put under the magneton of stirring, normal temperature and is stirred 30 minutes, treats fully molten
Xie Hou, the concentrated sulfuric acid 0.072g (0.0007mol) for adding 98% is acidified, and is stirred 30 minutes under normal temperature, reaction solution is by dark blue discoloration
Laking, then heats to 35~50 DEG C, and N, N- dihydroxymethyl tert-butylamine 0.352g (0.0026mol) is slowly added dropwise, and drop finishes
Afterwards, reaction solution is changed into navy blue from peony, continues insulation reaction 2 hours, is cooled to room temperature, adds and be added dropwise into reaction solution
The aqueous solution 200mL of 2 drop glacial acetic acids, intermittent stirring has a large amount of blue precipitates, reaction terminate after (with tlc silica gel plate with
Track reacts) separate out, stand overnight, filter, appropriate washing can obtain the sharp good fortune of 1.03g blue solid materials, i.e. oxazine after drying
Mycin；
2) rifamycin-isoniazid heterozygosis medicine is synthesized：By step 1) Suo get oxazine rifamycin 20mL absolute ethyl alcohols
Dissolving, get is Dao oxazine rifamycin solution, Zhuan Ru oxazine rifamycin solution and piperazine 0.13g in 100mL there-necked flasks
(0.0015mol) and 0.039g isoniazid, are warming up to 55-60 DEG C, reaction solution is changed into rufous, insulation reaction 3 from navy blue
Hour, reaction (tracks reaction) after terminating with tlc silica gel plate, revolves etoh solvent at 45 DEG C in Rotary Evaporators
It is dry, brick-red solid material is obtained, i.e. rifamycin-isoniazid heterozygosis medicine；
3) synthesis thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid：
A. 10mg chitosan solids (CS) are dissolved in the acetum that 5mL volume fractions are 0.25%, are fully swelled 24 small
When, until chitosan all dissolves, obtain chitosan solution；
B. take 1.7mg thymopeptide-5s solid (TP5) to be dissolved in the NaOH solution that 0.1mL concentration is 0.1mol/L, make it
Fully dissolving obtains evaluation of thymopentin in solution；
C. 3mg rifamycins-isoniazid heterozygosis medicine (HYD) is taken to be dissolved in the NaOH solution that 1mL concentration is 0.1mol/L,
It is taken out 0.3mL to add in evaluation of thymopentin in solution prepared by step b, adds the sodium tripolyphosphate that 1mL concentration is 2g/L
(TPP) aqueous solution, is sufficiently mixed, and obtains mixed solution；
D. by step c obtain dissolved with TP5, HYD, TPP mixed solution is slowly dropped to the shell after being swelled obtained by step a
In glycan solution, 30min is stirred at room temperature, adds a small amount of lactose and cooks protective agent, be then freeze-dried 48h, obtain thymopeptide-5, profit
The chitosan inclusion compound of good fortune mycin-isoniazid.
To thymopeptide-5 (TP5), chitosan nano particle, the present embodiment step 2) prepare rifamycin-isoniazid it is miscellaneous
Composite medicine and the present embodiment step 3) prepare thymopeptide-5, rifamycin-isoniazid chitosan inclusion compound carry out it is infrared
Test, gained infrared spectrum is shown in Fig. 1, wherein 1 is thymopeptide-5,2 be rifamycin-isoniazid heterozygosis medicine, and 3 be chitosan nano
Rice grain, 4 be thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid, and as can be seen from Figure, chitosan is acted on TPP
Afterwards ,-OH the stretching vibration absworption peaks at 3409 are moved at 3383, and to low ripple end movement, this suggests the formation of stronger intramolecular
And intermolecular hydrogen bonding；TP5 characteristic absorption peak is acid amides peak 1656,1566,1242cm, and the amino stretching vibration at 3346
Peak, the intensity enhancing at peak in 4, because TP5 acid amides peak 1656 and 1566 and the amino peak 1637 of chitosan nano particle
With 1564 superpositions, the inclusion compound described above for foring Chitosan-coated TP5 and rifamycin-isoniazid heterozygosis medicine.
Embodiment 2
Testing example 1 prepare thymopeptide-5, rifamycin-isoniazid chitosan inclusion compound (wherein rifamycin-
Isoniazid heterozygosis drug quality content is 6%, and thymopeptide-5 mass content is diluted to different times for lyophilized products 11.6%)
Number, tests its drug resistance to cultured M. tuberculosis strains, and with rifamycin and the mixture (Li Fu of isoniazid
Mycin is 1 with isoniazid mass ratio:1) compare.
Experimental method：Above-mentioned inclusion compound and mixture be made into concentration be 1mg/mL decoction, it is sterilized after, use sterile film
Seal standby.
(1) the μ L of 7H9 culture mediums 100 are added per hole in sterile 96 orifice plate (1~12 hole).1st hole adds the resistive connection suitably diluted
The μ L of core medicine stoste 100, to serial dilution again to the 12nd hole.Each hole medicine ultimate density:Rifamycin and the mixture of isoniazid
17~0.017 μ g/mL, thymopeptide-5, the μ g/mL of chitosan inclusion compound 17~0.017 of rifamycin-isoniazid；
(2) 2 are added in glass bacteria grinder bottom and drips 10%Tween-80 physiological saline and 2~3 weeks cell ages being clinically separated
Fresh cultured thing, be ground in cheese sample, with normal saline dilution into the turbidity (1mg/mL) of No. 1 Maxwell opacity tube, use 7H9
Culture medium 1:1~8 hole is inoculated with 100 μ L per hole after 20 times of dilutions.Blank well compares for culture medium；
(3) sterile film shrouding is used, is put into wet box, 37 DEG C of culture 5d add filtration sterilization 0.1g/L resazurins on the 6th day and shown
The μ L of color liquid 30 continue to incubate 24h, such as blank well (non-dosing thing) becomes pink, then add the colour developing of same amount resazurin to the 12nd hole
Liquid records color change to other each holes after 24h.If blank well is still blueness, respectively the 7th, observation in 9 days.Color is from blueness
It is changed into pink colour and indicates bacterial growth.
Thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid prepared by embodiment 1 is diluted to after various concentrations
Test its drug resistance to mycobacterium tuberculosis, and carried out pair with the rifamycin under comparable sodium and the mixture of isoniazid
Than test result is shown in Table 1.
Table 1
Remarks：R is the drug resistance to mycobacterium tuberculosis, i.e., inactive；S is the sensitiveness to mycobacterium tuberculosis, i.e.,
For active (concentration unit is μ g/mL).
From table 1 it can be seen that thymopeptide-5, rifamycin-isoniazid chitosan inclusion compound concentration 0.133 μ g/mL when
Time begins to fungistatic effect occur, and the concentration of rifamycin and the mixture of isoniazid just occurs when 1.063 μ g/mL
Fungistatic effect, it is believed that thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid are than rifamycin and isoniazid mixture
Good antimicrobial effect.
Claims (10)
1. a kind of thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid, it is characterised in that：The inclusion compound is poly- for shell
The nano particle that sugar cladding thymopeptide-5 and rifamycin-isoniazid heterocomplex are obtained.
2. thymopeptide-5 according to claim 1, the chitosan inclusion compound of rifamycin-isoniazid, it is characterised in that institute
The preparation method for stating rifamycin-isoniazid heterocomplex is as follows：
1) He Cheng oxazines rifamycin：Rifamicina is dissolved in DMF, rifamycin sodium solution is obtained,
Add the concentrated sulfuric acid to be acidified rifamicina, be warming up to 35-50 DEG C after solution is changed into peony, N, N- bis- is slowly added dropwise
Continue ring-closure reaction after methylol tert-butylamine, completion of dropping, reaction is cooled to room temperature after terminating, it is heavy to be separated out with the glacial acetic acid aqueous solution
Starch, sediment is filtered, washed, the dry get of Gan Dao oxazine rifamycin；
2) rifamycin-isoniazid heterozygosis medicine is synthesized：Step 1) Suo get oxazine rifamycins are dissolved in absolute ethyl alcohol get Dao Evil
Piperazine rifamycin solution, piperazine and isoniazid are then added into Suo Shu oxazine rifamycin solution, 55-60 DEG C of progress is warming up to
Condensation reaction, post processing obtains good fortune mycin-isoniazid heterocomplex after reaction terminates.
3. thymopeptide-5 according to claim 2, the chitosan inclusion compound of rifamycin-isoniazid, it is characterised in that step
Rapid 1) described rifamicina solution concentration is 0.02-0.08g/mL.
4. thymopeptide-5 according to claim 2, the chitosan inclusion compound of rifamycin-isoniazid, it is characterised in that step
Rapid 1) described concentrated sulfuric acid concentration is 98%, and wherein sulfuric acid and rifamicina mol ratio are 1:2.
5. thymopeptide-5 according to claim 2, the chitosan inclusion compound of rifamycin-isoniazid, it is characterised in that step
Rapid 2) Suo Shu oxazine rifamycins solution concentration is 0.03-0.08g/mL.
6. a kind of any described thymopeptide-5s of claim 1-5, the preparation side of the chitosan inclusion compound of rifamycin-isoniazid
Method, it is characterised in that step is as follows：Rifamycin-isoniazid heterocomplex is dissolved in NaOH solution, rifamycin-different cigarette is obtained
Hydrazine solution, then rifamycin-isoniazid solution added in the NaOH solution of thymopeptide-5, add the water of sodium tripolyphosphate
Solution, is sufficiently mixed to obtain mixed liquor, then mixed liquor is slowly dropped in chitosan-acetic acid solution, and 30min is stirred at room temperature, plus
Enter lactose as protective agent, thymopeptide-5, the chitosan inclusion compound of rifamycin-isoniazid are obtained after carrying out freeze-drying 48h.
7. preparation method according to claim 6, it is characterised in that chitosan, rifamycin-isoniazid heterocomplex, chest
The mass ratio of gland pentapeptide and sodium tripolyphosphate is 5-10：0.5-1.5：1.5-3：1-2.
8. preparation method according to claim 6, it is characterised in that mixed liquor is slowly dropped to chitosan-acetic acid solution
In in obtained reaction solution the concentration of chitosan be 1.5-6.0g/L.
9. a kind of include any described thymopeptide-5s of claim 1-5, the medicine of the chitosan inclusion compound of rifamycin-isoniazid
Compositions.
10. any thymopeptide-5s of claim 1-5, the chitosan inclusion compound of rifamycin-isoniazid are used to treat tuberculosis
The purposes of disease.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109908366A (en) * | 2019-03-20 | 2019-06-21 | 佛山科学技术学院 | Modification of chitosan carrier and the inclusion compound of drug and preparation method thereof |
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|---|---|---|---|---|
| FR2311017A1 (en) * | 1975-05-16 | 1976-12-10 | Aries Robert | (Hexahydro)rifamycin (3)-hydrazones - antibiotics having improved solubility in the digestive tract |
| US4179439A (en) * | 1977-07-01 | 1979-12-18 | Intreprinderea De Antibiotice Iasi | Rifamycins and method for their preparation |
| CN103709177A (en) * | 2013-12-20 | 2014-04-09 | 武汉工程大学 | Rifamycin and valnemulin hybrid antibiotic and preparation method thereof |
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2017
- 2017-05-27 CN CN201710388148.0A patent/CN107261106A/en active Pending
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| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| FR2311017A1 (en) * | 1975-05-16 | 1976-12-10 | Aries Robert | (Hexahydro)rifamycin (3)-hydrazones - antibiotics having improved solubility in the digestive tract |
| US4179439A (en) * | 1977-07-01 | 1979-12-18 | Intreprinderea De Antibiotice Iasi | Rifamycins and method for their preparation |
| CN103709177A (en) * | 2013-12-20 | 2014-04-09 | 武汉工程大学 | Rifamycin and valnemulin hybrid antibiotic and preparation method thereof |
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| Title |
|---|
| BHAGWAT PRASAD等: "LC–MS/TOF and UHPLC–MS/MS study of in vivo fate of rifamycin isonicotinyl hydrazone formed on oral co-administration of rifampicin and isoniazid", 《JOURNAL OF PHARMACEUTICAL AND BIOMEDICAL ANALYSIS》 * |
| 奥格雷迪等著: "《抗生素及化学药物治疗》", 31 January 2000, 辽宁教育出版社 * |
| 李泽贵等: "胸腺五肽联合常规抗结核药物治疗耐药性肺结核33例", 《中国药业》 * |
| 郑爱萍等: "胸腺五肽pH-敏感壳聚糖纳米粒的制备、体外释放及生物活性", 《中国药学杂志》 * |
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| 魏萍编著: "《临床医技新编》", 30 June 2014, 云南科技出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN109908366A (en) * | 2019-03-20 | 2019-06-21 | 佛山科学技术学院 | Modification of chitosan carrier and the inclusion compound of drug and preparation method thereof |
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