CN102205129A - Novel nasal mucosa absorption enhancer - Google Patents
Novel nasal mucosa absorption enhancer Download PDFInfo
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- CN102205129A CN102205129A CN 201110090720 CN201110090720A CN102205129A CN 102205129 A CN102205129 A CN 102205129A CN 201110090720 CN201110090720 CN 201110090720 CN 201110090720 A CN201110090720 A CN 201110090720A CN 102205129 A CN102205129 A CN 102205129A
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- chitosan
- succinylation
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- nasal mucosa
- succinylation chitosan
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- 238000010521 absorption reaction Methods 0.000 title claims abstract description 57
- 210000002850 nasal mucosa Anatomy 0.000 title claims abstract description 32
- 239000003623 enhancer Substances 0.000 title claims description 11
- 239000003814 drug Substances 0.000 claims abstract description 81
- 229920001661 Chitosan Polymers 0.000 claims abstract description 70
- 238000010613 succinylation reaction Methods 0.000 claims description 36
- 230000035322 succinylation Effects 0.000 claims description 35
- 229940079593 drug Drugs 0.000 claims description 28
- 238000006467 substitution reaction Methods 0.000 claims description 25
- 125000003277 amino group Chemical group 0.000 claims description 23
- 239000000243 solution Substances 0.000 claims description 16
- 210000003928 nasal cavity Anatomy 0.000 claims description 13
- 238000002360 preparation method Methods 0.000 claims description 8
- -1 suspensoid Substances 0.000 claims description 7
- 239000002671 adjuvant Substances 0.000 claims description 4
- 239000002552 dosage form Substances 0.000 claims description 3
- 238000013329 compounding Methods 0.000 claims description 2
- 239000000839 emulsion Substances 0.000 claims description 2
- 238000009472 formulation Methods 0.000 claims description 2
- 239000002502 liposome Substances 0.000 claims description 2
- 239000004005 microsphere Substances 0.000 claims description 2
- 239000000203 mixture Substances 0.000 claims description 2
- 239000000825 pharmaceutical preparation Substances 0.000 claims description 2
- 239000003186 pharmaceutical solution Substances 0.000 claims description 2
- 239000000843 powder Substances 0.000 claims description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 abstract description 5
- 239000003655 absorption accelerator Substances 0.000 abstract 1
- 230000001737 promoting effect Effects 0.000 abstract 1
- 241000700159 Rattus Species 0.000 description 18
- 238000003756 stirring Methods 0.000 description 14
- MOYKHGMNXAOIAT-JGWLITMVSA-N isosorbide dinitrate Chemical compound [O-][N+](=O)O[C@H]1CO[C@@H]2[C@H](O[N+](=O)[O-])CO[C@@H]21 MOYKHGMNXAOIAT-JGWLITMVSA-N 0.000 description 13
- 230000000694 effects Effects 0.000 description 12
- 238000003556 assay Methods 0.000 description 7
- 239000008280 blood Substances 0.000 description 7
- 210000004369 blood Anatomy 0.000 description 7
- 210000003238 esophagus Anatomy 0.000 description 7
- 239000007788 liquid Substances 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 230000002572 peristaltic effect Effects 0.000 description 7
- 238000005070 sampling Methods 0.000 description 7
- 210000004081 cilia Anatomy 0.000 description 5
- 229960002479 isosorbide Drugs 0.000 description 5
- PWWVAXIEGOYWEE-UHFFFAOYSA-N Isophenergan Chemical compound C1=CC=C2N(CC(C)N(C)C)C3=CC=CC=C3SC2=C1 PWWVAXIEGOYWEE-UHFFFAOYSA-N 0.000 description 3
- 229940124532 absorption promoter Drugs 0.000 description 3
- KWWLGXNRLABSMP-UHFFFAOYSA-N phosphoric acid;2,3,5,6-tetramethylpyrazine Chemical compound OP(O)(O)=O.CC1=NC(C)=C(C)N=C1C KWWLGXNRLABSMP-UHFFFAOYSA-N 0.000 description 3
- 229960003910 promethazine Drugs 0.000 description 3
- 239000008186 active pharmaceutical agent Substances 0.000 description 2
- 238000004811 liquid chromatography Methods 0.000 description 2
- 210000004279 orbit Anatomy 0.000 description 2
- 230000001629 suppression Effects 0.000 description 2
- 229920002101 Chitin Polymers 0.000 description 1
- 108010054033 Chitin deacetylase Proteins 0.000 description 1
- 241000238424 Crustacea Species 0.000 description 1
- 229910002651 NO3 Inorganic materials 0.000 description 1
- NHNBFGGVMKEFGY-UHFFFAOYSA-N Nitrate Chemical compound [O-][N+]([O-])=O NHNBFGGVMKEFGY-UHFFFAOYSA-N 0.000 description 1
- 239000002253 acid Substances 0.000 description 1
- 238000013459 approach Methods 0.000 description 1
- 230000002146 bilateral effect Effects 0.000 description 1
- BHQCQFFYRZLCQQ-OELDTZBJSA-N cholic acid Chemical class C([C@H]1C[C@H]2O)[C@H](O)CC[C@]1(C)[C@@H]1[C@@H]2[C@@H]2CC[C@H]([C@@H](CCC(O)=O)C)[C@@]2(C)[C@@H](O)C1 BHQCQFFYRZLCQQ-OELDTZBJSA-N 0.000 description 1
- 230000007797 corrosion Effects 0.000 description 1
- 238000005260 corrosion Methods 0.000 description 1
- 235000014113 dietary fatty acids Nutrition 0.000 description 1
- 239000003937 drug carrier Substances 0.000 description 1
- 210000002919 epithelial cell Anatomy 0.000 description 1
- 229930195729 fatty acid Natural products 0.000 description 1
- 239000000194 fatty acid Substances 0.000 description 1
- 150000004665 fatty acids Chemical class 0.000 description 1
- 238000010579 first pass effect Methods 0.000 description 1
- 210000001035 gastrointestinal tract Anatomy 0.000 description 1
- 150000004676 glycans Chemical class 0.000 description 1
- 239000007924 injection Substances 0.000 description 1
- 238000002347 injection Methods 0.000 description 1
- 230000000968 intestinal effect Effects 0.000 description 1
- 210000004185 liver Anatomy 0.000 description 1
- 210000001365 lymphatic vessel Anatomy 0.000 description 1
- 239000000463 material Substances 0.000 description 1
- 210000004379 membrane Anatomy 0.000 description 1
- 239000012528 membrane Substances 0.000 description 1
- 210000004877 mucosa Anatomy 0.000 description 1
- 230000004677 mucosal permeability Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 230000003000 nontoxic effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 230000000241 respiratory effect Effects 0.000 description 1
- 210000002784 stomach Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 230000008337 systemic blood flow Effects 0.000 description 1
- 230000009967 tasteless effect Effects 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 231100000820 toxicity test Toxicity 0.000 description 1
- 210000003462 vein Anatomy 0.000 description 1
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- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
本发明属于医药技术领域，涉及琥珀酰化壳聚糖作为鼻黏膜吸收促进剂的应用,该促进剂具有水溶性好、促吸收效果好、使用安全的特点。 The invention belongs to the technical field of medicine and relates to the application of succinylated chitosan as a nasal mucosa absorption accelerator. The accelerator has the characteristics of good water solubility, good absorption promoting effect and safe use.
Description
Technical field
The present invention relates to medical technical field, relate to a kind of absorption enhancer of novel nasal mucosa medicine administration preparation, this promoter has good water solubility, short good absorbing effect, characteristics safe in utilization.
Background technology
The nasal mucosa route of administration is subjected to the extensive concern and the attention of pharmaceutical researchers owing to have characteristics such as absorption is fast, onset is rapid, bioavailability is high, side effect is little.This mainly is because people's nasal mucosa surface area is 150 ㎝
2Not only mucosa top layer epithelial cell has many fine hair in the respiratory region, similar to intestinal villi, can increase the effective area of drug absorption greatly, and the nasal mucosa propria lamina has abundant blood capillary and lymphatic capillaries, can make medicine avoid liver first-pass effect and the degraded in gastrointestinal tract, thereby make medicine after nasal absorption, enter the systemic blood circulation rapidly.But express lower mucosal permeability during some medicine nasal mucosa administration, cause the absorption of medicine to be subjected to very big restriction.The use of absorption enhancer becomes one of most effectual way that solves this difficult problem.Absorption enhancer commonly used has cholic acid salt, fatty acid, surfactant-based etc., but these traditional absorption enhancers have limited its application in pharmaceutical preparation because cilium toxicity is big and nasal mucosa is had in various degree damage.Therefore, the novel nasal mucosa absorption enhancer of research highly effective and safe becomes the key that addresses this problem.
Chitosan is the alkaline polysaccharide that is obtained by the chitin deacetylase base, and chitin extensively is present in the shell of Crustacean, is a quite abundant Renewable resource.Advantages such as that chitosan has is nontoxic, tasteless, alkaline-resisting, heat-resisting, corrosion-resistant, excellent biological compatibility and biological degradability are widely used in pharmaceutical carrier and organizational project at present.It can be used as the absorption enhancer of nasal-cavity administration, and is safe in utilization.But the organic solvent that chitosan is water insoluble and common can only dissolve under acid condition, and this has brought inconvenience to practical application.Therefore select good water solubility, to absorb the strong chitosan derivatives of facilitation significant as the absorption enhancer of nasal mucosa medicine administration preparation.
Summary of the invention
The objective of the invention is to seek good water solubility, absorb that facilitation effect is good, wide adaptability, Nasal Mucosa Absorption promoter safe in utilization, be applied to the nasal mucosa drug-supplying system, see through speed and the absorbtivity thereof that nasal mucosa absorbs thereby improve medicine.The novel nasal mucosa absorption enhancer that the present invention relates to is the succinylation chitosan.Fig. 1 is the structural formula of this novel Nasal Mucosa Absorption promoter.
Described succinylation chitosan comprises the chitosan of different molecular weight (Mw), different amino group substitution degree (DS).
The preferred mean molecule quantity of described succinylation chitosan is 20kDa～100kDa, and amino group substitution degree is 54.0% ~ 64.2%.
Described succinylation chitosan, the working concentration in nasal cavity administrated preparation are 0.1-1.0%, can significantly increase the Nasal Mucosa Absorption of lipophilic drugs and hydrophilic medicament.
Described succinylation chitosan can be applicable to nasal cavity administrated preparation.
Described nasal cavity administrated preparation comprises nasal cavity solution, suspensoid, Emulsion, microsphere, liposome, powder formulation etc.
Described succinylation chitosan can be applicable to various nasal mucosa drug-supplying systems, and concrete scheme is: this succinylation chitosan is water-soluble, and the preparation mass ratio is 0.1% ~ 1.0% succinylation chitosan solution, adds medicine and other adjuvant compounding pharmaceutical solution.Perhaps earlier medicine and other adjuvants are made suitable dosage forms, add a certain amount of succinylation chitosan again, making its final concentration in prescription is 0.1% ~ 1.0%.The solution of making is applied to the nasal membrane surface, the material that makes biologically active in the solution by the speed of Nasal Mucosa Absorption and drug absorption than not adding the absorption enhancer group and add the chitosan group and obviously improve, and to the nasal mucosa not damaged, safe in utilization.In frog cilium toxicity test, concentration is 0.1%, amino group substitution degree is the cilium suppression ratio (85.94% of 57.0%, 60.7% and 63.0% succinylation chitosan (Mw=50kDa), 85.37% and 86.22%) with 0.5% same molecular weight chitosan (Mw=50kDa) cilium suppression ratio (77.60%) all greater than 70%, show that both safeties are better; Be applied to research in the rat body, result of the test shows, compares with 0.5% chitosan, and 0.1% succinyl-chitosan can significantly improve medicine and (see Table 1, Fig. 9) in the intravital absorbtivity of rat.
Described succinylation chitosan is to micromolecular lipophilic drugs and hydrophilic medicament; as molecular weight less than 1000 medicine; its nasal mucosa absorbtivity is all above blank drug solution; and compare with chitosan; it significantly reduces the valid density that medicine produces the Nasal Mucosa Absorption facilitation; drug absorption obviously improves, and to the nasal mucosa not damaged, to intranasal cilium unrestraint effect.
Description of drawings
The chemical constitution of Fig. 1 succinylation chitosan.
Fig. 2 different time ligustrazine phosphate matched group drug absorption.0.1% chitosan (Mw=50kDa) group drug absorption and 0.1% amino group substitution degree are 63.0% succinyl-chitosan (Mw=50kDa) group drug absorption comparison (embodiment 1).
Fig. 3 different time promethazine matched group drug absorption.0.1% chitosan (Mw=50kDa) group drug absorption and 0.1% amino group substitution degree are 63.0% succinyl-chitosan (Mw=50kDa) group drug absorption (embodiment 2).
Fig. 4 different time sorbide nitrate matched group drug absorption.0.1% chitosan (Mw=20kDa) group drug absorption and 0.1% amino group substitution degree are 64.2% succinyl-chitosan (Mw=20kDa) group drug absorption (embodiment 3).
Fig. 5 different time sorbide nitrate matched group drug absorption.0.5% chitosan (Mw=50kDa) group drug absorption and 0.5% amino group substitution degree are 60.7% succinyl-chitosan (Mw=50kDa) group drug absorption (embodiment 4).
Fig. 6 different time sorbide nitrate matched group drug absorption.0.1% chitosan (Mw=100kDa) group drug absorption and 0.1% amino group substitution degree are 54.0% succinyl-chitosan (Mw=100kDa) group drug absorption (embodiment 5).
Fig. 7 different time sorbide nitrate matched group drug absorption.0.1% chitosan (Mw=50kDa) group drug absorption and 0.1%, amino group substitution degree are 57.0% succinyl-chitosan (Mw=50kDa) group drug absorption (embodiment 6).
Fig. 8 different time sorbide nitrate matched group drug absorption.1.0% chitosan (Mw=50kDa) group drug absorption and 1.0% amino group substitution degree are 60.7% succinyl-chitosan (Mw=50kDa) group drug absorption (embodiment 7).
Time front of blood concentration among Fig. 9 embodiment 8 after different prescriptions, the different approaches administration (mean ± SD,
n=5).
The specific embodiment
Example 1: the succinylation chitosan (50kDa) of amino group substitution degree 63.0% is to ligustrazine phosphate Nasal Mucosa Absorption facilitation
Male rat (180g～220g) be placed on top, storage medicine pond through the operation of esophagus intubate; add 5mL ligustrazine phosphate solution (4.0mg/mL) and constantly stirring in the storage medicine pond; feed 37 ± 0.5 ℃ circulator bath; add 0.1% amino group substitution degree at last and be 63.0% succinylation chitosan (Mw=50kDa), stirring and dissolving (matched group does not add).Medicinal liquid is back to storage medicine pond again from storage medicine pond from the nostril after peristaltic pump enters the rat nasal cavity, different time is at interval from storage medicine pond sampling carrying out assay in 2 hours.Investigate the absorption facilitation effect of 0.1% chitosan (Mw=50kDa) with method, the results are shown in Figure 2.
Example 2: the succinylation chitosan (Mw=50kDa) of amino group substitution degree 63.0% is to promethazine Nasal Mucosa Absorption facilitation
Male rat (180g～220g) be placed on top, storage medicine pond through the operation of esophagus intubate; add 5mL promethazine solution (0.35mg/mL) and constantly stirring in the storage medicine pond; feed 37 ± 0.5 ℃ circulator bath; add 0.1% amino group substitution degree at last and be 63.0% succinylation chitosan (Mw=50kDa), stirring and dissolving (matched group does not add).Medicinal liquid is back to storage medicine pond again from storage medicine pond from the nostril after peristaltic pump enters the rat nasal cavity, different time is at interval from storage medicine pond sampling carrying out assay in 2 hours.Investigate the absorption facilitation effect of 0.1% chitosan Mw=(50kDa) with method, the results are shown in Figure 3.
Example 3: the succinylation chitosan (Mw=20kDa) of amino group substitution degree 64.2% is to sorbide nitrate Nasal Mucosa Absorption facilitation
Male rat (180g～220g) be placed on top, storage medicine pond through the operation of esophagus intubate; add 5mL Isosorbide ester solution (0.5mg/mL) and constantly stirring in the storage medicine pond; feed 37 ± 0.5 ℃ circulator bath; add 0.1% amino group substitution degree at last and be 64.2% succinylation chitosan (Mw=20kDa), stirring and dissolving (matched group does not add).Medicinal liquid is back to storage medicine pond by the nostril from storage medicine pond after peristaltic pump enters the rat nasal cavity, different time is at interval from storage medicine pond sampling carrying out assay in 2 hours.Investigate the absorption facilitation effect of 0.1% chitosan (Mw=20kDa) with method, the results are shown in Figure 4.
Example 4: the succinylation chitosan (50kDa) of substitution value 60.7% is to sorbide nitrate Nasal Mucosa Absorption facilitation
Male rat (180g～220g) be placed on top, storage medicine pond through the operation of esophagus intubate; add 5mL Isosorbide ester solution (0.5mg/mL) and constantly stirring in the storage medicine pond; feed 37 ± 0.5 ℃ circulator bath; add 0.5% amino group substitution degree at last and be 60.7% succinylation chitosan (Mw=50kDa), stirring and dissolving (matched group does not add).Medicinal liquid is back to storage medicine pond again from storage medicine pond from the nostril after peristaltic pump enters the rat nasal cavity, different time is at interval from storage medicine pond sampling carrying out assay in 2 hours.Investigate the absorption facilitation effect of 0.5% chitosan (Mw=50kDa) with method, the results are shown in Figure 5.
Example 5: the succinylation chitosan (Mw=100kDa) of substitution value 54.0% is to sorbide nitrate Nasal Mucosa Absorption facilitation
Male rat (180g～220g) be placed on top, storage medicine pond through the operation of esophagus intubate; add 5mL Isosorbide ester solution (0.5mg/mL) and constantly stirring in the storage medicine pond; feed 37 ± 0.5 ℃ circulator bath; add 0.1% amino group substitution degree at last and be 54.0% succinylation chitosan (Mw=100kDa), stirring and dissolving (matched group does not add).Medicinal liquid is back to storage medicine pond again from storage medicine pond from the nostril after peristaltic pump enters the rat nasal cavity, different time is at interval from storage medicine pond sampling carrying out assay in 2 hours.Investigate the absorption facilitation effect of 0.1% chitosan (Mw=100kDa) with method, the results are shown in Figure 6.
Example 6: the succinylation chitosan (Mw=50kDa) of amino group substitution degree 57.0% is to sorbide nitrate Nasal Mucosa Absorption facilitation
Male rat (180g～220g) be placed on top, storage medicine pond through the operation of esophagus intubate, add 5mL Isosorbide ester solution (0.5mg/mL) and constantly stirring in the storage medicine pond, feed 37 ± 0.5 ℃ circulator bath, add 0.1% amino group substitution degree at last and be 57.0% succinyl-chitosan (Mw=50kDa), stirring and dissolving (matched group does not add).Medicinal liquid is back to storage medicine pond again from storage medicine pond from the nostril after peristaltic pump enters the rat nasal cavity, intervals different in 2 hours are from storage medicine pond sampling carrying out assay.Investigate the absorption facilitation effect of 0.1% chitosan (Mw=50kDa) with method, the results are shown in Figure 7.
Example 7: the succinylation chitosan (Mw=50kDa) of amino group substitution degree 60.7% is to sorbide nitrate Nasal Mucosa Absorption facilitation
Male rat (180g～220g) be placed on top, storage medicine pond through the operation of esophagus intubate; add 5mL Isosorbide ester solution (0.5mg/mL) and constantly stirring in the storage medicine pond; feed 37 ± 0.5 ℃ circulator bath; add 1.0% amino group substitution degree at last and be 60.7% succinylation chitosan (Mw=50kDa), stirring and dissolving (matched group does not add).Medicinal liquid is back to storage medicine pond again from storage medicine pond from the nostril after peristaltic pump enters the rat nasal cavity, different time is at interval from storage medicine pond sampling carrying out assay in 2 hours.Investigate the absorption facilitation effect of 1.0% chitosan (Mw=50kDa) with method, the results are shown in Figure 8.
Example 8: use zoopery and compare the succinylation chitosan to sorbide nitrate Nasal Mucosa Absorption facilitation effect
Get 15 of the male rats of 180～220g, be divided into three groups at random, giving dosage respectively is 1.04 mgkg
-1Sorbide nitrate (matched group), sorbide nitrate-chitosan solution (0.5%, Mw=50kDa) and sorbide nitrate-succinylation chitosan solution (0.1%, Mw=50kDa, DS=63.0%) bilateral nostril administration, every nostril 20 μ L are in 2,5,10,15,20,30,60,120, the 180min eye socket is got blood 0.3mL, and blood sample is handled, and gets 20 μ L high effective liquid chromatography for measuring content; Other gets 10 of the male rats of 180～220g, is divided into two groups at random, and irritating stomach dosage respectively is 2.58 mgkg
-1With tail vein injection dosage be 0.64mgkg
-1, in 2,5,10,20,30,60,120, the 180min eye socket is got blood 0.3mL, and blood sample is handled, and gets 20 μ L high effective liquid chromatography for measuring content.Experimental data sees Table 1, and Fig. 9 is a time front of blood concentration in the corresponding body.
The main pharmacokinetic parameter of table 1 (mean ± SD,
n=5)
Claims (7)
1. the succinylation chitosan is characterized in that as the application of nasal mucosa absorption enhancer the succinylation chitosan has following structure:
。
2. application according to claim 1 is characterized in that described succinylation chitosan mean molecule quantity is 20kDa～100kDa, and amino group substitution degree is 54.0%～64.2%.
3. application according to claim 1, the working concentration that it is characterized in that described succinylation chitosan is 0.1-1.0%.
4. application according to claim 1 is characterized in that described succinylation chitosan can be used for molecular weight less than 1000 lipophilic drugs and hydrophilic medicament.
5. application according to claim 1 is characterized in that described succinylation chitosan can be used for nasal cavity solution, suspensoid, Emulsion, microsphere, liposome, powder formulation etc.
6. application according to claim 1; it is characterized in that concrete scheme is: this succinylation chitosan is water-soluble; the preparation mass ratio is 0.1%～1.0% succinylation chitosan solution, adds medicine and other adjuvant compounding pharmaceutical solution or preparation suitable dosage forms.
7. application according to claim 1 is characterized in that concrete scheme is: earlier medicine and other adjuvants are made suitable dosage forms, add a certain amount of succinylation chitosan again, making its final concentration in prescription is 0.1% ~ 1.0%.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110090720 CN102205129B (en) | 2011-04-12 | 2011-04-12 | Novel nasal mucosa absorption enhancer |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN 201110090720 CN102205129B (en) | 2011-04-12 | 2011-04-12 | Novel nasal mucosa absorption enhancer |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110227059A (en) * | 2018-03-06 | 2019-09-13 | 沈阳药科大学 | A kind of nasal absorption promotor and its application |
| CN113116854A (en) * | 2020-01-10 | 2021-07-16 | 中国药科大学 | Chitosan lipoprotein nasal administration nano-composite and preparation method and application thereof |
-
2011
- 2011-04-12 CN CN 201110090720 patent/CN102205129B/en not_active Expired - Fee Related
Non-Patent Citations (3)
| Title |
|---|
| 《Int J Pharm》 20030512 Sinswat P, Tengamnuay P Enhancing effect of chitosan on nasal absorption of salmon calcitonin in rats: comparison with hydroxypropyl- and dimethyl-beta-cyclodextrins 第257卷, 第1-2期 * |
| 《功能高分子学报》 20040330 汪琴等 N-琥珀酰壳聚糖的合成和性能研究 第17卷, 第01期 * |
| 《现代食品科技》 20070715 陶露丝等 N-琥珀酰壳聚糖制备及理化特性研究 第23卷, 第07期 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN110227059A (en) * | 2018-03-06 | 2019-09-13 | 沈阳药科大学 | A kind of nasal absorption promotor and its application |
| CN110227059B (en) * | 2018-03-06 | 2022-11-01 | 沈阳药科大学 | Nasal cavity absorption enhancer and application thereof |
| CN113116854A (en) * | 2020-01-10 | 2021-07-16 | 中国药科大学 | Chitosan lipoprotein nasal administration nano-composite and preparation method and application thereof |
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