CN104586877A - Chitosan oligosaccharide-containing pharmaceutical composition and applications thereof - Google Patents
Chitosan oligosaccharide-containing pharmaceutical composition and applications thereof Download PDFInfo
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Abstract
The invention discloses a chitosan oligosaccharide-containing pharmaceutical composition and applications thereof, relating to a pharmaceutical preparation of the chitosan oligosaccharide-containing pharmaceutical composition. The pharmaceutical composition takes chitosan as an active ingredient and pharmaceutically acceptable carrier as an adjuvant, wherein the carrier is a mixture of all the or 2-6 of starch, powdered sugar, dextrin, lactose, microcrystalline cellulose, and manitol, and the usage weight ratio of the chitosan and the carrier is 1:(0.5-1.5); and the pharmaceutical composition is used for treating TMEM16A/CaCCs ion channel related diseases such as gastrointestinal dyskinesia as an activator of a TMEM16A ion channel, and the defect that the existing medicament causes different degrees of side effects during the treatment of the gastrointestinal dyskinesia disease, and the clinical application is limited can be overcome.
Description
Technical field
Technical scheme of the present invention relates to the pharmaceutical preparation of the pharmaceutical composition containing oligochitosan, specifically containing pharmaceutical composition and the application thereof of oligochitosan.
Background technology
Oligochitosan (chitosan oligosaccharide) is by chitin, the linear homogeneous polysaccharide formed with β (1 → 4) glycosidic bond condensation, dehydration.It is present in the ectoskeleton of some invertebrates, as insecticide, Eriocheir sinensis shrimp and spiral shell freshwater mussel etc.By can generating chitosan after the deacetylated process of these ectoskeleton compositions, then be decomposed by chitosan and obtain oligosaccharide.Oligochitosan molecule self with positive electricity, its can and some electronegative molecular actions; And with amino in its molecular structure, can combine with the molecule containing carboxyl.The molecular weight of oligochitosan be affect the most important characteristic of its biological activity (Zheng Bisheng etc. the research of oligochitosan is prepared in chitosan oxidative degradation. modern food science and technology .2012; 28 [8]: 959-63.).In prior art, oligochitosan is applied in some food and health care medicine, and be also the raw material of some cosmetics, oligochitosan all has effect in biological medicine and agriculture and forestry, also can participate in environmental conservation and field of disposing of sewage.The biological activity of oligochitosan possesses multiformity, and current research finds, oligochitosan can reduce the cholesterol level in blood; There is health-care effect (the .Molecular dynamics of paclitaxel encapsulated by salicylic acid-grafted chitosan oligosaccharide aggregates.Biomaterials.2013 such as Wang XY of infection, anticancer and immunity moderation; 34 [7]: 1843-51.).
Gastrointestinal motility disorders (Disorders of gastrointestinal motility, DGIM) common disease is belonged to, its form of expression is various, existing gastrointestinal function weakens, gastrointestinal function is hyperfunction, also gastrointestinal dysfunction is had, the major measure of current these diseases for the treatment of regulates digestive tract power, short digestive tract power reinforcing medicine is main treatment means, but all there is side reaction in various degree in these medicines, clinical practice is restricted (Mc Callum R W.Motility agenis and the gastrointestinai tract.Am J Med Sci, 1996, 312 (1): 19-25).Gastrointestinal motility disorder causes due to neural or muscle changes, comprises functional intestinal disease and gastrointestinal motility disorder, is mainly common in gastroesophageal reflux disease, functional dyspepsia, irritable bowel syndrome and chronic constipation etc.Along with the development of society, gastrointestinal motility disorder disease prevalence rises year by year and affects the quality of life of people, and this type of disease also becomes the focus of research both at home and abroad.The adjustment of gastrointestinal motility is mainly by the impact of two aspect factors: namely Nervous system is unified humoral factor.Recent research shows, TMEM16A ion channel can regulate the humoral selection of gastrointestinal, thus motion (the .Expression of anoctamin 1/TMEM16A by interstitial cells of Cajal is fundamental for slow wave activity in gastrointestinal muscles.The Journal of Physiology.2009 such as Hwang SJ of regulation and control gastrointestinal, 587.20:4887 – 4904), TMEM16A gene expression is in small intestinal Interstitial cell, and it can control the contraction rhythm and pace of moving things of smooth muscle.
In prior art, pharmaceutical composition containing oligochitosan has been used to suppress mouse teratocarcinoma cells F9 cell proliferation, treatment hyperlipidemia, liver injury medicament, lipid lowering agent and weight reducing effect of weight reducing medicine, but does not find so far also not retrieve about the pharmaceutical composition containing oligochitosan is used for the treatment of TMEM16A/CaCCs ion channel relevant disease as the report of the medicine of gastrointestinal motility disorder aspect and pertinent literature.
Summary of the invention
Technical problem to be solved by this invention is: provide the pharmaceutical composition containing oligochitosan and application thereof, should containing the pharmaceutical composition of oligochitosan using oligochitosan as a kind of activator of TMEM16A ion channel, be used for the treatment of TMEM16A/CaCCs ion channel relevant disease as the medicine of gastrointestinal motility disorder aspect, overcome existing medicine in treatment gastrointestinal motility disorders, all there is the defect that side reaction in various degree and clinical practice be restricted.
The present invention solves this technical problem adopted technical scheme: containing the pharmaceutical composition of oligochitosan, take oligochitosan as active component, is aided with pharmaceutically acceptable carrier.
The above-mentioned pharmaceutical composition containing oligochitosan, described pharmaceutically acceptable carrier is starch, Icing Sugar, dextrin, lactose, microcrystalline Cellulose, mannitol or its mixture of 2 ~ 6 kinds, and the oligochitosan of described active component is 1: 0.5 ~ 1.5 with the weight ratio of the consumption being aided with pharmaceutically acceptable carrier.
The above-mentioned pharmaceutical composition containing oligochitosan, described pharmaceutical composition is oral type administration.
The above-mentioned pharmaceutical composition containing oligochitosan, the dosage form of the oral type administration of described pharmaceutical composition is powder, granule, capsule, tablet, drop pill or oral liquid.
The above-mentioned pharmaceutical composition containing oligochitosan, described pharmaceutical composition is parenteral type administration.
The above-mentioned pharmaceutical composition containing oligochitosan, the parenteral type administration of described pharmaceutical composition is injection.
The above-mentioned pharmaceutical composition containing oligochitosan, involved component materials all obtains by known approach, the collocation method of the oral type administration of described pharmaceutical composition and the parenteral type administration of described pharmaceutical composition all uses pharmaceutically known acceptable form, and its outfit method is that those skilled in the art can grasp.
The application of the above-mentioned pharmaceutical composition containing oligochitosan, as a kind of activator of TMEM16A ion channel, is used for the treatment of TMEM16A/CaCCs ion channel relevant disease.
The application of the above-mentioned pharmaceutical composition containing oligochitosan, described a kind of activator as TMEM16A ion channel is above-mentioned containing any one in the pharmaceutical composition of oligochitosan.
The application of the above-mentioned pharmaceutical composition containing oligochitosan, described TMEM16A/CaCCs ion channel relevant disease refers to the gastrointestinal motility disorder disease of people.
The above-mentioned pharmaceutical composition containing oligochitosan also can be applicable to treat the gastrointestinal motility disorder disease of cattle, horse, sheep, Canis familiaris L., cat, pig or Mus.
The application of the above-mentioned pharmaceutical composition containing oligochitosan, involved treatment operational approach is that those skilled in the art can grasp.
The invention has the beneficial effects as follows: outstanding substantive distinguishing features of the present invention is as follows:
(1) in the application of the pharmaceutical composition containing oligochitosan of the present invention, oligochitosan is by activating TMEM16A passage, and then affecting contraction frequency and the tension force of gastrointestinal smooth muscle, oligochitosan is used for the control of digestive tract power disease particularly gastrointestinal motility disorder by activating TMEM16A passage.
(2), in the application of the pharmaceutical composition containing oligochitosan of the present invention, the principle for the treatment of gastrointestinal motility disorder disease is that to activate TMEM16A ionophorous protein by oligochitosan active, makes intestinal contraction and then promotes gastrointestinal peristalsis, improving gastrointestinal motility disorder.
(3) in the application of the pharmaceutical composition containing oligochitosan of the present invention, for stomach and intestine dynamics disorders, TMEM16A activator can be used for treatment digestive tract power deficiency (as constipation) (Namkung W, Yao Z, Finkbeiner WE, Verkman AS.Small-molecule activators of TMEM16A, a calcium-activated chloride channel, stimulate epithelial chloride secretion and intestinal contraction.FASEB J.2011.25:4048-4062).
Marked improvement of the present invention is as follows:
(1) oligochitosan can obviously activate TMEM16A passage, Be very effective.Oligochitosan is that the disease treatment of gastrointestinal motility disorder aspect provides potential application prospect.
(2) a kind of natural product of oligochitosan, abundance.
(3) the pharmaceutical composition collocation method containing oligochitosan of the present invention is simple, with low cost.
(4) application process of the pharmaceutical composition containing oligochitosan of the present invention is simple, easily operates.
Accompanying drawing explanation
Below in conjunction with drawings and Examples, the present invention is further described.
Fig. 1 is the experimental result of HEK293 cell curent change situation under the effect of variable concentrations free calcium ions and oligochitosan of transfection TMEM16A passage under inside-out pattern, wherein:
Figure 1A is the representative experimental results figure of the blank group activated current of the HEK293 cell of not transfection TMEM16A ion channel.
Figure 1B is the representative experimental results figure of activated current when containing 1 μM of free calcium ions in embodiment 13 in body lotion.
Fig. 1 C be in embodiment 13 in body lotion containing the representative experimental results figure of the activated current under concentration 1 μ g/ml oligochitosan condition.
Fig. 1 D be in embodiment 13 in body lotion containing the representative experimental results figure of the activated current under concentration 10 μ g/ml oligochitosan condition.
Fig. 1 E be in embodiment 13 in body lotion containing the representative experimental results figure of the activated current under concentration 100 μ g/ml oligochitosan condition.
Fig. 1 F is that 100 μMs of tannin are to the inhibiting representative experimental results figure of activated current contained in body lotion under concentration 100 μ g/ml oligochitosan condition.
Fig. 1 G is the amount effect curve figure inducing TMEM16A activated current under different oligochitosan concentration.
Fig. 2 is the representative experimental results that under the same visual field, oligochitosan affects the fluorescence intensity of yellow fluorescence protein as TMEM16A ion channel activator, wherein:
Fig. 2 A is the representative experimental results figure of yellow fluorescent protein fluorescence intensity in cell when not adding oligochitosan in embodiment 14.
Fig. 2 B is the representative experimental results adding yellow fluorescent protein fluorescence intensity in cell after oligochitosan in embodiment 14.
Fig. 3 is that in embodiment 15, oligochitosan causes guinea pig ileum contractile response to strengthen, and contractile response can be suppressed to rapidly the representative experimental results of background level by TMEM16A inhibitors of ion channels CaCCinh-A01.
Fig. 4 shows the block diagram that oligochitosan significantly can increase gastrointestinal tract contraction frequency in embodiment 15.
Fig. 5 shows oligochitosan can enlarge markedly gastrointestinal tract contraction tension force block diagram in embodiment 15.
Detailed description of the invention
Figure 1A illustrated embodiment shows, the blank group activated current of the HEK293 cell of not transfection TMEM16A ion channel is background current, and steady-state current is less than 6pA.
Figure 1B illustrated embodiment shows, in embodiment 13, containing activated current during 1 μM of free calcium ions in body lotion, it is about 100pA for exemplary currents when TMEM16A ion channel is activated, steady-state current size.
Fig. 1 C illustrated embodiment shows, in embodiment 13, containing the activated current under concentration 1 μ g/ml oligochitosan condition in body lotion, steady-state current size is about 30pA, and display obviously increases than blank group.
Fig. 1 D illustrated embodiment shows, in embodiment 13, containing the activated current under concentration 10 μ g/ml oligochitosan condition in body lotion, steady-state current size is about 50pA, and display obviously increases than blank group.
Fig. 1 E illustrated embodiment shows, in embodiment 13, containing the activated current under concentration 100 μ g/ml oligochitosan condition in body lotion, steady-state current size is about 90pA, and display obviously increases than blank group.
Fig. 1 F illustrated embodiment shows, 100 μMs of tannin are to the inhibitory action containing the activated current under concentration 100 μ g/ml oligochitosan condition in body lotion, because tannin is the inhibitor of calcium-activated potassium current, so Fig. 1 F shows be from the electric current the embodiment shown in Fig. 1 C to Fig. 1 E the electric current that TMEM16A ion channel mediates, TMEM16A ion channel can be activated by oligochitosan.
Fig. 1 G illustrated embodiment shows, induces the amount effect curve figure of TMEM16A activated current under different oligochitosan concentration, and display oligochitosan is concentration dependent for the activation of TMEM16A ion channel.
Fig. 2 A illustrated embodiment shows, in embodiment 14, the fluorescence intensity of yellow fluorescence protein in cell when not adding oligochitosan, each cell interior is strong yellow fluorescence.
Fig. 2 B illustrated embodiment shows, in embodiment 14, the fluorescence intensity of yellow fluorescence protein in cell when adding oligochitosan, because oligochitosan have activated TMEM16A ion channel, the iodide ion entered from this ion channel makes the yellow fluorescence protein generation fluorescent quenching in born of the same parents.
Embodiment illustrated in fig. 3ly show, in embodiment 15, in guinea pig ileum contractile response determination experiment, oligochitosan can cause guinea pig ileum contractile response to strengthen, and contractile response can be suppressed to background level rapidly by TMEM16A inhibitors of ion channels CaCCinh-A01.
Embodiment illustrated in fig. 4ly show, in embodiment 15, in guinea pig ileum contractile response determination experiment, oligochitosan significantly can increase the frequency promoting gastrointestinal tract contraction.The independent experiment number of times of the present embodiment is 6 times.In figure, * * represents compared with matched group, there is pole significant difference (P<0.01).
Embodiment illustrated in fig. 5ly show, in embodiment 15, in guinea pig ileum contractile response determination experiment, oligochitosan can enlarge markedly the tension force of gastrointestinal tract contraction.The independent experiment number of times of the present embodiment is 6 times.In figure, * * represents compared with matched group, there is pole significant difference (P<0.01).
Embodiment 1
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, be aided with starch carrier, the weight ratio of the consumption of oligochitosan and starch carrier is 1:0.5, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the powder of oral type administration.
Embodiment 2
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, be aided with Icing Sugar carrier, the weight ratio of the consumption of oligochitosan and Icing Sugar carrier is 1:0.5, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the granule of oral type administration.
Embodiment 3
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, be aided with dextrin carrier, the weight ratio of the consumption of oligochitosan and dextrin carrier is 1:1, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the capsule of oral type administration.
Embodiment 4
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, be aided with lactose carrier, the weight ratio of the consumption of oligochitosan and lactose carrier is 1:1.5, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the tablet of oral type administration.
Embodiment 5
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, be aided with microcrystalline Cellulose carrier, the weight ratio of the consumption of oligochitosan and microcrystalline Cellulose carrier is 1:1, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the drop pill of oral type administration.
Embodiment 6
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, be aided with mannitol carrier, the weight ratio of the consumption of oligochitosan and mannitol carrier is 1:0.5-1.5, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the injection of parenteral type administration.
Embodiment 7
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, be aided with the starch sugaring powder carrier of arbitrary proportion, the starch of oligochitosan and arbitrary proportion is 1:1 with the weight ratio of the consumption of Icing Sugar, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the powder of oral type administration.
Embodiment 8
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, the dextrin being aided with arbitrary proportion adds the carrier that lactose adds microcrystalline Cellulose, it is 1:1.5 that the dextrin of oligochitosan and arbitrary proportion adds the weight ratio that lactose adds the consumption of microcrystalline Cellulose, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the powder of oral type administration.
Embodiment 9
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, the dextrin being aided with arbitrary proportion adds lactose and adds the carrier of microcrystalline Cellulose with mannitol, oligochitosan and arbitrary proportion dextrin add lactose, and to add microcrystalline Cellulose with the weight ratio of the consumption of mannitol be 1:1.5, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the powder of oral type administration.
Embodiment 10
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, the dextrin being aided with arbitrary proportion adds lactose and adds microcrystalline Cellulose with mannitol sugaring powder carrier, the dextrin of oligochitosan and arbitrary proportion adds lactose, and to add microcrystalline Cellulose with mannitol be 1: 1 with the weight ratio of the consumption of Icing Sugar, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the powder of oral type administration.
Embodiment 11
The pharmaceutical composition containing oligochitosan of the present embodiment, take oligochitosan as active component, the dextrin being aided with arbitrary proportion adds lactose and adds microcrystalline Cellulose and add starch carrier with mannitol with Icing Sugar, it is 1:0.5 that oligochitosan and arbitrary proportion mush finishing lactose add microcrystalline Cellulose adds the consumption of starch with Icing Sugar weight ratio with mannitol, its outfit method uses pharmaceutically acceptable form, and the pharmaceutical composition containing oligochitosan of the present embodiment is the powder of oral type administration.
Embodiment 12
Get distilled water 500mL, add Tween-80 and make solution, then add oligochitosan 100g, heat while stirring and make it to be dissolved into the solution containing oligochitosan, in addition sucrose 50g added the antiseptic of known standard consumption and be dissolved in distilled water 100mL, obtained sucrose solution, then this sucrose solution under agitation being added above-mentioned containing in the solution of oligochitosan, adding distil water is to 1000mL, mixing, filters, is distributed into 200, sterilizing, the oral liquid of the pharmaceutical composition containing oligochitosan of obtained the present embodiment.
In the embodiment of following the present invention containing the application of the pharmaceutical composition of oligochitosan, the selected pharmaceutical composition containing oligochitosan be any one in above-described embodiment 1 to embodiment 12 containing the pharmaceutical composition of oligochitosan.
Embodiment 13
Any one pharmaceutical composition containing oligochitosan in above-described embodiment 1 to embodiment 12, as a kind of activator of TMEM16A ion channel, has the HEK293 cell currents value of TMEM16A ion channel to strengthen for making transfection:
Expression plasmid pEGFP-N1-TMEM16A is proceeded in mammalian cell HEK293, after cell transfecting within 24-72h, carry out electro physiology detection.Concrete grammar is as follows:
DMEM (high sugar) the culture fluid Secondary Culture (add penicillin and the 100 μ g/ml streptomycins of 100UI/ml) of HEK293 cell containing 10% hyclone.Transfection process Lipofectamine 2000 (Invitrogen company) liposome carries out.Cell in 37 DEG C, 5%CO
2exponential phase is cultured to for experiment in saturated humidity incubator.Electro physiology detects and carries out under the room temperature of 22 DEG C, adopt inside-out (Inside-Out) logging mode (EPC-10Amplifier, HEKA company, Germany), outside interior liquid and basis, the composition of liquid is (unit: mM): CsCl 140, MgCl
26H
2o, HEPES 10, EGTA 5, is adjusted to pH7.3 with CsOH.Add oligochitosan in the outer liquid of medicine, namely any one concentration containing the pharmaceutical composition of oligochitosan in embodiment 1 to embodiment 12 is set to 1,10,100 μ g/ml respectively, whether express with 500nM free calcium ions test TMEM16A passage, negative control is done without calcium solution with 10mM EGTA, the mixed solution finally adding 100 μMs of tannin suppresses calcium channel, and makes comparisons with the electric current under 1 μM of free calcium condition.By voltage depolarization activated membrane electric current, operating condition is: membrane depolarization voltage is from-80mV to+80mV, and step is 20mV, and ME for maintenance is 0mV.
As shown in Figure 1B, activated current increases along with the concentration increase of oligochitosan in body lotion result.The oligochitosan of high concentration (100 μ g/ml) is suitable with high concentration free calcium ions (1 μM) to the activation degree of TMEM16A passage, illustrating that oligochitosan has the HEK293 cell of TMEM16A plasmid to have obvious activation to transfection, may be the activator of TMEM16A modality specificity.
Embodiment 14
Any one pharmaceutical composition containing oligochitosan in above-described embodiment 1 to embodiment 12 as a kind of activator of TMEM16A ion channel, the cell fluorescence generation cancellation for making transfection have TMEM16A in iodide ion yellow fluorescence protein (YFP) Fluorimetric Quenching Method:
Yellow fluorescence protein (YFP) is the fluorescin that one derives from green fluorescent protein (GFP), can be excited and send yellow fluorescence under wavelength 515nm.Iodide ion can be combined with YFP and make fluorescent quenching, and two of the YFP that suddenlys change site H148Q and I152L can make YFP strengthen the sensitivity of iodide ion.CaCCs passage is not only a kind of chloride channel, and it has permeation to the most of anion comprising iodide ion.The method of the drug screening test liposome of the present embodiment, by two sudden change YFP channel genes HEK293 cells of external source, makes YFP great expression in born of the same parents; Itself and passage are fully acted on drug candidate and cell incubation again; Finally observe the cancellation degree of the later YFP fluorescence of the solution added containing iodide ion.In this kind of method, the medicine of the obvious cancellation of YFP can be made can be considered to the activator of CaCCs passage, and this result and patch clamp experiments result are confirmed mutually.
The HEK293 cell of stable transfection YFP is cultivated in experiment the previous day in laser confocal microscope special culture dish; Within second day, by transfection YFP and the HEK293 cell D-PBS of overnight incubation rinses 3 times, finally leave the D-PBS of 500 μ l; Add the solution 500 μ l containing 150mM I-, make I-concentration reach 75mM; Add 1mg/ml oligochitosan, any one storage of pharmaceutical composition containing the oligochitosan liquid 10 μ l namely in embodiment 1 to embodiment 12 makes its final concentration reach 100 μ g/ml, by laser confocal microscope real time record fluorescence intensity.
As shown in Figure 2 A, the fluorescence intensity first adding YFP during oligochitosan is very high; As shown in Figure 2 B, I is being added
-after, the obvious cancellation of YFP fluorescence, after 2min, fluorescence almost disappears completely; Only add in another group and do not add in the matched group of oligochitosan containing the solution of iodide ion, the fluorescence intensity of YFP does not change all the time, illustrates that oligochitosan is the activator of TMEM16A passage.
Embodiment 15
Any one pharmaceutical composition containing oligochitosan in above-described embodiment 1 to embodiment 12, as a kind of activator of TMEM16A ion channel, for activating TMEM16A passage, causes guinea pig ileum to shrink.
Get Hatley Cavia porcellus one, after killing, cut abdominal cavity open immediately, take out one section of ileum about 10cm, be placed in oxygen-saturated tyrode's solution culture dish.Along intestinal wall removing mesentery, then ileum is cut into the segment 3 ~ 8 sections that length is 1 ~ 1.5cm, draws tyrode's solution with 5ml syringe and intestinal contents is rinsed well, change with fresh tyrode's solution for subsequent use.
Get an above-mentioned intestinal tube section for subsequent use, be placed in the culture dish filling tyrode's solution, at its diagonal wall place, two ends, use suture needle threading respectively, and tie a knot.Note keeping intestinal tube unobstructed, do not make it close.Intestinal tube one end line lies on the fixation hook of bath, then puts into 37 DEG C of Magnus' baths.Again the other end of intestinal tube is bound on the cantilever beam of tonotransducer, regulates preload to 1g.After Ileum From A White stablizes 30 minutes, after recording one section of normal contraction curve, drip medicine successively in Magnus' bath, any one namely in embodiment 1 to embodiment 12, containing the pharmaceutical composition of oligochitosan, is observed and records its shrinkage curve.
As shown in Figure 3, add the oligochitosan 7ul of 100g/L, after the several seconds, oligochitosan enters cell-stimulating TMEM16A passage and impels the contraction of ileum significantly to increase; Change liquid after 3 minutes, add the TMEM16A inhibitor C aCCinh-A01 solution 14ul of 10mM, suppress TMEM16A passage that the contractile response of ileum is obviously declined, this shows that oligochitosan also has very significant activation to the TMEM16A passage on animal body.After adding oligochitosan 7ul and 7ul of 100g/L successively, the concentration of oligochitosan in bath is made to reach 0.1g/L and 0.2g/L, oligochitosan makes the contraction frequency of ileum obviously increase (as shown in Figure 4) by entering cell-stimulating TMEM16A passage, and contractility obviously strengthens (as shown in Figure 5).Oligochitosan has obvious activation to tensile force of ileum and contraction frequency within the scope of 0.1-0.4g/L, and the activation of oligochitosan when 0.2g/L is best.
Embodiment 16
Any one pharmaceutical composition containing oligochitosan in above-described embodiment 1 to embodiment 12 is as a kind of activator of TMEM16A ion channel, and be used for the treatment of the gastrointestinal motility disorder disease of people, the clinical trial of this pharmaceutical composition is as follows:
Case selection: gastrointestinal motility disorder patient 78 example, clinical manifestation based on inappetence, stomachache, abdominal distention, feel sick, early full, vomiting, diarrhoea and difficult defecation etc., all patients become, without medication history, without serious systemic disease without other digestive tract makings sexually transmitted disease (STD)s except gastrointestinal motility disorder.78 routine patients be divided at random oligochitosan treatment group and motilium treatment matched group, often organize each 39 example, treatment group male 18 example, women 21 example, age 16-65 year; Matched group male 19 example, women 20 example, age 18-69 year.The equal not statistically significant of clinical manifestation difference before the sex for the treatment of group and matched group, age, the course of disease, treatment.
Usage and dosage: advise patient to be careful in one's diet health during treatment.Oligochitosan treatment group adopt medicinal preparation for oral administration, every day 1 time, one time one; Motilium treatment group adopt motilium (Xian-Janssen Pharmaceutical Ltd.) oral tablet, every day 3 times, one time one.
The standard of curative effect evaluation:
(1) effective: medication is vomitted for 2 days afterwards, symptom of diarrhea goes down, and without nausea, appetite strengthens.
(2) effective: medication after 5 days clinical symptoms substantially disappear, appetite is strengthened.
(3) invalid: still had stomachache, abdominal distention more than 10 days, feel sick, early full, vomiting, the symptom such as diarrhoea and difficult defecation.
Therapeutic outcome: effective 35 examples of the oligochitosan pharmaceutical treatment group prepared by pharmaceutical composition of the present invention, account for 89.74%; Effective 4 examples, total effective rate is 100%; Effective 29 examples of motilium treatment group, effective 4 examples, invalid 6 examples, total effective rate is 84.61%.Oligochitosan treatment group total effective rate is apparently higher than motilium treatment group.
Claims (9)
1. containing the pharmaceutical composition of oligochitosan, it is characterized in that: be active component with oligochitosan, be aided with pharmaceutically acceptable carrier.
2. according to claim 1 containing the pharmaceutical composition of oligochitosan, it is characterized in that: described pharmaceutically acceptable carrier is starch, Icing Sugar, dextrin, lactose, microcrystalline Cellulose, mannitol or its mixture of 2 ~ 6 kinds, the oligochitosan of described active component is 1: 0.5 ~ 1.5 with the weight ratio of the consumption being aided with pharmaceutically acceptable carrier.
3. according to claim 1 or claim 2, contain the pharmaceutical composition of oligochitosan, it is characterized in that: described pharmaceutical composition is oral type administration.
4., according to claim 3 containing the pharmaceutical composition of oligochitosan, it is characterized in that: the dosage form of the oral type administration of described pharmaceutical composition is powder, granule, capsule, tablet, drop pill or oral liquid.
5. according to claim 1 or claim 2, contain the pharmaceutical composition of oligochitosan, it is characterized in that: described pharmaceutical composition is parenteral type administration.
6., according to claim 5 containing the pharmaceutical composition of oligochitosan, it is characterized in that: the parenteral type administration of described pharmaceutical composition is injection.
7. the application of the above-mentioned pharmaceutical composition containing oligochitosan, is characterized in that: as a kind of activator of TMEM16A ion channel, is used for the treatment of TMEM16A/CaCCs ion channel relevant disease.
8. according to claim 7 containing the application of the pharmaceutical composition of oligochitosan, it is characterized in that: described a kind of activator as TMEM16A ion channel is the pharmaceutical composition that described in claim 1 ~ claim 6, any one contains oligochitosan.
9., according to claim 7 containing the application of the pharmaceutical composition of oligochitosan, it is characterized in that: described TMEM16A/CaCCs ion channel relevant disease refers to the gastrointestinal motility disorder disease of people.
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| CN105380924A (en) * | 2015-12-24 | 2016-03-09 | 广东药学院 | Chtiosnaoligosaccharide (COS) capsule and preparation method thereof |
| CN105496981A (en) * | 2015-12-24 | 2016-04-20 | 广东药学院 | Chitosan oligosaccharide tablets and preparation method thereof |
| CN108553425A (en) * | 2018-06-01 | 2018-09-21 | 广东药科大学 | A kind of chitosan oligosaccharide dripping pill and preparation method thereof |
| CN116440295A (en) * | 2023-02-16 | 2023-07-18 | 安徽萍聚德医疗科技股份有限公司 | Gastrointestinal motility marker capsule and preparation method and preparation system thereof |
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Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105380924A (en) * | 2015-12-24 | 2016-03-09 | 广东药学院 | Chtiosnaoligosaccharide (COS) capsule and preparation method thereof |
| CN105496981A (en) * | 2015-12-24 | 2016-04-20 | 广东药学院 | Chitosan oligosaccharide tablets and preparation method thereof |
| WO2017107628A1 (en) * | 2015-12-24 | 2017-06-29 | 广东药科大学 | Chitosan oligosaccharide capsule and method for preparation thereof |
| CN105380924B (en) * | 2015-12-24 | 2018-01-16 | 广东药科大学 | A kind of chitosan oligosaccharide capsule agent and preparation method thereof |
| CN105496981B (en) * | 2015-12-24 | 2018-05-01 | 广东药科大学 | A kind of chitosan oligosaccharide tablet and preparation method thereof |
| CN108553425A (en) * | 2018-06-01 | 2018-09-21 | 广东药科大学 | A kind of chitosan oligosaccharide dripping pill and preparation method thereof |
| WO2019227743A1 (en) * | 2018-06-01 | 2019-12-05 | 广东药科大学 | Chitosan oligosaccharide dropping pill and preparation method therefor |
| CN116440295A (en) * | 2023-02-16 | 2023-07-18 | 安徽萍聚德医疗科技股份有限公司 | Gastrointestinal motility marker capsule and preparation method and preparation system thereof |
| CN116440295B (en) * | 2023-02-16 | 2023-09-08 | 安徽萍聚德医疗科技股份有限公司 | Gastrointestinal motility marker capsule and preparation method and preparation system thereof |
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Application publication date: 20150506 |