CN104546716B - A kind of nose temperature-sensitivtype type hydrogel spray - Google Patents
A kind of nose temperature-sensitivtype type hydrogel spray Download PDFInfo
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- CN104546716B CN104546716B CN201510016557.9A CN201510016557A CN104546716B CN 104546716 B CN104546716 B CN 104546716B CN 201510016557 A CN201510016557 A CN 201510016557A CN 104546716 B CN104546716 B CN 104546716B
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Abstract
The invention belongs to field of pharmaceutical preparations, is related to a kind of nose temperature-sensitivtype type hydrogel spray, by subtracting nasal congestion agent, resisting allergic rhinitis medicine, responsive to temperature type material poloxamer and low viscosity level bioadhesive material without mucosal toxicity, is dissolved in water and is made.This gel preparation is from gelation temperature, consider the viscosity of preparation when in use at the same time, it ensure that formulation temperature sensitiveness and sprayability, so that this preparation is administered under room temperature (25 DEG C) with liquid spray forms, after contacting nasal mucosal surface, being changed under nose temperature has the semi-solid gel of suitable intensity, coordinates the Mucoadhesive of bioadhesive polymer to act on, the preparation long period is stranded in nasal mucosal surface.The present invention facilitates patient medication, compared to common nasal mist, can extend holdup time of the medicine in nasal cavity, so as to increase medicine in local absorption, extension drug effect.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, is related to a kind of responsive to temperature type water-setting using nasal spray as final form of medication
Glue preparation, and preparation method thereof.
Background technology
Nose is the most important olfactory organ of human body, and external harmful substance or sensitization are also more vulnerable to while perceiving extraneous
The invasion of material, so as to trigger the common disease such as nasal congestion, allergic rhinitis.Nasal cavity is due to its special physiological structure, meeting
The normal work of other organs is influenced, as nasal congestion is likely to result in uncomfortable ear, the interference sense of hearing, influence pronunciation, serious nose
Hyperemia is likely to result in insomnia, or even sleep apnea.The treatment nasal congestion and the preparation of allergic rhinitis listed is main
There are oral (such as tablet) and nose administration (such as nasal drop, nasal spray).It need to pass through gastrointestinal tract mucous absorption compared to oral formulations
Nose is reached by blood circulation afterwards, there is abundant capillary and lymph net under schneiderian membrane cell, is conducive to straight after nose administration
Connect and pass through Nasal Mucosa Absorption, it is rapid-action, compliance is high, and the low enzyme environment of nasal cavity is also beneficial to some easily be degraded by enzymes or exist
The protracted drug drug effect of first pass effect.Medicine (such as hormone medicine) for systemic side effects may be caused, nasal-cavity administration
Site of action is more local, clear and definite, greatly reduces the side effect to body other systems, organ.
Although nose administration there are above-mentioned many advantages, difficulty undeniably is still suffered from across the process of Nasal Mucosa Absorption, is removed
But to the stringent limitation of medicine self property (such as molecular weight, polarity), the scavenging action of Nasal mucociliary is to influence medicine to inhale
The most important obstruction received, worked.The scavenging action of Nasal mucociliary is really one of immunization barrier of body itself, and cilium is about
With under 1000/the frequency swing backward of min, promote the rete malpighii of mucous membrane to moving at nasopharynx, the disease being trapped within rete malpighii
The harmful substances such as bacterium, particulate are finally eliminated to alimentary canal.Rung by individual difference and pathological state lamp shadow, the removing of mucomembranous cilium
Speed range can be from 1mm/min to 20mm/min, and average clearance rate is about 8mm/min.So usually preparation is stagnant in nasal cavity
The time stayed is about 15min, this absorption for pernasal preparation is a challenge.In order to extend delay of the medicine in nasal cavity
Time, reduction, which is eliminated, to gastral speed, makes the absorption of medicine more abundant, considers there is adhesion using novel form joint
Carrier of the material of ability as nasal-cavity administration.
Existing listing nasal formulations mainly include nasal drop, nasal mist and gel for nose, and nasal drop and nose are used
Gelling agent is all there are the indefinite shortcoming of dosage, and nasal drop requires patient to face upward head instillation, due to the drop body of instillation
Product it is larger, easily flow into nasopharynx at, in contrast nasal mist can accurate quantitative analysis, droplet and schneiderian membrane contact area are wider, and
Using health, conveniently, but retentivity is weaker than gelling agent.Temperature sensitive type water gel is that one kind can occur according to temperature change
The material of liquid-gel state phase in version, can be dexterously by the viscous of the sprayability of solution and gel by this kind of hydrogel material
Attached property is combined, and realizing increases the ability that preparation is detained in nasal cavity while spray delivery.
Poloxamer class high polymer is research and the gel-like material being most widely used, its structure is gathered for polyoxyethylene
Oxypropylene ether block copolymers, both ends are hydrophilic polyoxyethylene segment, and centre is hydrophobicity oxypropylene block, and temperature raises
When, the gradual dehydration of oxypropylene block is assembled, and concludes into the hydrophobic inner core of micellar structure, when temperature reaches critical value, micella
Align to form gel.Poloxamer188 is recorded by the GRAS databases of FDA.The hydrogel that poloxamer188 is formed has
Obvious concentration dependent, its gelation transition temperature increases and reduces with the concentration of polymer, when concentration is less than certain value,
Solution will lose the gelling ability under physiological temp.PLURONICS F87 be poloxamer188 analog, its difference lies in
The structure of PLURONICS F87 contains higher proportion of hydrophilic polyoxyethylene fragment, by poloxamer188 and PLURONICS F87 group
Close and use, adjust the gel transition temperature for the gel that the latter is formed, obtain the thermo-sensitive gel preparation with suitable gelation temperature.
Document shows that poloxamer gel itself has certain mucosal adhesive ability, but this adhesion is weaker, is more with gel
Adhesive attachment is in mucomembranous surface.Bioadhesive material causes the concern of people further in recent years, such material refer to can by from
The chemical bonds such as sub-key, covalent bond, hydrogen bond are adhered to biological tissue or mucus layer surface, and most common bioadhesive material is tied at it
Substantial amounts of hydrophilic radical is included in structure, such as-OH ,-COOH.Bioadhesive material passes through hydrogen bond and mucous membrane and mucoprotein phase interaction
With raising temperature sensitive type water gel strengthens the interaction of gel and mucous membrane, further extend preparation to the affinity of mucous membrane
Holdup time in nasal cavity.
Compared with other temperature sensing materials, the hydrophily of poloxamer is high, and the gel quality of formation is softer, and is dropped with concentration
Low, the speed for the corrosion that absorbs water is accelerated, and can adjust the concentration of poloxamer188 and PLURONICS F87 in prescription, and as needed
The hydroxypropyl methylcellulose (such as HPMC E50, HPMC K100LV) of low viscosity is properly added, increases the intensity of the gel of formation.But
The ciliary movement for allowing for schneiderian membrane is a kind of body protective barrier of itself, therefore the unsuitable intensity of the gel formed is too big, no
The foreign body sensation of nasal cavity can then be not only resulted in, it is also possible to which the recovery to nose ciliary movement causes obstacle, triggers new disease.
Searching document finds that many researchs are prepared for the moon using poloxamer or poloxamer joint bioadhesive material
Road temperature sensitive gel preparation in thermo-sensitive gel preparation and eye, has some scholars to attempt using poloxamer thermo-sensitive gel as nasal cavity
The carrier of administration, achievees the purpose that brain-targeted drug delivery.The Integrated comparative of the present invention characteristics of prescriptions of different documents, it is determined that final
Preparation formulation is nasal thermosensitive gel spray, from the sprayability of the Thermo-sensitive of preparation, in the lump consideration preparation, not only to place
The auxiliary materials such as the bioadhesive material in side propose to use the requirement of lower viscosity levels, also require ensureing suitable gelation temperature
Under the premise of, the relatively low combination of poloxamer concentration is selected, to reduce the viscosity of preparation, ensures smoothly can uniformly spraying for solution
Go out, while save raw material.The spraying of nasal thermosensitive gel that the present invention designs, preparation method is simple, raw material sources extensively, safety can
Control, is advantageously implemented industrialized production.
The content of the invention
It is an aspect of the present invention to provide a kind of nose temperature-sensitivtype type hydrogel spray, by temperature-sensitive hydrogel and biological slime
Enclosure material combines, and have selected the material that safe, viscosity is low, non-stimulated to mucous membrane, improves patient's compliance and preparation
Sprayability.
Another aspect of the present invention is to provide a kind of method for preparing the preparation.
The nose temperature-sensitivtype type hydrogel spray, its form include effective dose subtract nasal congestion agent or antiallergy
Property rhinitis medicine, responsive to temperature type hydrophilic gel material, water-soluble biological adhesion material and water.
The nasal congestion agent that subtracts is selected from PHENYLEPHRINE HYDROCHLORIDE, xylometazoline hydrochloride, pseudoephedrine hydrochloride, hydrochloric acid hydroxyl
First oxazoline and its mixture, antiallergy drug for treating rhinitis are selected from Cetirizine Hydrochloride, promethazine hydrochloride, budesonide, propionic acid fluorine for card
Pine, fexofenadine hydrochloride, hydrochloric acid levocabastine, azelastine hydrochloride and its mixture.
Described subtracts nasal congestion agent or resisting allergic rhinitis medicine, its solubility or suspension solution concentration are more than 3g/100ml
Water, the weight percent content shared by medicine are 0.05%~5%.
The responsive to temperature type hydrophilic gel material, including poloxamer, especially poloxamer188 and poloxamer
188, both are polyoxyethylene-poly-oxypropylene polyoxyethylene block copolymer, but the block ratio of polyoxyethylene and polyoxypropylene
Difference, poloxamer188 are main gel rubber material, its gelation temperature has concentration dependent, adds a small amount of poloxamer
188, to adjust the gelation temperature of poloxamer188 solution, comply with the physiological temp of nasal cavity；Poloxamer188 it is dense
Spend for 14%~18%, the concentration of PLURONICS F87 is 0%~2%, and the total concentration of mixtures of poloxamers is not more than 20%；
It can shorten dissolution time using the poloxamer188 and PLURONICS F87 of micronizing, not interfere with gelation temperature.
The bioadhesive material, the group comprising positively charged or hydrophilic radical such as-OH ,-COOH in its structure,
Such material can occur to interact to produce adhesiving effect by Electrostatic Absorption, Hydrogenbond etc. with mucous membrane.Such material bag
Include：Cellulose derivative class, such as hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC), methylcellulose (ME)；Polysaccharide
Class, such as Sodium Hyaluronate, sodium alginate, chitosan；Proteins and peptides class, such as gelatin, polylysine；Polyacrylic, such as
CARBOPOL 971, Polycarbophil AA-1.The wherein dissolution velocity of cellulose family adhesive in water is slower, and adhesion is relatively low；Card
Though ripple nurse is generally acknowledged strong bioadhesive polymer, its pH value of water solution is relatively low and viscosity is big, should not be used in and prepares nasal spray.It is logical
Screening is crossed, it is found that low viscosity Sodium Hyaluronate and polylysine have good compatibility with medicine and poloxamer, it is obtained
Preparation viscosity is relatively low, and non-stimulated to mucous membrane, pretends as preferable bioadhesive polymer；The content of bioadhesive material is 0.5%
~1.5%.
Described adds acceptable auxiliary material in other pharmacies, including gel strength conditioning agent, surfactant, suppression
Microbial inoculum and its mixture.Gel strength conditioning agent is selected from hydroxypropyl methylcellulose (HPMC), preferably HPMC E50 and HPMC
K100LV, its content is 0%~1.0%, for increasing the intensity of gel；Surfactant is selected from polyoxyethylene sorbitan monoleate or sapn
80, its content is 0%~1%；Bacteriostatic agent is selected from benzalkonium chloride, benzalkonium bromide, Nipasol, benzyl rope bromine ammonium etc., its content is
0.008%~0.5%；There is now commercial device can ensure preparation in use under conditions of bacteriostatic agent is not added
Germ-free condition, avoids the stimulation to schneiderian membrane as caused by bacteriostatic agent.
The nose temperature-sensitivtype type hydrogel spray, k value is relatively low under room temperature (25 DEG C), less than 200mPas,
Sprayability is good.
The preparation is liquid form under deepfreeze and room temperature (25 DEG C), and viscosity is raised with temperature and gradually increased
Add, the phase in version by liquid to gel state occurs at critical-temperature (i.e. gelation temperature), it is ensured that preparation is in nasal cavity temperature (32
DEG C~35 DEG C) under gelation transition occurs, and preparation will not be made to become sticky at room temperature can not spray, the gelation temperature of preparation
Nasal cavity temperature range lower limit should be less than, but be higher than room temperature (25 DEG C) as far as possible, consider and the gelling of preparation is set to 30 DEG C
~35 DEG C.
The preparation method considers poloxamer in low temperature environment, and at especially 4 DEG C, dissolution velocity is very fast, will
Other water-soluble components are sequentially added in the water of recipe quantity in prescription, after being completely dissolved, cooling, then the poloxamer by recipe quantity
Add while stirring into above-mentioned solution, be sufficiently stirred and place preservation after low temperature, until forming the solution of clear and bright bubble-free.
The thermo-sensitive gel preparation that the present invention designs has certain viscosity (50mPas~200mPas), uses existing nose
Spray apparatus can smoothly be sprayed with droplet form；It there is now some manufacturers and grasped nasal spray of the support without bacteriostatic agent prescription
Device manufacturing technology, the nasal cavity spray apparatus produced using such technology, need to ensure in raw material and whole preparation, filling process
Middle carry out sterile working.
Present invention design has the following advantages：(1) preparation has a reverse thermal sensitivity, with liquid under the conditions of room temperature and deepfreeze
Body form exists, into nasal cavity after phase in version occurs under nasal cavity temperature (32 DEG C -35 DEG C), be changed into by liquid semisolid solidifying
Colloidal state, extends the holdup time in nasal cavity.(2) material selects lower viscosity levels as far as possible, ensure that the sprayability of preparation.
(3) material irritation is small, and security is good.(4) raw material sources are extensive, easily obtain.(5) preparation process is concisely easy to operate.
Brief description of the drawings
The rheology vibration heating scan result of Fig. 1 PHENYLEPHRINE HYDROCHLORIDEs nasal thermosensitive gel spraying.
The release in vitro preparation of Fig. 2 PHENYLEPHRINE HYDROCHLORIDEs nasal thermosensitive gel spraying
The release in vitro unit area cumulative release amount of Fig. 3 PHENYLEPHRINE HYDROCHLORIDEs nasal thermosensitive gel spraying.
The mucosal toxicity experiment of Fig. 4 PHENYLEPHRINE HYDROCHLORIDEs nasal thermosensitive gel spraying
Fig. 4-a give the palate mucomembranous cilium form of physiological saline
Fig. 4-b give the palate mucomembranous cilium form of 1%PE/0.5%HA/17%P407/0.8%P188 preparations
Fig. 4-c give the palate mucomembranous cilium form of 1%PE/0.5% ε-PL/17%P407/0.5%P188 preparations
Embodiment：
Following embodiments illustrate the present invention, are not considered as limitation of the present invention in any way.With reference to enterprise
The production requirement that industry is widely recognized as, the concentration of following each component are weight percentage (w/w, %).
1 PHENYLEPHRINE HYDROCHLORIDE nasal thermosensitive gel of embodiment spraying I
1.0% PHENYLEPHRINE HYDROCHLORIDE is weighed, 0.5% polylysine, adds in the water of recipe quantity while stirring, dissolving
4 DEG C of coolings of postposition.0.5% PLURONICS F87 is weighed, 17% poloxamer188, adds the above-mentioned solution cooled down while stirring
In, after being sufficiently stirred, stand and preserve in 4 DEG C, until forming the solution of clear and bright bubble-free.Wherein each component percetage by weight is such as
Under：
2 PHENYLEPHRINE HYDROCHLORIDE nasal thermosensitive gel of embodiment spraying II
Weigh 1.0% PHENYLEPHRINE HYDROCHLORIDE, 0.5% Sodium Hyaluronate (MW：11000Da), 0.5% methyl hydroxybenzoate,
Add to while stirring in the water of recipe quantity, the 4 DEG C of coolings of dissolving postposition.Weigh 0.8% PLURONICS F87,17% poloxamer
407, add while stirring in the above-mentioned solution cooled down, after being sufficiently stirred, stand and preserve in 4 DEG C, until forming clear and bright no gas
The solution of bubble.Wherein each component percetage by weight is as follows：
3 xylometazoline hydrochloride nasal thermosensitive gel of embodiment is sprayed
Weigh 0.1% hydrochloric acid acid Xylometazoline, 1.5% Sodium Hyaluronate (MW：11000Da), prescription is added to while stirring
In the water of amount, the 4 DEG C of coolings of dissolving postposition.1.5% PLURONICS F87 is weighed, 18% poloxamer188, adds while stirring
State in the solution cooled down, after being sufficiently stirred, stand and preserve in 4 DEG C, until forming the solution of clear and bright bubble-free.Wherein each component
Percetage by weight is as follows：
4 Cetirizine Hydrochloride nasal thermosensitive gel of embodiment is sprayed
1.0% Cetirizine Hydrochloride is weighed, 1.0% polylysine, 0.02% benzalkonium chloride, adds to recipe quantity while stirring
Water in, dissolving 4 DEG C of postposition cooling.17% poloxamer188 is weighed, adds in the above-mentioned solution cooled down, fills while stirring
After dividing stirring, stand and preserve in 4 DEG C, until the solution of the clear and bright bubble-free of formation.Wherein each component percetage by weight is as follows：
5 promethazine hydrochloride nasal thermosensitive gel of embodiment is sprayed
5.0% promethazine hydrochloride is weighed, 0.5% polylysine, adds in the water of recipe quantity, weigh 1.0% while stirring
HPMC E50, are stirred to dissolve, and put 4 DEG C of coolings.0.5% PLURONICS F87 is weighed, 14% poloxamer188, adds while stirring
Enter in the above-mentioned solution cooled down, after being sufficiently stirred, stand and preserve in 4 DEG C, until forming the solution of clear and bright bubble-free.It is wherein each
Component weight percentage is as follows：
6 budesonide nasal thermosensitive gel of embodiment is sprayed
0.1% budesonide is weighed, 0.5% polyoxyethylene sorbitan monoleate, mixes, weigh 1.5% Sodium Hyaluronate (MW：
11000Da), add to while stirring in the water of recipe quantity, weigh 1.0%HPMC E50, be stirred to dissolve, put 4 DEG C of coolings.Weigh
1.5% PLURONICS F87,18% poloxamer188, adds in the above-mentioned solution cooled down while stirring, after being sufficiently stirred, in
4 DEG C stand preservation, until forming the solution of clear and bright bubble-free.Wherein each component percetage by weight is as follows：
7 fluticasone propionate nasal thermosensitive gel of embodiment is sprayed
Weighing 0.05% fluticasone propionate, 0.5% polyoxyethylene sorbitan monoleate, mixes, and weighs 1.0% polylysine, and 0.02%
Benzalkonium chloride, adds in the water of recipe quantity while stirring, weighs 0.5%HPMC E50, is stirred to dissolve, and puts 4 DEG C of coolings.Weigh
17% poloxamer188, adds in the above-mentioned solution cooled down while stirring, after being sufficiently stirred, stands and preserves in 4 DEG C, until
Form the solution of clear and bright bubble-free.Wherein each component percetage by weight is as follows：
8 fexofenadine hydrochloride nasal thermosensitive gel of embodiment is sprayed
Weigh 1.0% fexofenadine hydrochloride, 1.5% Sodium Hyaluronate (MW：11000Da), prescription is added to while stirring
In the water of amount, the 4 DEG C of coolings of dissolving postposition.0.5% PLURONICS F87 is weighed, 17% poloxamer188, adds while stirring
State in the solution cooled down, after being sufficiently stirred, stand and preserve in 4 DEG C, until forming the solution of clear and bright bubble-free.Wherein each component
Percetage by weight is as follows：
9 hydrochloric acid levocabastine nasal thermosensitive gel of embodiment is sprayed
0.05% hydrochloric acid levocabastine is weighed, 0.5% polyoxyethylene sorbitan monoleate, mixes, weighs 0.5% polylysine,
0.02% benzalkonium chloride, adds in the water of recipe quantity while stirring, weighs 0.5%HPMC E50, is stirred to dissolve, put 4 DEG C it is cold
But.0.5% PLURONICS F87 is weighed, 15% poloxamer188, adds in the above-mentioned solution cooled down, fully stir while stirring
After mixing, stand and preserve in 4 DEG C, until forming the solution of clear and bright bubble-free.Wherein each component percetage by weight is as follows：
The spraying rheology vibration heating scan experiment of 10 PHENYLEPHRINE HYDROCHLORIDE nasal thermosensitive gel of embodiment
Thermo-sensitive gel is during heating is changed into gel state by solution state, with the increase of elastic modulus G ' and prominent
Become, and the temperature being mutated is tested, strain is set to 0.05%, and frequency is set to close to gel transition temperature using rheometer
0.1Hz, gap are set to 500 μm, and temperature range is set to 20~40 DEG C, 1 DEG C/min of heating rate, and measure 1%PE/0.5% gathers bad ammonia
The poloxamer of the PLURONICS F87 of acid/17% poloxamer188/0.5% and 1%PE/0.5% low viscosities Sodium Hyaluronate/17%
The heating scan of 407/0.8% PLURONICS F87 is as a result, sample need to balance 4min at 20 DEG C before the assay, parallel determination 3 times,
Experimental result is shown in Fig. 1.
7 PHENYLEPHRINE HYDROCHLORIDE nasal thermosensitive gel of embodiment spraying extracorporeal releasing experiment
Using Franz diffusion cells, by pellicle (MWCO：1KD) it is fixed between two pond of Franz diffusion cells, this experiment uses
A diameter of 0.92cm, that is, the area that releases the drug is 0.665cm2Franz diffusion cells, acceptance pool volume is 10.5ml, be administered Chi Zhongzhun
0.5g samples really are weighed, 10min in 33 DEG C of baking ovens is put into, makes to form gel.Diffusion cell is put into 33 DEG C of water-baths, to acceptance pool
Middle addition is pre-heated to 33 DEG C of pH5.8PBS buffer solutions 10.5ml as accepting medium, put in acceptance pool a stirrer with
The rotational speed of 300rpm, takes respectively at 15min, 30min, 60min, 120min, 180min, 240min, 360min, 480min
Sample, the medicament contg in acceptable solution is measured through HPLC methods, investigate the poloxamer188 of 1%PE/0.5% polylysines/17%/
The poloxamer188 of 0.5% PLURONICS F87 and 1%PE/0.5% Sodium Hyaluronates/17%/0.8% PLURONICS F87 is external
Release conditions, each sample parallel determination 6 times.Calculate accumulative release rate and unit area cumulative release amount Q.Experimental result is shown
Show, the release in vitro behavior of two groups of preparations approaches, and slowly drug release can be achieved in 8h, to the release in vitro data point of two groups of prescriptions
Models fitting is not carried out with Zero order release, first-order release and Higuchi equations, as a result meets first-order release feature.Release is bent
Line is shown in Fig. 2 and Fig. 3.
11 PHENYLEPHRINE HYDROCHLORIDE nasal thermosensitive gel of embodiment spraying bioadhesion in vitro measure
Using mucoprotein piece peel strength method, the sample of about 20ml is measured into 50ml beakers, heating water bath simultaneously maintains
33 DEG C make into gel, and the lower end by mucoprotein piece with two-sided gluing and Texture instrument probe P/0.5, infiltrates mucoprotein piece before test
Probe, is connected on Texture instrument, starts to test by the 30s in 5% mucoprotein solution (experimental day is now made) at once, pop one's head in
0.5mm/s is moved down, and after contact gel reaches triggering force value (2g), is continued to move downward with 0.5mm/s speed, is reached to stress
Remains stationary is moved down to stopping during 4g, after gel contacts 180s, pops one's head in and 5mm stoppings is moved up to 0.5mm/s speed.Note
Stress time curve is recorded, stress maximum is to peel off required maximum, force, the index as mucoadhesive forces.Two groups of biologies
Prescription measurement result (the being shown in Table 1) display of adhesive, low viscosity Sodium Hyaluronate group have higher peeling force, polylysine group
Peeling force is smaller, this is also relevant with gel strength height.
The bioadhesion in vitro measurement result of table .1 difference bioadhesive polymer prescriptions
The mucosal toxicity experiment of 12 PHENYLEPHRINE HYDROCHLORIDE nasal thermosensitive gel of embodiment spraying
Using in body toad palate modelling, toad is ruined after brain ruins marrow with probe, lies on the back and is fixed on surgical plate, with only
Blood pincers drawing opens oral cavity, exposes palate, is closed with preventing from swallowing liquid and oral cavity.Liquid is added dropwise at upper palatine mucosa
0.5ml, makes palate be totally submerged wherein, comes into full contact with 30min.Net, palatine mucosa in separation is fully rinsed with physiological saline, immediately
With the net clot of normal saline flushing and debris etc., mucomembranous cilium is laid on glass slide upwardly, in 40*10 times of light microscope
Lower observation fibre swing situation.Observation finishes, and glass slide is put in the chromatography cylinder added with a small amount of distilled water, closed, makes vapor
Close to saturation.Hereafter take out observation once every 1~2h, if cilium has dancing, return the slide into chromatography cylinder, after
Continuous observation, close to 10h when, are changed to every 10~20min observations once.Record stops swinging lasting since administration to cilium
Time.Toad mucous membrane to give 0.5ml physiological saline investigates 1%PE/0.5% low viscosity hyaluronic acids as negative control
The poloxamer188 of the PLURONICS F87 of the poloxamer188 of sodium/17%/0.8% and 1%PE/0.5% polylysines/17%/
The influence that 0.5% PLURONICS F87 preparation moves mucomembranous cilium.
Cilia morphology after administration is shown in Fig. 4, gives two groups and physiological saline group contrast of preparation, cilium is complete, arrangement
Neatly, and to same direction swing.Two preparation groups, to fibre swing duration, are all higher than physiology salt since administration
The 85% of the time of water group, illustrates that preparation is non-toxic to cilium.
Claims (7)
1. a kind of nose temperature-sensitivtype type hydrogel spray, it is characterised in that include：
Effective dose subtracts nasal congestion agent or resisting allergic rhinitis medicine；Wherein subtract nasal congestion agent to be selected from：Hydrochloric acid deoxygenates adrenal gland
Element, xylometazoline hydrochloride, pseudoephedrine hydrochloride, oxymetazoline hydrochloride or its mixture；Antiallergy drug for treating rhinitis is selected from：Replace in hydrochloric acid west
Sharp piperazine, promethazine hydrochloride, azelastine hydrochloride or its mixture；
Responsive to temperature type hydrophilic gel material, is selected from：Poloxamer188, PLURONICS F87 or its mixture；
Water-soluble bioadhesive material, selected from polylysine, low viscosity Sodium Hyaluronate, shared weight percent content is
0.5% ~1.5%；
Water；
Wherein, the content of responsive to temperature type water wetted material poloxamer188 is 14% ~ 18%, and the concentration of PLURONICS F87 is 0%
~ 2%, the total concentration of mixtures of poloxamers is not more than 20%.
2. nose temperature-sensitivtype type hydrogel spray according to claim 1, it is characterised in that other medicines can also be added
The upper acceptable auxiliary material of agent, including gel strength conditioning agent, surfactant, bacteriostatic agent and its mixture；Gel strength tune
Section agent is selected from：Hydroxypropyl methylcellulose HPMC E50 or HPMC K100LV, its content are 0% ~ 1%；Surfactant is selected from：It is poly-
Sorb ester 80 or sorbester p17, its content are 0% ~ 1%；Bacteriostatic agent is selected from：Benzalkonium chloride, methyl hydroxybenzoate, benzalkonium bromide and benzyl rope
Bromine ammonium, its content are 0.008% ~ 0.5%.
3. nose temperature-sensitivtype type hydrogel spray according to claim 1, it is characterised in that described subtracts nasal congestion agent
Or resisting allergic rhinitis drug solubility or its suspension solution concentration are more than 3g/100ml water, the percentage by weight shared by medicine contains
Measure as 0.05% ~ 5%.
4. nose temperature-sensitivtype type hydrogel spray according to claim 1, it is characterised in that obtained nose temperature is quick
Sense type hydrogel be sprayed at 25 DEG C at room temperature viscosity be less than 200mPas.
5. nose temperature-sensitivtype type hydrogel spray according to claim 1, it is characterised in that obtained nose temperature is quick
It is at room temperature the liquid flowed freely that sense type hydrogel, which is sprayed at 25 DEG C, when temperature is 30 DEG C ~ 35 DEG C, is changed into by liquid
Gel state.
6. the preparation method of the nose temperature-sensitivtype type hydrogel spray described in claim 1, it is characterised in that including following step
Suddenly：Water miscible component in prescription, including medicine, bioadhesive material and/or gel strength conditioning agent are weighed respectively, at addition
In the water just measured, it is stirred to dissolve, cools down, weigh the poloxamer of recipe quantity, add in the above-mentioned solution cooled down, in low temperature
Placement makes fully to dissolve, until forming the solution of clear and bright bubble-free, to obtain the final product.
7. nose temperature-sensitivtype type hydrogel spray according to claim 1, it is characterised in that after preparation process
Answer in filling to suitable nasal cavity spray apparatus, be administered in the form of nasal spray.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201510016557.9A CN104546716B (en) | 2014-01-14 | 2015-01-13 | A kind of nose temperature-sensitivtype type hydrogel spray |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN2014100162792 | 2014-01-14 | ||
| CN201410016279.2A CN103705463A (en) | 2014-01-14 | 2014-01-14 | Nose temperature-sensitive type hydrogel spray |
| CN201510016557.9A CN104546716B (en) | 2014-01-14 | 2015-01-13 | A kind of nose temperature-sensitivtype type hydrogel spray |
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| Publication Number | Publication Date |
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| CN104546716A CN104546716A (en) | 2015-04-29 |
| CN104546716B true CN104546716B (en) | 2018-05-11 |
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| CN103705463A (en) * | 2014-01-14 | 2014-04-09 | 中国药科大学 | Nose temperature-sensitive type hydrogel spray |
| CN104173352B (en) * | 2014-09-10 | 2016-06-01 | 贵州云峰药业有限公司 | W-2979M pharmaceutical composition |
| CN105168119A (en) * | 2015-10-28 | 2015-12-23 | 周胜光 | Compound nasal inhalation gel preparation for treating rhinitis |
| CN106265664B (en) * | 2016-07-14 | 2019-05-07 | 重庆市人民医院 | A kind of the bioadhesive gel for nose product and preparation method of compound Rupatadine |
| ES2952863T3 (en) * | 2016-07-27 | 2023-11-06 | Fundacio Inst Dinvestigacio En Ciencies De La Salut Germans Trias I Pujol | Bioadhesive platform to perform bioactive treatment |
| CN109316441B (en) * | 2018-10-31 | 2021-04-23 | 成都医学院 | Budesonide rectal in-situ temperature-sensitive gel and preparation method and application thereof |
| CN112138202A (en) * | 2019-06-10 | 2020-12-29 | 戴建英 | Temperature sensitive digestive tract mucosa protective adhesive |
| CN110721189A (en) * | 2019-11-19 | 2020-01-24 | 贵州云峰药业有限公司 | Skin disinfectant |
| CN111671717B (en) * | 2020-06-15 | 2022-04-15 | 中国药科大学 | Temperature-sensitive type particulate matter adsorption gel and preparation method and application thereof |
| CN113456581B (en) * | 2021-08-09 | 2024-02-02 | 信阳农林学院 | Rosemary essential oil nasal in-situ gel and preparation method and application thereof |
| EP4404916A1 (en) * | 2021-09-22 | 2024-07-31 | JADRAN - GALENSKI LABORATORIJ d.d. | An improved pharmaceutical composition for nasal use, preparation, and use thereof |
| CN114028324B (en) * | 2021-12-06 | 2023-11-03 | 中国药科大学 | Uncaria base temperature-sensitive gel nasal administration preparation and preparation method thereof |
| CN115581666A (en) * | 2022-10-12 | 2023-01-10 | 福建中医药大学 | Evergreen gelsemine chitosan microemulsion temperature-sensitive gel and preparation method thereof |
| CN115531314A (en) * | 2022-10-12 | 2022-12-30 | 哈尔滨葵花药业有限公司 | Low-irritation levocabastine hydrochloride nasal spray and preparation method thereof |
| CN115607481A (en) * | 2022-10-13 | 2023-01-17 | 绍兴市柯桥区东纺纺织产业创新研究院 | Spray type mask and preparation method thereof |
| CN118021709A (en) * | 2022-11-07 | 2024-05-14 | 深圳善康医药科技股份有限公司 | Naltrexone in-situ gel nasal spray and preparation method and application thereof |
| CN116059327A (en) * | 2023-02-21 | 2023-05-05 | 杭州国光药业股份有限公司 | Lysozyme nasal spray and preparation method thereof |
| CN117982422B (en) * | 2024-04-03 | 2024-07-26 | 深圳大佛药业股份有限公司 | Spray for treating rhinitis |
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| CN104546716A (en) | 2015-04-29 |
| CN103705463A (en) | 2014-04-09 |
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