CN109276715A - Antiallergy nasal medicine composition, preparation method and the application of humectant - Google Patents
Antiallergy nasal medicine composition, preparation method and the application of humectant Download PDFInfo
- Publication number
- CN109276715A CN109276715A CN201710598138.XA CN201710598138A CN109276715A CN 109276715 A CN109276715 A CN 109276715A CN 201710598138 A CN201710598138 A CN 201710598138A CN 109276715 A CN109276715 A CN 109276715A
- Authority
- CN
- China
- Prior art keywords
- medicine composition
- nasal
- preparation
- solution
- nasal medicine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/53—Lamiaceae or Labiatae (Mint family), e.g. thyme, rosemary or lavender
- A61K36/534—Mentha (mint)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K36/00—Medicinal preparations of undetermined constitution containing material from algae, lichens, fungi or plants, or derivatives thereof, e.g. traditional herbal medicines
- A61K36/18—Magnoliophyta (angiosperms)
- A61K36/185—Magnoliopsida (dicotyledons)
- A61K36/75—Rutaceae (Rue family)
- A61K36/752—Citrus, e.g. lime, orange or lemon
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
- A61K47/10—Alcohols; Phenols; Salts thereof, e.g. glycerol; Polyethylene glycols [PEG]; Poloxamers; PEG/POE alkyl ethers
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
- A61K47/26—Carbohydrates, e.g. sugar alcohols, amino sugars, nucleic acids, mono-, di- or oligo-saccharides; Derivatives thereof, e.g. polysorbates, sorbitan fatty acid esters or glycyrrhizin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
- A61K9/0043—Nose
Landscapes
- Health & Medical Sciences (AREA)
- Natural Medicines & Medicinal Plants (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Biotechnology (AREA)
- Mycology (AREA)
- Microbiology (AREA)
- Medical Informatics (AREA)
- Botany (AREA)
- Alternative & Traditional Medicine (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Oil, Petroleum & Natural Gas (AREA)
- Biochemistry (AREA)
- Molecular Biology (AREA)
- Otolaryngology (AREA)
- Inorganic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Medicinal Preparation (AREA)
Abstract
The present invention provides a kind of antiallergy nasal medicine composition of humectant, and its preparation method and application.The prescription has humectant, it is non-stimulated to schneiderian membrance, the prescription includes the Claritin as main ingredient: levocetirizine, azatadine, Loratadine, Ebastine, setastine, bilastine, clemastine, Mizolastine, epinastine and Moxifloxacin, main ingredient can be salt or free alkali, the sea salt as osmotic pressure regulator；The Sodium Hyaluronate of different molecular weight as moisturizing auxiliary material and glycerol intermixture can contain plants essential oil in prescription；Preparation may is that the suspension or nanosuspension of aqueous solution, cyclodextrin package, and dosage form includes spraying, aerosol, nasal drop；Principal indication includes: nasal cavity dryness, runny nose, rhiocnesmus, the nasal obstruction etc. that allergic rhinitis occurs.
Description
Technical field
The invention belongs to pharmaceutical technology fields, and in particular to a kind of antiallergy nasal medicine composition of humectant and
Preparation method and application.
Background technique
Allergic rhinitis is a kind of allergic inflammation, also known as long-term allergic rhinitis, vasomotor rhinitis.
A large amount of water sample nasal mucus are flowed out in clinical manifestation when being mainly paroxysmal rhiocnesmus, nasal cavity dryness, sneeze, acute attack, when alleviation is few and thick, and
It sends out the infected to shed tears at viscous purulence, interval or duration, unilateral or bilateral nasal obstruction, hyposphresia or disappearance, tinnitus of having a headache, sound
It neighs chronic cough.Constitutional symptom has headache, loss of appetite, easily tired, failure of memory and insomnia etc..
The clinical symptoms of rhinitis morbidity are different, very harmful, when influencing the physiological function of nasal cavity, it may appear that breathing barrier
Hinder, causing blood oxygen concentration reduces, the function and metabolism of other tissues and organ are influenced, and there are some such as headaches, dizzy, memory
Power decline, the severe complications such as pectoralgia, uncomfortable in chest, apathetic etc., or even the concurrent pulmonary emphysema of meeting, pulmonary heart disease, asthma.And work as rhinitis
Fail to get timely medical treatment, when influencing smell mucous membrane, just will appear dysosmia, cause to hear not good and foul smells equal smells.When long-term
The nasosinusitis of recurrent exerbation is not got timely medical treatment, and inflammation will diffuse to adjacent organs, tissue, and concurrent such as frontal bone marrow
Scorching, socket of the eye bone wall osteitis and periostitis, subperiosteal orbital abscess, orbital cellulitis, retrobulbar neuritis, spinal epidural absceess,
A variety of critical acute diseases such as subdural abscess, purulent meningitis, brain abscess, cavernous sinus thrombophlebitis.
In terms of work and study, adult can be because rhinitis causes to have a headache, and brain is not regained consciousness, and is had dizzy spells, and work is imitated
Rate is low；And the symptoms such as nasal obstruction, headache that teenager then causes due to rhinitis cause distraction, memory and school grade
It is remarkably decreased.Other complication caused by rhinitis are also: because long-time is had a stuffy nose stuffiness, expiratory dyspnea can cause sleep and exhale
Inhale pause syndrome；Patient's hypertrophic inferior turbinate, oxygen is insufficient when sleep, can cause cerebral infarction, hypertension, burst under serious conditions
Heart disease etc., few patients even can night sudden deaths.World Health Organization's investigation, the nasopharynx carcinogenesis in the whole world 80% is in
State, and about ninety percent nasopharyngeal carcinoma are caused by deteriorating because of rhinitis obstinate, and the patients with rhinitis in China has 300,000,000 people or so, and with
Annual 3% speed increase, the death toll caused every year by nasopharynx canceration is more than 200,000 people.Rhinitis is high with its disease incidence,
Complication is more, it is refractory more the features such as cause the extensive concern of international medical community.Drug therapy rhinitis is most important hand at present
One of section.
There are many antiallergic species, commonly use clinical drug at present by glucocorticoid, antihistamine and Chinese medicine system
Agent.Wherein, glucocorticoid is by the permeability of reduction endothelium and epithelial cell, the high response of bronchia mucosal and to gallbladder
The reactivity of alkali stimulation, generates the effect for alleviating symptom.Main adverse reaction has: burning sensation, mucous membrane drying, sneeze and nose
The symptoms such as bleeding influence children growth speed, but do not influence height.It mainly include beclomethasone, Mometasone, budesonide, third
The drugs such as sour fluticasone, triamcinolone；Antihistamine drug mainly by with the histamine receptor on histamine competitive effect cell membrane,
Anti- H1 effect is played, mast cell or basophilic granulocyte is inhibited to discharge inflammatory cytokine, inhibits blood vessel exudation, mitigate tissue
Oedema, this kind of drug specifically include that first generation oral drugs chlorphenamine, diphenhydramine, cyproheptadine, the Te Feina of the second generation
Fixed, astemizole, loratadine tablet, cetirizine, levocetirizine piece, Desloratadine, the Mizolastine sustained release of the third generation
Piece, hydrochloric acid nitrogen mire sting nose-spray, bilastine, clemastine fumarate, clemastine fumarate capsule, hydrochloric acid according to this
Spit of fland, setastine hydrochloride, common Histamine agents object have central nervous system impression effect, can cause dizziness, dry, it is drowsiness,
The adverse reactions such as out of strength, tired, new three generations's antihistamine related side effects are smaller；Chinese materia medica preparation mainly have decoction, nasal drop, in
Medicine particle, ointment, washing lotion, medication of steaming nose etc., primarily serve auxiliary therapeutic action.
In addition, it is to compare the one kind praised highly in American-European countries in recent years that nasal wash, which treats rhinitis, in medical instruments field
New treatment of rhinitis method.Clinical trial confirms that wash nose has certain effect to treatment rhinitis really.Basic method is to make
With appropriate tool, nasal cavity is thoroughly rinsed, the dirts such as the intracavitary anaphylactogen of cue, germ, rheuminess object are clear
The case where removing, diminishing inflammation and continue the basis of development, eliminate the swelling of bronchia mucosal oedema, restores the normal physiological function of nasal cavity
Can, but symptom can only be alleviated for organic disease.Clinically used nasal wash main component is physiological sodium chloride or waits
The sea salt water of infiltration, however, the maximum problem of such instrument is that nasal wash flushing posterula is dried quickly, moisture retention is very short, often
Several times, patient is very inconvenient for it flushing.
Summary of the invention
Therefore, to overcome disadvantages described above in the prior art, the purpose of the present invention is to provide a kind of the anti-of humectant
Allergy nasal medicine composition, and its preparation method and application.
Before illustrating technical solution of the present invention, it is as follows to define term used herein:
Term " Tween-20 " refers to: polyoxyethylene (20) sorbitanmonolaureate；
Term " PLURONICS F87 " refers to: alpha -hydro-omega -hydroxypoly (oxygen second is dilute)aPoly- (oxypropylene)bPoly- (oxygen second is dilute)a
Block copolymer, chemical formula are H (C2H4O)a(C3H6O)b(C2H4O)aOH, ethylene oxide unit (a) is 75~85 in the copolymer,
Oxypropylene units (b) are 25~30, ethylene oxide (C2H4O) content 79.9%~83.7%, average molecular weight are 7680~9510.
Term " sea salt " refers to: the substance of (being such as made through solarization), sodium chloride-containing up to 85% or more is extracted from seawater.
To achieve the above object, the first aspect of the present invention provides a kind of antiallergy nasal medicine combination of humectant
Object, the nasal medicine composition include following component:
Antiallergy class drug as main ingredient；Hyaluronate and/or glycerol as moisturizing auxiliary material；
As the sea salt of osmotic pressure regulator, and
Water；
Preferably, the main ingredient is selected from one of following drug or a variety of, its alkali or its pharmaceutically acceptable salt: left
Cetirizine, azatadine, Loratadine, Ebastine, setastine, bilastine, clemastine, Mizolastine, according to
Sting, Moxifloxacin；It is highly preferred that the pharmaceutically acceptable salt is selected from one or more of: hydrochloride, maleic acid
Salt, fumarate, citrate；And/or
Preferably, the hyaluronate is selected from one or more of: Sodium Hyaluronate, calcium hyauronate, hyalomitome
Sour zinc；It is highly preferred that the molecular weight of the hyaluronate is 30~2,000,000 dalton；And/or
Preferably, the antiallergy nasal medicine composition, solution osmotic pressure are not less than 260mosmol/kg.
Nasal medicine composition according to a first aspect of the present invention, wherein each master described in the nasal medicine composition
The percent weight in volume content of medicine are as follows:
Levocetirizine 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably
0.5%；
Azatadine 0.1~2.0%, preferably 0.5~1.5%, more preferably 0.8~1.2%, most preferably 1.0%；
Loratadine 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%；
Ebastine 0.1~4.0%, preferably 0.5~3.0%, more preferably 1.0~2.5%, most preferably 2.0%；
Setastine 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%；
Bilastine 0.1~4.0%, preferably 0.5~3.0%, more preferably 1.0~2.5%, most preferably 2.0%；
Clemastine 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%；
Mizolastine 0.1~2.0%, preferably 0.5~1.5%, more preferably 0.8~1.2%, most preferably 1.0%；
Ebastine 0.1~2.0%, preferably 0.5~1.5%, more preferably 0.8~1.2%, most preferably 1.0%；
Epinastine 0.1~4.0%, preferably 0.5~3.0%, more preferably 1.0~2.5%, most preferably 2.0%；
Moxifloxacin 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%.
Nasal medicine composition according to a first aspect of the present invention, wherein respectively protected described in the nasal medicine composition
The percent weight in volume content of wet auxiliary material are as follows:
Glycerol 5.0~20.0%, preferably 5.0~15.0%, more preferably 8.0~12.0%, most preferably 10%；
Hyaluronate 0.05~0.5%, preferably 0.05~0.3%, more preferably 0.05~0.2%, most preferably
0.1%；And/or
The percent weight in volume content of sea salt described in the nasal medicine composition are as follows:
Sea salt 0.1~2.0%, preferably 0.1~1.5%, more preferably 0.1~1.0%, most preferably 0.9%.
Nasal medicine composition according to a first aspect of the present invention, wherein
One or more of adding ingredient: plants essential oil, tween-is further included in the nasal medicine composition
20, PLURONICS F87, dodecyl sodium sulfate, beta-cyclodextrin, ethyl alcohol and pH adjusting agent, in which:
The plants essential oil is preferably selected from one or more of: peppermint oil, Rosemary Oil, Bergamot smoke clothing
Careless essential oil, Geranium Essential, rose ethereal oil, Basil Essential and glycan essential oil, the pH adjusting agent are preferably the hydrogen of 1mol/L
Aqueous solution of sodium oxide；
Preferably, the percent weight in volume content of each adding ingredient are as follows:
Plants essential oil 0.01%~0.1%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably
0.05%；
Tween-20 0.05~1.0%, preferably 0.1~0.4%, more preferably 0.1~0.3%, most preferably
0.2%；
PLURONICS F87 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably
0.5%；
Dodecyl sodium sulfate 0.02~0.1%, preferably 0.02~0.08%, more preferably 0.03~0.06%, most
Preferably 0.05%；
Beta-cyclodextrin 0.2~0.8%, preferably 0.2~0.6%, more preferably 0.3~0.5%, most preferably 0.4%；
And/or
Ethyl alcohol 2.0%~8.0%, preferably 2.5~6.0%, more preferably 3.0~5.0%, most preferably 4.0%
Nasal medicine composition according to a first aspect of the present invention, wherein the dosage form of the nasal medicine composition is selected from
One or more of: spray, aerosol and nasal drops；And/or
The nasal medicine composition is one or more solution selected from the following: aqueous solution, beta-cyclodextrin inclusion compound solution
And nanosuspension；Preferably, the medical fluid viscosity is less than 2mpa.s.
The second aspect of the present invention provides the preparation method of nasal medicine composition described in first aspect, and the nose is used
Pharmaceutical composition is aqueous solution, which may comprise steps of:
(1) hyaluronate for weighing recipe quantity is dissolved in water, is stirred well to and is completely dissolved；
(2) the glycerol sea salt and main ingredient for sequentially adding recipe quantity stir evenly；With
(3) pH value of solution to 6.0~7.0 ranges are adjusted and obtains the nasal medicine composition.
The present invention also provides a kind of preparation method of nasal medicine composition described in first aspect, the nasal medicine
Composition is beta-cyclodextrin inclusion compound solution, which may comprise steps of:
(1) dissolution of raw material of recipe quantity is weighed in ethyl alcohol, obtains ethanol water；
(2) hyaluronate for weighing recipe quantity is dissolved in water, is stirred well to and is completely dissolved, and recipe quantity is added in solution
Glycerol, sea salt stir evenly, add the beta-cyclodextrin of recipe quantity, heating obtains aqueous solution.
(3) step (1) resulting ethanol solution is slowly added into step (2) acquired solution, stirring while adding, add after
The continuous beta-cyclodextrin inclusion compound solution left standstill that stirs to get is stayed overnight, and the nasal medicine composition is filtered to obtain；
Preferably, heating temperature described in step (2) is 20~50 DEG C, preferably 35~45 DEG C, most preferably 40 DEG C；
Mixing speed described in step (3) is 20~100rpm, preferably 45~55rpm, most preferably 40rpm；
Continuation mixing time described in step (3) is 10~30 minutes, preferably 15~25 minutes, most preferably 20 points
Clock.
The present invention also provides a kind of preparation method of nasal medicine composition described in first aspect, the nasal medicine
Composition is nanosuspension, the preparation method is that the anti-solvent precipitation method, comprising the following steps:
(1) raw material for weighing recipe quantity, adds ethanol in proper amount to dissolve；With
(2) ethanol solution obtained by step (1) is slowly added into containing dodecyl sodium sulfate, PLURONICS F87, sea salt
Solution in, it is stirring while adding, add and continue to stir up to the nasal medicine composition；
Preferably, mixing speed described in step (2) be 1000~2000rpm, preferably 1200~1800rpm, it is optimal
It is selected as 1500rpm；
Continuation mixing time described in step (3) is 5~30 minutes, preferably 5~20 minutes, most preferably 10 minutes.
The third aspect of the present invention provides nasal medicine composition described in first aspect in preparation for treating rhinitis
Drug in application, the rhinitis is preferably allergic rhinitis.
The pharmaceutical dosage form of application according to a third aspect of the present invention, the treatment rhinitis is spray, aerosol and/or drop
Nose liquid.
The present inventor analyzes the different type drug for treatment of rhinitis, considers medicine comprehensively by largely working
The dissolubility and side effect of object, the factors such as lasting medicine, safety, dependence, in conjunction with a large amount of animal efficacy test result.Through more
Kind trial and error, screening, surprisingly, it is found that: levo-cetirizine hydrochloride, Loratadine, azatadine maleate, Ebastine, department
His sting, bilastine, clemastine, epinastine, Moxifloxacin can be used as the nasal medicine of antiallergic, anti-inflammatory drug
Main ingredient ingredient.
Drug selected by the present invention is the specific drug of clinical use pharmacological action, and Levocetirizine Hydrochloride is originally mouth
Take antiallergy preparation, after spray formulation is made, it is more convenient with it is efficient, reduce dosage.Levocetirizine Hydrochloride passes through
It is directly absorbed, is worked faster by nasal cavity schneiderian membrane blood vessel abundant.And the bioavailability concerns after the medicine takes orally are overcome,
Gastrointestinal tract excretion is reduced, adverse reaction is reduced.
Azatadine maleate, Ebastine, setastine hydrochloride, clemastine fumarate, Mizolastine were oral originally
Antiallergy preparation, after nasal spray is made, the dosage of nasal spray is usually take orally 1/10th~15, can be lower
Dosage under the therapeutic effect bringd into play, overcome the medicine to take orally taking dose small, in the low disadvantage of human body blood concentration.
Bilastine of the invention have the characteristics that it is quick-acting, long-acting and potent, have antihistamine and anti-inflammatory double action, can
Histamine and IL-4 is inhibited to discharge from mast cell and periphery granulocyte；Safety is good, no maincenter sedation and cardiac toxic,
Meet requirement of the diagnosis and treatment guide in the world ARIA to preferred H1 receptor antagonist.It nasal spray is made expands the clinic of the medicine and answer
With.
Loratadine is the derivative of azatadine, can selectively antagonism periphery histamine H1-receptor effect.It is oral big
There is hepatotoxicity in part in liver metabolism.Nose spray preparation is made, drug directly acts on nasal cavity, has continued rapid-action excellent
Gesture, and hepatotoxicity is avoided, use is safer.
Moxifloxacin hydrochloride is a kind of novel spectrum Comprecin, have good resisting gram-positive bacteria and
Negative bacterium activity, with strong to streptococcus, staphylococcus aureus.The preparation of the medicine only takes orally and injects two kinds at present
Dosage form, it is oral to have the adverse reactions such as Nausea and vomiting, dizziness, headache, fatigue, diarrhea, fash.Injection removes above-mentioned adverse reaction
Outside, inconvenient to use.Therefore nasal spray, which is made, in the present invention can be reduced systemic adverse reactions, using more convenient.
In addition to basis sodium chloride, a large amount of microelement is also rich in sea salt, therefore, except maintenance organism physiology balance
Outside, sterilization, anti-inflammatory, antianaphylactic can also be played the role of.Sea salt can be used as osmotic pressure regulator divided by basis sodium chloride
Outside, it goes back while there is anti-inflammatory effect.It is sweet that this formula adds the high moisturizer of natural moisturizer Sodium Hyaluronate joint in sea salt water
Oil dramatically increases its moisture retention, extends the sea salt water anti-inflammatory effect time.
Pharmacodynamic experiment proves azatadine maleate, Emedastine, setastine hydrochloride, fumaric acid bilastine, richness
Horse acid clemastine, epinastine hydrochloride, sea salt water have certain anti-allergic effects.Loratadine, levo-cetirizine hydrochloride, salt
The rhinitis allergic reaction of the different degrees of inhibition cavy of sour Moxifloxacin.
Nasal medicine composition of the present invention has the characteristics that efficient moisture-retention, and the moisturizer in formula is hyaluronate and sweet
Fluid composition, compared with presently commercially available antiallergy nose external preparation, external experimental data shows moisturizing degree in vivo
Significantly extend with the time, result of study is shown, moisture preserving time is 3 times of presently commercially available preparation or more.It is expected that clinical use can
Patient's access times are significantly reduced, dosage is reduced, reduce adverse reaction, extend drug residence time in nasal cavity, improve medicine
Effect, while patient comfort significantly improves.
The characteristics of nasal medicine composition of the present invention be it is nonirritant, any preservative ingredient is not added in formula.Pass through
Zoopery has been proved this point, and nasal membrane irritant experiment is the results show that levo-cetirizine hydrochloride, maleic acid A Zhata
Fixed, Loratadine, Ebastine, setastine hydrochloride, fumaric acid bilastine, clemastine fumarate, epinastine hydrochloride,
Moxifloxacin hydrochloride, sea salt water formulation all have good safety, which does not add compared with current clinical use preparation
Adding preservative agent, moisture preserving time significantly improve, and non-stimulated.
Plants essential oil can be contained in nasal medicine composition of the present invention, plants essential oil mostly has aromatic odor, makes one essence
Mind loosens, and has the function of anti-melancholy, antianxiety, sleep aiding and nerve soothing.Such as Lavender has calmness, hypnosis, antianxity
Effect, adds the formula of a small amount of plants essential oil, in night use, can make to be palliated the agonizing sufferings by the patient that rhinitis perplexs for a long time, improve
Sleep quality.Peppermint oil, Rosemary Oil, Bergamot can be improved study, working efficiency, suffer from rhinitis with arousing brain, raising spirit
Person gets rid of psychiatric disturbance.
Nasal medicine composition of the invention can have but be not limited to it is following the utility model has the advantages that
1, product of the present invention has the characteristics that efficient moisture-retention, can obviously reduce patient's access times, reduces dosage, reduces
Adverse reaction extends drug residence time in nasal cavity, improves drug effect, while patient comfort significantly improves.
2, be the characteristics of product of the present invention it is nonirritant, any preservative ingredient is not added in formula.
3, plants essential oil can be contained in prescription of the present invention, plants essential oil mostly has aromatic odor, makes one mental relaxation, has
There are anti-melancholy, antianxiety, sleep aiding and nerve soothing.
Specific embodiment
Present invention will be further explained by specific examples below, it should be understood, however, that, these embodiments are only
It is used, is but should not be understood as present invention is limited in any form for specifically describing in more detail.
This part carries out general description to the material and test method that arrive used in present invention test.Although being
It realizes many materials used in the object of the invention and operating method is it is known in the art that still the present invention still uses up herein
It may detailed description.It will be apparent to those skilled in the art that within a context, if not specified, material therefor of the present invention and behaviour
It is well known in the art as method.
Reagent and instrument used in the following embodiment are as follows:
Reagent:
Levo-cetirizine hydrochloride, levocetirizine are purchased from Hunan Jiudian Pharmaceutical Co., Ltd；
Azatadine maleate, azatadine are purchased from Xi'an Li Bang pharmaceutical factory；
Setastine hydrochloride, setastine are purchased from Shanghai Han Xiang Biotechnology Co., Ltd；
Fumaric acid bilastine, bilastine are purchased from Shenzhen Wan Kaisi medical science Co., Ltd；
It is fervent to open up Chu purchased from Hubei for clemastine fumarate, Ebastine, epinastine hydrochloride, epinastine, Mizolastine
First Pharmaceuticals Ltd；
Moxifloxacin hydrochloride, Moxifloxacin, Loratadine are purchased from Hubei Kang Baotai Fine Chemical Co., Ltd；
Sea salt is purchased from Shanghai Zhan Yang Industrial Co., Ltd., Shui nationality Science and Technology Ltd., the autumn salinization of Shandong Shandong；
Medicinal NaCl is purchased from Beijing Beijing medicine company；
Hyaluronate, purchased from Qufu City, Shandong Province Li Yang Biotechnology Co., Ltd, the prosperous Fu Ruida of Shandong China；
Glycerol is purchased from Shantou Jiahe Biotechnology Co., Ltd.；
Beta-cyclodextrin is purchased from Shandong Binzhou Zhi Yuan Biotechnology Co., Ltd；
Sodium hydroxide, ethyl alcohol, dodecyl sodium sulfate are purchased from Chinese medicines group chemical reagent Co., Ltd；
PLURONICS F87 is purchased from Beijing Feng Lijingqiu commerce and trade Co., Ltd, genuine ground Germany BASF；
Hypromellose is purchased from Jinan Jin Hui Chemical Co., Ltd.；
Lavender is purchased from Shenzhen Ding Cheng plant perfume Co., Ltd；
Tween-20, Tween-40, Tween-60, Tween-80 are purchased from Xi'anizationization glass station laboratory；
Aluminum hydroxide adjuvant；Purchased from western precious biotechnology (Shanghai) limited liability company；
Ovalbumin is purchased from solarbio, lot number: 709B0530；
4% lidocaine is purchased from Shanghai He Feng pharmacy finite cluster, lot number: 71150816；
O-phthalaldehyde is purchased from sigma；
Amobarbital, concentrated hydrochloric acid, sodium hydroxide, May-Grunwald dyestuff, Giemsa dyestuff are purchased from Xi'an chemical reagent
Factory.
Cavy, rabbit, Xi'an Communications University's medical board Experimental Animal Center provide, and experimental animal uses credit number:
SYXK (Shan) 2014-003.
Instrument
Electronic balance is purchased from Shanghai precision instrument Co., Ltd, model YP502N；
Electronic balance is purchased from Sartorious, model BS201S；
PH meter, is purchased from METTLER, model FE20；
High performance liquid chromatograph is purchased from Waters, model 2695；
Digital display dispersion machine is purchased from ULTRA-TURRAX, model IKA type T25；
Full-automatic osmometer is purchased from GONOTEC, model Osmomat030 3000.
Preparation example 1
Nose provided by the invention sea salt aqueous solution forms (without main ingredient), as shown in table 1 substantially.
1 nasal medicine composition of table (aqueous solution) forms substantially
The preparation method of aqueous solution is: the Sodium Hyaluronate for weighing recipe quantity is dissolved in purified water, is stirred well to completely molten
Solution, sequentially add recipe quantity glycerol, sea salt and main ingredient stir evenly to get.
Preparation example 2
Nasal medicine composition (aqueous solution) provided by the invention composition substantially is as shown in table 2.
2 nasal medicine composition of table (aqueous solution) forms substantially
Main ingredient be selected from be levo-cetirizine hydrochloride, azatadine maleate, setastine hydrochloride, fumaric acid bilastine,
One of clemastine fumarate, epinastine hydrochloride, moxifloxacin hydrochloride are a variety of.
The preparation method of aqueous solution is: the Sodium Hyaluronate for weighing recipe quantity is dissolved in purified water, is stirred well to completely molten
Solution, the glycerol, sea salt and main ingredient for sequentially adding recipe quantity stir evenly, and qs pH adjuster is adjusted to pH in 6.0~7.0 models
In enclosing to obtain the final product.
Preparation example 3
Nasal medicine composition (beta-cyclodextrin inclusion compound solution) provided by the invention composition substantially is as shown in table 3.
3 nasal medicine composition of table (beta-cyclodextrin inclusion compound solution) forms substantially
Note: main ingredient is Loratadine.
The preparation method of beta-cyclodextrin inclusion compound solution is: the raw material for weighing recipe quantity adds ethanol in proper amount to dissolve, and obtains ethyl alcohol
Solution.Hyaluronate is dissolved in purified water, is stirred well to and is completely dissolved, and in solution plus the glycerol of recipe quantity, sea salt stir
It is even, the beta-cyclodextrin of recipe quantity is added, 40 DEG C is heated to, obtains aqueous solution.During slowly ethanol solution is added to, side edged
Stirring, mixing speed 50rpm.It adds and is stirred for 20min, stand overnight, filter to obtain the final product.
Preparation example 4
Nasal medicine composition (suspension) provided by the invention composition substantially is as shown in table 4.
4 nasal medicine composition of table (suspension) forms substantially
Note: main ingredient is selected from levocetirizine, azatadine, Ebastine, setastine, Moxifloxacin, bilastine, miaow
One of azoles sting, epinastine are a variety of.
The preparation method of nanosuspension is the anti-solvent precipitation method: the main ingredient of recipe quantity weighed, ethanol in proper amount is added to dissolve, second
Alcoholic solution be slowly added into containing 0.05% dodecyl sodium sulfate, 0.5% PLURONICS F87, sea salt aqueous solution in, Bian Jia
Side stirring, mixing speed 15000rpm.Add be stirred for 10min to get.
Preparation example 5
The present embodiment is for illustrating different molecular weight Sodium Hyaluronate concentration screening.
Under a certain concentration, aqueous solution of sodium hyaluronate cannot function as spray and spray in sticky state, therefore should select
Suitable concentration is selected, filters out suitable concentration by evaluating its solution viscosity.25 DEG C of experimental results are as follows:
5 different molecular weight Sodium Hyaluronate viscosity statistical form of table
Above-mentioned solution is packed into spray bottle and carries out examination spray, in conjunction with k value test result, only viscosity 2mpa.s with
The liquid sprayed when lower can be at fine mist.
Preparation example 6
The present embodiment is for illustrating different molecular weight Sodium Hyaluronate concentration screening.
Add the Sodium Hyaluronate of different molecular weight respectively in sea salt water, prepared solution precision measures, uniformly by it
It is applied to weighing disk bottom, is put into the drying box of constant temperature and humidity, is weighed after 1 hour, moisturizing rate is calculated；Pass through moisturizing rate
Size compare moistening effect.
6 different molecular weight Sodium Hyaluronate performance of keeping humidity of table counts (1)
7 different molecular weight Sodium Hyaluronate performance of keeping humidity of table counts (2)
8 different molecular weight Sodium Hyaluronate performance of keeping humidity of table counts (3)
9 different molecular weight Sodium Hyaluronate performance of keeping humidity of table counts (4)
In terms of above-mentioned experimental result, glycerol and 10% that sea salt water adds the Sodium Hyaluronate of different molecular weight to add 5% again
Glycerol, performance of keeping humidity are superior to simple extra large saline formulation.When 1,300,000 dalton of Sodium Hyaluronate molecular weight and 2,000,000 dongles
Immediately, concentration has shown that significant advantage, moisturizing rate are higher by about 3 times than simple extra large saline formulation at 0.1%.
Preparation example 7
The present embodiment is for illustrating different prescription solution stability.
According to " bulk pharmaceutical chemicals and preparation stability investigate guideline " (" Chinese Pharmacopoeia " the 4th), carries out solution and stablize
Property investigate accelerated test.
10 composition of table (1)
11 composition of table (2)
12 composition of table (3)
13 composition of table (4)
14 composition of table (5)
15 composition of table (6)
16 composition of table (7)
17 composition of table (8)
18 composition of table (9)
19 composition of table (10)
Solution manufacturing method: the Sodium Hyaluronate for weighing recipe quantity is dissolved in purified water, is stirred well to and is completely dissolved, then according to
Secondary glycerol, sea salt and the main ingredient that recipe quantity is added stirs evenly, and qs pH adjuster is adjusted to pH in 6.0~7.0 ranges i.e.
?.
Investigation method: the solution of above-mentioned preparation is put under conditions of 40 DEG C ± 2 DEG C of temperature, relative humidity 75% ± 5%
It sets 6 months, investigates appearance character, pH, predominant amount, the related substance of solution, whether observation solution is stable.
20 experimental result of table statistics
Pass through 6 months accelerated tests, levo-cetirizine hydrochloride, azatadine maleate, setastine hydrochloride, fumaric acid
Bilastine, clemastine fumarate, moxifloxacin hydrochloride are according to this prescription and preparation method, and there is no significantly becoming for quality
Change, SOLUTION PROPERTIES is more stable.Levo-cetirizine hydrochloride, azatadine maleate, the setastine hydrochloride, richness of sea salt is added
Horse acid bilastine, clemastine fumarate, moxifloxacin hydrochloride are according to this prescription and preparation method, up-to-standard, solution
Matter is more stable.
Preparation example 8
The present embodiment is for illustrating different nanometer suspension liquid and preparation method thereofs.
The preparation method of nanosuspension has media milling process, high pressure homogenization method, the anti-solvent precipitation method, micro jetting technology
Deng.It is that easy to operate, energy consumption is small since the anti-solvent precipitation method prepare nanosuspension advantage outstanding, industry easy to accomplish
Change, thus use the anti-solvent precipitation method, stabilizer screening on the basis of high spot reviews mixing speed and mixing time two it is important
Influence of the preparation parameter to nanosuspension partial size and distribution.
21 nanosuspension composition of table
Preparation method: the anti-solvent precipitation method weigh the main ingredient of recipe quantity, ethanol in proper amount are added to dissolve, and ethanol solution slowly adds
Enter to containing 0.05% dodecyl sodium sulfate, 0.5% PLURONICS F87,0.1% Sodium Hyaluronate, 10% glycerol,
It is stirring while adding in the aqueous solution of 0.9% sea salt.Between upon agitation degree one timing, mixing speed be respectively 8000rpm,
10000rpm,12000rpm,15000rpm,20000rpm.When the timing of mixing speed one, mixing time be respectively 4min, 6min,
8min、10min、12min。
The influence of 22 mixing time of table and speed to partial size and dispersion index
23 mixing speed of table is certain, influence of the different mixings time to partial size
Conclusion: it can be seen from the results above that mixing speed is 15000rpm, stirring 10min is best mixing parametric.
Preparation example 9
The present embodiment is for illustrating different beta-cyclodextrin inclusion compound solution manufacturing methods.
Loratadine category slightly solubility antihistamine increases its solubility when preparation, beta-cyclodextrin is selected to be included, by
In the difference of inclusion method, inclusion rate is also different, therefore is compared using two kinds of inclusion methods.By measuring the content of solution,
Investigate inclusion effect.
24 beta-cyclodextrin inclusion compound solution formula of table
Inclusion method one: after being dissolved with dehydrated alcohol, the β-of recipe quantity is added in accurately weighed recipe quantity drug and sea salt
Cyclodextrin saturated solution, agitation grinding 30min are dissolved in the aqueous solution containing Sodium Hyaluronate, glycerol sea salt after dry, quiet
It sets, filters to obtain the final product.
Inclusion method two: accurately weighed recipe quantity drug, after being dissolved with dehydrated alcohol.Sodium Hyaluronate is dissolved in purified water,
Glycerol, sea salt are added, aqueous solution is heated to 50 DEG C, and beta-cyclodextrin is added and sufficiently dissolves.Ethanol solution is slowly added to dropwise
Stirring while adding into above-mentioned aqueous solution, mixing speed is 60rpm, adds and is stirred for 30min, stands, filters to obtain the final product.
25 assay result of table statistics
Conclusion: in terms of assay result, the inclusion rate of inclusion method two is high, and two operating method of method is simple and easy to do.
Preparation example 10
The present embodiment is used to illustrate the preparation method of the different prescriptions containing essential oil.
Essential oil is generally insoluble in water, so adding essential oil in aqueous solution, it usually needs cosolvent appropriate increases essential oil
Solubility in water.Selected cosolvent is respectively Tween-20, Tween-40, Tween-60, Tween-80.
The 26 aqueous solution prescription of sea salt containing essential oil of table
Preparation method: main ingredient, sea salt, Sodium Hyaluronate, the glycerol for weighing recipe quantity are dissolved in water, Lavender stabilizer
Oil solution is dissolved in aqueous solution and is sufficiently stirred by tween, observes aqueous solution character, sees the oil droplet floating whether aqueous solution surface has.
The 27 aqueous stability result of sea salt containing essential oil of table statistics
Conclusion: Tween-20 is more excellent as the stabilizer of essential oil.
Embodiment 1
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 2
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 3
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 4
Preparation method: the anti-solvent precipitation method, preparation volume be 100ml, prescription:
Embodiment 5
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 6
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 7
Preparation method: the anti-solvent precipitation method, preparation volume be 100ml, prescription:
Embodiment 8
Preparation method: high pressure homogenization method, preparation volume be 100ml, prescription:
Embodiment 9
Preparation method: the anti-solvent precipitation method, preparation volume be 100ml, prescription:
Embodiment 10
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 11
Preparation method: beta-cyclodextrin inclusion compound method, preparation volume be 100ml, prescription:
Embodiment 12
Preparation method: beta-cyclodextrin inclusion compound method, preparation volume be 100ml, prescription:
Embodiment 13
Preparation method: the anti-solvent precipitation method, preparation volume be 100ml, prescription:
Embodiment 14
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 15
Preparation method: the anti-solvent precipitation method, preparation volume be 100ml, prescription:
Embodiment 16
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 17
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 18
Preparation method: the anti-solvent precipitation method/high pressure homogenization method, preparation volume be 100ml, prescription:
Embodiment 19
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 20
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 21
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 22
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 23
Preparation method: the anti-solvent precipitation method, preparation volume be 100ml, prescription:
Embodiment 24
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 25
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Embodiment 26
Preparation method: the direct preparation method of solution, preparation volume be 100ml, prescription:
Test example 1
The present embodiment is used to illustrate the comparative efficacy test of preparation provided by the invention.
It is that sensibiligen attacks cavy production allergic rhinitis model with ovalbumin (OVA).By observing cavy nose disease
Shape and schneiderian membrane lamina propria mast cell and eosinophil count investigate levo-cetirizine hydrochloride solution, levocetirizine
Nanosuspension, azatadine maleate solution, azatadine nanosuspension, Loratadine solution, Ebastine solution are received
Rice suspension, setastine hydrochloride solution, setastine nanosuspension, fumaric acid bilastine solution, fumaric acid chlorine Maas
Spit of fland solution, moxifloxacin hydrochloride solution, Moxifloxacin nanosuspension and sea salt water and pharmaceutical composition liquid, independent sea salt
Water nose spray preparation compares the therapeutic effect of cavy allergic rhinitis.
28 antiallergy drug effect contrast groups side of table
Test method
Sensitization: 20 μ g ovalbumin+0.5mg Al (OH) are respectively dripped in sensitization group cavy two sides nostril3Glue+0.1ml physiological saline
Sensitization, 2 times a day, continuous 10d.Before being sprayed every time, extended with 4% lidocaine spray nasal cavity with inhibiting nasal cavity ciliary movement
Quick original is in the nasal cavity residence time.Negative control group is with 0.5mg Al (OH)3The every side nostril of glue+0.1m l physiological saline is sprayed, together
Sample is first sprayed nasal cavity with 4% lidocaine.
Excitation: after the 5d of interval, with 1% ovalbumin physiological saline, 0.1~0.15ml of every side nasal cavity excitation excites for every 3 days
1 time, continuous agitation 10 times.Negative control group replaces ovalbumin with physiological saline.
Observation item
1. semiotics is observed:
(1) have a stuffy nose: on the guinea pig model of allergic rhinitis, the respiratory rate of cavy and its nasal airways resistance are in good
Negative correlation.Reflect nasal airways resistance using respiratory rate.Before cavy is stimulated every time and excitation after 0.5,1,
2,4h measures respiratory rate.
(2) it sneeze and grabs nose number: cavy behavior being recorded with video camera in 30min after excitation every time, it is then right
It cavy sneeze and grabs nose number and is counted one by one.
(3) nasal discharge: 10~20min period after excitation draws nose intracavity liquid with 2 × 80mm filter paper repeatedly.Filter
Weighing before and after paper, difference is calculated as nasal secretions object amount, in terms of mg.
2. the collection of nasal lavage fluid: 5h is after cavy excites in the 10th time with 1% amobarbital intraperitoneal anesthesia.Cavy is solid
Due to a low level of lying on the back, side nasal cavity is slowly dropped into physiological saline with the speed of 1ml/min, and opposite side nasal continuous lower negative pressure is taken out
It inhales.The irrigating solution of recycling is taken into a little merging blood cell counting plate, counts total white blood cells.EDTA is added in remaining irrigating solution
(7.7mmol/L) is centrifuged 5min through 4 DEG C of 600g, and supernatant is stored in -80 DEG C of histamine to be measured and uses.The cell of precipitating does cell painting
Piece, Giemsa-May dyeing, Arneth's count.
Experimental group:, being randomly divided into 25 groups by healthy guinea pig 150,24 medicine groups, a model control group, and every group 6
Cavy.
13 preparations and its liquor strength and dosage of 29 allergic rhinitis in guinea-pig zoopery of table
Administration: the successful cavy of sensitization group modeling is randomly divided into 25 groups, respectively medicine group and model group.Every group 6
Cavy.It is excited after medicine group drop relative medicine 40min with 1% ovalbumin physiological saline, in observation nose disease in 30min
Shape；Model group is directly excited with 1% ovalbumin physiological saline, in observing sniffle in 30min.According to table 28 to every
Mouse scores.
Table 30 induces animal pattern Nasal hypersensitivity sniffle grade form
Experimental result:
(1) to the influence of rhinitis cavy symptom score and sneeze
31 different pharmaceutical prescription of table administration front and back symptom compares
Influence of the different drugs to rhinitis cavy symptom score with sneeze is different, and symptom score and sneeze number obviously subtract
It is few, there is significant difference (P < 0.05 or P < 0.01) compared with model group.
(2) to the influence of nasal lavage fluid leukocyte count
32 different pharmaceutical prescription of table administration front and back nasal lavage fluid leukocyte count compares
Model group nasal lavage fluid leukocyte count is 313 ± 52/μ l, and compared with model group, nasal cavity fills each medicine group group
The leukocyte count of washing lotion is substantially less than model group (p < 0.01).
Synthesis result shows that the sea salt water of drug containing, which is not used alone, has certain anti-inflammatory effect, and effect is slightly lighter than anti-mistake
Sensitizing drug group, but the medicine group for adding sea salt is compared, anti-allergic effects are best, the results show that as osmotic pressure tune
The sea salt and Claritin for saving agent are shared with certain synergistic effect.
Test example 2
The present embodiment is used to illustrate the safety testing (bronchia mucosal irritation test) of preparation provided by the invention.
Whether there is irritation to investigate each group pharmaceutical formulation to bronchia mucosal, by observation cavy sniffle and
Constitutional symptom evaluates its irritation.
33 prescription list of table
Test method and criterion: 100 rabbit, weight (2.5 ± 0.2) kg divide control group (molten to blank at random
Liquid) and administration group, it is every group 4, female, male fifty-fifty.The dosage via intranasal application of every rabbit 0.2ml of administration group instills each group drug, right
The blank solution of meterings, 3 times a day, continuous 2 weeks are given etc. according to group.Observation rabbit overall health of patients (is breathed, is followed after administration every time
Ring, central nervous system) and the variation such as local stimulation symptom (symptoms such as asthma, cough, vomiting, asphyxia).Last dose for 24 hours after
Putting to death (every group 2) observation respiratory tract part (nose, larynx, trachea-bronchial epithelial cell) mucous membrane tissues of Some Animals, whether there is or not hyperemia, rednesses etc.
Phenomenon, and carry out histopathologic examination.It retains rabbit to continue to observe its overall health of patients and localized variation, until after the last administration the
7d is put to death, and nose, larynx, trachea-bronchial epithelial cell tissue is taken to make histopathologic examination.
Observe result: groups of animals rabbit overall health of patients (breathing, circulation, central nervous system) and local stimulation symptom
(symptoms such as asthma, cough, vomiting, asphyxia) are showed no exception.
Pathological examination result: after the last administration for 24 hours and the control group put to death of 7d and administration group rabbit nose, larynx, tracheae,
Bronchial mucosa is showed no exception.
Test example 3
Method: using full-automatic osmometer to measure the pressure of each prescription after the correction of 300 mosmol/kg correcting fluids,
Measurement is averaged three times, as follows:
Table 34: each embodiment osmolarity measure
| Prescription | Osmotic pressure mosmol/kg |
| Embodiment 1 | 282±9 |
| Embodiment 2 | 296±12 |
| Embodiment 3 | 286±9 |
| Embodiment 4 | 280±10 |
| Embodiment 5 | 284±10 |
| Embodiment 6 | 284±11 |
| Embodiment 7 | 283±8 |
| Embodiment 8 | 294±10 |
| Embodiment 9 | 272±11 |
| Embodiment 10 | 318±10 |
| Embodiment 11 | 286±8 |
| Embodiment 12 | 289±8 |
| Embodiment 13 | 274±9 |
| Embodiment 14 | 301±8 |
| Embodiment 15 | 298±10 |
| Embodiment 16 | 310±8 |
| Embodiment 17 | 304±7 |
| Embodiment 18 | 308±6 |
| Embodiment 19 | 301±5 |
| Embodiment 20 | 294±8 |
| Embodiment 21 | 306±7 |
| Embodiment 22 | 294±6 |
| Embodiment 23 | 302±8 |
| Embodiment 24 | 306±7 |
| Embodiment 25 | 298±5 |
| Embodiment 26 | 306±9 |
Note: measuring temperature is 20 DEG C.
As the result is shown: each embodiment osmotic pressure in 260mosmol/kg or more, meets the requirement of preparation solution, in nose
Certain astriction can be shown in chamber flushing process.
Although present invention has been a degree of descriptions, it will be apparent that, do not departing from the spirit and scope of the present invention
Under the conditions of, the appropriate variation of each condition can be carried out.It is appreciated that the present invention is not limited to the embodiments, and it is attributed to right
It is required that range comprising the equivalent replacement of each factor.
Claims (10)
1. a kind of antiallergy nose drug in solution composition of humectant, which is characterized in that the nasal medicine composition packet
Containing following component:
Antiallergy class drug as main ingredient；
Hyaluronate and/or glycerol as moisturizing auxiliary material；
As the sea salt of osmotic pressure regulator, and
Water；
Preferably, the main ingredient is selected from one of following drug or a variety of, its alkali or its pharmaceutically acceptable salt: replacing in left west
Sharp piperazine, azatadine, Loratadine, Ebastine, setastine, bilastine, clemastine, Mizolastine, epinastine,
Moxifloxacin；It is highly preferred that the pharmaceutically acceptable salt is selected from one or more of: hydrochloride, maleate, rich horse
Hydrochlorate, citrate；
Preferably, the hyaluronate is selected from one or more of: Sodium Hyaluronate, calcium hyauronate, zinc hyaluronate；
It is highly preferred that the molecular weight of the hyaluronate is 30~2,000,000 dalton；And/or
Preferably, the osmotic pressure of the drug in solution composition is not less than 260mosmol/kg.
2. nasal medicine composition according to claim 1, which is characterized in that each described in the nasal medicine composition
The percent weight in volume content of main ingredient are as follows:
Levocetirizine 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%；
Azatadine 0.1~2.0%, preferably 0.5~1.5%, more preferably 0.8~1.2%, most preferably 1.0%；
Loratadine 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%；
Ebastine 0.1~4.0%, preferably 0.5~3.0%, more preferably 1.0~2.5%, most preferably 2.0%；
Setastine 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%；
Bilastine 0.1~4.0%, preferably 0.5~3.0%, more preferably 1.0~2.5%, most preferably 2.0%；
Clemastine 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%；
Mizolastine 0.1~2.0%, preferably 0.5~1.5%, more preferably 0.8~1.2%, most preferably 1.0%；
Ebastine 0.1~2.0%, preferably 0.5~1.5%, more preferably 0.8~1.2%, most preferably 1.0%；
Epinastine 0.1~4.0%, preferably 0.5~3.0%, more preferably 1.0~2.5%, most preferably 2.0%；
Moxifloxacin 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%.
3. nasal medicine composition according to claim 1 or 2, which is characterized in that institute in the nasal medicine composition
State the percent weight in volume content of each moisturizing auxiliary material are as follows:
Glycerol 5.0~20.0%, preferably 5.0~15.0%, more preferably 8.0~12.0%, most preferably 10%；
Hyaluronate 0.05~0.5%, preferably 0.05~0.3%, more preferably 0.05~0.2%, most preferably
0.1%；And/or
The percent weight in volume content of the sea salt in the composition are as follows: sea salt 0.1~2.0%, preferably 0.1~1.5%,
More preferably 0.1~1.0%, most preferably 0.9%.
4. nasal medicine composition according to any one of claim 1 to 3, it is characterised in that:
One or more of adding ingredient: plants essential oil, Tween-20, pool is further included in the nasal medicine composition
Luo Shamu 188, dodecyl sodium sulfate, beta-cyclodextrin, ethyl alcohol and pH adjusting agent, wherein the plants essential oil be preferably selected from
Under it is one or more: peppermint oil, Rosemary Oil, Bergamot, Lavender, Geranium Essential, rose ethereal oil, sieve
It strangles essential oil and glycan essential oil, the pH adjusting agent is preferably the sodium hydrate aqueous solution of 1mol/L；
Preferably, the percent weight in volume content of each adding ingredient are as follows:
Plants essential oil 0.01~0.1%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.05%；
Tween-20 0.05~1.0%, preferably 0.1~0.4%, more preferably 0.1~0.3%, most preferably 0.2%；
PLURONICS F87 0.1~1.0%, preferably 0.3~0.8%, more preferably 0.4~0.6%, most preferably 0.5%；
Dodecyl sodium sulfate 0.02~0.1%, preferably 0.02~0.08%, more preferably 0.03~0.06%, most preferably
It is 0.05%；
Beta-cyclodextrin 0.2~0.8%, preferably 0.2~0.6%, more preferably 0.3~0.5%, most preferably 0.4%；With/
Or
Ethyl alcohol 2.0~8.0%, preferably 2.5~6.0%, more preferably 3.0~5.0%, most preferably 4.0%.
5. nasal medicine composition according to any one of claim 1 to 4, it is characterised in that:
The dosage form of the nasal medicine composition is selected from one or more of: spray, aerosol and nasal drops；And/or
The nasal medicine composition is one or more solution selected from the following: aqueous solution, beta-cyclodextrin inclusion compound solution and being received
Rice suspension；Preferably, the medical fluid viscosity is less than 2mpa.s.
6. the method for preparing 5 described in any item nasal medicine compositions into according to claim 1, which is characterized in that described
Nasal medicine composition is aqueous solution, and the preparation method comprises the following steps:
(1) hyaluronate for weighing recipe quantity is dissolved in water, is stirred well to and is completely dissolved；
(2) glycerol, sea salt and main ingredient for sequentially adding recipe quantity stir evenly；With
(3) pH value of solution to 6.0~7.0 ranges are adjusted and obtains the nasal medicine composition.
7. the method for preparing nasal medicine composition according to claim 5, which is characterized in that the nasal medicine combination
Object is beta-cyclodextrin inclusion compound solution, and the preparation method comprises the following steps:
(1) dissolution of raw material of recipe quantity is weighed in ethyl alcohol, obtains ethanol water；
(2) hyaluronate for weighing recipe quantity is dissolved in water, is stirred well to and is completely dissolved, and the sweet of recipe quantity is added in solution
Oil, sea salt stir evenly, and add the beta-cyclodextrin of recipe quantity, and heating obtains aqueous solution.
(3) step (1) resulting ethanol solution is slowly added into step (2) acquired solution, stirring while adding, is added and is continued to stir
It mixes to obtain beta-cyclodextrin inclusion compound solution left standstill to stay overnight, filters to obtain the nasal medicine composition；
Preferably, heating temperature described in step (2) is 20~50 DEG C, preferably 35~45 DEG C, most preferably 40 DEG C；
Mixing speed described in step (3) is 20~100rpm, preferably 45~55rpm, most preferably 40rpm；
Continuation mixing time described in step (3) is 10~30 minutes, preferably 15~25 minutes, most preferably 20 minutes.
8. the method for preparing nasal medicine composition according to claim 5, which is characterized in that the nasal medicine combination
Object is nanosuspension, the preparation method is that the anti-solvent precipitation method, comprising the following steps:
(1) raw material for weighing recipe quantity, adds ethanol in proper amount to dissolve；With
(2) by ethanol solution obtained by step (1) be slowly added into containing dodecyl sodium sulfate, PLURONICS F87, sea salt it is molten
It is stirring while adding in liquid, it adds and continues to stir up to the nasal medicine composition；
Preferably, mixing speed described in step (2) be 10000~20000rpm, preferably 12000~18000rpm, it is optimal
It is selected as 15000rpm；
Continuation mixing time described in step (3) is 5~30 minutes, preferably 5~20 minutes, most preferably 10 minutes.
9. nasal medicine composition described in any one of claims 1 to 5 is preparing answering in the drug for treating rhinitis
With the rhinitis is preferably allergic rhinitis.
10. the pharmaceutical dosage form of application according to claim 9, the treatment rhinitis is spray, aerosol and/or collunarium
Liquid.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710598138.XA CN109276715A (en) | 2017-07-20 | 2017-07-20 | Antiallergy nasal medicine composition, preparation method and the application of humectant |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710598138.XA CN109276715A (en) | 2017-07-20 | 2017-07-20 | Antiallergy nasal medicine composition, preparation method and the application of humectant |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN109276715A true CN109276715A (en) | 2019-01-29 |
Family
ID=65185525
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710598138.XA Pending CN109276715A (en) | 2017-07-20 | 2017-07-20 | Antiallergy nasal medicine composition, preparation method and the application of humectant |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN109276715A (en) |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111265590A (en) * | 2020-01-21 | 2020-06-12 | 华熙生物科技股份有限公司 | Hyaluronic acid freeze-drying preparation for nasal spray and preparation method and application thereof |
| CN113456581A (en) * | 2021-08-09 | 2021-10-01 | 信阳农林学院 | Rosemary essential oil nasal in-situ gel and preparation method and application thereof |
| RU2807374C1 (en) * | 2022-08-25 | 2023-11-14 | Общество с ограниченной ответственностью "РЕОТЕРА" | Nasal composition containing zinc salt of hyaluronic acid |
Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008011836A2 (en) * | 2006-07-25 | 2008-01-31 | Osmotica Corp. | Ophthalmic solutions |
| CN101669926A (en) * | 2008-09-11 | 2010-03-17 | 东莞太力生物工程有限公司 | Liquid preparation for dosing nasal cavities and method for making the same |
| CN102579334A (en) * | 2012-03-31 | 2012-07-18 | 济南康众医药科技开发有限公司 | Nasal drops containing sodium hyaluronate and preparation method thereof |
| CN102671182A (en) * | 2012-06-06 | 2012-09-19 | 深圳翰宇药业股份有限公司 | Degarelix-containing medicinal composition for nasal delivery and preparation method thereof |
| CN104173289A (en) * | 2014-07-21 | 2014-12-03 | 广州艾格生物科技有限公司 | Novel epinastine nasal drug delivery preparation and preparation method thereof |
| CN104906029A (en) * | 2015-05-22 | 2015-09-16 | 中山瑞福医疗器械科技有限公司 | Nasal cavity preparation and preparing method and application thereof |
-
2017
- 2017-07-20 CN CN201710598138.XA patent/CN109276715A/en active Pending
Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2008011836A2 (en) * | 2006-07-25 | 2008-01-31 | Osmotica Corp. | Ophthalmic solutions |
| CN101669926A (en) * | 2008-09-11 | 2010-03-17 | 东莞太力生物工程有限公司 | Liquid preparation for dosing nasal cavities and method for making the same |
| CN102579334A (en) * | 2012-03-31 | 2012-07-18 | 济南康众医药科技开发有限公司 | Nasal drops containing sodium hyaluronate and preparation method thereof |
| CN102671182A (en) * | 2012-06-06 | 2012-09-19 | 深圳翰宇药业股份有限公司 | Degarelix-containing medicinal composition for nasal delivery and preparation method thereof |
| CN104173289A (en) * | 2014-07-21 | 2014-12-03 | 广州艾格生物科技有限公司 | Novel epinastine nasal drug delivery preparation and preparation method thereof |
| CN104906029A (en) * | 2015-05-22 | 2015-09-16 | 中山瑞福医疗器械科技有限公司 | Nasal cavity preparation and preparing method and application thereof |
Non-Patent Citations (3)
| Title |
|---|
| 《药用高分子材料学》: "《药用高分子材料学》", 31 October 2014, 上海：华东理工大学出版社 * |
| 王晓波主编: "《药物运释系统》", 31 August 2007, 北京：中国医药科技出版社 * |
| 王玉主编: "《药品检验》", 31 October 2011, 北京：中国医药科技出版社 * |
Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111265590A (en) * | 2020-01-21 | 2020-06-12 | 华熙生物科技股份有限公司 | Hyaluronic acid freeze-drying preparation for nasal spray and preparation method and application thereof |
| CN111265590B (en) * | 2020-01-21 | 2022-03-01 | 华熙生物科技股份有限公司 | Hyaluronic acid freeze-drying preparation for nasal spray and preparation method and application thereof |
| CN113456581A (en) * | 2021-08-09 | 2021-10-01 | 信阳农林学院 | Rosemary essential oil nasal in-situ 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 |
| RU2807374C1 (en) * | 2022-08-25 | 2023-11-14 | Общество с ограниченной ответственностью "РЕОТЕРА" | Nasal composition containing zinc salt of hyaluronic acid |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN103269687A (en) | Bepotastine compositions | |
| CN103260623B (en) | 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy compositions | |
| CN101530473A (en) | Nose-dredging spraying agent and preparation method thereof | |
| CN105792828A (en) | Treatment of allergic rhinitis using a combination of mometasone and olopatadine | |
| CN102217879B (en) | Heart-nourishing and nerve-soothing pillow | |
| CN103432287B (en) | Camellia oleosa seed lavipeditum powder and preparation method thereof | |
| WO2023237124A1 (en) | Crocin suspension and use thereof in preparation of rapid-acting antidepressant drug | |
| CN103735437A (en) | Herbal mouthwash | |
| CN109276715A (en) | Antiallergy nasal medicine composition, preparation method and the application of humectant | |
| CN108523121A (en) | A kind of functional food and preparation method thereof of anti-haze clearing lung-heat | |
| CN110179843B (en) | External-use pharmaceutical composition for treating non-allergic rhinitis | |
| KR20140081738A (en) | Pharmaceutical composition in the form of an oral suspension comprising flavonoid fraction and xanthan gum | |
| CN105709081A (en) | Pharmaceutical composition used for treating infectious rhinitis of chicken, applications thereof, and feed | |
| CN109260180A (en) | A kind of moxifloxacin hydrochloride Neulized inhalation pharmaceutical solutions and preparation method thereof | |
| CN106963770A (en) | It is a kind of to be used to prevent and treat eye drops of drying property angle/conjunctivitis and its production and use | |
| CN101569684B (en) | Inhalation aerosol of plant extract for treating asthma and preparation method | |
| CN106236925B (en) | A kind of Chinese medicine inhalation aerosol and the preparation method and application thereof for treating asthma | |
| CN102217880B (en) | Heat-clearing and heatstroke-preventing health care drug pillow | |
| CN102217881B (en) | Liver-protecting and liver-benefiting health-care pillow | |
| EP3069723B1 (en) | Naringin and levocetirizine hydrochloride pharmaceutical composition and preparation thereof | |
| CN104274750B (en) | A kind of Chinese medicine composition for treating acute bronchitis, the infection of the upper respiratory tract | |
| CN104189081B (en) | It is a kind of to be used to treat Chinese medicine composition of allergic rhinitis and preparation method thereof | |
| CN102217885B (en) | Traditional Chinese medicine pillow for treating nervous headache | |
| CN102217884B (en) | Chinese medicinal pillow | |
| CN102217883B (en) | Chinese medicinal pillow capable of treating cervical spondylopathy |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| RJ01 | Rejection of invention patent application after publication | ||
| RJ01 | Rejection of invention patent application after publication |
Application publication date: 20190129 |