CN102078612A - Nasal in-situ gel containing mometasone furoate and H1 receptor antagonist - Google Patents

Abstract

The invention discloses nasal in-situ gel containing mometasone furoate and an H1 receptor antagonist. The nasal in-situ gel is prepared from mometasone furoate serving as an active ingredient and/or a hydrate of mometasone furoate, one or more H1 receptor antagonists, an environmentally-sensitive hydrophilic gel material, other pharmaceutically acceptable auxiliary materials and the balance of water.

Description

The nasal in situ gel that contains momestasone furoate and H1 receptor antagonist

Technical field:

The present invention relates to a kind of situ-gel that contains 17-hydroxy-11-dehydrocorticosterone and H1 receptor antagonist.

Background technology:

Allergic rhinitis (allergic rhintis) claim allergic rhinitis again, is the allergic disease of nasal membrane, and can causes multiple complications.Allergic rhinitis can betide any age, and the men and women all has, and easily see youngster.The allergic rhinitis that calendar year 2001 countries in the world expert formulates and to influence (the allergic rhinitis and its impact on asthma.ARIA) guide of asthma, and become The World Health Organization (WHO)) part of proposing, in the ARIA guide, point out, corticosteroid is the most effective medicines of treatment allergic rhinitis, is applicable to that therefrom the severe intermittence is to the treatment of the allergic rhinitis of all degree of middle severe persistence.Different with the 17-hydroxy-11-dehydrocorticosterone of general action, ideal nose should possess following condition (1) receptor affinity (receptor-binding affinity) height, potency (potency) height with 17-hydroxy-11-dehydrocorticosterone; (2) do not influence height to hypothalamic-pituitary-adrenal hpa axis (3) Local security.

Momestasone furoate (fluticasone propionate is a kind of potent local action glucocorticoid hormone preparation CAS:80474-14-2), and its molecular formula is as follows:

Because the effect of whole body glucocorticoid is very little, momestasone furoate extensively is used to treat anaphylactic diseases and respond well such as local inflammation such as asthma, allergic rhinitis and skin.The existing preparation that is used for the treatment of allergic rhinitis is 0.1% nasal spray (trade name " nasonex, Schering Plough production)

In addition, antihistaminic also is used to treat allergic rhinitis, is used for the treatment of the antihistaminic of allergic rhinitis. be essentially histamine receptor antagonists.Histamine has two kinds of different receptor H1 and H2, and the latter is main relevant with visceral smooth muscle; And the former main and skin, mucosa are relevant, and generally the indication antihistaminic promptly belongs to this class in the treatment allergic rhinitis, is generally called the H1 receptor antagonist.

Chinese patent application 97195225.6 discloses a kind of intranasal corticosteroid and antihistaminic nasal spray of containing, give in the application specification and think that intranasal corticosteroid and antihistaminic combination can be with rapid onset and continuous actions, and reduce the dosage that hydryllin needs, thereby reduced potential the minimizing as side effect such as drowsinesses, yet, the concrete pharmacological experiment data of this application and the above-mentioned effect of unexposed any proof, and we found through experiments the less stable of the disclosed nasal medicine composition of this application, can not satisfy in the existing pharmacopeia requirement to stability.

Chinese patent application 03819170 discloses the compound preparation of a kind of A-5610 and glucocorticoid, disclose A-5610 and glucocorticoid compound recipe have been made dosage forms such as nasal spray, aerosol, powder spray, we test discovery for wherein process, disclosed nasal spray less stable in this application can not satisfy in the existing pharmacopeia requirement to stability.

Nose with medicament such as common nasal drop, nasal spray, because nasal membrane secreting mucus, the motion of bronchia mucosal cilium has the effect that purifies foreign body and dust on the nasal cavity slime layer, and medicine is eliminated very soon behind the nasal-cavity administration, and bioavailability of medicament is reduced.

Illum L etc. report (Int J Pharm, 1987,39 (3): 189) mucociliary is removed from concha nasalis the medicine that is splashed into the speed of average 5mm/min in the nasal cavity to nasopharynx part, has shortened the contacted time of medicine and mucomembranous surface greatly, directly influences the absorption and the curative effect of medicine.

(allergic rhinitis progress (three): nose is with the pharmacological action of corticosteroid people's report such as to raise, " ear,nose ﹠ throat: head and neck surgery ", 2004 11 1 phases of volume, 67-72, what 22) the medicine systemic bioavailability is played primary effect is the first inactivation ratio of crossing of liver of medicine, under the first excessively situation that inactivation ratio is more or less the same of liver, medicine via intranasal application absorbtivity just seems particularly important.The nasal absorption amount of nasal membrane surface mucociliary clearance system appreciable impact medicine, fat-solubility and low fat-soluble medicine all are difficult for being absorbed.Fat-soluble height and the lower medicine (as: FLUTICASONE PROPIONATE and momestasone furoate) of water solublity, its local dissolution/absorbance is relatively low, the ciliary movement of nasal mucosa surface epithelial cell is pushed medicine to swallow to rear wall fast, make the patient behind the spray medicine, taste the special flavour of medicine usually in 30 seconds, enter gastrointestinal tract by swallowing movement then.It is different with the asal agent type to inhale people's cortex steroid, owing to the transportation function of pulmonary's mucociliary transmission system than nasal cavity a little less than, fat-soluble high medicine is longer in pulmonary's holdup time, can bring into play its pharmacotoxicological effect lentamente.Fat-soluble low and medicine (as: budesonide) that water solublity is higher, its local dissolution/absorbance is higher relatively, and medicine dissolves in the slurry layer of mucociliary transmission system easily, in more easily by Nasal Mucosa Absorption, is also swallowed easily and enters gastrointestinal tract.Therefore improve the time of staying of nasal medicine on the nasal mucosa surface, reduce systemic bioavailability, the local bioavailability that improves medicine becomes the problem that nasal formulations will solve.

Summary of the invention:

Our surprised by experiment discovery passes through to adopt situ-gel, can make said preparation in intranasal retention time lengthening, reduce nasal cavital mucus cilium transmission system transporting to medicine, thereby increase the absorption of medicine at the intranasal mucosa, reduce the ratio that medicine is swallowed by gastrointestinal tract, improved the bioavailability of medicine, can also reduce the zest of medicine simultaneously at the intranasal mucosa, avoid the nose ciliary movement fast medicine to be pushed swallow to rear wall preferably, increase especially suitable the being subjected to property of child patient of patient.Also can improve stability of formulation by this preparation simultaneously.Situ-gel (in situ gel) is meant to take place to change the non-chemically crosslinked semi-solid preparation of formation mutually at agents area immediately after the solution state administration.Situ-gel has the hydrophilic three-dimensional net structure and the favorable tissue compatibility of gel preparation, simultaneously, unique solution one gel conversion character make its have concurrently preparation simple, easy to use, with agents area advantages such as particularly the mucous membrane tissue affinity is strong, the holdup time is long, purposes and good control Release Performance widely in addition, the formation mechanism of situ-gel is the response that utilizes macromolecular material to stimulate to external world, make polymer issue the reversible change of diffusing state estranged or conformation, finish by the conversion process of solution to gel at physiological condition.Correspondingly, this special gel can be divided into types such as temperature, ionic strength or pH sensitivity.

For overcoming shortcoming of the prior art, we provide a kind of nasal in situ gel, being of its feature is by making as the water of acceptable auxiliary and surplus on the momestasone furoate of effective ingredient and/or its monohydrate and one or more H1 receptor antagonists, environment sensitive type hydrophilic gel material, other pharmaceutics.

The component of preparation consists of: momestasone furoate and/or its monohydrate 0.01-0.2% (in momestasone furoate), the content of H1 receptor antagonist is 0.05%～1%, environment sensitive type hydrophilic gel material 0.05-40%, acceptable auxiliary 0.01-50% on other pharmaceutics.

The content of described momestasone furoate and/or its monohydrate is preferably 0.05～0.1% (in momestasone furoate).Preferably make micropowder, the D90 particle diameter is 0.1～30 μ m, more preferably 1-10 μ m.

Wherein the environmental sensitivity gel is divided into responsive to temperature type, ion-sensitive type, pH responsive type and mixed type.

Nasal in-situ gel of the present invention is the ion-sensitive type gel, is free-pouring solution at room temperature, and the cation that runs in the snotter forms by cation mediated gel.It is characterized in that described ion-sensitive type hydrophilic gel material is selected from one or more the combination in deacetylation gellan gum, sodium alginate, xanthan gum, welan gum, the carrageenan; preferred deacetylation gellan gum and/or sodium alginate; wherein; the concentration of deacetylation gellan gum is 0.05-2%; the concentration of carrageenan is 0.3-8%; the concentration of welan gum is 0.1-10%, and concentration of xanthan gum is 0.1-10%, and the concentration of sodium alginate is 0.2-9%.

Nasal in-situ gel of the present invention is the responsive to temperature type gel, is free-pouring solution under the room temperature, and gelling becomes semisolid gel state under the nasal cavity temperature.It is characterized in that described responsive to temperature type hydrophilic gel material is selected from poloxamer 407, poloxamer 188, methylcellulose, polyethylene glycol-lactic acid block copolymer (PEG-PLGA); In N-N-isopropylacrylamide (NiPAAM) copolymer, ethylhydroxyethylcellulose (EHEC) or the xylan one or both and two or more combinations thereof, preferred poloxamer 407, poloxamer 188, methylcellulose, polyethylene glycol-lactic acid block copolymer (PEG-PLGA), wherein, the concentration of poloxamer 407 is 12-40%, the concentration of poloxamer 188 is 5-30%, and the concentration of methylcellulose is 1-10%.The concentration of NiPAAM copolymer is 20-40%, and the concentration of PEG-PLGA is 15-40%, and the concentration of EHEC is 0.1-2%.

Nasal in-situ gel of the present invention is a pH responsive type gel, and pH is free-pouring solution during for 3.5-5.0, and the acidic-group when pH is elevated to 5.5-6.5 on the polymer chain is neutralized, and electric charge repels mutually and causes strand to extend tangling forming gel.The hydrophilic gel material that it is characterized in that described pH sensitivity is selected from cellulose acetate phthalate ester (CAP), carbomer, the combination in any of one or more in polyethylene acetal diethylamine acetate (AEA), the chitosan, wherein the concentration of CAP is 10-40%, the concentration of carbomer is 0.1-2.0%, and the concentration of chitosan is 1-10%.

Nasal in-situ gel of the present invention is the mixed type gel, is free-pouring solution under the natural conditions, and physiological condition forms gel down.It is characterized in that described mixed type hydrophilic gel material is the two or more combination in any of responsive to temperature type, pH responsive type, ion-sensitive type macromolecular material, as combinations such as methylcellulose and sodium alginate, poloxamer 407 and sodium alginate, poloxamer 407 and deacetylation gellan gum, poloxamer 407 and carbomers.

Nasal in-situ gel of the present invention, described pharmaceutically useful adjuvant also comprises osmotic pressure regulator, in gel regulator, antiseptic, pH regulator agent, suspending agent, the wetting agent one or more, and the water of surplus, described osmotic pressure regulator is selected from one or more in mannitol, sorbitol, glycerol, propylene glycol and/or the sodium chloride.

Nasal in-situ gel of the present invention, its described gel regulator is selected from Polyethylene Glycol (PEG, molecular weight are 6000-11000), polyvidone, sodium citrate, polyoxyethylene, single oleic acid glycerol vinegar, the hydrophilic cellulose base polymer (hydroxypropyl cellulose, methylcellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose etc.) one or more.

Nasal in-situ gel of the present invention, its described pH regulator agent is an acceptable pH regulator on the pharmaceutics, as sodium hydroxide, triethanolamine, potassium hydroxide, hydrochloric acid etc.Wherein the pH responsive type is adjusted to 3.5-5.0 with the pH value that contains the mixed type gel of pH responsive type material, and the pH value of the gel of other type is adjusted to 5.0-8.0.

Nasal in-situ gel of the present invention, its described antiseptic are acceptable antiseptic on the pharmaceutics, prick chlorine by in, thimerosal, methyl hydroxybenzoate, ethyl hydroxybenzoate, the propylparaben etc. one or more as chlorobutanol, benzoic acid, benzene.

Nasal in-situ gel of the present invention, its described gel preparation are to pass through nasal-cavity administration with the form of spraying or collunarium.

Described H1 receptor antagonist includes but are not limited to one or more in chlorphenamine, hydroxyzine, diphenhydramine, teldane, astemizole, loratadine, alerlisin, acrivastine, emedastine, ketotifen, plug Lip river imidazoles, azelastine, ebastine, levocabastine, Primalan, Desloratadine, olopatadine, left alerlisin and pharmaceutically useful salt thereof, ester, the optical isomer.Preferred azelastine, levocabastine, left alerlisin, emedastine, olopatadine, loratadine, Desloratadine and pharmaceutically useful salt thereof, ester, one or more, more preferably water-soluble azelastine and pharmaceutically useful salt thereof, ester.

The content of H1 receptor antagonist is 0.05%～1%, preferred 0.05%～0.5%.

Not soluble in waterly in the described H1 receptor antagonist can be beta-schardinger dextrin-or derivatives thereof institute enclose.

Described in beta-schardinger dextrin-and derivant thereof, can be selected from beta-schardinger dextrin-, 2-HP-(CAS:128446-35-5), 2,6-O-DM-(CAS:51166-71-3, be called for short DM-, DM-β-CD), 2-hydroxyethyl-(CAS:98513-20-3), 3-HP-; (partly methylated β-cyclodextrin), (Randomlymethlated-β-Cyclodextrin arbitrarily methylates-beta-schardinger dextrin-for 2-O-methyl-beta-schardinger dextrin-(be called for short methyl-beta-schardinger dextrin-), RAMEB, a kind of among the RM-β-CD), preferred 2-HP-.

Described H1 receptor antagonist by the technology of cyclodextrin institute enclose is: beta-schardinger dextrin-or derivatives thereof, H1 receptor antagonist are added in the moisture or water-free polar organic solvent, make it molten clear, add or do not add dilution water, steam organic solvent, obtain cyclodextrin clathrate or its aqueous solution of glucocorticoid and/or H1 receptor antagonist.Preferred for preparation becomes the aqueous solution of cyclodextrin clathrate.In the above-mentioned technology, the mol ratio of described H1 receptor antagonist and cyclodextrin or derivatives thereof is 1: 1～20, be preferably 1: 2～and 10; The weight ratio of H1 receptor antagonist and water is 1: 2～20, be preferably 1: 5～and 10, the weight ratio of H1 receptor antagonist and organic solvent is 1: 3～30, be preferably 1: 5～15.

Described polar organic solvent can be selected from ethanol and acetone.The moisture requirement of this organic solvent is not high, can dissolve cyclodextrin derivative and 17-hydroxy-11-dehydrocorticosterone is as the criterion with process for preparation.Such as the ethanol water that can select 80%-96% for use, general medicinal alcohol (94%-96%) all can use; Be no more than 10% acetone such as moisture, can use.The dilution water that process for preparation adds can steam except that disposable adding before and after the organic solvent, also can gradation add; The method that adds such as dilution water is divided into concentrating to steam and adds once before removing, and concentrates to steam in the process of removing to add twice again; Perhaps divide three addings in the concentrated process of removing of steaming.The process for preparation temperature requirement is not strict, under 0-50 ℃ can, under the general room temperature 20-25 ℃ best.

Dilution water is distilled water, sterilized water, deionized water, water for injection; Preferred sterilized water, water for injection; More preferably water for injection.If use aqueous organic solvent, under the situation that the enough whole process for preparation of its water content uses, can add dilution water, perhaps only add a spot of dilution water.

Adopt the aqueous stability of H1 receptor antagonist clathrate of above-mentioned prepared better, stable content, H1 receptor antagonist clathrate water solublity is fine, concentration can be controlled according to adding the water yield in the preparing process process, can be controlled at and contain 17-hydroxy-11-dehydrocorticosterone and/or H1 receptor antagonist weight 1% to 15%, be convenient to next step use.

Preferably also contain suspending agent in the described in-situ gel, described suspending agent is one or more in xanthan gum, methylcellulose (MC), tragacanth, arabic gum, pectin, hydroxypropyl emthylcellulose (HPMC) or the sodium carboxymethyl cellulose (CMC-Na).Wherein concentration of xanthan gum is 0.1-6%, the concentration of MC is 1-5%, the concentration of tragacanth is 0.5-4%, the concentration of arabic gum is 5-10%, the concentration of pectin is 1-7%, the concentration of HPMC is 0.1-10%, and the concentration of CMC-Na is 0.5-10%, and needs were selected when concrete concentration can be according to preparation.When preparation, can also add wetting agent, the preferred polysorbate esters of described wetting agent (Tween) non-ionic surface active agent.The concentration of polysorbate is 0.1-8%.The polysorbate esters is selected from the preferred Tween-80 of Tween-20, Tween-40, Tween-60, Tween-65, Tween-80 and/or Tween-85.

The described percentage ratio of technical solution of the present invention all is weight percentage.

The present invention also aims to provide a kind of method for preparing nasal in-situ gel, this method comprises and is prepared as follows step: with the fully dissolving in water or in the buffer of environment sensitive type hydrophilic gel material, respectively acceptable auxiliary on momestasone furoate, H1 receptor antagonist/H1 receptor antagonist clathrate or clathrate aqueous solution and the pharmaceutics is mixed into suspension, with this suspension and environment sensitive type hydrophilic gel material solution, regulate pH value, add water to full dose.Described environment sensitive type hydrophilic gel material is selected from the hydrophilic gel material of ion-sensitive type, responsive to temperature type, pH responsive type and mixed type; Acceptable auxiliary comprises one or more in osmotic pressure regulator, gel regulator, pH regulator agent and the antiseptic on the described pharmaceutics.

Various pharmaceutical composition of the present invention all is isoosmotic, nasal in-situ gel of the present invention can be made nasal drop, nasal spray, when making nasal spray, can adopt known spray form of medication, use the known quantitative aerosol apparatus that is applicable to nasal administration, the consumption of each spraying is 30 μ L to 150 μ L.

Described environment sensitive type hydrophilic gel material is selected from the hydrophilic gel material of ion-sensitive type, responsive to temperature type, pH responsive type and mixed type; Acceptable auxiliary comprises one or more in osmotic pressure regulator, gel regulator, pH regulator agent and the antiseptic on the described pharmaceutics.

Compared with prior art, adopt nasal in-situ gel of the present invention, owing to adopted the environment sensitive type gel rubber material, make the gel that makes after entering nasal cavity, just undergo phase transition into gel form, can be retained in nasal cavity for more time, realize the continual and steady release of effective ingredient, thereby can improve bioavailability of medicament, reached better therapeutic effect.Simultaneously in order to utilize gel water content when nasal cavity becomes glue to reduce, can separate out the characteristic of certain amount of fluid, preferred water miscible H1 receptor antagonist azelastine or with other water-fast H1 receptor antagonists be prepared into can be water-soluble clathrate, like this after administration, the gelatigenous while of gel, contain certain amount of H 1 receptor antagonist in the liquid of separating out, thereby can quick acting, pharmacological evaluation shows, aspect the effect of the rapid alleviation of Cavia porcellus allergic rhinitis symptom, the H1 receptor antagonist and the momestasone furoate compound preparation of the curative effect of pharmaceutical composition provided by the invention and regular dosage form are suitable substantially, and continue the above-mentioned preparation of the prior art that is better than evident in efficacy.

The specific embodiment:

The preparation of H1 receptor antagonist clathrate/clathrate aqueous solution

1, the preparation of hydrochloric acid left side alerlisin cyclodextrin clathrate

Beta-schardinger dextrin-2.5g adds an amount of distilled water and is stirred to its whole dissolvings in 60 ℃, adds 0.5g hydrochloric acid left side alerlisin, pours in the evaporating dish after continuing to stir 30min, in 90 ℃ of water bath methods, dry in the exsiccator, porphyrize promptly gets hydrochloric acid left side alerlisin/Benexate Hydrochloride, and is standby.

2, the preparation of Desloratadine cyclodextrin inclusion compound aqueous solution

Under the room temperature 2-HP-4g is dissolved among the 80% ethanol 25ml, it is fixed for him to add 0.2g ground chlorine, stir molten clear, restir 30 minutes, micro-pore-film filtration (220nm), the water for injection that adds 10mL, stirred 5 minutes, concentrating under reduced pressure steams and removes acetone, obtain ground chlorine for his fixed/2-HP-enclose aqueous solution, standby.

3, the preparation of hydrochloric acid levocabastine cyclodextrin inclusion compound aqueous solution

Under the room temperature 2-HP-5g is dissolved among the 90% ethanol 20ml, add 0.5g hydrochloric acid levocabastine, stir molten clear, restir 30 minutes, micro-pore-film filtration (220nm), the water for injection that adds 15mL, stirred 5 minutes, concentrating under reduced pressure steams and removes solvent, obtain hydrochloric acid levocabastine/2-hydroxyethyl-enclose aqueous solution, standby.

Used H1 receptor antagonist all adopts the form of above-mentioned clathrate or clathrate aqueous solution in following examples, and described momestasone furoate or monohydrate content are all in momestasone furoate, and described content all by weight percentage.

Embodiment 1 preparation ion-sensitive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel, write out a prescription following (seeing Table 1):

Table 1 ion-sensitive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel prescription

Content %	Embodiment 1-1	Embodiment 1-2	Embodiment 1-3	Embodiment 1-4
					17-hydroxy-11-dehydrocorticosterone content %	Momestasone furoate 0.05	Momestasone furoate monohydrate 0.05	Momestasone furoate 0.1	Momestasone furoate monohydrate 0.1
H1 receptor antagonist agent content %	Hydrochloric acid levocabastine 0.05	A-5610 0.1	Hydrochloric acid levocabastine 0.05	Hydrochloric acid left side alerlisin 0.1
					Suspending agent %	Xanthan gum 0.15	Methylcellulose 3	Arabic gum 5	HPMC?1
Wetting agent %	Tween-80?0.1	Tween-80?0.15	Tween-80?0.3	Tween-80?0.5
					Sodium alginate %	6	0.8
Go acetyl-removed gellan gum			0.3	1.2
					Osmotic pressure regulator %	Glycerol 1.8	Sorbitol 4.5	Glycerol 2	Mannitol 5
Antiseptic %	Chlorobutanol 0.5	Benzalkonium chloride	Chlorobutanol 0.5	Ethyl hydroxybenzoate 0.02
					The pH regulator agent	HCl transfers pH to 6.2	HCl transfers pH to 6.2	HCl transfers pH to 6.2	HCl transfers pH to 6.2
Water for injection %	Surplus	Surplus	Surplus	Surplus

Preparation technology: above-mentioned ion-sensitive type macromolecule is placed proper amount of deionized water, make its dispersing and dissolving in 80-100 ℃ of stirred in water bath, cooling obtains clear and bright solution (1) as for leaving standstill 12h in 4 ℃ of refrigerators.Embodiment 1-1 is mixed in 17-hydroxy-11-dehydrocorticosterone micropowder and H1 receptor antagonist or its clathrate/clathrate aqueous solution and other water soluble adjuvants to embodiment 1-4 and makes suspension (2) in the water for injection, (1) and (2) is mixed, transfer pH to 6.2, add water to full dose and get final product.Use BrookfieldDV-m type rotating cylinder viscometer under room temperature (20 ℃) condition, to measure the rheological property of above-mentioned five prescriptions.Above-mentioned prescription is along with the increase viscosity of shear rate presents in various degree downward trend, belong to pseudoplastic fluid, embodiment 1-1, embodiment 1-4, viscosity＞250cP are suitable for using as nasal drop, embodiment 1-2, embodiment 1-3 viscosity＜60cP are suitable for using as nasal spray.Cationic solution according to artificial nose liquid proportional preparation different ions concentration, to mix with it respectively in 32 ℃ of water-baths of above-mentioned 5 embodiment, the point of viscosity generation significant change is critical phase transformation cation concn, and result's (seeing Table 5) shows that the phase transformation cation concn of above-mentioned 5 prescriptions all is less than or equal to the cation concn of snotter.Therefore estimate that said preparation can form gel at nasal cavity.Under the nasal cavity cation concn, above-mentioned 5 preparations all become glue in 5min.

Embodiment 2 preparation temperature responsive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gels, write out a prescription following (seeing Table 2):

Table 1 responsive to temperature type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel prescription

Content %	Embodiment 2-1	Embodiment 2-2	Embodiment 2-3	Embodiment 2-4
					Active constituent content %	Momestasone furoate monohydrate 0.05	Momestasone furoate 0.05	Momestasone furoate 0.1	Momestasone furoate monohydrate 0.1
H1 receptor antagonist agent content %	Hydrochloric acid levocabastine 0.05	A-5610 0.1	Hydrochloric acid left side alerlisin 0.1	Hydrochloric acid levocabastine 0.05
					Poloxamer 407	20	35		12
Poloxamer 188	5		28	15
					PEG(6000-11000)	2
Polyoxyethylene (PEO)				2.5
					Hydroxypropyl methylcellulose (HPMC)		2	1.5
Suspending agent	Xanthan gum 0.15		Arabic gum 5
					Wetting agent	Tween-80?0.1	Tween-80?0.15	Tween-80?0.3	Tween-80?0.5
Osmotic pressure regulator	Sodium chloride 0.9	Sorbitol 4.5	Glycerol 2	Mannitol 5
					Antiseptic	Benzalkonium chloride 0.03	Methyl hydroxybenzoate 0.02	Chlorobutanol 0.5	Ethyl hydroxybenzoate 0.05
The pH regulator agent	NaOH transfers pH to 6.5	Triethanolamine is transferred pH to 6.5	Triethanolamine is transferred pH to 6.5	NaOH transfers pH to 6.5
					Water for injection	Surplus	Surplus	Surplus	Surplus

Preparation technology:

Said temperature responsive type macromolecule is joined in the cryogenic phosphate buffer (pH6.5), make its dispersing and dissolving under the magnetic agitation, in 4 ℃ of refrigerators, leave standstill 12h and obtain clear and bright solution (1).(HPMC) stirring makes its dissolving, static 12h obtain clear and bright solution (2) under the room temperature for PEG, PEO with the gelling properties regulator.17-hydroxy-11-dehydrocorticosterone micropowder and H1 receptor antagonist or its clathrate/clathrate aqueous solution and other water soluble adjuvants be mixed in obtain suspension (3) in the water for injection, three solution mix and stir evenly, and transfer pH to 6.5, add water to full dose and get final product.Use Brookfield DV-III type rotating cylinder viscometer in the rheological property of measuring under room temperature (20 ℃) condition under embodiment 2-1 to the embodiment 2-4 different shear rate.The above-mentioned square everywhere increase viscosity along with shear rate presents downward trend in various degree, belongs to pseudoplastic fluid.Elevated temperature is measured the viscosity under the different temperatures, and the result shows that in nasal cavity (25 ℃-33 ℃) temperature range, there is tangible phase transition temperature (seeing Table 6) in room temperature in the temperature that above-mentioned each preparation viscosity all increases.Under 32 ℃ of the physiology of the nose temperature, above-mentioned preparation all becomes glue in 2min.

Embodiment 3

Preparation pH responsive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel, write out a prescription following (seeing Table 3)

Table 3 pH responsive type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel prescription

Content %	Embodiment 3-1	Embodiment 3-2	Embodiment 3-3
				Active constituent content %	Momestasone furoate monohydrate 0.05	Momestasone furoate 0.05	Momestasone furoate 0.1
H1 receptor antagonist agent content %	A-5610 0.1	Hydrochloric acid levocabastine 0.05	Hydrochloric acid levocabastine 0.05
				Cellulose acetate phthalate ester (CAP)	30
Carbomer 934		0.8
				Chitosan			3
Glyceryl monooleate (GMO)			3
				Hydroxypropyl methylcellulose (HPMC)	0.5	1
Suspending agent	Xanthan gum 0.15	Methylcellulose 3	Arabic gum 5
				Wetting agent	Tween-80?0.1	Tween-80?0.15	Tween-80?0.3
Osmotic pressure regulator	Glycerol 1.5	Glycerol 2	Sorbitol 4.5
				Antiseptic	Benzalkonium chloride 0.03	Methyl hydroxybenzoate 0.02	Chlorobutanol 0.5
The pH regulator agent	HCl regulates pH to 4.0	HCl regulates pH to 4.0	HCl regulates pH to 4.0
				Water for injection	Surplus	Surplus	Surplus

Preparation method: pH responsive type gel rubber material is dissolved in distilled water, and wherein CAP stirring and dissolving in the HCl of pH3.0 solution leaves standstill 12h and obtains clear and bright solution in 4 ℃ of refrigerators; Carbomer 934 is dissolved in a certain amount of water and obtains solution; Chitosan dissolves in the citric acid solution of 0.33M, leaves standstill 12h and obtain clear and bright solution in 4 ℃ of refrigerators.

Momestasone furoate micropowder and H1 receptor antagonist or its clathrate/clathrate aqueous solution and other water soluble adjuvants be mixed in a certain amount of distilled water obtain suspension, the solution that is mixed with gel regulator (HPMC, GMO) mixes, be added dropwise in the responsive gel solution of above-mentioned pH, regulate pH to 4.0, the water that replenishes surplus is to full dose.

Use Brookfield DV-III type rotating cylinder viscometer to measure the rheological property of above-mentioned three prescriptions under different shear rate at ambient temperature.Above-mentioned three prescriptions belong to pseudoplastic fluid along with the increase viscosity of shear rate presents in various degree downward trend.Above-mentioned prescription is mixed with the phosphate buffer of different pH value according to 1: 1 ratio, and in 32 ℃ of mensuration viscosity, the result shows that each preparation is viscosity generation significant change in the scope of pH5-6.5, and critical phase transformation pH sees Table 7.Under pH value 5.5 conditions, above-mentioned preparation all becomes glue in 5min.

Embodiment 4

Preparation mixed type 17-hydroxy-11-dehydrocorticosterone nasal in-situ gel, write out a prescription following (seeing Table 4)

Content %	Embodiment 4-1	Embodiment 4-2	Embodiment 4-3	Embodiment 4-4
					Active constituent content %	Momestasone furoate 0.05	Momestasone furoate monohydrate 0.05	Momestasone furoate 0.1	Momestasone furoate monohydrate 0.1
H1 receptor antagonist agent content %	Hydrochloric acid levocabastine 0.05	A-5610 0.1	Hydrochloric acid levocabastine 0.05	Hydrochloric acid left side alerlisin 0.5
					Methylcellulose	2
Poloxamer 407		18	18	18
					Poloxamer 188			0.3	1.2
Carbomer 934				0.5
					Sodium alginate	0.8	0.5
Go acetyl-removed gellan gum			0.2
					PEG(6000-11000)	8
Sodium citrate	3.2
					Osmotic pressure regulator	Mannitol 4.5	Glycerol 2	Glycerol 2	Sorbitol 4.5
Antiseptic	Benzalkonium chloride 0.03	Methyl hydroxybenzoate 0.02	Chlorobutanol 0.5	Ethyl hydroxybenzoate 0.05
					Suspending agent	Xanthan gum 0.15	Methylcellulose 3	Arabic gum 5	HPMC?1
Wetting agent	Tween-80 0.1	Tween-80?0.15	Tween-80 0.3	Tween-80?0.5
					The pH regulator agent	NaOH transfers pH to 6.5	Triethanolamine is transferred pH to 6.5	Triethanolamine is transferred pH to 6.5	HCl transfers pH to 4.0
Water for injection	Surplus	Surplus	Surplus	Surplus

Ion-sensitive type gel rubber material (sodium alginate, go acetyl-removed gellan gum) is dissolved in 80-90 ℃ distilled water, in 4 ℃ of refrigerators, leave standstill 12h and obtain clear and bright solution; Carbomer 934 is dissolved in a certain amount of water and obtains solution; Be scattered in the phosphate buffer (pH6.5) under responsive to temperature type gel rubber material (poloxamer 407, poloxamer 188, the methylcellulose) low temperature, stir and make its dispersing and dissolving, in 4 ℃ of refrigerators, leave standstill 12h and obtain clear and bright solution.

Momestasone furoate micropowder and H1 receptor antagonist or its clathrate/clathrate aqueous solution and water soluble adjuvant mix with gel solution after being mixed in and making suspension in the water, regulate pH value by prescription, and the water that replenishes surplus is to full dose.

Use Brookfiekl DV-III type rotating cylinder viscometer under room temperature (20 ℃) condition, to measure the rheological property of above-mentioned four prescriptions under different shear rate.The above-mentioned square everywhere increase viscosity along with shear rate presents downward trend in various degree, belongs to pseudoplastic fluid.

Cationic solution according to artificial nose liquid proportional preparation different ionic strength, embodiment 4-1 to 4-3 is mixed with it respectively, under different temperatures, measure viscosity, the result shows that critical phase transformation cation intensity all is less than or equal to the cation intensity of snotter, critical phase transition temperature is 25 ℃-33 ℃, the results are shown in Table 8.To mix with the phosphate buffer of different pH value according to 1: 1 ratio, and measure viscosity under different temperatures, the result shows that embodiment 4-4 is in pH5.5 place viscosity generation significant change, and critical phase transition temperature is 33.5 ℃.Under physiological condition, each preparation all presents good gelling property, uses separately with the environment sensitive type material that to compare gelation rate fast.

Pharmacology embodiment 1-1: test implementation example 1 gained preparation phase transformation cation concn

Preparation artificial nose liquid adopts to add sodium chloride 7.91g, sodium bicarbonate 2.56g in every 1000ml water.Potassium chloride 3.68g and calcium chloride 0.51g

Adopting above-mentioned electrolyte solution is standard artificial nose liquid, prepares the artificial nose liquid of different ionic strength in proportion, is 1 with the ionic strength of standard artificial nose liquid

32 ℃ of water-baths with the artificial nose liquid of the gel that obtains and different ionic strength volume mixture according to 1: 1, the ionic strength of the viscosity generation significant change critical phase transformation cation concn of ascending the throne,

Table 5, the critical phase transformation ionic strength of embodiment 1-1 to 1-4

	Embodiment 1-1	Embodiment 1-2	Embodiment 1-3	Embodiment 1-4
					Phase transformation cation intensity (with standard artificial nose liquid cation intensity rate)	0.9	0.9	0.5	?0.4

Pharmacology embodiment 1-2

Table 6: the critical phase transition temperature of embodiment 2-1 to 2-4 gained preparation

	Embodiment 1-1	Embodiment 1-2	Embodiment 1-3	Embodiment 1-4
					Phase transition temperature	29.5℃	26.9℃	30.7℃	28.2℃

Pharmacology embodiment 1-3

Table 7: embodiment 3-1 to 3-3 gained preparation critical phase change pH values

	Embodiment 3-1	Embodiment 3-2	Embodiment 3-3
				The phase change pH values	5.5	?5.2	5.4

Pharmacology embodiment 1-4

Table 8: the critical phase change conditions of embodiment 4-1 to 4-4 gained preparation

	Embodiment 1-1	Embodiment 1-2	Embodiment 1-3	Embodiment 1-4
					Phase transition temperature	26.6℃	33.0℃	30.8℃	?33.5℃
Phase transformation cation intensity (with standard artificial nose liquid cation intensity rate)	0.9	0.9	0.5
					The phase change pH values				?5.5

The research of pharmacology embodiment 2 medicine release in vitro behaviors

With reference to the dissolution determination three therapeutic methods of traditional Chinese medicine under two appendix XC of 2005 editions Pharmacopoeias of the People's Republic of China item, adopt the bag filter method to measure the dissolution of each preparation.Getting the foregoing description gained and be originally each 1ml of gel in bag filter, place in the stripping rotor, is dissolution medium with artificial nose mucus described in the pharmacology embodiment 1, and rotating speed is that per minute 25 changes, respectively at 5,15,30,45,60,90,120,180,240,360, the 480min sampling filters, filtrate is measured absorbance according to ultraviolet one visible spectrophotometry (appendix WA) at wavelength 235nm, calculates the cumulative release degree of medicine.The result shows that above-mentioned preparation all has slow release characteristic, and release reaches more than 80% behind the 3h.And all have the prominent phenomenon of releasing of medicine, this be since during gel gelling on the throne aqueous solution efflux.This feature helps medicine and reaches treatment concentration faster.

Pharmacology embodiment 3 cilium toxicity tests

Employing is the crocodile model on the body frog, and observation by light microscope cilium persistent movement time method is estimated the nasal ciliary toxicity of preparation.The frog is fixed, drip medicinal liquid in last palatine mucosa, flush away after contact a period of time separates mucosa and observes the ciliary movement situation.The result shows that the persistent movement time of nose cilium does not have significant change with after above-mentioned preparation contacts, and cilium comes off less, the mucosa complete form.Illustrate that preparation fibre-less toxicity or toxicity that the embodiment of the invention provides are less.

Pharmacology embodiment 4

Carry out the drug effect contrast by the pharmaceutical composition of this EXPERIMENTAL EXAMPLE proof technical solution of the present invention gained and the drug suspension or the solution of same effective ingredient.

Experiment medicine: chicken ovalbumin (OVA, U.S. Sigma company, V level), histamine (U.S. Sigma company).The preparation of adjuvant aluminium hydroxide: according to reaction equation (AlCl+NaOH (OH)+NaCl) be prepared.Product is through mixing, moisture aspirate and wash the aluminum hydroxide adjuvant that can obtain fresh preparation peptization state repeatedly.4% lignocaine (preparation voluntarily).

Modeling: according to Chinese document: ovalbumin per nasal sensitization is set up the allergic rhinitis animal model, and give birth to etc. the Kure, Chinese ENT ﹠ HN Surgery Dept. magazine the 40th the 3rd phase of volume of March in 2005,176～180; Disclosed sensitization, exciting method carry out modeling to positive controls, each experimental group and matched group respectively., simultaneously to negative control group, the normal saline that sprays into same amount in contrast.

Laboratory animal: 120 of adult Cavia porcelluss, body weight 500 ± 50g, male and female are not limit.Be divided into 12 groups, 10 every group.Grouping sees the following form with administration

Grouping	Administration
		Negative control group	Do not carry out modeling, adopt normal saline
Positive controls	After the modeling success, with the spray of normal saline nose
		Experimental group 1-1	Embodiment 1-1 makes pharmaceutical composition (momestasone furoate 0.05%, hydrochloric acid levocabastine 0.05%)
Experimental group 1-2	Embodiment 1-2 makes pharmaceutical composition (momestasone furoate 0.05%, A-5610 0.1%)
		Experimental group 2-1	Embodiment 2-1 makes pharmaceutical composition (momestasone furoate 0.05%, hydrochloric acid levocabastine 0.05%)
Experimental group 2-2	Embodiment 2-2 makes pharmaceutical composition (momestasone furoate 0.05%, A-5610 0.1%)
		Experimental group 3-1	Embodiment 3-1 makes pharmaceutical composition (momestasone furoate 0.05%, A-5610 0.1%)
Experimental group 3-2	Embodiment 3-2 makes pharmaceutical composition (momestasone furoate 0.05%, hydrochloric acid levocabastine 0.05%)
		Experimental group 4-1	Embodiment 4-1 makes pharmaceutical composition (momestasone furoate 0.05%, hydrochloric acid levocabastine 0.05%)
Experimental group 4-2	Embodiment 4-2 makes pharmaceutical composition (momestasone furoate 0.05%, A-5610 0.1%)
		Matched group 1	Suspension, (momestasone furoate 0.05%, hydrochloric acid levocabastine 0.05%)
Matched group 2	Suspension, (momestasone furoate 0.05%, A-5610 0.1%)

Matched group 1 is to the preparation of matched group 2 used control drug: adopt normal saline to add the momestasone furoate micropowder of recipe quantity respectively, and hydrochloric acid levocabastine inclusion complex in solution or A-5610, and add 1%HPMC as suspending agent, obtain corresponding suspension and organize administration in contrast.

Experimental technique:

After the sensitization the 5th day with 1% ovalbumin normal saline solution, every side nasal cavity 0.1-0.15ml excites, each treated animal in excite the back during 30min every by nasal-cavity administration 20 μ L (every nostril administration 10 μ L) during in first time administration, before the record administration, 10min after the administration, 30min, 2h, the respiratory frequency of Cavia porcellus during 4h, the positive controls physiologic saline for substitute, the interior animal of 30min is scratched nose after the record administration, the sneeze number of times, 30min after the administration, 2mm * 30mm filter paper bar is put into nasal cavity, wherein an end is kept somewhere 5min in the nasal cavity external fixation, takes out accurately weighing nasal secretion amount of back.。Date processing adopts the check of t in groups of SAS system.

Experimental result:

The influence of 1 pair of Cavia porcellus nasal secretion amount sees Table 1:

Compare with positive controls as can be seen from Table 9, each experimental group is compared with positive controls with the nasal secretion amount of matched group 1-2 all has significance (P＜0.01), and matched group 1-2 compares with each experimental group group and also has significance (P＜0.05), explanation is compared with the compound recipe of H1 receptor antagonist with the momestasone furoate of prior art, pharmaceutical composition provided by the invention can better suppress the secretions increase of Cavia porcellus nasal cavity, produces better therapeutic.

The influence of 2 pairs of Cavia porcellus sneeze number of times

As can be seen from Table 10, compare with positive controls, the animal sneeze of each experimental group and matched group 1-2 time number average has significance (P＜0.01), and matched group 1-2 compares with each experimental group and also has significance (P＜0.05).Illustrate that pharmaceutical composition provided by the invention compares the symptom that can better suppress the Cavia porcellus sneeze with momestasone furoate of the prior art with the compound recipe of H1 receptor antagonist, produce better therapeutic.

3 pairs of Cavia porcelluss are scratched the influence of nose number of times

As can be seen from Table 11, compare with positive controls, the animal of each experimental group and matched group 1-3 is scratched nose time number average and has significance (P＜0.01), and matched group 1-2 compares with each experimental group and also has significance (P＜0.05).Illustrating that pharmaceutical composition provided by the invention is compared with the compound recipe of H1 receptor antagonist with momestasone furoate of the prior art can better suppress the symptom that Cavia porcellus is scratched nose, produces better therapeutic.

4. to the influence of Cavia porcellus respiratory frequency

Because Cavia porcellus can only be used nasal respiration, therefore the decline of respiratory frequency can show the nasal obstruction degree of Cavia porcellus, as can be seen from Table 12, compare with positive controls, each experimental group is compared with positive controls with the frequency of respiration of matched group 1-3 all has significance (P＜0.01), and adopt the experimental group that the invention provides pharmaceutical composition to compare with matched group 1-2, at administration 30min with the interior Cavia porcellus respiratory frequency basically identical of respectively organizing, the alleviation degree that nasal obstruction is described is suitable, prolongation along with the time, the Cavia porcellus respiratory frequency of each experimental group is apparently higher than matched group (P＜0.05), illustrate that pharmaceutical composition provided by the invention can realize the continued treatment effect of longer time, and the therapeutic effect that finally reaches is also apparently higher than the matched group that adopts the prior art scheme.

Claims (10)

1. nasal in situ gel, being of its feature is by making as the water of acceptable auxiliary and surplus on effective ingredient momestasone furoate and/or its monohydrate, one or more H1 receptor antagonists, environment sensitive type hydrophilic gel material, other pharmaceutics.

2. nasal in situ gel as claimed in claim 1, the component that it is characterized in that described preparation consists of: momestasone furoate and/or its monohydrate 0.01-0.2%, the content of H1 receptor antagonist is 0.05%～1% environment sensitive type hydrophilic gel material 0.05-40%, acceptable auxiliary 0.01-50% on other pharmaceutics.

3. nasal in situ gel as claimed in claim 2; it is characterized in that described preparation is the ion-sensitive type gel; described ion-sensitive type hydrophilic gel material is selected from one or more the combination in deacetylation gellan gum, sodium alginate, welan gum, the carrageenan; the concentration of deacetylation gellan gum is 0.05-2%; the concentration of carrageenan is 0.3-8%; the concentration of welan gum is 0.1-10%, and the concentration of sodium alginate is 0.2-9%.

4. nasal in situ gel as claimed in claim 2, it is characterized in that described preparation is the responsive to temperature type gel, described responsive to temperature type hydrophilic gel material is selected from poloxamer 407, poloxamer 188, methylcellulose, polyethylene glycol-lactic acid block copolymer (PEG-PLGA); In N-N-isopropylacrylamide (NiPAAM) copolymer, ethylhydroxyethylcellulose (EHEC) or the xylan one or both and two or more combinations thereof, the concentration of poloxamer 407 is 12-40%, the concentration of poloxamer 188 is 5-30%, and the concentration of methylcellulose is 1-10%.The concentration of NiPAAM copolymer is 20-40%, and the concentration of PEG-PLGA is 15-40%, and the concentration of EHEC is 0.1-2%.

5. nasal in situ gel as claimed in claim 2, it is characterized in that described preparation is a pH responsive type gel, the hydrophilic gel material of described pH sensitivity is selected from cellulose acetate phthalate ester (CAP), carbomer, the combination in any of one or more in polyethylene acetal diethylamine acetate (AEA), the chitosan, wherein the concentration of CAP is 10-40%, the concentration of carbomer is 0.1-2.0%, the concentration of chitosan is 1-10%, and the pH value of described pH responsive type gel is adjusted to 3.5-5.0.

6. nasal in situ gel as claimed in claim 2, the described preparation of its feature is the mixed type gel, described mixed type hydrophilic gel material is the two or more combination in any of responsive to temperature type, pH responsive type, ion-sensitive type macromolecular material.

7. as arbitrary described nasal in situ gel in the claim 1 to 8, it is characterized in that described pharmaceutically useful adjuvant also comprises osmotic pressure regulator, one or more in gel regulator antiseptic pH regulator agent suspending agent, the wetting agent, and excess water.

8. as the arbitrary described nasal in situ gel of claim 1 to 19, it is characterized in that described H1 receptor antagonist is selected from one or more in chlorphenamine, hydroxyzine, diphenhydramine, teldane, astemizole, loratadine, alerlisin, acrivastine, emedastine, ketotifen, plug Lip river imidazoles, azelastine, ebastine, levocabastine, Primalan, Desloratadine, olopatadine, left alerlisin and pharmaceutically useful salt thereof, ester, the optical isomer, consumption preferred 0.05%～0.5%.

9. nasal in situ gel as claimed in claim 21 is characterized in that preferred water-soluble azelastine of described H1 receptor antagonist and pharmaceutically useful salt thereof, ester.

10. as claim 21 or 20 described nasal in situ gel, it is characterized in that not soluble in waterly in the described H1 receptor antagonist can being beta-schardinger dextrin-or derivatives thereof institute enclose.