CN109288790A - Nasal pharmaceutical composition and preparation method thereof - Google Patents

Nasal pharmaceutical composition and preparation method thereof Download PDF

Info

Publication number
CN109288790A
CN109288790A CN201710610100.XA CN201710610100A CN109288790A CN 109288790 A CN109288790 A CN 109288790A CN 201710610100 A CN201710610100 A CN 201710610100A CN 109288790 A CN109288790 A CN 109288790A
Authority
CN
China
Prior art keywords
preservative
pharmaceutical composition
suspension
accounts
nasal pharmaceutical
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
Application number
CN201710610100.XA
Other languages
Chinese (zh)
Inventor
孙培坚
陈伯亮
丁美雪
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
SYNMOSA BIOPHARMA CORP
Original Assignee
SYNMOSA BIOPHARMA CORP
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by SYNMOSA BIOPHARMA CORP filed Critical SYNMOSA BIOPHARMA CORP
Priority to CN201710610100.XA priority Critical patent/CN109288790A/en
Publication of CN109288790A publication Critical patent/CN109288790A/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/0048—Eye, e.g. artificial tears
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4174—Arylalkylimidazoles, e.g. oxymetazolin, naphazoline, miconazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/56—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids
    • A61K31/57—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone
    • A61K31/573—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids substituted in position 17 beta by a chain of two carbon atoms, e.g. pregnane or progesterone substituted in position 21, e.g. cortisone, dexamethasone, prednisone or aldosterone
    • 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
    • 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
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • A61K9/10—Dispersions; Emulsions

Abstract

The present invention provides a kind of nasal medicine product or preparation, wherein the drug products or preparation and does not include surfactant.

Description

Nasal pharmaceutical composition and preparation method thereof
Technical field
The present invention relates to a kind of nasal pharmaceutical compositions, cure in particular to a kind of nose without surfactant Drug composition.
Background technique
It in general, can be by water-soluble active drug ingredient (water- when preparing the suspension of nasal pharmaceutical composition Soluble API) it is mixed in advance with other excipient (such as suspending agent, preservative, osmotic pressure regulator etc.), and be mixed into simultaneously Surfactant, and then mixed with liposoluble active drug ingedient (liposoluble API), carry out the operation that homogenizes.Separately Outside, to ask preparation method quick and convenient, also there is selection that above-mentioned each ingredient is done disposable mixing, what is homogenized together does Method.
However, resulting finished product was stood in the short time (about 24 hours) in the preparation of nasal pharmaceutical composition suspension Afterwards, it often will appear lamination, people of causing a disease is in use, can not obtain identical absorbent for different activities drug ingedient Amount, causes the problem in curative effect.
In addition, the surfactant used in above-mentioned preparation method, due to for artificial chemicals, when a large amount of It is bound to cause the impact to environment when production, while improving dealer's cost.And patient's nasal cavity may cause due to chemicals Excitement can also reduce patient's medication wish.Very or, part of the surface activating agent has in drug solution promotes active ingredient The disadvantage of chemical degradation.
Summary of the invention
The present invention relates to drug, formulation chemist and area of pharmacology.The present invention relates to for pre- hypo-allergenic, inflammatory response or It is allowed to the drug products slowed down or preparation.Specifically, but without limitation, the present invention relates to nasal pharmaceutical compositions.The present invention Being related to treatment includes symptom related with angiokinesis and/or the related symptom of rhinovirus, viral respiratory infection (" VRTI ") or the infection of the upper respiratory tract (" URI ").The present invention relates to the symptom for the treatment of including but not limited to seasonality or perennially Rhinitis, seasonality or long-term membranous conjunctivitis, hay fever, nasal obstruction, sneezing, bronchus hyperemia, edema oculi, headache, rhinorrhea, sense The symptoms such as emit.
The invention discloses preferred embodiment may include antihistamine or one or more its is medically acceptable It is or mixtures thereof salt, solvate, prodrug and steroid compound or its one or more medically acceptable salt, molten Or mixtures thereof object, prodrug are closed in agent；It can be stable aqueous solution or aqueous suspensions；It can be inhalation solution, spray, pressurized aerosol Agent, the form use for the inhalation aerosol that quantitatively pressurizes；In particularly preferred embodiments, with spray (preferably nasal spray) Form use.For example, the spray can be formed by using conventional spray-squeeze bottle or pump vaporizer.In addition, may be used also To use compressed gas aerosol.
The invention discloses preferred embodiment may include liposoluble active drug ingedient or its one or more medicine Or mixtures thereof upper acceptable salt, solvate, prodrug and water-soluble active drug ingredient or its one or more medicine Or mixtures thereof upper acceptable salt, solvate, prodrug；It is preferred that the liposoluble active drug ingedient is steroid compound, The water-soluble active drug ingredient is antihistamine.Preferred embodiment can form stable aqueous solution or aqueous suspensions；It can be The form use of inhalation solution, spray, pressurised aerosol, the inhalation aerosol that quantitatively pressurizes；In particularly preferred embodiment In, it is used in the form of spray (preferably nasal spray).For example, the spray can by using conventional spray-squeeze bottle or Vaporizer is pumped to be formed.Further, it is also possible to use compressed gas aerosol.The compressed gas preferred fluorinated gas, more preferably not Fluorinated gas containing chlorine.
This exposure purpose is to provide a kind of nasal pharmaceutical composition, for uniformly not stratified compound suspension.However, base In the total weight of compound suspension, this exposure tolerable contains the surfactant no more than 0.0005% (w/v).Preferably, Compound suspension is free of surfactant.
This exposure purpose is to provide a kind of medical composition without surfactant, especially nasal pharmaceutical composition, It can have extremely low irritation and/or extremely low taste beastly, such as bitter taste；Or its is nonirritant and/or not With taste beastly.
This exposure purpose is to provide a kind of medical composition without surfactant, especially nasal pharmaceutical composition, The medical composition is uniformly not stratified compound suspension；Detailed description is outstanding for stable and uniformly not stratified compound Supernatant liquid；It further explains, can be reserved for and maintains at least one moon uniform and not stratified state；Or it can be reserved for and maintains At least three moon uniform and not stratified state；Or it can be reserved for and maintains at least six moon uniform and not stratified state.
An embodiment according to the present invention, provides a kind of nasal pharmaceutical composition, comprising: liposoluble active drug at Point, it accounts for 0.01-1.5% (w/v), preferably 0.02-1.0% (w/v), more preferably 0.03-0.8% (w/v)；Suspending agent accounts for 0.5-3.0% (w/v), preferably 0.75-2.0% (w/v), more preferably 1.0-1.5% (w/v)；Preservative accounts for 0.004- 0.54% (w/v), preferably 0.008-0.42% (w/v), more preferably 0.009-0.315% (w/v)；And water-soluble active Drug ingedient accounts for 0.001-2.0% (w/v), preferably 0.01-1.0% (w/v), more preferably 0.05-0.5% (w/v), In in the nasal pharmaceutical composition, and do not include surfactant.
An embodiment according to the present invention, wherein added by preservative can for one, two, three or Determination of Preservatives or It is mixed.
Another target of this exposure is to provide a kind of method for preparing the nasal pharmaceutical composition without surfactant.
Another target of this exposure is to provide a kind of method for preparing the medical composition without surfactant, especially Prepare nasal pharmaceutical composition；This method is the uniform not stratified compound suspension of preparation；Detailed description is free of for preparation Surfactant and stabilization, uniform not stratified compound suspension；It further explains, obtained by the preparation method according to this exposure Compound suspension can be reserved for and maintain at least one moon uniform and not stratified state；Or it can be reserved for and maintains at least three moon Uniform and not stratified state；Or it can be reserved for and maintains at least six moon uniform and not stratified state.
This exposure purpose is to provide a kind of method for preparing the medical composition without surfactant, especially prepares nose Use medical composition；It can have extremely low irritation and/or extremely low taste beastly, such as bitter taste；Or its nothing Irritation and/or do not have taste beastly.
An embodiment according to the present invention, provides a kind of preparation method of nasal pharmaceutical composition, comprising: mixing rouge Insoluble active drug ingedient and suspending agent, and stir evenly, with formulated suspension；The first preservative is added in the suspension, And it stirs evenly；The second preservative is added in the suspension, and is stirred evenly；And addition water-soluble active drug ingredient in It in the suspension, and stirs evenly, to prepare nasal pharmaceutical composition, wherein it is living not add surface in the preparation method Property agent.
An embodiment according to the present invention, provides a kind of nasal pharmaceutical composition, as obtained by following method: mixing Liposoluble active drug ingedient and suspending agent, and stir evenly, with formulated suspension；The first preservative is added in the suspension In, and stir evenly；The second preservative is added in the suspension, and is stirred evenly；And addition water-soluble active drug at Divide in the suspension, and stir evenly, to prepare nasal pharmaceutical composition, wherein it is living not add surface in this method Property agent.
In one embodiment of the invention, a kind of nasal pharmaceutical composition is provided, as obtained by following method:
A) by liposoluble active dry powder drug and suspending agent dry powder, after being sufficiently mixed uniformly, it is configured to aqueous suspension A；
B) the first aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension A to form aqueous suspension B；
C) the second aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension B to form aqueous suspension C；
D) addition water-soluble active drug aqueous solution is sufficiently mixed uniformly to aqueous suspension C to form aqueous suspension D；
E) dosage form is made in aqueous suspension D.
In one embodiment of the invention, a kind of nasal pharmaceutical composition is provided, as obtained by following method:
A) it by liposoluble active drug and suspending agent, is sufficiently mixed uniformly into aqueous suspension A；
B) the first aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension A to form aqueous suspension B；
C) the second aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension B to form aqueous suspension C；
D) addition water-soluble active drug aqueous solution is sufficiently mixed uniformly to aqueous suspension C to form aqueous suspension D；
E) dosage form is made in aqueous suspension D.
In one embodiment of the invention, a kind of nasal pharmaceutical composition is provided, as obtained by following method:
A) it by liposoluble active drug and suspending agent, is sufficiently mixed uniformly into aqueous suspension A；
B) the first aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension A to form aqueous suspension B；
C) addition the second preservative of mixing and the aqueous solution of osmotic pressure regulator are sufficiently mixed uniformly to aqueous suspension B To form aqueous suspension C；
D) addition water-soluble active drug aqueous solution is sufficiently mixed uniformly to aqueous suspension C to form aqueous suspension D；
E) dosage form is made in aqueous suspension D.
In one embodiment of the invention, a kind of nasal pharmaceutical composition is provided, as obtained by following method:
A) it by liposoluble active drug and suspending agent, is sufficiently mixed uniformly into aqueous suspension A；
B) the first aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension A to form aqueous suspension B；
C) addition the second preservative of mixing and the aqueous solution of osmotic pressure regulator are sufficiently mixed uniformly to aqueous suspension B To form aqueous suspension C；
D) aqueous solution of addition mixing water-soluble active drug, chelating agent and sweetener is sufficiently mixed to aqueous suspension C Uniformly to form aqueous suspension D；
E) dosage form is made in aqueous suspension D.
In one embodiment of the invention, a kind of nasal pharmaceutical composition is provided, as obtained by following method:
A) by liposoluble active dry powder drug and suspending agent dry powder, after being sufficiently mixed uniformly, then it is configured to aqueous suspension A；
B) the first aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension A to form aqueous suspension B；
C) addition the second preservative of mixing and the aqueous solution of osmotic pressure regulator are sufficiently mixed uniformly to aqueous suspension B To form aqueous suspension C；
D) aqueous solution of addition mixing water-soluble active drug, chelating agent and sweetener is sufficiently mixed to aqueous suspension C Uniformly to form aqueous suspension D；
E) dosage form is made in aqueous suspension D.
In one embodiment of the invention, wherein the first preservative with the second preservative can be identical or different；The One preservative and the second preservative also may respectively be one, two Determination of Preservatives or its mix.
In one embodiment of the invention, a kind of nasal pharmaceutical composition is provided, wherein made by aqueous suspension D Dosage form is that aqueous suspension D is fills up in medicinal cupping.Wherein the medicinal cupping can for high-density polyethylene bottle, metal bottle or include appoint The plastic bottle of which kind of class plated film.
In one embodiment of the invention, a kind of nasal pharmaceutical composition is provided, wherein made by aqueous suspension D Dosage form may include being fills up to aqueous suspension D in tank, bottle or any kind of closed or semi-hermetic container；Or it is fills up to Contain or does not contain in medicinal cupping, medicine bottle or any form, type, the drug container of size of valve member by spraying.The wherein spray valve Part can provide quantitative pharmacy use.
In the preparation method of this exposure, liposoluble active drug ingedient (liposoluble API) and suspending agent system with The form of dry powder is mutually mixed, in this way, the uniformly dispersed of liposoluble active drug ingedient can effectively be promoted.After adding preservative, By mixer means, it can avoid bubble and generate, liposoluble active drug ingedient can also be made to remain good evenly dispersed.This exposure It can avoid liposoluble active drug in the way of final step addition water-soluble active drug ingredient (water-soluble API) Both ingredient and water-soluble active drug ingredient generated chemistry Competition when adding simultaneously, to ensure that finished product uniformly divides It dissipates, lamination will not be presented.In the preparation method of this exposure, each ingredient passes through agitating mode after each step is mutually mixed Make it up to the degree that is sufficiently mixed, and then carry out mutually mixing for next step, so, it can be ensured that each ingredient added by the process Fine dispersion effect can be all maintained, final finished is made to be unlikely to generate layering.
In the preparation method of this exposure, water-soluble active drug ingredient tie up to one or more preservatives be added to it is fat-soluble Active pharmaceutical ingredient is simultaneously just mutually mixed with the liposoluble active medicinal mixture after mixing, in this way, can avoid liposoluble active Both drug ingedient and water-soluble active drug ingredient generated chemistry Competition when adding simultaneously, to ensure that finished product is uniform Dispersion, will not be presented lamination.
When patient's not stratified medical composition uniform using this exposures, since two kinds of active pharmaceutical ingredients have reached sufficiently Admixture, therefore, patient can be in the dosage absorbed in the same time for two kinds of active pharmaceutical ingredients it is identical, such as This, it can be ensured that the drug safety of patient avoids causing the problem in curative effect because of absorbed dose unevenness.
For above-mentioned purpose, feature and the advantage of this exposure can be clearer and more comprehensible, several embodiments are cited below particularly, make detailed It is described as follows.
Embodiment
An embodiment according to the present invention, provides a kind of nasal pharmaceutical composition, comprising: liposoluble active drug at Point, it accounts for 0.01-1.5% (w/v), preferably 0.02-1.0% (w/v), more preferably 0.03-0.8% (w/v)；Suspending agent accounts for 0.5-3.0% (w/v), preferably 0.75-2.0% (w/v), more preferably 1.0-1.5% (w/v)；Preservative accounts for 0.004- 0.54% (w/v), preferably 0.008-0.42% (w/v), more preferably 0.009-0.315% (w/v)；And water-soluble active Drug ingedient accounts for 0.001-2% (w/v), preferably 0.01-1.0% (w/v), more preferably 0.05-0.5% (w/v), wherein In the nasal pharmaceutical composition, and surfactant is not included.
In pharmaceutical preparation or product, product, each component dose is the total weight (w/ that final product is accounted for each formulation ingredients V% it) counts.
In certain embodiments, above-mentioned liposoluble active drug ingedient can be steroid compound.
In certain embodiments, above-mentioned steroid compound may include flunisolide (flunisolide), fluticasone (fluticasone), Mometasone (mometasone), beclomethasone (beclomethasone), fluticasone furoate (fluticasone furoate), song An Nai get (triamcinolone), budesonide (budesonide), prednisone (prednisone) or mixtures thereof any or in ciclesonide (ciclesonide).
In certain embodiments, above-mentioned suspending agent includes but is not limited to cellulose (cellulose) derivative, crystallite fibre Tie up element (microcrystalline cellulose), methylcellulose (methyl cellulose), sodium carboxymethylcellulose (carboxymethyl cellulose sodium), hydroxypropyl methyl cellulose (hydroxypropylmethylcellulose), gelatin (gelatin), polyvinylpyrrolidone (polyvinylpyrrolidone), bassora gum (tragacanth), alginic acid (alginic acid), polyvinyl alcohol Or mixtures thereof (polyvinyl alcohol), polyacrylic acid (polyacrylic acid), pectin (pectin) etc..If These substances contain corresponding acid, alkali foundation group, and pharmaceutically acceptable salt also can be used.It is preferred that above-mentioned suspending agent is crystallite Cellulose (microcrystalline cellulose) and sodium carboxymethylcellulose (carboxymethyl cellulose Sodium combination) orRC591。
In certain embodiments, preservative may include benzyl carbinol (phenylethyl alcohol), ethylenediamine tetra-acetic acid (ethylene diamine tetra-acetic acid or edetic acid) or its esters (such as disodium salt, calcium salt, calcium Sodium salt), alkyl paraben (alkyl p-hydroxybenzoates), Chlorhexidine (chlorhexidine) (such as The form of acetate or gluconate), Phenylmercuric Borate (phenyl mercury borate) or quaternary ammonium compounds, such as Pyrisept (cetylpyridinium chloride), tetradecyltrimethylammonium bromide (tetradecyltrimethyl ammonium bromide, commonly referred to as cetrimonium bromide (cetrimide)), benzethonium chloride (benzethonium chloride), myristyl picoline chloride (myristyl picolinium ) or the mixture of benzalkonium chloride (benzalkonium chloride) compound or foregoing preservatives chloride.
An embodiment according to the present invention, wherein added by preservative can for one, two, three or Determination of Preservatives or Its mixture.
In certain embodiments, above-mentioned water-soluble active drug ingredient can be antihistaminic compound.
In certain embodiments, above-mentioned antihistaminic compound may include azelastine (azelastine), Ao Luota Fixed (olopatadine), Xylometazoline (xylometazoline), Acrivastine (acrivastine), carbinoxamine (carbinoxamine), chlorphenamine (chlorpheniramine), cyproheptadine (cyproheptadine), astemizole (astemizole), cetirizine (cetirizine), Loratadine (loratadine), Mizolastine (mizolastine), It is RMI 9918 (terfenadine), levocabastine (levocabastine), Desloratadine (desloratadine), non- It is or mixtures thereof any in Fexofenadine (fexofenadine) or levocetirizine (levocetirizine).
In certain embodiments, the nasal pharmaceutical composition of this exposure further includes osmotic pressure regulator, chelating agent or sweet tea Taste agent.
In certain embodiments, osmotic pressure regulator includes but is not limited to sucrose, glucose, glycerol, D-sorbite, 1, The isotonic agent of 2- propylene glycol or sodium chloride etc..The purpose of osmotic pressure regulator is for the osmotic pressure of preparation to be adjusted to be secreted with nose Environment is identical.For this purpose, the dosage that these substances are used for solution in each case should can make this compared with pure water Solution is about 0.50 to 0.56 DEG C low compared with the freezing point of pure water.
In certain embodiments, above-mentioned osmotic pressure regulator accounts for about 0.5-4.0% (w/v), preferably 1.0-3.5% (w/v), more preferably 2.0-3.0% (w/v).
In certain embodiments, above-mentioned chelating agent may include but be not limited to ethylenediamine tetra-acetic acid (EDTA).
In certain embodiments, above-mentioned chelating agent accounts for about 0.001-0.2% (w/v), preferably 0.005-0.1% (w/v), more preferably 0.01-0.05% (w/v).
In certain embodiments, above-mentioned sweetener may include Sucralose (sucralose), thaumatin (thaumatin), caffeine (caffeine), Aspartame (aspartame), sucrose (sucrose), saccharin (saccharin), fructose (fructose), corn syrup (corn syrup), xylitol (xylitol), ammonium glycyrrhetate (ammonium glycyrrhizinate) or mannitol (mannitol) or other natural or artificial flavors or flavouring agent or its Mixture.
In certain embodiments, above-mentioned sweetener accounts for about 0.03-0.24% (w/v), preferably 0.08-0.2% (w/ V), more preferably 0.1-0.18% (w/v).
In certain embodiments, buffer, such as citric acid/sodium bisulfate borate can also be added in said preparation Buffer, phosphate (sodium hydroxide, disodium hydrogen phosphate) buffer, tromethamine buffer or the buffering with identity function Liquid, so that said preparation pH-value is adjusted to 3 to 7, preferably 4.5 to 6.8, more preferably 5.5 to 6.5.
In certain embodiments, the nasal pharmaceutical composition of this exposure can be suspension, preferably aqueous suspension.
An embodiment according to the present invention, provides a kind of preparation method of nasal pharmaceutical composition, comprising: mixing rouge Insoluble active drug ingedient and suspending agent, and stir evenly, with formulated suspension；The first preservative is added in the suspension, And it stirs evenly；The second preservative is added in the suspension, and is stirred evenly；And addition water-soluble active drug ingredient in It in the suspension, and stirs evenly, to prepare nasal pharmaceutical composition, wherein it is living not add surface in the preparation method Property agent.
An embodiment according to the present invention, provides a kind of nasal pharmaceutical composition, as obtained by following method:
A) by liposoluble active dry powder drug and suspending agent dry powder, after being sufficiently mixed uniformly, it is configured to aqueous suspension A；
B) the first aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension A to form aqueous suspension B；
C) the second aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension B to form aqueous suspension C；
D) addition water-soluble active drug aqueous solution is sufficiently mixed uniformly to aqueous suspension C to form aqueous suspension D；
E) dosage form is made in aqueous suspension D.
An embodiment according to the present invention, provides a kind of nasal pharmaceutical composition, as obtained by following method:
A) it by liposoluble active dry powder drug and suspending agent dry powder, is sufficiently mixed uniformly, is configured to aqueous suspension A；
B) the first aqueous preservative solution of addition is sufficiently mixed uniformly to aqueous suspension A to form aqueous suspension B；
C) addition the second preservative of mixing and the aqueous solution of osmotic pressure regulator are sufficiently mixed uniformly to aqueous suspension B To form aqueous suspension C；
D) aqueous solution of addition mixing water-soluble active drug, chelating agent and sweetener is sufficiently mixed to aqueous suspension C Uniformly to form aqueous suspension D；
E) dosage form is made in aqueous suspension D.
In certain embodiments, after above-mentioned liposoluble active drug ingedient mixes in dry powder form with above-mentioned suspending agent system It is configured to solution again.
In certain embodiments, above-mentioned liposoluble active drug ingedient may include flunisolide (flunisolide), fluorine For Kathon CG (fluticasone), Mometasone (mometasone), beclomethasone (beclomethasone), fluticasone furoate (fluticasone furoate), song An Nai get (triamcinolone), budesonide (budesonide), prednisone (prednisone) or mixtures thereof any or in ciclesonide (ciclesonide).
In certain embodiments, above-mentioned liposoluble active drug ingedient accounts for about 0.01-1.5% (w/v), preferably 0.02-1.0% (w/v), more preferably 0.03-0.8% (w/v).
In certain embodiments, above-mentioned suspending agent may include but be not limited to cellulose (cellulose) derivative, crystallite Cellulose (microcrystalline cellulose), methylcellulose (methyl cellulose), carboxymethyl cellulose Sodium (carboxymethyl cellulose sodium), hydroxypropyl methyl cellulose (hydroxypropylmethylcellulose), gelatin (gelatin), polyvinylpyrrolidone (polyvinylpyrrolidone), bassora gum (tragacanth), alginic acid (alginic acid), polyvinyl alcohol Or mixtures thereof (polyvinyl alcohol), polyacrylic acid (polyacrylic acid), pectin (pectin) etc..If These substances contain corresponding acid, alkali foundation group, and pharmaceutically acceptable salt also can be used.
In certain embodiments, above-mentioned suspending agent accounts for about 0.5-3.0% (w/v), preferably 0.75-2.0% (w/ V), more preferably 1.0-1.5% (w/v).
In certain embodiments, above-mentioned first preservative may include benzyl carbinol (phenylethyl alcohol), second two Amine tetraacethyl (ethylene diamine tetra-acetic acid or edetic acid) or its esters (such as disodium salt, Calcium salt, calcium disodium), alkyl paraben (alkyl p-hydroxybenzoates), Chlorhexidine (chlorhexidine) (such as form of acetate or gluconate), Phenylmercuric Borate (phenyl mercury ) or quaternary ammonium compounds, such as pyrisept (cetylpyridinium chloride), ten borate Tetraalkyl trimethylammonium bromide (tetradecyltrimethyl ammonium bromide, commonly referred to as cetrimonium bromide (cetrimide)), benzethonium chloride (benzethonium chloride), myristyl picoline chloride (myristyl picolinium chloride) or benzalkonium chloride (benzalkonium chloride) compound are above-mentioned anti- The mixture of rotten agent.
In certain embodiments, above-mentioned first preservative accounts for about 0.002-0.04% (w/v), preferably 0.004- 0.02% (w/v), more preferably 0.0045-0.015% (w/v).
In certain embodiments, above-mentioned second preservative may include benzyl carbinol (phenylethyl alcohol), second two Amine tetraacethyl (ethylene diamine tetra-acetic acid or edetic acid) or its esters (such as disodium salt, Calcium salt, calcium disodium), alkyl paraben (alkyl p-hydroxybenzoates), Chlorhexidine (chlorhexidine) (such as form of acetate or gluconate), Phenylmercuric Borate (phenyl mercury ) or quaternary ammonium compounds, such as pyrisept (cetylpyridinium chloride), ten borate Tetraalkyl trimethylammonium bromide (tetradecyltrimethyl ammonium bromide, commonly referred to as cetrimonium bromide (cetrimide)), benzethonium chloride (benzethonium chloride), myristyl picoline chloride (myristyl picolinium chloride) or benzalkonium chloride (benzalkonium chloride) compound are above-mentioned anti- The mixture of rotten agent.
In certain embodiments, above-mentioned second preservative accounts for about 0.002-0.5% (w/v), preferably 0.004- 0.4% (w/v), more preferably 0.0045-0.3% (w/v).
In certain embodiments, the preparation method of this exposure nasal pharmaceutical composition is further included, in addition above-mentioned second Preservative mixes above-mentioned second preservative and osmotic pressure regulator before above-mentioned suspension, and stirs evenly.
In certain embodiments, above-mentioned osmotic pressure regulator may include sucrose, glucose, glycerol, D-sorbite, 1,2- The isotonic agent of propylene glycol or sodium chloride etc..
In certain embodiments, above-mentioned osmotic pressure regulator accounts for about 0.5-4.0% (w/v), preferably 1.0-3.5% (w/v), more preferably 2.0-3.0% (w/v).
In certain embodiments, above-mentioned water-soluble active drug ingredient may include above-mentioned antihistaminic compound, this is anti- Group aminated compounds may include azelastine (azelastine), olopatadine (olopatadine), Xylometazoline (xylometazoline), Acrivastine (acrivastine), carbinoxamine (carbinoxamine), chlorphenamine (chlorpheniramine), cyproheptadine (cyproheptadine), astemizole (astemizole), cetirizine (cetirizine), Loratadine (loratadine), Mizolastine (mizolastine), RMI 9918 (terfenadine), levocabastine (levocabastine), Desloratadine (desloratadine), fexofenadine (fexofenadine) or mixtures thereof any or in levocetirizine (levocetirizine).
In certain embodiments, above-mentioned water-soluble active drug ingredient accounts for about 0.001-2.0% (w/v), preferably 0.01-1.0% (w/v), more preferably 0.05-0.5% (w/v).
In certain embodiments, the preparation method of this exposure nasal pharmaceutical composition is further included, above-mentioned water-soluble in adding Property active pharmaceutical ingredient mixes above-mentioned water-soluble active drug ingredient, chelating agent and sweetener before above-mentioned suspension, and stirs It mixes uniformly.
In certain embodiments, above-mentioned chelating agent may include but be not limited to ethylenediamine tetra-acetic acid (EDTA).
In certain embodiments, above-mentioned chelating agent accounts for about 0.001-0.2% (w/v), preferably 0.005-0.1% (w/v), more preferably 0.01-0.05% (w/v).
In certain embodiments, above-mentioned sweetener may include Sucralose (sucralose), thaumatin (thaumatin), caffeine (caffeine), Aspartame (aspartame), sucrose (sucrose), saccharin (saccharin), fructose (fructose), corn syrup (corn syrup), xylitol (xylitol), ammonium glycyrrhetate (ammonium glycyrrhizinate) or mannitol (mannitol) or other natural or artificial flavors or flavouring agent or its Mixture.
In certain embodiments, above-mentioned sweetener accounts for about 0.03-0.24% (w/v), preferably 0.08-0.2% (w/ V), more preferably 0.1-0.18% (w/v).
An embodiment according to the present invention, provides a kind of nasal pharmaceutical composition, as obtained by following method: mixing Liposoluble active drug ingedient and suspending agent, and stir evenly, with formulated suspension；The first preservative is added in the suspension In, and stir evenly；The second preservative is added in the suspension, and is stirred evenly；And addition water-soluble active drug at Divide in the suspension, and stir evenly, to prepare nasal pharmaceutical composition, wherein it is living not add surface in this method Property agent.
In certain embodiments, above-mentioned liposoluble active drug ingedient can mix in dry powder form with above-mentioned suspending agent.
In certain embodiments, above-mentioned liposoluble active drug ingedient may include flunisolide (flunisolide), fluorine For Kathon CG (fluticasone), Mometasone (mometasone), beclomethasone (beclomethasone), fluticasone furoate (fluticasone furoate), song An Nai get (triamcinolone), budesonide (budesonide), prednisone (prednisone) or ciclesonide (ciclesonide) etc..
In certain embodiments, above-mentioned liposoluble active drug ingedient accounts for about 0.01-1.5% (w/v), preferably 0.02-1% (w/v), more preferably 0.03-0.8% (w/v).
In certain embodiments, above-mentioned suspending agent may include microcrystalline cellulose (microcrystalline Cellulose) with the combination of sodium carboxymethylcellulose (carboxymethyl cellulose sodium) or RC591。
In certain embodiments, above-mentioned suspending agent is accounted for about 0.5-3.0% (w/v), preferably 0.75-2% (w/v), More preferably 1-1.5% (w/v).
In certain embodiments, above-mentioned first preservative may include benzyl carbinol (phenylethyl alcohol), second two Amine tetraacethyl (ethylene diamine tetra-acetic acid or edetic acid) or its esters (such as disodium salt, Calcium salt, calcium disodium), alkyl paraben (alkyl p-hydroxybenzoates), Chlorhexidine (chlorhexidine) (such as form of acetate or gluconate), Phenylmercuric Borate (phenyl mercury ) or quaternary ammonium compounds, such as pyrisept (cetylpyridinium chloride), ten borate Tetraalkyl trimethylammonium bromide (tetradecyltrimethyl ammonium bromide, commonly referred to as cetrimonium bromide (cetrimide)), benzethonium chloride (benzethonium chloride), myristyl picoline chloride (myristyl picolinium chloride) or benzalkonium chloride (benzalkonium chloride) compound are above-mentioned anti- The mixture of rotten agent.
In certain embodiments, above-mentioned first preservative accounts for about 0.002-0.04% (w/v), preferably 0.004- 0.02% (w/v), more preferably 0.0045-0.015% (w/v).
In certain embodiments, above-mentioned second preservative may include benzyl carbinol (phenylethyl alcohol), second two Amine tetraacethyl (ethylene diamine tetra-acetic acid or edetic acid) or its esters (such as disodium salt, Calcium salt, calcium disodium), alkyl paraben (alkyl p-hydroxybenzoates), Chlorhexidine (chlorhexidine) (such as form of acetate or gluconate), Phenylmercuric Borate (phenyl mercury ) or quaternary ammonium compounds, such as pyrisept (cetylpyridinium chloride), ten borate Tetraalkyl trimethylammonium bromide (tetradecyltrimethyl ammonium bromide, commonly referred to as cetrimonium bromide (cetrimide)), benzethonium chloride (benzethonium chloride), myristyl picoline chloride (myristyl picolinium chloride) or benzalkonium chloride (benzalkonium chloride) compound are above-mentioned anti- The mixture of rotten agent.
In certain embodiments, above-mentioned second preservative accounts for about 0.002-0.5% (w/v), preferably 0.004- 0.4% (w/v), more preferably 0.0045-0.3% (w/v).
In one embodiment of the invention, wherein the first preservative with the second preservative can be identical or different；The One preservative and the second preservative also may respectively be or mixtures thereof one, two or Determination of Preservatives.
In certain embodiments, the preparation method of this exposure nasal pharmaceutical composition is further included, in addition above-mentioned second Preservative mixes above-mentioned second preservative and osmotic pressure regulator before above-mentioned suspension, and stirs evenly.
In certain embodiments, above-mentioned osmotic pressure regulator may include sucrose, glucose, glycerol, D-sorbite, 1,2- The isotonic agent of propylene glycol or sodium chloride etc..
In certain embodiments, above-mentioned osmotic pressure regulator accounts for about 0.5-4.0%, preferably 1.0-3.5% (w/ V), more preferably 2.0-3.0% (w/v).
In certain embodiments, above-mentioned water-soluble active drug ingredient may include azelastine (azelastine), Austria Luo Tading (olopatadine), Xylometazoline (xylometazoline), Acrivastine (acrivastine), carbinoxamine (carbinoxamine), chlorphenamine (chlorpheniramine), cyproheptadine (cyproheptadine), astemizole (astemizole), cetirizine (cetirizine), Loratadine (loratadine), Mizolastine (mizolastine), It is RMI 9918 (terfenadine), levocabastine (levocabastine), Desloratadine (desloratadine), non- It is or mixtures thereof any in Fexofenadine (fexofenadine) or levocetirizine (levocetirizine).
In certain embodiments, above-mentioned water-soluble active drug ingredient accounts for about 0.001-2.0% (w/v), preferably 0.01-1.0% (w/v), more preferably 0.05-0.5% (w/v).
In certain embodiments, the preparation method of this exposure nasal pharmaceutical composition is further included, above-mentioned water-soluble in adding Property active pharmaceutical ingredient mixes above-mentioned water-soluble active drug ingredient, chelating agent and sweetener before above-mentioned suspension, and stirs It mixes uniformly.
In certain embodiments, above-mentioned chelating agent may include but be not limited to ethylenediamine tetra-acetic acid (EDTA).
In certain embodiments, above-mentioned chelating agent accounts for about 0.001-0.2% (w/v), preferably 0.005-0.1% (w/v), more preferably 0.01-0.05% (w/v).
In certain embodiments, above-mentioned sweetener may include Sucralose (sucralose), thaumatin (thaumatin), caffeine (caffeine), Aspartame (aspartame), sucrose (sucrose), saccharin (saccharin), fructose (fructose), corn syrup (corn syrup), xylitol (xylitol), ammonium glycyrrhetate (ammonium glycyrrhizinate) or mannitol (mannitol) or other natural or artificial flavors or flavouring agent or its Mixing.
In certain embodiments, above-mentioned sweetener accounts for about 0.03-0.24% (w/v), preferably 0.08-0.2% (w/ V), more preferably 0.1-0.18% (w/v).
The medical composition of this exposure a, embodiment according to the present invention, provides a kind of nasal pharmaceutical composition, Viscosity is using the viscosimeter (rotating the needle number is S18) such as BROOKFIELD-DV II+PRO type, sample volume 7ml, sample temperature Measured viscosity is 5-40 centipoise (cps) under conditions of 25 DEG C and revolving speed 100rpm of degree.
The medical composition of this exposure can be made in the form of inhalation solution, nasal spray, pressurised aerosol or nasal drop With；Particularly preferred embodiment is used in the form of nasal spray, such as the nasal spray can be by using general spraying extruding Bottle or atomizer come using, or using compressed gas aerosol come using.
The nasal spray medical composition of this exposure has been typically free of surfactant.Such as natural oil, it is such as beautiful Rice bran oil, olive oil, cottonseed oil or sunflower seed oil, there are also phosphatide, lecithin, oleic acid (oleic acid), anhydro sorbitol oil Acid esters (sorbitan oleate), PEG, polyoxyethylene sorbitan monoleate (polysorbate 80) etc..
The medical composition of this exposure also provides a kind for the treatment of or prevention allergic rhinitis for giving patient safety, nasal sinus Inflammation, inflammation, harms the related indication methods of respiratory tracts such as breathing, Respiratory Distress Syndrome(RDS) at Pulmonary Vascular contraction.According to this exposure Medical composition, can give the composition through any appropriate administration mode to patient, including intranasal, intraocular, oral cavity, Mouth containing, sublingual, lung etc..This exposure is preferably directly (i.e. intranasal, such as spray nose to nasal mucosa medicine administration by the composition The form of agent or nasal drop).
Term " about " and general use scope (regardless of whether about being limited by term) all mean that included numerical value is not It is limited to exact numerical values recited described in this paper, and means substantially in cited range without departing from the range of the scope of the invention. As used herein, " about " will be known and be understood by art technology person, and its by using in its context certain It is varied in degree.If art technology person does not know the use of the term in the context using the term, " about " it mean that ± the 10% of at most specific value.
The terms such as term " drug ", " active constituent ", " drug principal component ", " active principle " all refer to compound, resist The ingredients such as body, protein have effects that pharmaceutically physiological activity, term may be used interchangeably, and meaning, intension are all identical.
Term " stirring ", " mixing ", " homogeneous mixing " or " mutually mixing " are the common mode or hand of pharmacy fields Section, such as mechanical stirring, ultrasonic vibrating, extruding blendes together, rolling mixes, those skilled in the art still can optionally carry out phase When the displacement of degree, the purpose for reaching cause all makes each ingredient maintain certain proportion, content in single dose.
Term " one ", have has clear expression in context unless otherwise stated or in the present specification, such as " one " lives Sexual element, " one " surfactant etc., it is intended that related noun is "an" or "at least one".
In the preparation method of this exposure, liposoluble active drug ingedient (liposoluble API) and suspending agent system with The form of dry powder is mutually mixed, in this way, the uniformly dispersed of liposoluble active drug ingedient can effectively be promoted.After adding preservative, By mixer means, it can avoid bubble and generate, liposoluble active drug ingedient can also be made to remain good evenly dispersed.This exposure It can avoid liposoluble active drug in the way of final step addition water-soluble active drug ingredient (water-soluble API) Both ingredient and water-soluble active drug ingredient generated chemistry Competition when adding simultaneously, to ensure that finished product uniformly divides It dissipates, lamination will not be presented.In the preparation method of this exposure, each ingredient is after each step is mutually mixed, all with agitating mode Make it up to the degree that is sufficiently mixed, and then carry out mutually mixing for next step, so, it can be ensured that each ingredient added by the process Fine dispersion effect can be all maintained, final finished is made to be unlikely to generate layering.When patient discloses not stratified medical group using this When closing object, since two kinds of active pharmaceutical ingredients have reached the state of being sufficiently mixed, patient is for two kinds of active pharmaceutical ingredients in same The dosage absorbed in one time can be it is identical, so, it can be ensured that the drug safety of patient avoids due to absorbed dose unevenness Cause the problem in curative effect.
In the preparation method of this exposure, by the medicament to add water or other solvents to a certain amount of means as this field The usual technological means of technical staff, the means surely belong to the range that the present invention is covered.
In conclusion all technical and scientific term that this specification is described all is subordinate to unless in addition being defined In the meaning that can be understood jointly in the fields with usual those skilled in the art.System of the present invention is demonstrated with the following examples explains It is bright, allow those skilled in the art to complete it accordingly, however the implementation of the present invention can not be limited by the following example It making it and implements kenel, those skilled in the art still can deduce out other embodiments according to the spirit except the embodiment both disclosed, this A little embodiments are all when belonging to the scope of the present invention.The present invention with drug, material come under it is commercially available be easy to obtain, it is following only For the obtainable channel of example.
Embodiment/comparative example
Embodiment 1
The preparation (1) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate (Fluticasone Propionate) suspension is prepared
135g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: benzalkonium chloride (Benzalkonium Chloride) pure water solution 300mL (1/300w/v), benzene are prepared Oronain is pricked to be mixed with water to being completely dissolved.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride (Azelastine HCl) solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose (Sucralose) is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 1.35% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 2
The preparation (2) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
80g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 0.8% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 3
The preparation (3) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
100g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 1% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/ v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 4
The preparation (4) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
105g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 1.05% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 5
The preparation (5) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
110g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 1.1% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 6
The preparation (6) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
120g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 1.2% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 7
The preparation (7) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
125g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 1.25% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 8
The preparation (8) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
230g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 2.3% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 9
The preparation (9) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
240g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 2.4% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 10
The preparation (10) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
260g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 2.6% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Azelastine hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Comparative example 1
The preparation of nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
65g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, i.e., (fluticasone propionate accounts for 0.0357% (w/v) to completion compound suspension； Avicel RC-591 accounts for 0.65% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Hydrochloric acid nitrogen is tall and erect Sting accounts for 0.1% (w/v)).Suspension is stood into 24 hours presentation stratification states.
Comparative example 2
The preparation of nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
70g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour azelastine solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, i.e., (fluticasone propionate accounts for 0.0357% (w/v) to completion compound suspension； Avicel RC-591 accounts for 0.7% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Hydrochloric acid nitrogen is tall and erect Sting accounts for 0.1% (w/v)).Suspension is stood into 24 hours presentation stratification states.
Embodiment 11
The preparation (11) of this exposure nasal pharmaceutical composition
(1) momestasone furoate (Mometasone Furoate) suspension is prepared
By 135g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) and 5.17g furancarboxylic acid not rice After loose powder is sufficiently mixed, merging is had been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to dividing completely It dissipates uniform.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Momestasone furoate suspension and preservative A, preservative B mixed liquor after mixing, are added into hydrochloric acid in order Azelastine solution, homogeneous mix and confirm be completely dispersed uniformly, detect suspension pH value between 5.50-6.50 (target value: PH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (momestasone furoate accounts for 0.0517% (w/v)；Avicel RC-591 accounts for 1.35% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Salt Sour azelastine accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 12
The preparation (12) of this exposure nasal pharmaceutical composition
(1) momestasone furoate suspension is prepared
By 135g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) and 5.17g furancarboxylic acid not rice After loose powder is sufficiently mixed, merging is had been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to dividing completely It dissipates uniform.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) xylometazoline hydrochloride (Xylometazoline HCl) solution is prepared
10g xylometazoline hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Momestasone furoate suspension and preservative A, preservative B mixed liquor after mixing, are added into hydrochloric acid in order Xylometazoline solution, homogeneous mix and confirm be completely dispersed uniformly, detect suspension pH value between 5.50-6.50 (target value: PH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (momestasone furoate accounts for 0.0517% (w/v)；Avicel RC-591 accounts for 1.35% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Salt Sour Xylometazoline accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Embodiment 13
The preparation (13) of this exposure nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
135g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) xylometazoline hydrochloride solution is prepared
10g xylometazoline hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
Fluticasone propionate suspension and preservative A, preservative B mixed liquor after mixing, are added into salt in order Sour Xylometazoline solution, homogeneous mix and confirm and be completely dispersed uniformly, detect suspension pH value (target between 5.50-6.50 Value: pH 6.0), and quantify total volume to 10L, that is, completing uniformly not stratified compound suspension, (fluticasone propionate accounts for 0.0357% (w/v)；Avicel RC-591 accounts for 1.35% (w/v)；Benzalkonium chloride accounts for 0.01% (w/v)；Benzyl carbinol accounts for 0.25% (w/v)；Xylometazoline hydrochloride accounts for 0.1% (w/v)).Suspension is stood into 1-3 month still not shown stratification states.
Comparative example 3
The preparation of nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
135g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
After mixing by azelastine hydrochloride solution and preservative B mixed liquor first, then sequentially preservative A mixing is added Liquid, fluticasone propionate suspension carry out homogeneous mixing, and confirm and be completely dispersed uniformly.After the completion of finished product, 24 hours are stood Show lamination.
Comparative example 4
The preparation of nasal pharmaceutical composition
(1) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(2) product is prepared
1g benzalkonium chloride, 25g benzyl carbinol and pure water 6.5kg are placed in modulation bucket (40 DEG C of temperature or less), stirred and true Recognize and be sufficiently mixed uniformly, 260g glycerol is added and mixes to being completely dissolved.Azelastine hydrochloride solution is placed in modulation bucket again and is filled Divide and be uniformly mixed, 135g Avicel RC-591 then is added and 3.57g fluticasone propionate carries out homogeneous in the modulation bucket Mixing.After the completion of gained finished product, standing 24 hours shows lamination.
Comparative example 5
The preparation of nasal pharmaceutical composition
(1) fluticasone propionate suspension is prepared
135g Avicel RC-591 (combination of microcrystalline cellulose and sodium carboxymethylcellulose) is replaced with 3.57g propionic acid fluorine After Kathon CG dry powder is sufficiently mixed, merging has been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), and homogeneous is mixed to complete It is uniformly dispersed.
(2) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.At this point, additionally adding 2.5g Polysorbate (Polysorbate) surfactant forms surfactant mixture.
(3) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(4) product is prepared
By the abundant homogeneous of mixture of surfactant mixture and fluticasone propionate suspension, preservative A mixed liquor After mixing, azelastine hydrochloride solution is added, homogeneous mixes and confirms and is completely dispersed uniformly, detects suspension pH value in 5.50- Between 6.50 (target value: pH 6.0), and total volume is quantified to 10L, that is, complete uniformly not stratified compound suspension.Though not dividing Layer but foam excessively cause principal component evenly dispersed.
Comparative example 6
The preparation of nasal pharmaceutical composition
(1) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.At this point, additionally adding 2.5g Polysorbate surfactant forms surfactant mixture.
(2) product is prepared
The merging of 10.0g azelastine hydrochloride is had been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), stirring is extremely After being completely dispersed uniformly, sequentially addition surfactant mixture, preservative A mixed liquor are mixed to being completely dissolved, and form mixing Object (1).In addition, taking 1.5g EDTA, 135g Avicel RC-591,15g Sucralose and pure water 2kg after mixing, add Enter the stirring of 3.57g fluticasone propionate dry powder, forms homogeneous suspension.The homogeneous suspension is added containing mixture (1) It modulates and carries out homogeneous mixing in bucket, detect suspension pH value (target value: pH 6.0) between 5.50-6.50, and quantify totality It accumulates to 10L.After the completion of finished product, 24 hours presentation stratification states are stood.
Comparative example 7
The preparation of nasal pharmaceutical composition
(1) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.At this point, additionally adding 2.5g Polysorbate surfactant forms surfactant mixture.
(2) azelastine hydrochloride solution is prepared
10g azelastine hydrochloride is uniformly mixed to pure water 2kg and is confirmed dissolution, it is molten that the solution is added in 1.5g EDTA It solves and is uniformly mixed, stir finally, 15g Sucralose is added and confirm dissolution.
(3) product is prepared
Surfactant mixture merging is had been loaded in the modulation bucket of pure water 6.5kg (40 DEG C of temperature or less), stirring is extremely After being completely dispersed uniformly, preservative A mixed liquor is added and mixes to being completely dissolved, is formed mixture (2).In addition, taking 13.5g After Avicel RC-591 and 3.57g fluticasone propionate dry powder are sufficiently mixed, it is mixed that azelastine hydrochloride solution progress homogeneous is added It closes, is formed compound suspension (1), it is mixed which adds progress homogeneous in the modulation bucket containing mixture (2) It closes, detects suspension pH value (target value: pH 6.0) between 5.50-6.50, and quantify total volume and completed to 10L.Finished product After the completion, 24 hours presentation stratification states are stood and generate excessive foam.
Comparative example 8
The preparation of nasal pharmaceutical composition
(1) antiseptic mixed solution is prepared
Preservative A: preparing benzalkonium chloride pure water solution 300mL (1/300w/v), and benzalkonium chloride is mixed with water to completely molten Solution.
Preservative B: 260g glycerol and 25g benzyl carbinol are stirred and confirm be sufficiently mixed uniformly.At this point, additionally adding 2.5g Polysorbate surfactant forms surfactant mixture.
(2) product is prepared
After 10g azelastine hydrochloride is mixed with 3.57g fluticasone propionate, merging has been loaded with the modulation of pure water 6.5kg In bucket (40 DEG C of temperature or less), homogeneous mixes uniform to being completely dispersed；Surfactant mixture, preservative is then sequentially added A mixed liquor is simultaneously uniformly mixed, and is formed compound suspension (2).In addition, taking pure water 2kg and 1.5g EDTA, 15g tri- being sequentially added Chlorine sucrose, 135g Avicel RC-591 stir and confirm dissolution, are formed mixture (3).Mixture (3) are added and contain compound Homogeneous mixing is carried out in the modulation bucket of suspension (2), is detected suspension pH value (target value: pH 6.0) between 5.50-6.50, And it quantifies total volume and is completed to 10L.After the completion of finished product, 24 hours presentation stratification states are stood.
Embodiment 14
The viscosity test of nasal pharmaceutical composition
The nasal pharmaceutical composition of this exposure embodiment 1 (is turned using the viscosimeter of such as BROOKFIELD-DV II+PRO type Needle number is S18), measured viscosity can be situated between under conditions of sample volume 7ml, 25 DEG C of sample temperature and revolving speed are 100rpm Between 5-40 centipoise (cps).
Although the present invention is disclosed above with several preferred embodiments, however, it is not to limit the invention, any affiliated Have usually intellectual in technical field, without departing from the spirit and scope of the invention, when can make it is any change and retouch, Therefore the protection scope of the present invention is subject to view the attached claims institute defender.

Claims (15)

1. a kind of nasal pharmaceutical composition, comprising:
Liposoluble active drug ingedient accounts for 0.01-1.5% (w/v)；
Suspending agent accounts for 0.5-3.0% (w/v)；
Preservative accounts for 0.004-0.54% (w/v)；And
Water-soluble active drug ingredient accounts for 0.001-2% (w/v), and wherein in the nasal pharmaceutical composition, and it is living not include surface Property agent.
2. nasal pharmaceutical composition as described in claim 1, wherein the liposoluble active drug ingedient is steroid compound, And the water-soluble active drug ingredient is antihistaminic compound.
3. nasal pharmaceutical composition as claimed in claim 2, wherein the steroid compound includes flunisolide (flunisolide), fluticasone (fluticasone), Mometasone (mometasone), beclomethasone (beclomethasone), fluticasone furoate (fluticasone furoate), song An Nai get (triamcinolone), cloth Any or its mixing in desonide (budesonide), prednisone (prednisone) or ciclesonide (ciclesonide) Object；And the antihistaminic compound includes azelastine (azelastine), olopatadine (olopatadine), celo azoles Quinoline (xylometazoline), Acrivastine (acrivastine), carbinoxamine (carbinoxamine), chlorphenamine (chlorpheniramine), cyproheptadine (cyproheptadine), astemizole (astemizole), cetirizine (cetirizine), Loratadine (loratadine), Mizolastine (mizolastine), RMI 9918 (terfenadine), levocabastine (levocabastine), Desloratadine (desloratadine), fexofenadine (fexofenadine) or mixtures thereof any or in levocetirizine (levocetirizine).
4. nasal pharmaceutical composition as claimed in any one of claims 1-3, wherein the suspending agent includes microcrystalline cellulose (microcrystalline cellulose) and sodium carboxymethylcellulose (carboxymethyl cellulose sodium) Combination；And the preservative includes benzalkonium chloride (benzalkonium chloride), benzyl carbinol (phenylethyl ) or disodium ethylene diamine tetraacetate (edetate disodium) alcohol.
5. nasal pharmaceutical composition as claimed in claim 4 further includes osmotic pressure regulator, chelating agent or sweetener.
6. nasal pharmaceutical composition as claimed in claim 5, wherein the osmotic pressure regulator be glycerol, 1,2-PD or It is or mixtures thereof any in sodium chloride；The chelating agent is ethylenediamine tetra-acetic acid (EDTA)；And the sweetener is Sucralose (sucralose), thaumatin (thaumatin), caffeine (caffeine), Aspartame (aspartame), sucrose (sucrose), saccharin (saccharin), fructose (fructose), corn syrup (corn syrup), xylitol (xylitol), ammonium glycyrrhetate (ammonium glycyrrhizinate), mannitol (mannitol), flavouring agent or its mixing Object.
7. nasal pharmaceutical composition as claimed in claim 4, wherein the nasal pharmaceutical composition is aqueous suspension.
8. a kind of nasal pharmaceutical composition as claimed in claim 7 be used to prepare treat or prevent allergic rhinitis, nasosinusitis, Pulmonary Vascular contraction, inflammation, allergy, impairment breathes or the method for the drug of Respiratory Distress Syndrome(RDS).
9. a kind of preparation method of nasal pharmaceutical composition, comprising:
Liposoluble active drug ingedient and suspending agent are mixed, and is stirred evenly, with formulated suspension；
The first preservative is added in the suspension, and is stirred evenly；
The second preservative is added in the suspension, and is stirred evenly；And
Water-soluble active drug ingredient is added in the suspension, and is stirred evenly, to prepare nasal pharmaceutical composition, wherein in In the preparation method, surfactant is not added；Wherein first preservative is identical, different or more from second preservative The mixture of kind preservative.
10. the preparation method of nasal pharmaceutical composition as claimed in claim 9, wherein the liposoluble active drug ingedient with should Suspending agent mixes in dry powder form.
11. the preparation method of nasal pharmaceutical composition as claimed in claim 10, the wherein liposoluble active drug ingedient packet Include flunisolide (flunisolide), fluticasone (fluticasone), Mometasone (mometasone), beclomethasone (beclomethasone), fluticasone furoate (fluticasone furoate), song An Nai get (triamcinolone), cloth Desonide (budesonide), prednisone (prednisone) or ciclesonide (ciclesonide)) in it is any or its mixing Object；And the water-soluble active drug ingredient includes azelastine (azelastine), olopatadine (olopatadine), match Lip river oxazoline (xylometazoline), Acrivastine (acrivastine), carbinoxamine (carbinoxamine), chlorphenamine (chlorpheniramine), cyproheptadine (cyproheptadine), astemizole (astemizole), cetirizine (cetirizine), Loratadine (loratadine), Mizolastine (mizolastine), RMI 9918 (terfenadine), levocabastine (levocabastine), Desloratadine (desloratadine), fexofenadine (fexofenadine) or mixtures thereof any or in levocetirizine (levocetirizine).
12. the preparation method of nasal pharmaceutical composition as claimed in claim 11, wherein the suspending agent includes microcrystalline cellulose (microcrystalline cellulose) and sodium carboxymethylcellulose (carboxymethyl cellulose sodium) Combination.
13. the preparation method of nasal pharmaceutical composition as claimed in claim 12, wherein the liposoluble active drug ingedient accounts for 0.01-1.5% (w/v)；The water-soluble active drug ingredient accounts for 0.001-2.0% (w/v)；The suspending agent accounts for 0.5-3.0% (w/ v)；First preservative accounts for 0.002-0.04% (w/v)；And second preservative accounts for 0.002-0.5% (w/v).
14. the preparation method of nasal pharmaceutical composition as claimed in claim 13, wherein first preservative and this is second anti- Rotten agent includes benzyl carbinol (phenylethyl alcohol), ethylenediamine tetra-acetic acid (ethylene diamine tetra- Acetic acid) or its esters, alkyl paraben (alkyl p-hydroxybenzoates), Chlorhexidine (chlorhexidine) or its esters, Phenylmercuric Borate (phenyl mercury borate), quaternary ammonium compounds or its mixing Object.
15. a kind of nasal pharmaceutical composition, as prepared by preparation method as claimed in claim 14.
CN201710610100.XA 2017-07-25 2017-07-25 Nasal pharmaceutical composition and preparation method thereof Pending CN109288790A (en)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN201710610100.XA CN109288790A (en) 2017-07-25 2017-07-25 Nasal pharmaceutical composition and preparation method thereof

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
CN201710610100.XA CN109288790A (en) 2017-07-25 2017-07-25 Nasal pharmaceutical composition and preparation method thereof

Publications (1)

Publication Number Publication Date
CN109288790A true CN109288790A (en) 2019-02-01

Family

ID=65167772

Family Applications (1)

Application Number Title Priority Date Filing Date
CN201710610100.XA Pending CN109288790A (en) 2017-07-25 2017-07-25 Nasal pharmaceutical composition and preparation method thereof

Country Status (1)

Country Link
CN (1) CN109288790A (en)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024063712A1 (en) * 2022-09-20 2024-03-28 Pharmactive Ilac Sanayi Ve Ticaret A.S. Pharmaceutical compositions comprising azelastine hci, fluticasone propionate and relevant excipients

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN103237550A (en) * 2010-11-29 2013-08-07 韩林制药株式会社 Pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration
WO2014087347A1 (en) * 2012-12-06 2014-06-12 Glenmark Pharmaceuticals Limited Fixed dose pharmaceutical composition comprising mometasone and azelastine
US20150190405A1 (en) * 2002-06-14 2015-07-09 Cipla Limited Combination of Azelastine and Fluticasone for Nasal Administration
US20160220583A1 (en) * 2015-01-31 2016-08-04 Gavis Pharmaceuticals Aqueous nasal spray composition of corticosteroids and antihistaminic agents
CN106806342A (en) * 2015-12-01 2017-06-09 四川海思科制药有限公司 A kind of azelastine hydrochloride fluticasone propionate nasal spray pharmaceutical composition and preparation method thereof

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150190405A1 (en) * 2002-06-14 2015-07-09 Cipla Limited Combination of Azelastine and Fluticasone for Nasal Administration
CN103237550A (en) * 2010-11-29 2013-08-07 韩林制药株式会社 Pharmaceutical composition including mometasone furoate and azelastine hydrochloride for nasal administration
WO2014087347A1 (en) * 2012-12-06 2014-06-12 Glenmark Pharmaceuticals Limited Fixed dose pharmaceutical composition comprising mometasone and azelastine
US20160220583A1 (en) * 2015-01-31 2016-08-04 Gavis Pharmaceuticals Aqueous nasal spray composition of corticosteroids and antihistaminic agents
CN106806342A (en) * 2015-12-01 2017-06-09 四川海思科制药有限公司 A kind of azelastine hydrochloride fluticasone propionate nasal spray pharmaceutical composition and preparation method thereof

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DRUG@FDAHTTPS://WWW.ACCESSDATA.FDA.GOV/SCRIPTS/CDER/DAF/INDEX.CF: "DYMISTA (azelastine hydrochloride and fluticasone propionate) Nasal Spray说明书", 《FDA》 *
JEAN BOUSQUET ET AL.: "Advances in pharmacotherapy for the treatment of allergic rhinitis; MP29-02 (a novel formulation of azelastine hydrochloride and fluticasone propionate in an advanced delivery system) fills the gaps", 《EXPERT OPIN. PHARMACOTHER.》 *
付艳丽等: "丙酸氟替卡松联合氮卓斯汀鼻喷剂治疗过敏性鼻炎疗效观察", 《山西医药杂志》 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2024063712A1 (en) * 2022-09-20 2024-03-28 Pharmactive Ilac Sanayi Ve Ticaret A.S. Pharmaceutical compositions comprising azelastine hci, fluticasone propionate and relevant excipients

Similar Documents

Publication Publication Date Title
CN103269687B (en) 4-[(S)-(4-chlorophenyl)-2-pyridinylmethoxy compositions
CN100389771C (en) Use of composition comprising Formoterol and Budesonide for prevention or treatment of acute condition of asthma
JP3638289B2 (en) Treatment of upper respiratory allergic response using a combination of histamine receptor antagonists
US20210077382A1 (en) Compositions, devices, and methods for the treatment of opioid-receptor-mediated conditions
AU757772B2 (en) Medicinal compositions for application to mucosa
EA023839B1 (en) Combinations of a muscarinic receptor antagonist and a beta-2 adrenoreceptor agonist
CN103501776A (en) Composition of glycopyrrolate and a beta2-agonist
CN101801378A (en) Novel combination of therapeutic agents
TW200524639A (en) Memantine oral dosage forms
CN103501781A (en) Use of glycopyrrolate for treating tachycardia
AU2017281941A1 (en) Compositions, devices, and methods for the treatment of alcohol use disorder
JP2008502699A (en) Lung disease treatment method and composition therefor
CN109288790A (en) Nasal pharmaceutical composition and preparation method thereof
CN100542539C (en) The pharmaceutical composition that is used for acute glucocorticoid therapy
US20110269844A1 (en) Thin film with propofol active ingredient
CN101564396A (en) Two chamber type nose spraying agent for treating allergic rhinitis
JP2014513708A (en) Pharmaceutical composition comprising fexofenadine
TWI717539B (en) Pharmaceutical compositions for intranasal administration and its preparation method and compound suspension for intranasal administration
TW201238591A (en) The preparation for formulation composition and manufacturing processes of metered dose inhalers treated respiratory diseases
JP2010538081A (en) DHEAS inhalation composition
US20220370445A1 (en) Methods for administering (r)-n-[4-(1,4,5,6-tetrahydro-6-oxo-3-pyridazinyl)phenyl]acetamide
CN109922795A (en) Epiphysin tabloid and preparation method thereof
CN101972230A (en) Pirfenidone for suspension and preparation method
TWI762449B (en) Composition for nebulizer
JPH11130660A (en) Aqueous suspension preparation for intranasal administration

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
WD01 Invention patent application deemed withdrawn after publication

Application publication date: 20190201

WD01 Invention patent application deemed withdrawn after publication