CN101669926B - Liquid preparation for dosing nasal cavities and method for making the same - Google Patents
Liquid preparation for dosing nasal cavities and method for making the same Download PDFInfo
- Publication number
- CN101669926B CN101669926B CN2008102120182A CN200810212018A CN101669926B CN 101669926 B CN101669926 B CN 101669926B CN 2008102120182 A CN2008102120182 A CN 2008102120182A CN 200810212018 A CN200810212018 A CN 200810212018A CN 101669926 B CN101669926 B CN 101669926B
- Authority
- CN
- China
- Prior art keywords
- rupatadine
- nasal
- cyclodextrin
- beta
- liquid preparation
- 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.)
- Expired - Fee Related
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- 238000002360 preparation method Methods 0.000 title claims abstract description 53
- 238000000034 method Methods 0.000 title claims abstract description 27
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- 229960005328 rupatadine Drugs 0.000 claims abstract description 107
- 229920000858 Cyclodextrin Polymers 0.000 claims abstract description 7
- HFHDHCJBZVLPGP-UHFFFAOYSA-N schardinger α-dextrin Chemical class O1C(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC(C(O)C2O)C(CO)OC2OC(C(C2O)O)C(CO)OC2OC2C(O)C(O)C1OC2CO HFHDHCJBZVLPGP-UHFFFAOYSA-N 0.000 claims description 50
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Abstract
The invention relates to a liquid preparation for dosing nasal cavities, which comprises 0.1 to 25 g/100 mL of rupatadine and 0.5 to 30 g/100 mL of cyclodextrin compound. The invention also relates to a method for making the liquid preparation. The liquid preparation of the invention has the characteristics of convenient use, high patient compliance and rapid absorption speed after dosing.
Description
Technical field
The present invention relates to field of medicaments, specifically, what the present invention relates to be used for nasal-cavity administration contains liquid preparation of Rupatadine and preparation method thereof.
Background technology
Allergic rhinitis claims allergic rhinitis again, and it is a kind of commonly encountered diseases and frequently-occurring disease, and it can be divided into seasonal rhinitis and two kinds of property rhinitis all the year round, and cardinal symptom is sneeze, watery nasal discharge, nasal obstruction and nasopharynx pruritus etc.Along with the rapid variation of industrialization progress, modern way of life and human ecological environment, the sickness rate of allergic rhinitis has global growth trend, and its sickness rate accounts for 5～50% of population.China's report in 1998, the allergic rhinitis prevalence is 6.32%, calculates in view of the above, the patient surpasses 8,000 ten thousand now.Allergic rhinitis is the starting point of airway disorders such as asthma, chronic obstructive pulmonary disease, bronchiectasis, and 66% asthma is to bring out because of allergic rhinitis according to statistics, and at least 70% asthma patient is with allergic rhinitis.Oneself causes serious harm to human health, life, study and productive labor allergic rhinitis, must cause enough attention.
Rupatadine is novel, the potent antiallergic agent by the development of Spain Uriach drugmaker, goes on the market in Spain first in March, 2003, is used for seasonality and catarrhus perennialis, and dosage is 10mg.The chemical constitution of Rupatadine is as follows:
English chemical name:
8-Chloro-6，11-dihydro-11-{1-[(5-methyl-3-pyridyl)methyl]-4-piperidylidene}-5H-benzo[5，6]cyclohepta[1，2-b]pyridine
Molecular formula: C
26H
26ClN
3
Physicochemical properties: Rupatadine is white or off-white powder, and molten in the methanol part omitted, dissolubility is lower in water, and is molten in the part omitted of 0.1mol/L hydrochloric acid solution.Fusing point: 196 ℃～200 ℃, decompose simultaneously during fusion.
Rupatadine has the dual function of antihistamine and antagonism platelet activating factor (PAF) concurrently.Studies show that irritated and diseases associated with inflammation is the process by the multifactor complexity that generation and release produced of multiple medium.Histamine promptly is the maximum inflammatory mediator that contains when early stage and this class disease symptoms occurs in allergy.It is by being discharged by the mastocyte of antigenic activation and basophilic leukocyte and producing.This class disease symptoms as sneeze, rhinocnesmus, shed tears and the watery nasal discharge great majority are caused by histamine H1-receptor.PAF then is an another important inflammatory mediator in the airway inflammation.As histamine, PAF also can cause the enhancing of bronchial contraction and vascular permeability, thereby causes watery nasal discharge and nasal congestion.Simultaneously, it can also cause the rising of bronchus sensitivity, and the rising of bronchus sensitivity is the main cause of bringing out asthma.The mechanism of action of new relevant PAF thinks that the PAF indirect action makes it obstruction and high quick hyperfunction in air flue, causes leukotriene then and discharges.At present, the antiallergic agent of Shi Yonging all has only anti-histamine activity clinically, and does not have the PAF antagonism.Obviously, the medicine of blocking histamine and PAF will be than only blocking wherein a kind of better clinical effectiveness that has simultaneously.Rupatadine is the effect but also the active antiallergic agent of antagonism PAF of the anti-resistance amine of not only having of present unique listing.
At present, commercially available Rupatadine is the form of oral administrations such as tablet or capsule, using it for treatment anaphylaxis (symptom is sneeze, rhinocnesmus, shed tears and watery nasal discharge etc.) when waiting, oral administration exist administration absorb onset slowly, the shortcoming of patient dependence difference.Therefore be necessary to develop a kind of novel Rupatadine medicament, it has easy to use, patient's compliance height, and has fast, the eutherapeutic characteristics of administration post-absorption speed.
Summary of the invention
The purpose of this invention is to provide a kind of absorb rapid-action, at the liquid preparation that contains Rupatadine of rhinitis site of pathological change administration.
The present invention also aims to provide this to contain the preparation method of the liquid preparation of Rupatadine.
In order to realize purpose of the present invention, a first aspect of the present invention provides a kind of liquid preparation that is used for nasal-cavity administration, it contains Rupatadine, cyclodextrin compounds and solvent, the content of wherein said cyclodextrin compounds is 0.5～30g/100mL, and the content of described Rupatadine is 0.1～25g/100mL.
In liquid preparation of the present invention, preferably, the content of described cyclodextrin compounds is 0.5～15g/100mL, and the content of described Rupatadine is 0.2～15g/100mL.What choosing was more arranged is, the content of described cyclodextrin compounds is 0.5～10g/100mL, and the content of described Rupatadine is 0.2～10g/100mL.Further preferably, the content of described cyclodextrin compounds is 0.5～5g/100mL, and the content of described Rupatadine is 0.2～2.5g/100mL.Most preferably, the content of described cyclodextrin compounds is 0.5～2.5g/100mL, and the content of described Rupatadine is 0.2～1.25g/100mL.
In liquid preparation of the present invention, described cyclodextrin compounds preferably is selected from least a in beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, DM-, HP-, sulfobutyl ether-beta-cyclodextrin and the malt sugar group-beta-cyclodextrin, and preferred especially described cyclodextrin compounds is a sulfobutyl ether-beta-cyclodextrin.
Preferably liquid preparation of the present invention is made the form of nasal spray or nasal drop.In this case, the pH of liquid preparation of the present invention is preferably 4.5～6.5.
A second aspect of the present invention provides a kind of method for preparing liquid preparation of the present invention, and this method comprises that the cyclodextrin compounds with the Rupatadine of 0.1～25g/100mL and 0.5～30g/100mL is dissolved in the solvent, and sterilization is in the intranasal medicator of packing into then.Wherein, described cyclodextrin compounds is preferably sulfobutyl ether-beta-cyclodextrin.
Hereinafter with reference to concrete example the present invention is described in detail.
Learn that after the human nasal cavity configuration is studied people's nasal membrane surface area reaches 150 square centimeters, the top layer epithelium has a large amount of nose ciliums, and it not only can remove foreign body in nose, prevents that airborne granule from entering pulmonary; And can prevent that ectogenic albumen, virus and antibacterial are inhaled in the body, be the important immunologic barrier of human body.Therefore, extremely important for keeping the human body normal physiological function.
At the nasal cavity structure of human body, people have developed nasal drug delivery system.Usually, nasal drug delivery system has following advantages: 1, be different from orally because of the approach of nasal absorption, directly advance human circulation after the drug absorption, no liver first-pass effect, there be not the Degradation of pipe intestinal digesting liquid, so absorb more oral complete to medicine yet; 2, blood vessel, lymphatic vessel are very abundant under the nasal mucosa, are woven into net, and mucosa is thin again, and for drug absorption causes fabulous condition, so drug absorption is very rapid, onset time is fast, have in addition can be comparable with intravenous injection; 3, good patient compliance is applicable to the patient who needs long-term prescription, and to child, dysphagia and comatose patient, nasal-cavity administration is comparatively convenient; 4, the bioavailability of macromolecular drug can be by the improve that should be used for of absorption enhancer or other method; 5, small-molecule drug and the gastrointestinal tract strongly hydrophilic medicine that is difficult to absorb helps nasal-cavity administration.Therefore, nasal drug delivery system becomes the focus in the drug research field just day by day.
But in the development process of nasal drug delivery system, more scabrous problem is the dissolubility of how balance insoluble drug and the relation between the degree of absorption.As everyone knows, insoluble drug dissolubility in solvent (for example water) is low, and therefore the content in nasal administration composition is difficult to improve.On the other hand, iff adopting conventional solubilizing agent to its solubilising, then the medicine behind the solubilising is present in the solvent with the form of ion or hydrated ion, is difficult to see through fat-soluble nasal membrane, therefore, can't guarantee good degree of absorption.
In the present invention, solved the problems referred to above well by using cyclodextrin compounds, it can play increases dissolubility and sorbefacient dual function.When using cyclodextrin compounds, at every kind of concrete medicine, the selection of its consumption is difficulty often, and its reason just is that people do not understand the detailed action principle of cyclodextrin compounds as yet fully.For example, under different condition, relation between the dissolubility of insoluble drug and the concentration of cyclodextrin compounds with regard to more complicated (referring to list of references " novel pharmaceutical formulation and new technique " the 2nd edition, the Lu Bin chief editor, just point out in the 31st～32 page, for the insoluble drug clathrate, when the enclose of insoluble drug molecule and cyclodextrin than the quantity of two kinds of molecules (be equivalent to approximately than) during for 1:1, then the dissolubility of insoluble drug is along with the concentration ground of cyclodextrin increases and linear increasing, when with the ratio enclose of 1:2, the relation between them is non-linear).
The inventor is through research in depth, find preparation be applicable to nasal-cavity administration contain the liquid preparation of Rupatadine the time, with the Rupatadine of 0.1～25g/100mL cooperate the cyclodextrin compounds of 0.5～30g/100mL desirable beyond thought effect.In the liquid preparation of the present invention, the content of cyclodextrin compounds is 0.5～30g/100mL, and is preferably 0.5～15g/100mL.When the content of cyclodextrin compounds is lower than 0.5g/100mL, solubilizing effect is relatively poor; When the content of cyclodextrin compounds is 15g/100mL, accessible higher solubilizing effect.At the content of cyclodextrin compounds during greater than 15g/100mL, although still may reach higher solubilizing effect, but this moment, the concentration of cyclodextrin compounds solution was too big, and it is oversize that solution reaches the required time of dissolution equilibrium, and the osmotic pressure of solution and viscosity are all bigger.In the present invention, when using cyclodextrin compounds, can be directly the cyclodextrin compounds in the described content range and Rupatadine and/or other pharmaceutically acceptable auxiliaries be dissolved in the solvent, have so just simplified production technology greatly, be applicable to practical application more.In this application, except as otherwise noted, used unit " g/100mL " is based on the whole liquid preparation.
In liquid preparation of the present invention, preferably, the content of described cyclodextrin compounds is 0.5～15g/100mL, and the content of described Rupatadine is 0.2～15g/100mL.What choosing was more arranged is, the content of described cyclodextrin compounds is 0.5～10g/100mL, and the content of described Rupatadine is 0.2～10g/100mL.Further preferably, the content of described cyclodextrin compounds is 0.5～5g/100mL, and the content of described Rupatadine is 0.2～2.5g/100mL.Most preferably, the content of described cyclodextrin compounds is 0.5～2.5g/100mL, and the content of described Rupatadine is 0.2～1.25g/100mL.The inventor is through in depth discovering,, begins to aware liquid preparation and is clamminess a bit greater than 2.5g/100mL at the content of Rupatadine, and osmotic pressure strengthens.Along with the increase of the content of Rupatadine, need further to add the effect that cyclodextrin compounds reaches solubilising, thereby the viscosity of liquid preparation increases further.During greater than 10g/100mL, the viscosity of liquid preparation becomes bigger at the content of Rupatadine.Consider the viscosity situation of liquid preparation, can adopt suitable manner to carry out administration.For example under the lower situation of liquid preparation viscosity, can carry out administration by the mode of spray or nasal drop; Be difficult to prepare under the situation of spray or nasal drop higher the making of liquid preparation viscosity, can adopt medicinal liquid is clamp-oned nasal cavity inside, with the outside of the gentle nose of have gentle hands, the medicinal liquid of nasal cavity is coated on the nasal membrane surface equably then; If desired, can also use cotton rod to help coating.
According to the present invention, preferably, described cyclodextrin compounds is selected from least a in beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, DM-, HP-, sulfobutyl ether-beta-cyclodextrin and the malt sugar group-beta-cyclodextrin, more preferably sulfobutyl ether-beta-cyclodextrin.Only be in order exemplarily cyclodextrin compounds to be described, not constitute limiting the scope of the invention herein.Any suitable cyclodextrin compounds known to those skilled in the art all is applicable to the present invention.
In this article, term " Rupatadine " is meant Rupatadine and pharmaceutically useful salt thereof.The pharmaceutically useful salt of described Rupatadine can have the salt that forms with the mineral acid of all example hydrochloric acids, hydrobromic acid, sulphuric acid and so on for example, perhaps the salt that forms with organic acid such as methanesulfonic acid, benzenesulfonic acid, toluenesulfonic acid, camphorsulfonic acid, fumaric acid, maleic acid, mandelic acid, citric acid, salicylic acid, malonic acid, 1,3-propanedicarboxylic acid, succinic acid, aminoacid, glycocholic acid.Only be in order exemplarily Rupatadine to be described, not constitute limiting the scope of the invention herein.Any suitable pharmaceutically useful salt of Rupatadine known to those skilled in the art all is applicable to the present invention.
According to the present invention, the liquid preparation that is used for nasal-cavity administration is preferably spray or nasal drop.The pH of described liquid preparation is preferably 4.5～6.5.When pH is lower than 4.5 or when being higher than 6.5, described liquid preparation is excessive to the toxicity and the zest of nasal cavity cilium, causes the loss of medicine to increase, and then drug effect is reduced.
According to the present invention, in liquid preparation of the present invention, except above-mentioned Rupatadine, cyclodextrin compounds and solvent, also can further comprise one or more and be selected from pharmaceutic adjuvant in osmotic pressure regulator, buffer salt, pH regulator agent, thickening agent, solubilizing agent, antiseptic or the absorption enhancer.
According to the present invention, preferably, described osmotic pressure regulator is selected from one or more in lactose, glucose, dextran, sorbitol, mannitol, sodium chloride and the sucrose.Its consumption is generally 0.2～5.0g/100mL.Only be in order exemplarily osmotic pressure regulator to be described, not constitute limiting the scope of the invention herein.Any suitable osmotic pressure regulator known to those skilled in the art all is applicable to the present invention.
According to the present invention, preferably, described buffer salt is selected from one or more in phosphate, borate, citrate, tartrate, acetate and the amino acid salts, and its consumption is generally 0.5～15.0g/100mL.Only be in order exemplarily buffer salt to be described, not constitute limiting the scope of the invention herein.Any suitable buffer salt known to those skilled in the art all is applicable to the present invention.
According to the present invention, preferably, described pH regulator agent is selected from sodium hydroxide or potassium hydroxide.Only be for exemplarily agent describes to pH regulator herein, do not constitute limiting the scope of the invention.Any suitable pH regulator agent known to those skilled in the art all is applicable to the present invention.
According to the present invention, preferably, described antiseptic is selected from one or more in ethyl hydroxybenzoate, parabens, benzoic acid and salt thereof, sorbic acid, chlorobutanol, benzyl alcohol, phenethanol, chlorhexidine acetate and the quaternary ammonium compound cationoid type surfactant, and its consumption is generally 0.005～10.0g/100mL.Only be in order exemplarily antiseptic to be described, not constitute limiting the scope of the invention herein.Any suitable antiseptic known to those skilled in the art all is applicable to the present invention.
According to the present invention, preferably, described thickening agent is selected from water-soluble polymer (for example polyvidone, Polyethylene Glycol, polyvinyl alcohol etc.) or water-soluble cellulose (for example hydroxyethyl-cellulose, methylcellulose, hydroxypropyl methylcellulose, sodium carboxymethyl cellulose, carbopol etc.), and its consumption is generally 0.01～2.0g/100mL.Only be in order exemplarily thickening agent to be described, not constitute limiting the scope of the invention herein.Any suitable thickening known to those skilled in the art all is applicable to the present invention.
According to the present invention, preferably, described solubilizing agent is selected from ionic surfactant or nonionic surfactant, for example sodium lauryl sulphate, Tween 80, span 20 etc., and its consumption is generally 0.01～20.0g/100mL.Only be in order exemplarily solubilizing agent to be described, not constitute limiting the scope of the invention herein.Any suitable solubilizing agent known to those skilled in the art all is applicable to the present invention.
According to the present invention, preferably, described absorption enhancer is selected from one or more in cholic acid salt absorption enhancer, saturated or unsaturated fatty acid and esters absorption enhancer, alcohols absorption enhancer, ethers absorption enhancer, sulfoxide class absorption enhancer, lactams absorption enhancer, surfactant, salicylic acid absorption enhancer, amino acids absorption enhancer or the metal-chelator, and its consumption is generally 0.005～5.0g/100mL.
More preferably, described cholic acid salt absorption enhancer is selected from one or more in glycocholate, cholate, deoxycholate, taurocholate and the glucose cholate; Described saturated or unsaturated fatty acid and esters absorption enhancer thereof are selected from one or more in lauric acid, oleic acid, myristic acid, caprylate and the ethyl lactate; Described alcohols absorption enhancer is selected from one or more in propylene glycol, isopropyl alcohol, hexadecanol, lauryl alcohol and the oleyl alcohol; Described ethers absorption enhancer is selected from polyoxyethylene laurel ether and/or polyoxyethylene octyl ether; Described sulfoxide class absorption enhancer is selected from dodecyl methyl sulfoxide and/or dimethyl sulfoxide; Described lactams absorption enhancer is selected from the tall and erect ketone of dodecyl nitrogen and/or holds together the tall and erect ketone of cattle base nitrogen; Described surfactant is selected from one or more in sodium lauryl sulphate, Tween 80 and the span 20; Described salicylic acid absorption enhancer is selected from one or more in salicylic acid, aspirin, salsalate and the sodium aminosalicylate benorylate; Described amino acids absorption enhancer is selected from PCP-cysteine paddy Guang, vitamin B
12, in the leucine one or more; Described metal-chelator is selected from one or more in ethylenediaminetetraacetic acid, disodiumedetate and the calcio-disodium edetate.Only be in order exemplarily absorption enhancer to be described, not constitute limiting the scope of the invention herein.Any suitable absorption enhancer known to those skilled in the art all is applicable to the present invention.
At the liquid preparation that is used for nasal-cavity administration of the present invention, can select appropriate solvent as required.For the consideration of aspects such as price, environmental protection, only solvent is a water.Its consumption can be regulated according to Rupatadine that is added and pharmaceutic adjuvant.
According to the present invention, a kind of method for preparing liquid preparation of the present invention also is provided, and this method comprises behind the Rupatadine crushing screening, and the Rupatadine of 0.1～25g/100mL and the cyclodextrin compounds of 0.5～30g/100mL are dissolved in the solvent, sterilization is in the intranasal medicator of packing into then.Wherein, described cyclodextrin compounds is preferably sulfobutyl ether-beta-cyclodextrin.
The liquid preparation that is used for nasal-cavity administration of the present invention has easy to use, patient's compliance height, and have the fast characteristics of administration infiltration rate.Result of the test shows, can pass through Nasal Mucosa Absorption according to liquid preparation of the present invention, brings into play its antihistamine and anti-PAF activity fast, removes symptoms such as rhinitis patient sneeze, watery nasal discharge, nasal obstruction and nasopharynx pruritus.Under the situation of using the Rupatadine nasal mist, drug level is generally 0.2～1.25g/100mL, each administration 100 μ L, administration every day 1～3 time.
The specific embodiment
Below the invention will be further described for the description by the specific embodiment, but this is not to be limitation of the present invention, those skilled in the art are according to basic thought of the present invention, can make various modifications or improvement, but only otherwise break away from basic thought of the present invention, all within the scope of the present invention.
Hereinafter raw material of Shi Yonging and reagent are as follows:
Rupatadine: our company's self-control, purity: 99.8%;
Mannitol: available from last Hydron is medical auxiliary materials technology company limited;
Ethyl hydroxybenzoate: the chemical industry company limited is got over by unit available from Shanghai;
HP-: available from the new big Fine Chemical Co., Ltd in Shandong;
DM-: available from Bokai Biological Tech. Co., Ltd., Guangzhou;
Methyl-beta-schardinger dextrin-: available from the new big Fine Chemical Co., Ltd in Shandong;
Hydroxypropyl methylcellulose: available from Anhui Shanhe Medical Accessary Material Co., Ltd.;
Sulfobutyl ether-beta-cyclodextrin: available from the new big Fine Chemical Co., Ltd in Shandong;
Chlorobutanol: available from Xuzhou mole pharmaceutical reagent factory;
Phenol: available from the safe chemical industry company limited of Shanghai promise;
5% benzalkonium bromide: available from Shanghai Jingwei Chemical Co., Ltd.;
Sodium glycocholate: available from Guangzhou big uncle chemical industry company limited;
Potassium dihydrogen phosphate, dipotassium hydrogen phosphate: available from Jinan, Shandong Yunxiang chemical industry company limited.
The preparation of embodiment 1 Rupatadine nasal mist
Principal agent and adjuvant title consumption
Rupatadine 0.625g
Sulfobutyl ether-beta-cyclodextrin 1.50g
5% benzalkonium bromide 0.20mL
Distilled water is an amount of, and adds to 100mL
Method for making: sulfobutyl ether-beta-cyclodextrin and 5% benzalkonium bromide are dissolved in about 90mL water, add Rupatadine then, ultrasonicly make its dissolving, add distilled water to 100mL, 0.45 the filtering with microporous membrane of μ m, adopt the sterilization of flowing steam method, promptly get the medicinal liquid of the nasal mist of Rupatadine, pH is 4.5～5.0.Above-mentioned medicinal liquid is divided in the multiple dose administration device promptly.
The preparation of embodiment 2 Rupatadine nasal drop
Principal agent and adjuvant title consumption
Rupatadine 25.0g
Chlorobutanol 0.50g
Sodium glycocholate 0.05g
Potassium dihydrogen phosphate 0.56g
Sulfobutyl ether-beta-cyclodextrin 30.0g
Potassium hydroxide is an amount of, transfers pH to 4.5
Distilled water is an amount of, and adds to 100mL
Method for making: potassium dihydrogen phosphate, sodium glycocholate, chlorobutanol are placed beaker, add the 90mL dissolved in distilled water after, transfer pH to 4.5～5.0 in right amount with potassium hydroxide solution.Again sulfobutyl ether-beta-cyclodextrin is added mixing in the above-mentioned solution, slowly add Rupatadine and ultrasonic dissolution, add distilled water to 100mL.0.45 the filtering with microporous membrane of μ m adopts the sterilization of flowing steam method, promptly gets the medicinal liquid of the nasal drop of Rupatadine.Above-mentioned medicinal liquid is divided in the multiple dose administration device promptly.During use, nasal drop is clamp-oned nasal cavity inside, the outside with the gentle nose of have gentle hands is coated on the nasal membrane surface medicinal liquid of nasal cavity equably.
The preparation of embodiment 3. Rupatadine nasal mists
Principal agent and adjuvant title consumption
Rupatadine 0.38g
DM-2.50g
Ethyl hydroxybenzoate 0.50g
Distilled water is to 100mL
Method for making: ethyl hydroxybenzoate and DM-are dissolved in the 90mL water, add Rupatadine then, ultrasonicly make its dissolving, add distilled water to 100mL, 0.45 μ m filtering with microporous membrane, flowing steam sterilization, promptly get the medicinal liquid of Rupatadine nasal mist, recording pH is 4.5～5.0.Above-mentioned medicinal liquid is divided in the multiple dose administration device promptly.
The preparation of embodiment 4. Rupatadine nasal drop
Principal agent and adjuvant title consumption
Rupatadine 0.10g
Chlorobutanol 0.50g
HP-1.0g
Dipotassium hydrogen phosphate 0.84g
Potassium dihydrogen phosphate 0.09g
Mannitol 0.5g
Distilled water is to 100mL
Method for making: Rupatadine is crossed 80 mesh sieves, add HP-, chlorobutanol, mannitol, dipotassium hydrogen phosphate and potassium dihydrogen phosphate mix homogeneously then, be dissolved in the 90mL water, ultrasonic it is dissolved fully after, add distilled water to 100mL, record pH5.5～6.0, filter the back flowing steam sterilization, promptly get Rupatadine nasal drop medicinal liquid, above-mentioned medicinal liquid is divided in the multiple dose administration device promptly.
The preparation of embodiment 5. Rupatadine nasal drop
Principal agent and adjuvant title consumption
Rupatadine 10.0g
Sulfobutyl ether-beta-cyclodextrin 10.0g
Phenol 0.5g
Dipotassium hydrogen phosphate 0.68g
Sodium hydroxide is an amount of
Distilled water is to 100mL
Method for making: sulfobutyl ether-beta-cyclodextrin and dipotassium hydrogen phosphate are dissolved in the 90mL water, add phenol and Rupatadine, ultrasonicly make its dissolving, transfer pH to 6.0～6.5 with sodium hydroxide, add distilled water to 100mL, 0.45 μ m filtering with microporous membrane, flowing steam sterilization, promptly get Rupatadine nasal drop medicinal liquid, above-mentioned medicinal liquid is divided in the multiple dose administration device promptly.
The preparation of embodiment 6. Rupatadine nasal mists
Principal agent and adjuvant title consumption
Rupatadine 2.50g
Methyl-beta-schardinger dextrin-5.00g
Ethyl hydroxybenzoate 0.50g
Distilled water is to 100mL
Method for making: ethyl hydroxybenzoate and methyl-beta-schardinger dextrin-are dissolved in the 90mL water, add Rupatadine then, ultrasonicly make its dissolving, add distilled water to 100mL, 0.45 μ m filtering with microporous membrane, flowing steam sterilization, promptly get the medicinal liquid of Rupatadine nasal mist, recording pH is 5.0～5.5.Above-mentioned medicinal liquid is divided in the multiple dose administration device promptly.
Experimental example 1 Rupatadine nasal mist stability test
Prepare the Rupatadine nasal mist by embodiment 1 described method, and use it for the study on the stability test.
1. influence factor's test
The Rupatadine nasal mist is placed under 60 ℃, the condition of 4500Lx (lux) respectively, in sampling in the 5th, 10 day, appearance character, pH value, assay and the related substance of calibrating Rupatadine nasal mist, the result is shown in table 1,2.Result of the test shows that Rupatadine nasal mist stability better.
Table 1 high-temperature sample result of the test
Table 2 sample exposure experiments to light result
2. low temperature freezing-thawing test
The Rupatadine nasal mist was placed 2 days under-10 ℃ to-20 ℃ condition, taken out to be placed under 40 ℃ of conditions and placed 2 days, promptly finish a circulation, carry out three such circulations altogether.Sampling when first loop ends (4 days) and the 3rd loop ends (12 days), appearance character, content and the related substance of calibrating Rupatadine nasal mist, with 0 day data comparison, the result was as shown in table 3.Result of the test shows: compared with 0 day, respectively investigate index all less than obviously changing after three circulations.
Table 3 low temperature freezing-thawing test result
3. accelerated test
The Rupatadine nasal mist was placed 6 months in 40 ℃ calorstat, in 1,2,3,6 sampling at the end of month, appearance character, assay and the related substance of calibrating Rupatadine nasal mist, the result is as shown in table 4.The result shows: this product was preserved 6 months under 40 ℃ condition under the commercially available back condition, and the quality of sample was compared no significant change with 0 month.
4. long term test
The Rupatadine nasal mist is placed the chamber that keeps sample (25 ℃ ± 2 ℃ of temperature), in sampling at 0,6,12 the end of month, appearance character, content and the related substance of calibrating Rupatadine nasal mist, the result is as shown in table 4.Long-term test results shows: this product was preserved 12 months at ambient temperature, and the quality of sample was compared no significant change with 0 month.
Table 4 accelerated test and long-term test results
Experimental example 2 Rupatadine nasal mist pharmacodynamicss are investigated
Prepare the Rupatadine nasal mist by embodiment 1 described method, and use it for pharmacodynamics and investigate test.Test grouping and modeling method are as follows:
With 48 rat (SD rats, male and female half and half, available from Zhongshan University experimental animal center) be divided into 4 groups at random, every group of 12 rats, be denoted as Rupatadine nasal mist group, negative control group (normal saline), positive controls (loratadine is available from Changzhou Yabang Pharmaceutical Co., Ltd) and blank group.In Rupatadine nasal mist group, negative control group and positive controls, the use pipettor splashes into 10% TDI (Toluene-2,4-diisocyanate, 4-vulcabond) olive oil solution 10 μ L in the bilateral nostril, every side nostril 5 μ L, once a day, continuous 7 days.Collunarium once to keep the sensitization state, finishes up to observing medicine next day of changing into after 7 days.In the blank group, olive oil is splashed in the bilateral nostril, every day every side nostril 5 μ L, the collunarium method is as implied above.By behavioristics's scoring judgment models success or not.
Behavioristics's standards of grading
With sniffle and sign is main observed content, begins from sensitization, and how many time length, light and heavy degree, number of times of occurring according to rhinocnesmus, sneeze, watery nasal discharge etc. are standards of grading and record scoring.Rhinocnesmus degree: dab nose several times, remember 1 part; Severe: scratching nose, face is more than, and friction is remembered 2 parts everywhere.Sneeze: 1～3 is 1 minute, and 4～10 is 2 minutes, is 3 minutes more than 11.Watery nasal discharge: flowing to the nostril is 1 minute, and exceeding anterior nares is 2 minutes, and it is 3 minutes that watery nasal discharge is had one's face covered with.With the stack of keeping the score of various symptoms, gross score reaches 5 and is divided into the modeling success.Each sensitizer of giving observed the symptoms after 30 minutes.
Medication
Rupatadine nasal mist group, positive controls be in the 8th day every each every side of animal of modeling nostril administration 10 μ L, and negative control group (normal saline) and blank group are with isometric 0.9% normal saline collunarium, successive administration 15 days.
The collection of specimens method
Last medication after 1 hour the TDI olive oil solution collunarium with 10% excite animal, and write down symptom score.After 30 minutes with 25% urethane (0.75mL/kg) anesthetized animal.Ventral aorta blood sampling 2mL adds the 1.8mL distilled water and makes it haemolysis, after add that 0.2mL is dense to be crossed chloric acid (10～12mol/L) fully shake up vibration, under 40 ℃, 5000rpm centrifugal 10 minutes, get the supernatant 2mL after centrifugal, place liquid nitrogen rapidly, transfer to-70 ℃ of refrigerators and preserve until mensuration.Take off animal bilateral nasal cavity, cut fraction and put into 10% neutral formalin solution rapidly, under the condition of ice bath, separate nasal mucosa, wash down blood and mucus with distilled water, filter paper blots more than moisture, places liquid nitrogen after weighing rapidly, transfers in 70 ℃ to-70 ℃ the refrigerator and preserves.
The histamine assay method adopts fluorescence spectrophotometry in serum and the nasal mucosa.Concrete method and condition are referring to following document: Shore PA, Burkhalter A, Cohn VH. " Amethod for the fluorometric assay of histamin in tissue. " " J PharmacExp Ther " 1959.127:182.Measurement result is shown in table 5-6.
Measurement result shows that the result of Rupatadine nasal mist group and the result of negative control group and positive controls have significance difference (P＜0.05), thereby explanation Rupatadine nasal mist treatment of allergic rhinitis effect is obvious.
Histamine content in each treated animal serum of table 5
Histamine content in each treated animal nasal mucosa of table 6
Experimental example 3 cilium toxicity tests are investigated
Prepare the Rupatadine nasal mist by embodiment 1 described method, and use it for the cilium toxicity test and investigate.Test method is as follows:
Behind the Bufo siccus broken end, cut its palate with operating scissors, be fixed on the frog board, rapidly with the sharp about 3 * 3mm of ophthalmologic operation clip
2Last palatine mucosa, normal saline is cleaned clot and foreign material, mucomembranous cilium towards on be tiled on the microscope slide, drip the 0.1mL medicinal liquid on mucomembranous surface, covered is observed the ciliary movement situation down in 15 * 10 times of optical microscopes gently, with being placed in the chromatography cylinder that is added with a small amount of distilled water, airtight, make the nearly saturation of steam, ambient temperature 20-25 ℃.After this take out to observe every appropriate time, continue motion as cilium and then put back in the chromatography cylinder, stop until ciliary movement, record begins to stop the time to be continued to ciliary movement from administration.Whether the medicinal liquid with on the carefully clean mucosa of normal saline continues to observe ciliary movement and recovers, and writes down recovery time.Be contrast with the normal saline group in the test, with cilium persistent movement time cilium persistent movement time of administration group divided by matched group, the relative motion percentage rate of cilium persistent movement time.Percentage rate is high more, shows that medicine is more little to the ciliary movement influence.
Feminine gender and positive control test
The deoxycholic acid sodium water solution of selecting serious cilium toxic 1% for use is as positive control, and the cilium persistent movement time (LTCM) is measured in the negative contrast of normal saline.
The test solution preparation
Prepare the phosphate buffered solution of pH5.0, the isotonic phosphate buffer solution of pH5.0,0.5% benzalkonium bromide normal saline solution and Rupatadine nasal mist respectively.The result is as shown in table 7.
Result of the test shows that the Rupatadine nasal mist has less cilium toxicity.
Table 7 cilium toxicity test result (n=6)
The different cyclodextrin compounds of experimental example 4 is to the influence of Rupatadine nasal absorption
1. the preparation of testing liquid
Precision takes by weighing HP-, methyl-beta-schardinger dextrin-and sulfobutyl ether-beta-cyclodextrin, and join respectively in the Rupatadine solution of 0.1g/100mL, thereby be mixed with HP-, methyl-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin that contains 2.5g/100mL and the Rupatadine solution that does not have the cyclodextrin compounds.
2. test method
The anesthesia of rats by intraperitoneal injection 1% pentobarbital sodium is lain on the back and is fixed on the flat board, does a kerf at cervical region, exposes trachea and esophagus.Get 2 of polyethylene tubes, one is inserted trachea, and another a end inserts esophagus, until the nasal cavity rear portion.The nose palate passage in nasal cavity and oral cavity is sealed with adhesive plaster, in case medicinal liquid runs off from the oral cavity, the other end of pipe contacts with medicinal liquid, will fill 37 ℃ of constant temperature water baths of circulatory pool of medicinal liquid, and constant flow pump makes the circulation of medicinal liquid via intranasal application, circulation fluid flow velocity 2.5mL/min.Medicine advances in the people rat body by Nasal Mucosa Absorption.The circulation fluid Chinese medicine is eliminated with a step velocity, and circulating system seals in the entire test, and the secretion of nasal cavity and heavily absorb and can ignore is so the volume of circulation fluid remains unchanged substantially.Wherein residual dose Q and time t have following relation: Q=Q
0e
-kt
Formula C=C through after divided by volume
0e
-kt
Back lnC=lnC takes the logarithm
0-Kt
Q in the formula
0Be initial dose in the circulation fluid; K is the infiltration rate constant; C is a left drug concentration; C
0Be initial drug concentration in the circulation fluid.
The sample concentration C and the corresponding time t substitution formula of different time are returned, and the slope of regression straight line is the infiltration rate constant K, the nasal absorption situation of the big I reflection medicine of K.
3. result of the test
Different cyclodextrin compounds is as shown in table 8 to the absorption facilitation effect of Rupatadine.
The different cyclodextrin compounds of table 8 is to the influence (n=3) of Rupatadine nasal absorption
This shows that HP-, methyl-beta-schardinger dextrin-and sulfobutyl ether-beta-cyclodextrin all can play the effect of the absorption that promotes Rupatadine, wherein the absorption facilitation effect of sulfobutyl ether-beta-cyclodextrin is the strongest.
The solubilising test of experimental example 5 Rupatadines
Test method:
Prepare pH3.0,4.0,5.0,6.0,7.0 phosphate buffer respectively, excessive Rupatadine is added in the above-mentioned solution, bathe constant temperature vibration 72h, make dissolubility reach balance in room temperature (25 ℃), supernatant is measured the wherein content of Rupatadine with 0.45 μ m filtering with microporous membrane.The result is as shown in table 9.
The dissolubility of table 9 Rupatadine under different pH
Select for use HP-, methyl-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin as solubilizing agent respectively.Prepare the solubilizing agent solution (0～30g/100mL) of a series of variable concentrations with distilled water, excessive Rupatadine is added in the above-mentioned solubilizing agent solution, bathe constant temperature vibration 72 hours in room temperature (25 ℃), make dissolubility reach balance, supernatant adopts the wherein content of Rupatadine of high effective liquid chromatography for measuring with the filtering with microporous membrane of 0.45 μ m.The result is shown in table 10-12.
Table 10 sulfobutyl ether-beta-cyclodextrin is to the solubilizing effect of Rupatadine
Table 11 methyl-beta-schardinger dextrin-is to the solubilizing effect of Rupatadine
Table 12 HP-is to the solubilizing effect of Rupatadine
Hence one can see that, with respect to the dissolubility of Rupatadine in the table 9 under each pH, all can increase its dissolubility significantly behind adding HP-, methyl-beta-schardinger dextrin-, the sulfobutyl ether-beta-cyclodextrin.Along with the increase of the concentration of HP-, methyl-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, the dissolubility of Rupatadine also increases, and the solubilizing effect of sulfobutyl ether-beta-cyclodextrin is best.Find that in test under the situation of concentration greater than 15g/100mL of HP-, methyl-beta-schardinger dextrin-, sulfobutyl ether-beta-cyclodextrin, it is oversize that solution reaches the required time of dissolution equilibrium, and the osmotic pressure of solution and viscosity are all bigger.
Claims (9)
1. liquid preparation that is used for nasal-cavity administration, it contains Rupatadine, cyclodextrin compounds and solvent, the content that it is characterized in that described cyclodextrin compounds is 0.5～30g/100mL, the content of described Rupatadine is 0.1～25g/100mL, and described cyclodextrin compounds is selected from least a in beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, DM-, HP-, sulfobutyl ether-beta-cyclodextrin and the malt sugar group-beta-cyclodextrin.
2. liquid preparation according to claim 1, the content that it is characterized in that described cyclodextrin compounds is 0.5～15g/100mL, the content of described Rupatadine is 0.2～15g/100mL.
3. liquid preparation according to claim 2, the content that it is characterized in that described cyclodextrin compounds is 0.5～10g/100mL, the content of described Rupatadine is 0.2～10g/100mL.
4. liquid preparation according to claim 3, the content that it is characterized in that described cyclodextrin compounds is 0.5～5g/100mL, the content of described Rupatadine is 0.2～2.5g/100mL.
5. liquid preparation according to claim 4, the content that it is characterized in that described cyclodextrin compounds is 0.5～2.5g/100mL, the content of described Rupatadine is 0.2～1.25g/100mL.
6. liquid preparation according to claim 1 is characterized in that described cyclodextrin compounds is a sulfobutyl ether-beta-cyclodextrin.
7. liquid preparation according to claim 6 is characterized in that described liquid preparation is spray or nasal drop.
8. method for preparing any described liquid preparation among the claim 1-7, comprise: the Rupatadine of 0.1～25g/100mL and the cyclodextrin compounds of 0.5～30g/100mL are dissolved in the solvent, sterilization, pack into then in the intranasal medicator, wherein said cyclodextrin compounds is selected from least a in beta-schardinger dextrin-, methyl-beta-schardinger dextrin-, DM-, HP-, sulfobutyl ether-beta-cyclodextrin and the malt sugar group-beta-cyclodextrin.
9. method according to claim 8 is characterized in that described cyclodextrin compounds is a sulfobutyl ether-beta-cyclodextrin.
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| CN103108635B (en) | 2010-06-30 | 2014-10-15 | J·乌里亚奇·Y股份有限公司 | Liquid formulations of rupatadine fumarate |
| CN101926762B (en) * | 2010-08-27 | 2012-07-18 | 海昌隐形眼镜有限公司 | Rupatadine fumarate eye drops and preparation method thereof |
| CN102652740A (en) * | 2011-12-17 | 2012-09-05 | 东莞达信生物技术有限公司 | Rupatadine fumarate dry powder inhalation and preparation method thereof |
| CN102614177B (en) * | 2012-03-06 | 2014-08-06 | 北京伟峰益民科技有限公司 | Application of rupatadine to preparation of medicinal compositions for treating chronic obstructive pulmonary disease |
| CN103637987B (en) * | 2013-12-09 | 2015-12-02 | 韩彬 | The composition of liquid medicine of oxycodone |
| CN109276715A (en) * | 2017-07-20 | 2019-01-29 | 西安力邦医药科技有限责任公司 | Antiallergy nasal medicine composition, preparation method and the application of humectant |
| CN110200915A (en) * | 2019-05-14 | 2019-09-06 | 扬子江药业集团江苏紫龙药业有限公司 | A kind of Rupatadine fumarate emulsion-type nasal mist and preparation method thereof |
| CN110123756A (en) * | 2019-05-14 | 2019-08-16 | 扬子江药业集团江苏紫龙药业有限公司 | A kind of Rupatadine fumarate nasal spray and preparation method thereof |
| CN111298134A (en) * | 2020-02-26 | 2020-06-19 | 江苏艾立康药业股份有限公司 | Rupatadine fumarate solid preparation composition and preparation method thereof |
| CN111956630A (en) * | 2020-08-20 | 2020-11-20 | 大连理工大学 | Liquid preparation for atomizer of Reidesciclovir, preparation method and application thereof |
| CN112494429B (en) * | 2020-12-29 | 2022-07-26 | 北京华氏开元医药科技有限公司 | Rupatadine fumarate nano emulsion and preparation method and application thereof |
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