CN103830731A - Glucocorticoid/H1 receptor antagonist compound inhalation composition - Google Patents
Glucocorticoid/H1 receptor antagonist compound inhalation composition Download PDFInfo
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- CN103830731A CN103830731A CN201210494862.5A CN201210494862A CN103830731A CN 103830731 A CN103830731 A CN 103830731A CN 201210494862 A CN201210494862 A CN 201210494862A CN 103830731 A CN103830731 A CN 103830731A
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Abstract
The invention relates to a glucocorticoid/H1 receptor antagonist compound inhalation composition which contains glucocorticoid and one or more H1 receptor antagonists used as active components, and one or more composition auxiliary materials suitable for inhalation administration. The H1 receptor antagonist is one or more of loratadine, desloratadine, cetirizine, levocetirizine, astemizole, ketotifen, ebastine, fexofenadine, avastin, mequitazine, mizolastine and salts thereof, and preferably one or more of loratadine, desloratadine, cetirizine, levocetirizine, ebastine, mizolastine, avastin, mequitazine, ketotifen and hydrochlorides or fumarates thereof.
Description
Technical field:
The present invention relates to the compound recipe composition for inhalation that contains glucocorticoid H1 receptor antagonist.
Background technology:
Histamine is a kind of chemical mediator, is present in the in-house mastocyte of human body and the basophil of blood.When these cells are subject to after immunity reason or the stimulation of other chemical factors, antigen is combined with the IgE of cell surface, makes a large amount of histamine of the injured release of cell etc.Histamine causes that by H1 and the H2 receptor of each histoorgan skin and mucosa telangiectasis and permeability increase, and produces erythema and welt; Cerebral vasodilators (headache); Blood pressure drops; Heart rate accelerates and heart output increases; Make bronchus and gastrointestinal smooth muscle spasm; Gastric secretion increases; The histamine tip that excites nerve also causes pruritus and pain.
H1 receptors bind on H1 receptor antagonist selectivity and histamine target cell, blocking histamine H1 receptor and bring into play antihistamine effect; Adhesion molecule is to participate in body inflammatory reaction and immunoreactive important component, the inflammatory reaction that antihistamine drug energy anti-adhesion is numerator mediated.H1 receptor antagonist can be according to its onset speed, and having or not of Pharmacokinetic Characteristics and the selectivity to H1 receptor and sedation, is divided into the first generation and the second filial generation.
H1 receptor antagonist also has side effect in having antianaphylactic effect, and wherein the most outstanding is central inhibitory action, as drowsiness etc., no matter is that the first generation or second filial generation H1 receptor antagonist all have similar untoward reaction.
This kind of untoward reaction is mainly because H1 receptor antagonist in use all adopts the drug systemic administration route such as oral, drug dose is larger simultaneously, substantially all more than 5mg/ days, in performance anti-allergic effects, also can produce untoward reaction to central nervous system.
Summary of the invention:
The discovery that we are surprised, in the time that micro-H1 receptor antagonist is made suction preparation, in the anaphylaxis for the treatment of respiratory tract, untoward reaction obviously reduces, and especially, when with glucocorticoid medicine composition compound medicine, also can produce good effect in the time for the treatment of asthma, curative effect is more obvious, its effect had both been better than independent inhaled or H1 receptor antagonist, was also better than and successively sucked two kinds of medicines, illustrated that both have produced synergy while suction at the same time.
A kind of Inhaled pharmaceutical composition, contain one or more H1 receptor antagonists and one or more glucocorticoids as active component, and one or more is applicable to the pharmaceutic adjuvant of inhalation.
Described H1 receptor antagonist is one or more in loratadine, Desloratadine, cetirizine, levocetirizine, astemizole, ketotifen, ebastine, fexofenadine, acrivastine, Primalan, mizolastine and salt thereof.Be preferably one or more in loratadine, Desloratadine, cetirizine, levocetirizine, ebastine, mizolastine, acrivastine, Primalan, ketotifen and hydrochlorate thereof, fumarate.More preferably one or more in loratadine, Desloratadine, cetirizine hydrochloride, levo-cetirizine hydrochloride.
Described glucocorticoid is the one of beclometasone, ciclesonide, budesonide, mometasone, fluticasone or its ester, is preferably the one in ciclesonide, budesonide, momestasone furoate, fluticasone propionate, fluticasone furoate.
Described Inhaled pharmaceutical composition, the weight proportion of glucocorticoid and H1 receptor antagonist is 1:0.1-10.Be preferably 1:0.5-5.
Described Inhaled pharmaceutical composition is Foradil Aerolizer formoterol fumarate or aerosol.Be preferably Foradil Aerolizer formoterol fumarate.Described Foradil Aerolizer formoterol fumarate, the D90 particle diameter of active component is 1～10 μ m.Preferably D90 particle diameter is 5～10 μ m, and more preferably D90 particle diameter is 5～9 μ m.
Described Foradil Aerolizer formoterol fumarate, described pharmaceutic adjuvant comprises one or more in carrier, additives.Described carrier is one or more in saccharide, aminoacid, lecithin, phosphatidylcholine.
Described aminoacid is one or more in glycine, valine, leucine.
Described saccharide is monosaccharide, disaccharide, derived carbohydrate, monosaccharide is mannitol, fructose, glucose, described disaccharide is maltose, trehalose, cellobiose, lactose, sucrose, and described derived carbohydrate is eight acetate fiber two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid Sargassum sugar esters.
Described carrier is one or both the combination in saccharide and lecithin, phosphatidylcholine.Preferably lactose.Described lactose is alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, crystallizing and drying lactose, Lactis Anhydrous.Preferably Lactis Anhydrous.
Described additives comprise one or more in surfactant, lubricant, antistatic additive.The preferred poloxamer of described surfactant.Described lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci.
Described Foradil Aerolizer formoterol fumarate, the mean diameter of described carrier is 40～80 μ m.Be preferably 50～70 μ m.
Described Foradil Aerolizer formoterol fumarate, is characterized in that the summation of described active component and the weight ratio of carrier are 1:10 ~ 1000.Be preferably 1:10 ~ 200.
Described Foradil Aerolizer formoterol fumarate, the mode subpackage take the packaged of single or multiple dosage as capsule.Capsule is plant capsule.
Described Inhaled pharmaceutical composition, preparation becomes aerosol, and described pharmaceutic adjuvant comprises pharmaceutically useful propellant and other additives of being applicable to aerosol.Described propellant is one or more in fluorohydrocarbon compounds.Be preferably a kind of or its combination in HFA 134a (HFA134a) and 1,1,1.2,3,3,3-heptafluoro-propane (HFA 227).Particularly preferably HFA134a.
Described aerosol, comprises solvent in described additives, is selected from glycerol, one or more in propylene glycol, Polyethylene Glycol, ethanol or oleic acid.Preferred alcohol.Described active component is that D90 particle diameter is the micropowder of 0.5-10 μ m.
Described Inhaled pharmaceutical composition, the dosage of H1 receptor antagonist is 50-1000 μ g/ time.Preferably 50-500 μ g/ time.
Described Inhaled pharmaceutical composition, the consumption of H1 receptor antagonist is 100-1600 μ g/ days.Preferably 100-800 μ g/ days.
Described Inhaled pharmaceutical composition, the application in the medicine of preparation treatment asthma.
Packaged that can single or multiple dosage when aforementioned pharmaceutical compositions is prepared into Foradil Aerolizer formoterol fumarate.
The preparation method of described aerosol is: to the active component micropowder that adds recipe quantity in aerosol bottle, open the valve on bottle, the mixture of premixed propellant and optional additives is imported by valve, valve-off, obtains required aerosol.Optional aerosol bottle is carried out to ultra sonic bath with solubilising
Or can adopt following preparation method: micronized active component is distributed in additives, then adds in the propellant after pre-cooling and mix, then divide and install in aerosol bottle.
Should be appreciated that because of known reason, as the retention of active component in suction apparatus, the amount of every kind of active component that patient sucks can be different from the amount of metering.Therefore the applicating ratio between active component can be different from the ratio of metering.The ratio of preferably using is in the described metered proportions indicating.
Described aerosol bottle and valve system can be selected disclosed aerosol bottle and valve system in Chinese patent CN98805261.X.
In this patent, the dosage of said medicine, with the weighing scale of medicine itself, does not comprise the weight of its salt or ester, and for example cetirizine hydrochloride 100mg, in fact refers to cetirizine 100mg, rather than the hydrochlorate 100mg of cetirizine.
Particle diameter in the present invention is equivalent volume footpath, is the diameter of the ball identical with actual particle volume.It is generally acknowledged that the diameter that laser method is surveyed is equivalent volume footpath.
D90 particle diameter refers to corresponding particle diameter when the cumulative particle sizes distribution number of a sample reaches 90%.Its physical significance be particle diameter be less than it amounts of particles account for 90%, this numerical value can detect by laser particle instrument.
Mean diameter refers to meso-position radius, can detect with laser particle analyzer.
The specific embodiment
Micronization of the present invention can use known mechanical crushing method or spray drying method.Mechanical crushing method refers to and utilizes the method for fluid energy mill (using the QM-3A of Nanjing Univ. Instrument Factory) respectively medicine and/or carrier powder to be broken into needed particle diameter.Spray drying method refers to medicine and/or carrier is dissolved in to organic solvent entirely as in ethanol, process spray dryer (as Buli Minispray, 190 types, Germany or QW-500, Xishan city Lin Zhou drying machine factory), solid material is made to needed particle diameter.Use and can also add when spray drying method surfactant as poloxamer etc.The process conditions of spray drying method can be: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Powder spray adopts No. 3 plant capsules (sino-america joint-venture Suzhou Capsule Co., Ltd produces, trade name: Vcaps), and each embodiment feeds intake according to 1000 capsules.It is aluminum-plastic packaged that the capsule of powder spray packs bubble-cap type into, when use, takes out, and packs powder spray inhaler (Shanghai balance pharmaceutical factory) into and use.
Medicine mist (dripping) the grain abundance of measuring in embodiment is below to detect according to the method in 2010 editions pharmacopeia appendix XH.
Embodiment 1
By H1 receptor antagonist, other active component fluid energy mill micronization, Lactis Anhydrous 10g is micronized to mean diameter 56 μ m with fluid energy mill, after mixing, crosses after 200 mesh sieve mixes for 3 times and is divided in 1000 No. 3 capsules.Formula sees the following form.
Reference examples 1-1～reference examples 1-25, for according to the composition and engineering of embodiment 1 corresponding numbering embodiment, the H1 receptor antagonist composition for inhalation that does not add glucocorticoid to be prepared into.
Reference examples 2-1～reference examples 2-25, for according to the composition and engineering of embodiment 1 corresponding numbering embodiment, the glucocorticoid composition for inhalation that does not add H1 receptor antagonist to be prepared into.
The preparation of aerosol, ethanol used is 95% ethanol, active component used is 0.5-10 μ m for being micronized to D90 particle diameter.
Embodiment 2
Ethanol 500g
HFA227 1000.g
Preparation technology: recipe quantity active component is added to ethanol, stir, divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, to obtain final product.Formula sees the following form.
| No. embodiment | H1 receptor antagonist | Consumption (mg) | Glucocorticoid | Consumption (mg) |
| 2-1 | Loratadine | 200 | Ciclesonide | 100 |
| 2-2 | Levo-cetirizine hydrochloride | 200 | Budesonide | 200 |
| 2-3 | Ebastine | 500 | Fluticasone propionate | 100 |
| 2-4 | Mizolastine | 100 | Momestasone furoate | 200 |
| 2-5 | Fexofenadine | 500 | Fluticasone propionate | 50 |
Embodiment 3
Ethanol 500g
HFA134a 1098g
Preparation technology: the active component of recipe quantity is added to ethanol, stir, divided dose fill, sealing-in dosage valve system, HFA134a is injected in pressurization more respectively, to obtain final product.Formula sees the following form.
| No. embodiment | Active component | Consumption (mg) | Glucocorticoid | Consumption (mg) |
| 3-1 | Loratadine | 200 | Ciclesonide | 100 |
| 3-2 | Levo-cetirizine hydrochloride | 200 | Budesonide | 200 |
| 3-3 | Ebastine | 500 | Fluticasone propionate | 100 |
| 3-4 | Mizolastine | 100 | Momestasone furoate | 200 |
| 3-5 | Fexofenadine | 500 | Fluticasone propionate | 50 |
Pharmacology embodiment 1 asthma pharmacological evaluation
1, animal model
Choose male Wistar rat, body weight is 200 ± 10g, puts into the bell glass of 5 liters of left and right, sprays into 2% acecoline and 0.1% 15 seconds of histamine phosphate's volume mixed liquor with the pressure of 400mmHg.After spraying stops, observing the drawing and breathe heavily incubation period of rat (asthma occur, breathe and be the devil, until twitch the time of falling), draw and breathe heavily the phase of diving and be less than 70 seconds or be greater than the rat of 120 seconds and will not select.
2, experimental technique
Learn from else's experience to measure to draw and breathe heavily qualified rat incubation period, carry out random packet according to the group in following table, every group 10: model group 1 gives according to inhalation route the Lactis Anhydrous that mean diameter is 55 μ m, dosage is 10mg/kg, other give respectively the medicine that embodiment and reference examples obtain, once a day, inhalation, grouping sees the following form with dosage, dosage 1 is H1 receptor antagonist agent dose, dosage 2 is glucocorticoid dosage, unit is μ g/kg, matched group 2-1～matched group 2-25 is after the H1 receptor antagonist 10min giving according to inhalation route in reference examples 1-1～1-25, resorb the glucocorticoid of reference examples 2-1～2-25, effective ingredient dosage with identical with matched group 1-1～matched group 1-25 respectively (be that matched group 2-1 is identical with matched group 1-1, matched group 2-2 is identical with matched group 1-2, the rest may be inferred).
The 4th day of administration give 0.25% 2 hydrochloric acid histamine when giving after whole medicines spraying after 1.5 hours, observe to drawing before and after medicine and breathe heavily preclinical variation (draw while breathing heavily animal and do not occur in 6 minutes that the person of falling breathes heavily the volt phase and calculated as 360 seconds to draw).
Table 1 sucks the impact (n=10, mean ± SD) of induction asthma attack on histamine phosphate's spraying
4, conclusion: suck preparation by the table visible glucocorticoid of l and H1 receptor antagonist agent method and can obviously extend the Experimental Asthma In Guinea-pigs outbreak incubation period of histamine phosphate's induction, with independent inhaled or H1 receptor antagonist, and successively suck both and compare, compound recipe provided by the invention sucks preparation, can obviously extend to draw and breathe heavily incubation period, determined curative effect has clinical use value very much.
Pharmacology embodiment 2 nervus centralis untoward reaction pharmacological evaluation
2.1 laboratory animals: Kunming mouse, body weight 20 ± 2g.
2.2 instrument JZZ98-CM mice activity inventory instrument, RM86 Xing Ba road physiograph.
The experimental technique of 2.3 impacts on central nervous system
2.3.1.1 on the freely impact of activity of mice
Get Kunming mouse, male and female half and half, by body weight random packet, every group 10, give respectively the medicine of corresponding dosage with gavage, suction according to following table, blank group 1 gives 1%CMC-Na (sodium carboxymethyl cellulose) solution 20ml/kg gavage, and blank group 2 gives 5mg/kg lactose and sucks.After 10 minutes, put into JZZ98-CM mice activity inventory instrument with administration, record is take 10 minutes as unit record mice autonomic activities number of times and observe the variation of its outward appearance behavior, and continuous record 60 minutes, gets minimum and add up.
2.3.1.2 on the freely experimental result of movable impact of mice
The impact of 2.3.2.1 falling asleep on giving the mice of subliminal hypnosis metering pentobarbital sodium
Get Kunming mouse, male and female half and half, by body weight random packet, every group 10, give respectively the medicine of corresponding dosage with gavage, suction according to following table, blank group 1 gives 1%CMC-Na (sodium carboxymethyl cellulose) the solution 20ml/kg of same volume, and blank group 2 gives 5mg/kg lactose and sucks.After inhalation behind 30 minutes, oral administration 60 minutes, all at lumbar injection pentobarbital sodium 30mg/kg, above as the index of falling asleep using righting reflex loss 1min, observe in 10min each treated animal number of falling asleep, the calculating quantity of falling asleep.
The experimental result of impact 2.3.2.2 mice falls asleep
Can prove by above-mentioned untoward reaction experiment, compound preparation provided by the invention, the untoward reaction of nervus centralis is less compared with oral H1 receptor antagonist.
Claims (10)
1. an Inhaled pharmaceutical composition, contains one or more H1 receptor antagonists and one or more glucocorticoids and one or more and is applicable to the pharmaceutic adjuvant of inhalation.
2. Inhaled pharmaceutical composition as claimed in claim 1, the pharmaceutic adjuvant that it is characterized in that being applicable to inhalation contains one or both in lactose and aminoacid, magnesium stearate.
3. Inhaled pharmaceutical composition as claimed in claim 1, is characterized in that described glucocorticoid is the one of beclometasone, ciclesonide, budesonide, mometasone, fluticasone or its ester.
4. the Inhaled pharmaceutical composition as described in as arbitrary in claim 1-8, is characterized in that described Inhaled pharmaceutical composition is Foradil Aerolizer formoterol fumarate or aerosol.
5. Inhaled pharmaceutical composition as claimed in claim 10, is characterized in that D90 particle diameter is 5～9 μ m.
6. Inhaled pharmaceutical composition as claimed in claim 9, is characterized in that described Foradil Aerolizer formoterol fumarate, and described pharmaceutic adjuvant comprises one or more in carrier, additives.
7. Inhaled pharmaceutical composition as claimed in claim 13, is characterized in that described carrier is one or more in saccharide, aminoacid, lecithin, phosphatidylcholine.
8. Inhaled pharmaceutical composition as claimed in claim 14, is characterized in that described carrier is one or both the combination in saccharide and lecithin, phosphatidylcholine.
9. Inhaled pharmaceutical composition as claimed in claim 13, is characterized in that the mean diameter of described carrier is 50～70 μ m.
10. Inhaled pharmaceutical composition as claimed in claim 13, is characterized in that the summation of described active component and the weight ratio of carrier are 1:10 ~ 200.
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| CN201210494862.5A CN103830731A (en) | 2012-11-26 | 2012-11-26 | Glucocorticoid/H1 receptor antagonist compound inhalation composition |
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| CN201210494862.5A CN103830731A (en) | 2012-11-26 | 2012-11-26 | Glucocorticoid/H1 receptor antagonist compound inhalation composition |
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101102760A (en) * | 2003-09-15 | 2008-01-09 | 康宾纳特克斯公司 | Methods and reagents for the treatment of immunoinflammatory disorders |
| CN102247597A (en) * | 2010-05-19 | 2011-11-23 | 天津金耀集团有限公司 | Novel inhalant containing glucocorticoid and bronchodilator |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101102760A (en) * | 2003-09-15 | 2008-01-09 | 康宾纳特克斯公司 | Methods and reagents for the treatment of immunoinflammatory disorders |
| CN102247597A (en) * | 2010-05-19 | 2011-11-23 | 天津金耀集团有限公司 | Novel inhalant containing glucocorticoid and bronchodilator |
Non-Patent Citations (1)
| Title |
|---|
| 崔福德: "《药剂学》", 31 January 2006 * |
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