CN102247385A - Inhalation preparation containing calcitriol and budesonide and preparation method thereof - Google Patents
Inhalation preparation containing calcitriol and budesonide and preparation method thereof Download PDFInfo
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Abstract
The invention discloses an inhalation preparation containing calcitriol and budesonide and a preparation method thereof. The inhalation preparation containing calcitriol and budesonide comprises calcitriol and budesonide as active components and one or more pharmaceutic adjuvants suitable for inhaled drugs, wherein, the weight ratio of calcitriol to budesonide is 100-800:1. The inhalation preparation containing calcitriol and budesonide can be used for treating bronchial diseases in humans or mammals.
Description
Technical field:
The present invention relates to treat the especially medicine of asthma of respiratory tract disease, particularly suck powder spray and preparation method thereof.
Background technology:
Asthma is a kind of chronic airway inflammation, it is characterized by reversibility airway obstruction and airway reactivity and increases, and the secretions increase that airway obstruction is caused by the bronchial mucosa inflammation, myxedema and two kinds of factors of inflammatory stimulus smooth muscle spasm cause; And airway reactivity to increase also be because the result of the bronchial epithelial cell damage that airway inflammation causes.People recognize to have only the inflammation of control air flue mucosa, just can reach the purpose of final reduction airway hyperreactivity, relieving asthma symptoms.The medicine for the treatment of pulmonary disease such as asthma at present mainly contains following several: (1) broxaterol, (2) xanthine drug, (3) anticholinergic agent, (4) glucocorticoid, (5) antiallergic agent.China document " imbedibility hormone pharmacokinetics and pharmacodynamics " (Wang Changzheng, practical hospital clinical magazine, the 4th the 1st phase of volume of January in 2007,16-18) point out, suction parahormone (ICS) has become a line medicine of asthma long-term treatment, as ciclesonide, fluticasone propionate, momestasone furoate, budesonide etc.; Wherein budesonide (Budesonide BP) is a kind of novel suction parahormone,
The document points out that also ideal ICS should be the perfect adaptation of effectiveness and safety, although ICS has great advance than the general hormone aspect the safety of treatment, still can not satisfy the needs of clinical treatment well.Untoward reaction such as adrenal cortex function inhibition still can appear in long-term heavy dose of ICS that uses, and use the ICS (inferior heavy dose) of so-called safe dose can't control severe asthma in the majority effectively separately.
Calcitriol (1, the 25-dihydroxy vitamin d3) be that vitamin D3 is at the intravital active metabolite of people, Li Pei etc. (1,25-dihydroxyvitamin D3 and analog thereof are to immune regulating action, journal is given birth in medical research, the 20th the 3rd phase of volume of March in 2007, calcitriol is disclosed except playing a role 298-301) in the metabolism of calcium and skeleton, also influence the growth and the differentiation of various kinds of cell, have immunoregulatory effect, can produce the effect of prevention and treatment the various autoimmune disease.Yet the document also points out, because required dosage is bigger when carrying out immune modulating treatment, so prolonged application causes side effect such as hypercalcemia easily, and the application of calcitriol has been subjected to certain restriction.
Summary of the invention:
The discovery that we are surprised, when the calcitriol of trace and budesonide are made compound recipe and are sucked preparation, produced significant synergism, therapeutic effect when having improved treatment asthma, by control dosage, avoid the side effect such as hypercalcemia that when life-time service, produce, simultaneously, because the use of calcitriol has also reduced the side effect of 17-hydroxy-11-dehydrocorticosterone unexpectedly.
The invention provides a kind of inhalation compositions, by constituting as the budesonide of active component and calcitriol and one or more pharmaceutic adjuvants that is applicable to inhalation.
Described inhalation compositions, the mass ratio that it is characterized in that described budesonide and calcitriol is 100-800: 1.
Described inhalation compositions is preferably made micropowder as the budesonide and the calcitriol of active component, and the particle diameter of described micropowder is 0.5～10 μ m, and preferred 1～8 μ m is preferably 2～5 μ m especially.
Described inhalation compositions is preferably made powder spray or aerosol.
Described inhalation compositions is made powder spray, and preferred described pharmaceutic adjuvant comprises carrier and additives, and the particle diameter of described carrier micropowder is 25～45 μ m.
Described carrier micropowder also can mixing for the micropowder of the micropowder of particle diameter 5-15 μ m and particle diameter 25-45 μ m.
Described carrier is one or more in saccharide carrier, the aminoacid, and described aminoacid includes but are not limited to glycine, valine.Described saccharide comprises monosaccharide, disaccharide and/or its derived carbohydrate, described monosaccharide includes but are not limited to mannitol, fructose, glucose, described disaccharide includes but are not limited to maltose, trehalose, cellobiose, lactose, sucrose, described derived carbohydrate is meant that the straight or branched hydrocarbon chain of involved 20 carbon atoms at the most of at least one hydroxyl on the glycan molecule replaces, include but are not limited to eight acetate fibers, 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 derived carbohydrate can also description with reference to international monopoly WO99/33853 in disclosed derived carbohydrate example, preferred in derived carbohydrate is eight acetic acid-D-cellobiose ester as carrier; In above-mentioned various carriers, most preferably carrier is a lactose.Described lactose is the alpha-lactose monohydrate, β-Lactis Anhydrous, one or more in amorphous spray-dried lactose, the crystallizing and drying lactose, preferred especially crystallizing and drying lactose.
Preferably add additives in described carrier micropowder, described additives include but are not limited to surfactant, lubricant, antistatic additive.The consumption of described additives and kind can be with reference to any known prior art and documents, and (Cui Fude etc., 2006-11-1, People's Health Publisher) is disclosed as " pharmaceutics ".
The preferred poloxamer of described surfactant.The summation of active component: the poloxamer weight ratio is 1: 0.01～5.Poloxamer is also as antistatic additive.Described lubricant can also include but are not limited to one or more in magnesium stearate, micropowder silica gel, the Pulvis Talci, and consumption is 0.01%～1% of a carrier micropowder weight.
The summation of described active component and the weight ratio of carrier are 1: 10～1000; Preferred 1: 10～200.
The method of micronization of described active component can adopt spray drying method, fluid bed supersonic airstream comminuting method, and high speed polishing, ball-milling method, fluid energy mill method, solvent method etc. preferably adopt spray drying method.
Described composition for inhalation, packaged that can single or multiple dosage when being prepared into powder spray preferably adopts the mode packing of capsule, and each capsule contains the above-mentioned powder spray of 5-40mg.Preferred each capsule contains the above-mentioned powder spray of 10-30mg.
The described capsule that contains powder spray can adopt known powder spray capsule inhaler to suck.Described inhaler for example WO94/28958 is disclosed.
Described composition for inhalation, preparation method when being prepared into powder spray is that the active component micronization is become particle diameter is the micropowder of 0.5-10 μ m, again carrier being become particle diameter with the additives micronization is the micropowder of 20～45 μ m, or part carrier micronization is become particle diameter is the micropowder of 5-15 μ m, it is the micropowder of 20～45 μ m that all the other carrier micronizations become particle diameter, is contained in the capsule carrier micropowder was mixed 3 mixings of 200 mesh sieves with the active component micropowder after.
Particle diameter of the present invention is mass median diameter (mass mean diameter).
Described composition for inhalation, can also prepare becomes aerosol, and described pharmaceutic adjuvant comprises pharmaceutically useful propellant and other the optional additives that are applicable to aerosol.
Described propellant is one or more in the fluorohydrocarbon compounds.Be preferably 1,1,1,2-tetrafluoroethane (HFA134a) and 1,1,1,2,3,3, a kind of or its combination in the 3-heptafluoro-propane (HFA227).The preferred HFA134a that adopts.
Comprise solvent in the described additives, be selected from glycerol, propylene glycol, Polyethylene Glycol, ethanol or oleic acid preferably use ethanol.
Described additives can also comprise other low volatility component, comprise other alcohol, glycol, alkanol for example is as decanol (decyl alcohol), the sugar alcohol that comprises Sorbitol, mannitol, lactose, maltose alcohol, glycofural (tetrahydrofuran base methanol) and dipropylene glycol.Comprise that vegetable oil, organic acid are as comprising dodecylic acid and tetradecanoic acid and stearic saturated carboxylic acid; Comprise sorbic acid, particularly oleic unsaturated carboxylic acid, the known aerosol that is applied to, to improve the physical stability of drug suspension, it is used to keep the na non agglomerating composition of particle to have as dispersant: glucide, ascorbic acid, cyclamic acid, aminoacid or aspartame; Alkane such as dodecane and octadecane; Terpenes such as menthol, eucalyptol, limonene; Sugar is as lactose, glucose, sucrose; Polysaccharide such as ethyl cellulose, dextran; Antioxidant such as Yoshinox BHT, ascorbic acid, sodium pyrosulfite, butylated hydroxyanisol; Polymer such as polyvinyl alcohol, polyvinyl acetate, polyvinylpyrrolidone; Amine such as ethanolamine, diethanolamine, triethanolamine; Steroid class such as cholesterol, cholesteryl ester.Can not add other low volatile components.
Described composition for inhalation, when making aerosol, optimization formula is: active component summation content is 0.5-8mg/ml, is preferably 1-5mg/ml; Ethanol weight percent content as solvent is 5-20%, and the propellant of surplus.
The preparation method of described aerosol is: add the active component micropowder of recipe quantity in the aerosol bottle, open the valve on the bottle, the mixture of premixed propellant and optional additives is imported by valve, valve-off obtains required aerosol.Optional the aerosol bottle is carried out ultra sonic bath with solubilising
Perhaps can adopt following preparation method: micronized active component is distributed in the additives, adds mixing in the propellant after the pre-cooling again, divide again to install in the aerosol bottle.
Required active component is crushed into the micropowder that particle diameter is 0.5-10 μ m
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 the patient sucks can be different from the amount of metering.Therefore the applicating ratio between the active component can be different from the ratio of metering.The ratio of preferably using is in described indicated metered proportions.
Described aerosol bottle and valve system adopt known aerosol bottle and valve system, can select disclosed aerosol bottle and valve system among the Chinese patent CN98805261.X for use.
Inhalation compositions provided by the invention, the compound preparation of a kind of budesonide and calcitriol is provided, compare with independent inhalation, pharmacology embodiment shows, compound recipe inhalation compositions provided by the invention can significantly reduce asthmatic model rat blood serum IgE, IL-4 and IL-5 content, can also suppress the long-term bone density of using glucocorticoid to cause separately descends, thereby realize better therapeutic effect, particularly when inhalation compositions prescription adopts preferred budesonide of the present invention and calcitriol ratio, except realizing the above-mentioned therapeutic effect, when life-time service, can not cause blood calcium to raise, make the pharmaceutical composition that makes more help life-time service.
The specific embodiment
Micronization of the present invention can use known mechanical crushing method or spray drying method.Mechanical crushing method is meant that the method for utilizing fluid energy mill is broken into needed particle diameter with budesonide and carrier powder respectively.Spray drying method is meant budesonide or carrier is dissolved in organic solvent such as the ethanol entirely, through spray dryer, solid material is made needed particle diameter.Can also add surfactant such as poloxamer etc. when using spray drying method.
Powder spray adopts No. 3 plant capsules, and (sino-america joint-venture Suzhou Capsule Co., Ltd produces, and trade name: Vcaps), each embodiment feeds intake according to 1000 capsules.The capsule of the powder spray bubble-cap formula of packing into is aluminum-plastic packaged, takes out during use, and the powder spray inhaler of packing into (Shanghai balance pharmaceutical factory) uses.
Embodiment 1
With budesonide 200mg, calcitriol 1mg is dissolved in ethanol, after the filtration, filtrate spray drying, micronization make it mean diameter and reach 2 μ m, and lactose 10g is micronized to mean diameter 20 μ m with fluid energy mill, after the mixing, cross and to be divided in behind 3 mixings of 200 mesh sieves in No. 3 capsules.Every capsules has budesonide 200 μ g, calcitriol 1 μ g
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h
Embodiment 2-1
With budesonide 100mg, calcitriol 1mg is dissolved in ethanol, after the filtration, filtrate spray drying, micronization make it mean diameter and reach 4 μ m, lactose 20g, be micronized to mean diameter 30 μ m with fluid energy mill, mixing installs in No. 3 capsules with dividing behind 3 mixings of 200 mesh sieves.Every capsules has budesonide 100 μ g, calcitriol 1 μ g.
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 2-2
According to the prescription of embodiment 2-1, budesonide and calcitriol are made it mean diameter with the fluid energy mill micronization reach 3 μ m, carrier is changed into eight acetic acid-D-cellobiose ester of mean diameter 35 μ m, according to the prepared powder spray of embodiment 2-1.
Embodiment 3
With budesonide 200mg, calcitriol 0.25mg is dissolved in ethanol, and after the filtration, the filtrate spray drying makes it mean diameter and reaches 5 μ m, and lactose 5g is micronized to mean diameter 40 μ m with fluid energy mill, mixes, and crosses to divide behind 3 mixings of 200 mesh sieves to install in No. 3 capsules.Every capsules has budesonide 200 μ g, calcitriol 0.25 μ g
Process conditions are: inlet temperature is 105 ℃, and outlet temperature is 68 ℃, throughput 90%, and the jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Embodiment 4
Get budesonide 100mg, calcitriol 0.25mg is dissolved in ethanol, filters the rear filtrate spray drying, makes it mean diameter and reaches 7 μ m, and lactose 40g is micronized to mean diameter 45 μ m with fluid energy mill, crosses to divide behind 3 mixings of 150 mesh sieves to install in No. 3 capsules.Every capsules has budesonide 100 μ g, calcitriol 0.25 μ g
The preparation of aerosol, used ethanol are dehydrated alcohol, and used active component is 0.5-10 μ m for being micronized to particle diameter.
Embodiment 5
Budesonide 1000mg calcitriol 12.5mg
Ethanol 67.8g
HFA227?1287.g
Preparation technology: the budesonide and the calcitriol of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, promptly.
Embodiment 6
Budesonide 8000mg calcitriol 100mg
Ethanol 244g
HFA227 970g
Preparation technology: the budesonide and the calcitriol of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, promptly.
Embodiment 7
Budesonide 5000mg calcitriol 10mg
Ethanol 82.7g
HFA134a?1098g
Preparation technology: the budesonide and the calcitriol of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA227 is injected in pressurization more respectively, promptly.
Embodiment 8
Budesonide 2000mg calcitriol 10mg
Ethanol 94.7g
HFA134a?1098g
Preparation technology: the budesonide and the calcitriol of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA134a is injected in pressurization more respectively, promptly.
Embodiment 9
Budesonide 4000mg calcitriol 10mg
Ethanol 94.7g
HFA134a?1098g
Preparation technology: the budesonide and the calcitriol of recipe quantity are added ethanol, stir, make material dissolution, the divided dose fill, sealing-in dosage valve system, HFA134a is injected in pressurization more respectively, promptly.
Pharmacology embodiment 1
According to Chinese document " airway inflammation disease " (Liu Chuntao, People's Health Publisher, 2004; 506-507) open, SERUM IgE, IL-4, IL-5 occupies critical role in pathogenesis of asthma mechanism, so changes with the serum content of above-mentioned three kinds of factors among this pharmacology embodiment and characterize the therapeutic effect of medicine to the asthmatic model rat.
1, laboratory animal, male wistar rat, age in 6-8 week, body weight 180 ± 20g, 10 every group.Grouping and administration situation such as following table:
| Numbering | Matched group | Model group | Experimental group 1 | Experimental group 2 | Experimental group 3 | Experimental group 4 | Experimental group 5 | Experimental group 6 | Experimental group 7 | Experimental group 8 | Experimental group 9 |
| Budesonide dosage μ g/ (kg*d) | 0 | 0 | 10 | 10 | 20 | 20 | 10 | 10 | 0 | 20 | 10 |
| Calcitriol dosage μ g/ (kg*d) | 0 | 0 | 0.025 | 0.1 | 0.025 | 0.1 | 0.2 | 0.3 | 0.1 | 0 | 0.1 |
Experimental group 1,2,5,6 adopts following prescription: budesonide 2000mg ethanol 94.7g HFA134a 1098g, the addition of calcitriol is prepared according to the ratio in the last table.Experimental group 3,4,8 adopts following prescription: budesonide 4000mg ethanol 94.7g HFA134a 1098g, the addition of calcitriol is prepared according to the ratio in the last table.Experimental group 7 adopts according to calcitriol 50mg, ethanol 94.7g, and the aerosol that the formulated of HFA134a 1098g becomes carries out administration, and each group experiment medicine is according to the method preparation of embodiment 8.During experimental group 9 administrations, first with experimental group 7 pharmaceutical compositions for use administrations, reuse experimental group 8 pharmaceutical compositions for use administrations behind the 1h excessively, matched group and model group adopt blank HFA134a propellant to suck.
All experimental animals adopt the conventional feed feeding, feed formula such as following table:
| Raw material | Corn | Semen Glycines | Salt | Sorghum vulgare Pers. | Testa Tritici | Yeast | Fish flour | Bone meal |
| Proportioning % | 48 | 20 | 0.5 | 7 | 15 | 2 | 5 | 2.5 |
Feedstuff essential element content see the following form (unit, mg/kg):
| Element | Ca | Mg | K | Na |
| Content mg/kg | 7900 | 1600 | 2800 | 3000 |
2, experiment medicine, chicken egg protein (OVA) ((U.S. SIGMA company), deactivation pertussis vaccine (5 * 10
9/ ml)
3, modeling and administration are according to Chinese document " dexamethasone is to the influence of asthmatic guinea pigs airway wall thickness " (Wang Luning etc., Chinese Journal of Pathophysiology, 2002,18 (5); Disclosed method is carried out modeling 564-565), and the 1st, model group and each treated animal of experiment (contained OVA10mg, deactivation pertussis vaccine 5 * 10 with 1ml sensitization liquid
9Individual, gel aluminum hydroxide 100mg) lumbar injection sensitization; The 8th repeats sensitization once; Pattern drawing group on the 15th places the atomizing inlet box with each treated animal of experiment, and (60cm * 40cm * 40cm), suck to excite with the 1%OVA solution atomization with ultrasound atomizer once a day puts into 10 rats at every turn, sucks 20min, sucks for eight weeks continuously.Matched group adopts the suction of injecting and atomize of same amount physiologic saline for substitute modeling medicine.30min employing aerosol inhalation before experiment is respectively organized and excited every day, matched group and model group adopt blank HFA134a to replace, the aerosol drug delivery method is: animal is fixed on the operating-table becomes 60-70 ° of placement with level, seal the nostril with adhesive tape, make animal can only per os air-breathing, aerosol nozzle place connects a plastic tube (3cm), the animal tongue is pulled out and plastic tube is extended the throat position, treats that animal is air-breathing to finish administration.
4, after exciting, gets last in the 24h with opening breast under the 1% pentobarbital intraperitoneal anesthesia (40mg/kg), through the right ventricle intubate to pulmonary artery, get middle lobe of right lung after getting express developed with normal saline, place 10% formaldehyde fixing, carry out HE dyeing and under light microscopic, observe experimental rat model of asthma lung tissue disease Neo-Confucianism.Get blood survey blood calcium value before facing anesthesia.
5, SERUM IgE, IL-4 and IL5 assay, according to experimental rat model of asthma abdominal aortic blood after anaesthetizing, in 4 ℃ leave standstill 30min after, with the centrifugal 15rain of 1500r/rain, collect upper serum, adopt the ELISA method to measure SERUM IgE, the content of IL-4 and IL-5), ELISA test kit (the biological company limited of Wuhan doctor's moral), result such as following table (
N=10)
| Numbering | Matched group | Model group | Experimental group 1 | Experimental group 2 | Experimental group 3 | Experimental group 4 | Experimental group 5 | Experimental group 6 | Experimental group 7 | Experimental group 8 | Experimental group 9 |
| IgE(×10 3I U/L) | 35.3±2 .7 | 385.1± 8.0 | 95.5±4 .4 | 81.0±4 .3 | 69.9±3 .9 | 65.4±4 .3 | 79.5±3 .7 | 79.6±4 .2 | 255±8. 2 | 123±5. 8 | 109±6. 0 |
| IL-4(ng/L ) | 8.23±0 .58 | 24.4±1 .3 | 13.1±0 .60 | 12.2±0 .58 | 10.8±0 .52 | 10.0±0 .65 | 12.5±0 .26 | 12.7±0 .55 | 18.4±0 .59 | 15.3±0 .61 | 14.7±0 .60 |
| IL-5(ng/L ) | 12.2±1 .5 | 60.9±3 .6 | 20.8±2 .1 | 18.1±1 .9 | 16.5±1 .7 | 14.9±1 .3 | 18.0±1 .7 | 18.0±2 .1 | 45.3±2 .9 | 25.0±2 2 | 23.3±1 .8 |
| Blood calcium mmol/L | 2.60±0 .12 | 2.48±0 .12 | 2.55±0 .13 | 2.61±0 .08 | 2.58±0 .12 | 2.60±0 .07 | 2.91±0 .13 | 3.12±0 .15 | 2.65±0 .09 | 2.40±0 .09 | 2.59±0 .12 |
SERUM IgE, IL-4 and IL-5 content and blood calcium value testing result show, compare experimental group 1-6 SERUM IgE with model group, IL-4 and IL-5 content all have remarkable decline (P＜0.01), and compare with the experimental group 7,8 of medicine with single, experimental group 1-6 SERUM IgE, IL-4 and IL-5 content also have remarkable decline (P＜0.05), illustrate that budesonide and calcitriol make compound preparation and can produce significant effect than single preparations of ephedrine to the asthmatic model rat.In addition, adopt the experimental group 5-6 of higher calcitriol dosage to compare with experimental group 2 than low dosage, do not produce better therapeutic effect, explanation adds more a high proportion of calcitriol in budesonide can not produce more positive therapeutic effect, opposite, in experimental group 1-6, higher calcitriol dosage causes the animal blood calcium of experimental group 5,6 to be higher than can to cause blood calcium to raise after medicine that normal value (rat blood calcium normal value is 2.2-2.8mmol/L) illustrates high calcitriol ratio used in the long period, thereby has influence on the persistence of drug use.By the proportion of preferred calcitriol and budesonide, the animal pattern of experimental group 1-4 had both overcome single blood calcium that causes with budesonide and had descended, and can not cause the rising of calcium level again simultaneously.In addition, adopt the experimental group 9 of administration successively to compare with the experimental group 2 that adopts the compound recipe administration, therapeutic effect also has certain gap, and it is relevant that this may be that two kinds of active component are made the synergism that compound preparation produces in the treatment.
7, experimental rat model of asthma lung tissue pathological change, light microscopic is observed down, compares with matched group, and model group rat airway wall and smooth muscle obviously thicken, epithelial cell shedding, inflammatory cell infiltration around reaching in the luminal stenosis, tube wall, collagen deposition increases.The above-mentioned change of experimental group 1-6 obviously alleviates.Experimental group 7 is compared no significant difference with model group, and the effect of experimental group 8,9 adopts experimental group 9 its therapeutic effect of two kinds of active component of priority inhalation and the experimental group 2 that adopts compound preparation that notable difference is also arranged between experimental group 1-6 and experimental group 7.Compare with the experimental group 9 of administration successively with single experimental group 7,8 that sucks with budesonide or calcitriol, experimental group 1-4 demonstrates and budesonide and calcitriol are made compound preparation sucks treatment the airway remodeling of inhibition asthmatic model rat has been produced significant synergistic therapeutic effect.
8, all rats are put to death the whole body bone density measurement that moves ahead.Adopt U.S. HologicQDR-4000A type fladellum dual intensity X line absorption instrument, a year measurement coefficient of variation is 0.52%; Metering system is selected the toy scan mode, and sweep parameter is as follows: voltage 140/100kVp, electric current 2.5mA, sweep length 5.8cm, width 5.0cm, sweep span 0.31mm * 0.31mm, speed 4.8s/cm.
Testing result following (
N=10, bone density unit: g/cm
2)
| Numbering | Matched group | Model group | Experimental group 1 | Experimental group 2 | Experimental group 3 | Experimental group 4 | Experimental group 5 | Experimental group 6 | Experimental group 7 | Experimental group 8 | Experimental group 9 |
| The whole body bone density | ?0.205±?0.004 | 0.203± 0.003 | 0.205± 0.004 | 0.206± 0.004 | 0.204± 0.005 | 0.206± 0.004 | 0.206± 0.004 | 0.207± 0.004 | 0.206± 0.003 | 0.203± 0.004 | 0.205± 0.004 |
The bone density testing result shows that the bone density that the experimental group 1-4 of employing compound preparation can overcome experimental group 8 generations of simple use hormone descends.
Claims (10)
1. inhalation compositions is by constituting as the budesonide of active component and calcitriol and one or more pharmaceutic adjuvants that is applicable to inhalation.
2. pharmaceutical composition as claimed in claim 1, the mass ratio that it is characterized in that described budesonide and calcitriol is 100-800: 1.
3. as the pharmaceutical composition of claim 1 or 2, it is characterized in that described budesonide and calcitriol as active component make micropowder, the particle diameter of described micropowder is 0.5～10 μ m.
4. as the arbitrary described pharmaceutical composition of claim 1-3, preferably make powder spray or aerosol.
5. as powder spray as described in the claim 4, preferred described pharmaceutic adjuvant comprises carrier and additives.
6. as the arbitrary described pharmaceutical composition of claim 5, it is characterized in that the preferred lactose of described carrier.
7. as the arbitrary described pharmaceutical composition of claim 5-6, it is characterized in that the summation of described active component and the weight ratio of carrier are 1: 10～1000.
8. aerosol as claimed in claim 4, described pharmaceutic adjuvant comprise pharmaceutically useful propellant and other the optional additives that are applicable to aerosol.
9. pharmaceutical composition as claimed in claim 8 is characterized in that described propellant is preferably 1,1,1,2-tetrafluoroethane and 1,1,1,2,3,3, a kind of or its combination in the 3-heptafluoro-propane.
As claim 8-9 arbitrary as described in composition for inhalation, when making aerosol, optimization formula is: active component content is 0.5-8mg/ml; Ethanol weight percent content as solvent is 5-20%, and the propellant of surplus.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102949724A (en) * | 2011-11-30 | 2013-03-06 | 天津金耀集团有限公司 | Inhalation medicine composition containing glucocorticoid and NOS (nitric oxide synthase) inhibitor |
| CN103156863A (en) * | 2011-12-14 | 2013-06-19 | 天津金耀集团有限公司 | Inhalation pharmaceutical composition containing budesonide and terbutaline |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1700921A (en) * | 2002-09-24 | 2005-11-23 | 康宾纳特克斯公司 | Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines |
| CN101237838A (en) * | 2005-06-17 | 2008-08-06 | 康宾纳特克斯公司 | Combination therapy for the treatment of immunoinflammatory disorders |
| CN101347437A (en) * | 2007-07-20 | 2009-01-21 | 天津药业集团有限公司 | Medicament composition for treating respiratory disease |
-
2010
- 2010-05-19 CN CN2010101756963A patent/CN102247385A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1700921A (en) * | 2002-09-24 | 2005-11-23 | 康宾纳特克斯公司 | Methods and reagents for the treatment of diseases and disorders associated with increased levels of proinflammatory cytokines |
| CN101237838A (en) * | 2005-06-17 | 2008-08-06 | 康宾纳特克斯公司 | Combination therapy for the treatment of immunoinflammatory disorders |
| CN101347437A (en) * | 2007-07-20 | 2009-01-21 | 天津药业集团有限公司 | Medicament composition for treating respiratory disease |
Non-Patent Citations (2)
| Title |
|---|
| 《第四军医大学学报》 20081231 马雅心，等 维生素D3联合地塞米松对哮喘大鼠的治疗作用及机制 1407-1409 3-31 第29卷, 第15期 * |
| 马雅心，等: "维生素D3联合地塞米松对哮喘大鼠的治疗作用及机制", 《第四军医大学学报》 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102949724A (en) * | 2011-11-30 | 2013-03-06 | 天津金耀集团有限公司 | Inhalation medicine composition containing glucocorticoid and NOS (nitric oxide synthase) inhibitor |
| CN103156863A (en) * | 2011-12-14 | 2013-06-19 | 天津金耀集团有限公司 | Inhalation pharmaceutical composition containing budesonide and terbutaline |
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