CN101926767A - Budesonide-foaming agent combination - Google Patents
Budesonide-foaming agent combination Download PDFInfo
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- CN101926767A CN101926767A CN2009100694115A CN200910069411A CN101926767A CN 101926767 A CN101926767 A CN 101926767A CN 2009100694115 A CN2009100694115 A CN 2009100694115A CN 200910069411 A CN200910069411 A CN 200910069411A CN 101926767 A CN101926767 A CN 101926767A
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- foaming agent
- agent combination
- budesonide
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Abstract
The invention relates to a Budesonide-foaming agent combination which contains Budesonide as the active component and one or various pharmaceutically acceptable auxiliary materials applicable to a foaming agent, wherein the content of the Budesonide or R-Budesonide as the active component is 0.05-0.2% (w/w), and the volumetric expansion ratio of the foaming agent combination is 25-50.
Description
Invention field
The present invention relates to a kind of foaming agent combination, particularly a kind of foaming agent combination that contains budesonide.
Background technology
Budesonide (Budesonide is a kind of potent local action glucocorticoid hormone preparation CAS:51333-22-3), and its molecular formula is as follows:
Because the effect of whole body glucocorticoid is very little, budesonide extensively is used to treat local inflammation and anaphylactic diseases such as asthma, allergic rhinitis and ulcerative colitis.
At present medicinal budesonide is 22 (S) and the racemic mixture of two kinds of optical isomers of 22 (R), and experiment shows, for the S-budesonide 1.5 times of tiring of R-budesonide.
Chronic non-specific ulcerative colitis (ulcerativecolitis, UC) being a kind of cause of disease chronic disease still not fully aware of, mainly is to invade and the chronic nonspecific inflammatory diseases of colonic mucosa, often starts from left hemicolon, can make progress gradually in a continuous manner to colon near-end and even total colectomy.The clinical symptoms weight differs, and can have to alleviate with outbreak to alternate, and the patient can only have the colon symptom, and General Symptoms also can occur together.The medicine of UC mainly contains aminosallcylic acid class such as mesalazine, antibiotic, glucocorticoid and thyroliberin, immunomodulator etc.Wherein, the short term effect of glucocorticoid is better, and effective percentage can reach 90% energy inflammation-inhibiting and immunoreation, alleviates poisoning symptom.Be applicable to generally that sulfa drugs is failed to respond to any medical treatment, acute attack stage or fulminant type case.
Germany Dr.Falk Pharma GmbH company has produced the budesonide rectum foam of a kind of commodity BUDENOFALK by name in Europe in 1998, be used for the treatment of UC.But said preparation can only arrive near section sigmoid colon because expansion ratio is lower.Extended capability for the far-end colon is very weak.And the budesonide as active component in this foam is to be dissolved in propylene glycol, though FDA (Food and Drug Adminstration) (FDA) and U.S. cosmetic composition audit committee, assert all that haply the propylene glycol safety is higher, and Chinese Pharmacopoeia version in 2005 has been recorded propylene glycol for the 896th page, but on the material safety data sheet (Material Safty Date Sheets) of propylene glycol, then speak of propylene glycol skin has been had the constitutional stimulation, might cause subjective burning sensation, sensation of pricking and gargalesthesia; In addition, because propylene glycol has the characteristic of fat-soluble solvent, the propylene glycol of life-time service high concentration can be influential to epidermis sebum structure; In addition, especially higher because propylene glycol might cause irritant dermatitis to the zest of skin and mucosa in concentration, under the situation that sealing is used, easier skin rubefaction, an erythema, the scratchy and coarse situation of decortication of causing; There is 1～5% people can when touching propylene glycol, produce local skin allergic eczema reaction allergic dermatitis approximately, and, taking or using the food or the medicine that contain the propylene glycol composition can cause the general skin allergy for the people of anaphylaxis system.This shows that propylene glycol has potential zest to colonic mucosa, might increase the weight of ulcer.In addition, we find in stability experiment, though the active component of this foam can meet the demands before the deadline, the decomposition of its effective ingredient is still comparatively serious, and this preparation production to this medicine produces and stores to sell and all produced adverse effect.
Chinese patent application CN200780002784.x discloses a kind of glucocorticoid foam that does not contain the high expansion ratio of emulsifing wax and/or mineral oil, can be budesonide, trimethylace tonitric tixocortol, mesalazine and pharmaceutically useful salt thereof though also disclose its effective ingredient in this application description, but the water miscible sodium salt with a kind of prednisolone is only disclosed in its description---sodium sulfo benzoate is the technical scheme that active component prepares foam between meticortelone, and unexposed any how preparation with above-mentioned non-water-soluble active component is called foam.On galenic pharmacy, water solublity and non-water-soluble active component are that technology, prescription all are very different when being prepared into preparation.Disclosed technical scheme can't be applicable to numerous other non-water-soluble active component in this application.We find in the experiment in addition, though this application is claimed between water miscible meticortelone and to be absorbed seldom when the sodium sulfo benzoate rectal treatment is used and local action is stronger, but actual therapeutic effect is also unsatisfactory, be because water miscible composition is not easy to keep in colon according to one's analysis, and for the patient who suffers from ulcerative colitis, its colonic mucosa is because the destruction of top layer goblet cell slimy, its surface is difficult to absorb the drug owing to lacking mucus, has caused the local action of medicine can't bring into play on the ulcer surface of colon.
Summary of the invention:
For overcoming defective of the prior art, the invention provides a kind of new be active component with budesonide or R-budesonide, do not contain propylene glycol, have the foaming agent combination of high expansion ratio.
The invention provides a kind of foaming agent combination, the budesonide or the R-budesonide that contain as active component are 0.05%～0.2% (w/w), with its acceptable accessories, it is characterized in that active component is micronized budesonide in the described compositions, do not contain propylene glycol, the volume expansion ratio of described foaming agent combination is 25～50.
Described volume expansion ratio V is the volume (Vb) and the ratio of initial volume (Va) of the parent material of foaming not behind the foam expansion, be V=Vb/Va, the detection method of described volume expansion ratio can be according to the disclosed method of Chinese patent application CN200780002784.x.The volume expansion ratio of described foaming agent combination is preferably 25～40, is preferably 25～35 especially, most preferably is 30.
The D90 particle diameter of described micronized budesonide or R-budesonide is preferably 0.1～10 μ m, more preferably 0.5-10 μ m.
Described foaming agent combination, described pharmaceutically useful adjuvant contains pH buffer agent, surfactant, viscosity-controlling agent, the water of propellant, lubricant and surplus.
Described pH buffer agent is selected from one or more in phosphoric acid/phosphate buffer, acetic acid/acetate buffer, citric acid/citrate buffer agent, the boric acid/borate buffer, preferably phosphoric acid/phosphate buffer.The pH value of described foam is buffered to 5～7.Preferably be buffered to 5.5～6.5, described phosphoric acid/phosphate buffer consumption is 0.01%～0.1% (w/w) of foam gross mass.
Described surfactant preferred nonionic surfactants is selected from fatty glyceride, as single fatty acid glyceride; Polyol esters of fatty acids such as propylene glycol mono-oleate, polyethylene glycol mono stearate, polyethenoxy ether class such as peregal A-20, Polyoxyethylene Sorbitol Fatty Acid Esters such as polyoxyethylene 20 sorbitan monooleate (tween-80), polyoxyethylene 20 sorbitan monostearate (tween-60), polyoxyethylene 20 sorbitan monostearate (tween-40) polyoxyethylene 20 sorbitan monostearate (tween-60), sorbitan ester such as sorbitan monooleate (span-80), sorbitan ester such as sorbitan monostearate (span-60), sorbitan ester such as anhydrous sorbitol monopalmitate (span-40), and in the Polyethylene Glycol-caprylic/capric glyceride of commodity by name " Labrasol " one or more, the combination of preferred especially tween-80 and Labrasol.The total amount of described surfactant is 1%～15% (w/w) of compositions.Be preferably 1%～10% (w/w).
The preferred water-soluble cellulose polymer of described viscosity-controlling agent, as in hydroxypropyl emthylcellulose (HPMC), methylcellulose (MC), hydroxypropyl cellulose (HPC), the hydroxyethyl-cellulose (HEC) one or more, preferred hydroxypropyl emthylcellulose, described viscosity-controlling agent consumption is preferably 0.1%～1% (w/w) of foam,, be preferably 0.3% especially.Described viscosity-controlling agent in technical scheme of the present invention also as the suspending agent of micronized budesonide.
The preferred polydimethylsiloxane of described lubricant (simethicone), preferred especially viscosity is the simethicone of 50～500 centistokes.The consumption of described lubricant is 0.5%～5% (w/w), is preferably 1%～3% (w/w).
Described propellant is selected from the gas of any suitable preparation aerosol type foamable composite, is selected from propane, normal butane, iso-butane, pentane, fluorochloroparaffins, the halothane hydrocarbon one or more.Preferred halothane hydrocarbon such as HFA227, HFA134a or alkane such as propane, iso-butane, butane.The consumption of propellant is 1～10% (w/w) in the described compositions, preferred 3%～9% (w/w).
Further, foaming agent combination provided by the invention can also contain pharmaceutically useful other additives, include but are not limited to benzoic acid and salt thereof as antibiotic antiseptic, chelating agen, described antibiotic antiseptic, sorbic acid and salt thereof, p-Hydroxybenzoate, benzyl alcohol, benzalkonium chloride, benzalkonium bromide, preferred p-Hydroxybenzoate (Nipagin ester), as in methyl hydroxybenzoate, ethyl hydroxybenzoate, the propylparaben one or more.The consumption of described antibiotic antiseptic is 0.01%～1% (w/w), preferred 0.05～0.1% (w/w).The preferred ethylenediaminetetraacetic acid of described chelating agen (EDTA) or its alkali metal salt, preferred disodiumedetate (EDTA-2Na), the consumption of described chelating agen is preferably 0.01%～0.1% of compositions.
The preferred viscosity of foaming agent combination provided by the present invention is 5～20 centipoises, more preferably 5～10 centipoises.The viscosity of described foam is meant the viscosity of the compositions that all do not foam except that propellant.
Foam provided by the invention preferably adopts following method preparation.
(1) principal agent suspension: active component, water, pH buffer agent, suspending agent are placed container, and stirring or ultrasonic obtains the principal agent suspension;
(2) surfactant, lubricant and other additives are added in the principal agent suspension, continue stirring or ultrasonic to forming even emulsus suspension.
(3) under the pressurization condition, with the emulsus suspension of step (2) gained and propellant is mixed and according to single dose or the quantitative packing of multiple dose.
The invention also discloses the application of described foaming agent combination in the medicine of preparation treatment people or mammal ulcer colon.
Foaming agent combination provided by the invention is when treatment people or mammal ulcerative colitis, and the dosage of use is counted 0.01mgkg with budesonide (R-budesonide)
-1D
-1To 0.2mgkg
-1D
-1, preferred 0.02mgkg
-1D
-1To 0.1mgkg
-1D
-1, 0.04mgkg most preferably
-1D
-1To 0.06mgkg
-1D
-1When acting on human body, people's body weight is in 50kg.
Foaming agent combination provided by the invention, the preferred single dose or the multiple dose that are applicable to rectally of adopting encapsulates, and more preferably adopts multiple dose pressurization encapsulation, and on multiple dose pressurization packaging container metering valve is housed, and the foam of whenever pressing ejection is 1～5ml.
Foaming agent combination provided by the invention, because the budesonide micropowder of the preferred particle size range that is fit to, thereby avoided colonic mucosa is had the use of the propylene glycol of potential stimulus, in addition, compare with the existing budesonide-foaming agent that is dissolved in organic solvent, the present invention adopts micronized budesonide or R-budesonide, makes the stability of active component increase.Be beneficial to production more, store and sell.And, compare with the foam of available technology adopting water-soluble sugar 17-hydroxy-11-dehydrocorticosterone, owing to adopted fat-soluble budesonide or R-budesonide, micronized active component is easier in being retained in colon, thereby can realize better therapeutic effect.
The specific embodiment:
In embodiments of the present invention, preparation is during foaming agent combination, and the aerosol aluminium pot of quantitative valve system that has been packaged in sealing-in adopts the multiple dose packing forms.2208 type hydroxypropyl emthylcelluloses of hydroxypropyl methyl fiber American Pharmacopeia (USP25) regulation that adopts in the embodiment of the invention, the nominal viscosity is 11250～21000 centipoises (2% aqueous solutions).Used budesonide adopts fluid energy mill to be crushed into the micropowder of D90 particle diameter 0.5～10 μ m in the embodiment of the invention.
Embodiment 1
Budesonide micropowder 2g, tween 80 45g, Polyethylene Glycol-caprylic/capric glyceride (Labrasol) 45g, hydroxypropyl emthylcellulose 3g, simethicone 15g (viscosity is 100 centistokes), the phosphate buffer 1g of pH6.5, butane 50g,
EDTA-2Na 0.1g, ethyl hydroxybenzoate 1g, purified water adds to 1000ml
Compound method, budesonide, the hydroxypropyl methyl fiber of recipe quantity are dissolved among the purified water 600ml, ultrasonic or stir and to make it form the principal agent suspension, Polyethylene Glycol-caprylic/capric glyceride, tween 80, simethicone and the pH buffer agent that adds recipe quantity while stirring fully stirs or is ultrasonic to the emulsus suspension that forms homogeneous.
The butane propellant of above-mentioned emulsus suspension and recipe quantity is mixed, and the sealing fill is to the aerosol aluminium pot, and encapsulation quantitative valve system.Whenever press and contain budesonide 2mg.
Embodiment 2
Budesonide micropowder 0.5g, tween 80 30g hydroxypropyl emthylcellulose 0.5g, simethicone 25g (viscosity is 50 centistokes), the phosphate buffer 0.5g of pH6.5, iso-butane 15g
EDTA-2Na 0.2g, methyl hydroxybenzoate 0.5g purified water adds to 1000ml
Method branch according to embodiment 1 is filled in the aerosol aluminium pot, and encapsulation quantitative valve system, whenever presses to contain budesonide 0.5mg.
Embodiment 3
Budesonide micropowder 1g, tween 80 120g, hydroxypropyl emthylcellulose 1g, simethicone 25g (viscosity is 50 centistokes), the phosphate buffer 0.5g of pH6.5, iso-butane 15g
EDTA-2Na 0.2g, benzyl alcohol 5g purified water adds to 1000ml
Method branch according to embodiment 1 is filled in the aerosol aluminium pot, and encapsulation quantitative valve system, whenever presses to contain budesonide 1mg.
Embodiment 4
R-budesonide micropowder 0.5g, peregal a-2050g, hydroxypropyl emthylcellulose 0.5g, phosphate buffer 1g, the HFA22710g of simethicone 20g (viscosity is 200 centistokes) pH6.5
EDTA-2Na 0.5g, benzyl alcohol 7g purified water adds to 1000ml
Method branch according to embodiment 1 is filled in the aerosol aluminium pot, and encapsulation quantitative valve system, whenever presses to contain R-budesonide 0.5mg.
The mensuration of embodiment 5 foam expansion ratios
Adopt embodiment 1～4 prepared foam respectively, adopt 3ml quantitative valve system when encapsulation, the 3ml foam sprays into the internal diameter 1.2cm of vertical placement, highly is in the plastic cylinder of 100cm, measures the volume after expanding.Shake up before the spray, during measurement plastic cylinder is inserted in 37 ℃ of waters bath with thermostatic control.The foam spray 3 that each embodiment makes is pressed, and averages and calculates expansion ratio (Va/Vb)
Test result such as following table
| Sequence number | Embodiment 1 | Embodiment 2 | Embodiment 3 | Embodiment 4 |
| Expansion ratio | 38 | 31 | 29 | 26 |
Embodiment 6, and it is that the existing foam of active component keeps the effect experiment at rat colon that embodiment makes foam and water-soluble sugar 17-hydroxy-11-dehydrocorticosterone
Laboratory animal: the SD rat, male and female half and half, body weight 200 ± 20g is divided into 2 groups, and 10 every group,
Experimental group 1 gives by the foam emulsus suspension that makes among the Chinese patent application CN200780002784.x embodiment 1 (changing active component content into 2g/100ml emulsus suspension, in prednisolone).
Experimental group 2 gives the foam emulsus suspension (changing active component content into 2g/100ml emulsus suspension, in budesonide) that makes by embodiment 1 prescription
Rat ulcer colitis replication of Model:
TNBS (trinitro-benzene-sulfonic acid) is made into the solution of 50mg/ml with 45% ethanol.Fasting 24h before the SD rat experiment, etherization slowly inserts dark about 8cm place with the rubber tube of a diameter 2mm by the rat anus, presses the dosage injection TNBS solution of 125mg/kg.
Experimental technique gives the foam emulsus suspension coloclysis of the not repropellenting of experimental group separately respectively behind the rat fasting 24h after the modeling, pour into 0.5ml emulsus suspension respectively.Give the rat normal diet, guarantee every laboratory animal food ration unanimity, collect solid feces in every laboratory animal 48 hours, active component in the Excreta is detected in dry back, adopts SPSS software to carry out the t check to experimental result.
Experimental result sees the following form: (n=10,
)
| Sequence number | Experimental group 1 | Experimental group 2 |
| Content/mg | 8.7±2.1 | 5.2±1.2 |
Show that by above-mentioned experiment foaming agent combination provided by the invention compared with prior art can significantly reduce the discharge rate (P＜0.05) of effective ingredient, has also just improved the retention rate of effective ingredient accordingly.
Embodiment 7: pharmacology embodiment
Laboratory animal: the SD rat, male and female half and half, body weight 200 ± 20g is divided into 7 groups, 10 every group.
Grouping administration situation: the foam emulsus suspension (suitably transferring to active constituent content makes its effective ingredient be respectively 2mg/ml, 0.5mg/ml, 1mg/ml) that adopts the present invention to be provided according to embodiment 1～4 prescription respectively is provided experimental group 1～4, experimental group 5 adopts 5% hydrocortisone suspension enema (50mg/ml), and dosage is 0.25ml.Matched group 1 positive matched group carries out modeling according to the method among the embodiment 6, only pours into the 0.25ml normal saline during treatment; Matched group 2 negative matched groups with physiologic saline for substitute modeling medicine, also only pour into normal saline during treatment when modeling.
Experimental technique: according to Chinese document disclosed " solution of zinc sulfate is to the research of rat trinitrobenzene sulphuric acid experimental colitis therapeutical effect " (Liu Jianxiang etc., China's digestion magazine the 23rd the 4th phase of volume of April in 2003; 203～206) disclosed experimental technique in.Administration behind 24h after the modeling adopts the rubber tube of diameter 2mm that medicine slowly is poured into the affected part during administration, once a day, continue 6d, suffocates behind the 24h after the last administration and puts to death rat, gets the far-end colon, and longitudinal incision is surveyed the colon mucosa ulcer area.With 4 ℃ of normal saline content is rinsed well, mucosa upwards is tiled on the ice cube, and overlay is placed on it, draws ulcer surface, calculate ulcer area percentage (that is: ulcer area/8cm intestinal segment total area x 100%), weigh after blotting moisture on the intestinal tissue with filter paper; Get part colon and measure the MPO enzymatic activity.The mensuration of MPO (myeloperoxidase (MPO)) enzyme activity circulates a notice of 1990 with reference to Chinese document Chinese Pharmacological; Reported method among the 6:264-266, experimental result is carried out one factor analysis of variance, and P＜0.05 expression difference has statistical significance.Experimental result sees the following form: (
N=10)
Show by experiment: adopt the experimental group 1～3 that the invention provides foam emulsus suspension coloclysis to compare with the matched group 1 of positive control, all produced on colonic ulcer area, colon weight and three item indexs of the MPO of colon enzymatic activity and all produced significant effect (P＜0.01), and adopting budesonide concentration is that the experimental group 1 of 2mg/ml is that the experimental group 5 of 50mg/ml is compared with adopting hydrocortisone concentration, and above-mentioned three indexs have also all been produced remarkable result (P＜0.05).And budesonide concentration is the experimental group 3 of 1mg/ml, and its therapeutic effect is better than adopting the experimental group 5 of hydrocortisone.Even only comparing with the experimental group 5 that adopts hydrocortisone for experimental group 2 its therapeutic effect of 0.5mg/ml, budesonide concentration do not have significant difference yet, in addition, compare with experimental group 2, adopt experimental group 4 therapeutic effect of 0.5mg/ml R-budesonide better, shown with the R-budesonide to be that the foam of active component has potential curative effect advantage in use.
Claims (10)
1. a foaming agent combination contains the budesonide 0.05%-0.2% (w/w) as active component, and pharmaceutically acceptable foam adjuvant, it is characterized in that described active component is micronized budesonide or R budesonide, does not contain propylene glycol.
2. foaming agent combination according to claim 1, the volume expansion ratio that it is characterized in that described foaming agent combination is 25-50.
3. foaming agent combination as claimed in claim 1 or 2, the D90 particle diameter that it is characterized in that described micronized active component are 0.1-10 μ m.
4. as arbitrary described foaming agent combination in the claim 1 to 3, it is characterized in that described pharmaceutically useful adjuvant contains pH buffer agent, surfactant, viscosity-controlling agent, the water of propellant, lubricant and surplus.
5. foaming agent combination as claimed in claim 4, it is characterized in that described pH buffer agent preferably phosphoric acid/phosphate buffer, the 0.01%-0.1% (w/w) that described phosphoric acid/phosphate buffer consumption is the foam gross mass, the pH of described foaming agent combination is buffered to 5.5-6.5.
6. as arbitrary described foaming agent combination in the claim 1 to 5, it is characterized in that described surfactant preferred nonionic surfactants, consumption is that total amount is the 1%-15% (w/w) of compositions.
7. as arbitrary described foaming agent combination in the claim 1 to 6, it is characterized in that the preferred water-soluble cellulose polymer of described viscosity-controlling agent, described viscosity-controlling agent consumption is preferably the 0.1%-1% (w/w) of foam.
8. as arbitrary described foaming agent combination in the claim 1 to 7, it is characterized in that the preferred polydimethylsiloxane of described lubricant, consumption is 0.5%-5% (w/w).
9. as arbitrary described foaming agent combination in the claim 1 to 8, it is characterized in that described propellant is selected from one or more in propane, normal butane, iso-butane, pentane, fluorochloroparaffins, the halothane hydrocarbon, consumption is 1-10% (w/w).
10. as the application of arbitrary described foaming agent combination in the claim 1 to 9 in the medicine of preparation treatment people or mammal ulcer colon.
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|---|---|---|---|
| CN2009100694115A CN101926767A (en) | 2009-06-24 | 2009-06-24 | Budesonide-foaming agent combination |
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| CN2009100694115A CN101926767A (en) | 2009-06-24 | 2009-06-24 | Budesonide-foaming agent combination |
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014189955A1 (en) * | 2013-05-21 | 2014-11-27 | Salix Pharmaceuticals, Inc. | Methods of treating ulcerative colitis |
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2009
- 2009-06-24 CN CN2009100694115A patent/CN101926767A/en active Pending
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO2014189955A1 (en) * | 2013-05-21 | 2014-11-27 | Salix Pharmaceuticals, Inc. | Methods of treating ulcerative colitis |
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Application publication date: 20101229 |