CN100589805C - External preparation of Levocetirizine hydrochloric acid - Google Patents
External preparation of Levocetirizine hydrochloric acid Download PDFInfo
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- CN100589805C CN100589805C CN200610145385A CN200610145385A CN100589805C CN 100589805 C CN100589805 C CN 100589805C CN 200610145385 A CN200610145385 A CN 200610145385A CN 200610145385 A CN200610145385 A CN 200610145385A CN 100589805 C CN100589805 C CN 100589805C
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Abstract
An exterior-applied levocetirizine hydrochloride for preventing and treating the anaphylaxia and inflammation without untoward effect is disclosed.
Description
Affiliated technical field
The invention belongs to pharmaceutical preparations technology.
Background technology
Along with the variation of weather and environment, various harmful gass, dust and other polluter emerge in multitudes become and cause people to produce various anaphylactoid sensitinogens.The transition in season, field work, pollen hypersensitivity, suck harmful gas and grit etc., cause increasing crowd to suffer from various dissimilar anaphylactic diseases, allergic rhinitis, urticaria, the asthma that red swelling of the skin, pruritus, a red point and anaphylactogen cause etc. are very common.Therefore, the medicine of exploitation treatment anaphylactic disease is very important.
At present, in the clinical application of treatment anaphylactic disease mainly is second filial generation antihistamine drug, wherein the strongest with the cetirizine pharmaceutically active, antiinflammatory and anti-allergic effects are preferably arranged, and have the highest bioavailability, can not only suppress urticaria on a large scale after the administration and skin is general red, can also suppress inflammatory cell simultaneously and divide a word with a hyphen at the end of a line to the anaphylaxis position, thereby suppressing the later stage anaphylaxis, is a medicine with dual anti-allergic effects.
Although this medication is imitated good, but still have central nervous system's activity, still have the drowsiness untoward reaction of Denging, studies show that this mainly is because d-isomer and brain inner recipient in the cetirizine have due to certain affinity, discovers that further d-isomer does not have antiallergic activity.And its single optical isomer levo form not only has antiallergic activity, and does not have calmness, central nervous system's side effect such as drowsiness, and levo form has longer action time.Sepracor company has developed the dihydrochloride of this single optically pure isomer, i.e. Levoceti rizine dihydrochloride.The levo-cetirizine hydrochloride anti-histamine activity obviously improves than raceme, is being better than loratadine aspect the clinical resisting allergic rhinitis.This product 2.5mg is stronger for lasting antihistamine energy force rate cetirizine 5mg, loratadine 10mg and the fexofenadine 180mg of welt and flushing etc.
In a word, studies show that now levo-cetirizine hydrochloride compared following different with cetirizine:
1. the drug effect of levo-cetirizine hydrochloride is longer;
2. the affinity of levo-cetirizine hydrochloride and H1 receptor is 2 times of cetirizine;
3. absorb rapid, limited distribution in the levo-cetirizine hydrochloride body, metabolic rate is low;
4. levo-cetirizine hydrochloride is without liver metabolism, with the original shape medicine through renal excretion, be difficult for seeing through in blood brain barrier, no central nervous system's sedation, the body do not put aside, acardia toxicity etc.
Though levo-cetirizine hydrochloride has above-mentioned good characteristics, oral and after gastrointestinal absorption, be recycled to through blood and reach skin, can reach certain therapeutic effect, but local blood concentration is difficult to reach a very high concentration, and its therapeutic effect just is restricted.
Common oral preparation for present levo-cetirizine hydrochloride, as tablet, capsule, syrup etc., mainly be by after the gastrointestinal absorption, be distributed in the dermal tissue of skin by blood circulation again, thereby play antagonism inflammatory mediator histamine, reach therapeutic purposes the whole skin allergic inflammation.It is less relatively that but the blood flow of skin histology distributes, this makes the tissue distribution of levo-cetirizine hydrochloride be unfavorable for very much its treatment to skin allergic disease and dermatitis, the heavy dose of administration of oral route simultaneously is applied to dermatosis, inevitably can bring some beyond thought serious systemic adverse reactions, be a kind of very unfavorable administering mode.
Summary of the invention
The invention provides several levo-cetirizine hydrochloride external preparation, zoopery finds that compare with the levo-cetirizine hydrochloride oral administration, the external preparation of levo-cetirizine hydrochloride has beyond thought effect to several skin allergy models.
Levo-cetirizine hydrochloride is the extremely strong medicine of water solublity, be difficult to percutaneous horny layer, be merely able to rest on the surface of skin, think at present that its external can not see through keratodermatitis more, be difficult in skin histology, reaching effective tissue concentration, thereby can't bring into play its antiallergic and antiphlogistic curative effect.
And the present invention is prepared into the local topical preparation with levo-cetirizine hydrochloride, Transdermal absorption is good, can effectively increase the local organization free drug concentration of the irritated inflammation part skin of body, the sensitization of effective antagonism histamine, better its local antiallergic of performance and antiinflammatory curative effect greatly reduce untoward reaction.
The present invention with levo-cetirizine hydrochloride preparation become can external dosage forms such as liniment, ointment, and when further having confirmed the topical application of levo-cetirizine hydrochloride skin surface by a large amount of pharmacological experiments, absorb good, anti-histamine activity that can more efficiently performance levo-cetirizine hydrochloride.Of particular concern is our unexpected discovery the in pharmacodynamic experiment: the external preparation of levo-cetirizine hydrochloride not only has powerful antagonism to the inductive skin allergy of histamine, and to being that the skin delayed hypersensitivity that the chemical substance of representative causes also has quite ideal effect with the dinitrofluorobenzene, mouse ear acute inflammation effect due to the xylol is also quite desirable, and in drug systemic administration route, without any sign can point out levo-cetirizine hydrochloride to have this kind pharmacological activity.The external administration mode of levo-cetirizine hydrochloride can have the good curing effect to the delayed hypersensitivity of skin, this prompting levo-cetirizine hydrochloride external preparation has good curative effect to the chronic skin inflammation that clinical common various chemical substances cause, might solve the clinical for many years problem that scytitis is not had the ideal treatment medicine, and the discovery of the new pharmacologically active of this levo-cetirizine hydrochloride of picture, pharmacological mechanism research for levo-cetirizine hydrochloride also has important enlightenment meaning, simultaneously, brought theoretical enlightenment also for multipath administration research, give external preparation especially with technical support.
We are according to the physicochemical property of levo-cetirizine hydrochloride, screen proper supplementary material in experimentation, invention has prepared the external preparation of levo-cetirizine hydrochloride such as the liniment, ointment, gel, aerosol, spray, transdermal patch of levo-cetirizine hydrochloride.We have selected ethanol, propylene glycol and distilled water, the phosphate buffer basis as liniment in the prescription of liniment; In experiment, selected carboxymethyl cellulose, glycerol, ethyl hydroxybenzoate, carbamide, carbomer, Tween 80, triethanolamine and distilled water to be used for preparing ointment, and absorb in order better to promote, can select suitable penetrating agent in the preparation, we have selected penetrating agents such as dimethyl sulfoxide, lauryl alcohol, propylene glycol, laurocapram, carbamide, oleic acid to increase absorption in the practical operation, have obtained good effect.
The specific embodiment
1. levo-cetirizine hydrochloride external preparation antiallergic inflammatory effect research
Experiment purpose
Checking levo-cetirizine hydrochloride external preparation is to the anti-allergic effects of rat passive cutaneous anaphylaxis, PCA of the same race (Rat PCA) model, to the antiinflammatory action of the scorching model of mouse ear caused by dimethylbenzene xylene and to the influence of the inductive delayed hypersensitivity of dinitrofluorobenzene.
Group is provided with
Set up model control group, gastric infusion group and cetirizine matched group, levo-cetirizine hydrochloride liniment and ointment are established the high and low dose group respectively.The concentration of high and low dose group is respectively 10mg/ml and 3mg/ml, and the dosage of irritating the stomach matched group is rat 1.2mg/kg, mice 1.5mg/kg.
Operating procedure
1. the levo-cetirizine hydrochloride external preparation is to the influence of rat passive cutaneous anaphylaxis, PCA of the same race (PCA)
Sero-fast preparation: get 8 of the healthy rats of body weight 90-100g, the both sides intramuscular injection of back thigh is through Na
2SO
4The ovalbumin that recrystallization is 3-5 time (10mg/kg), lumbar injection pertussis triple vaccine 2 * 10 simultaneously
10/ only.After the sensitization 10-14 days, put to death the animal blood sampling, through low-speed centrifugal, separation of serum, it is standby to put-40 ℃ of refrigerators.
Operational approach: in normal rat stomach wall or back, every forms a skin mound with serum (the including abundant IgE antibody) intradermal injection of sensitization rat.The Fc receptors bind of IgE and local skin mastocyte makes it passive sensitization.When antigen is attacked, cause that local mastocyte discharged sensitive media, thereby the permeability of local vascular is increased, inject azovan blue, can ooze out in Pi Qiunei, form a locus coeruleus.According to locus coeruleus scope or depth degree, judge that vascular permeability changes, with the degree of reflection skin allergy.
Passive sensitization of skin and antigen are attacked: other gets 80 of body weight 150-200g healthy rats, is divided into model control group, liniment high dose group, liniment low dose group, ointment high dose group, ointment low dose group, cetirizine ointment high dose group, cetirizine ointment low dose group at random and irritates the stomach matched group by body weight.With rat under narcotism, cut off the back the hair, with the dilution antiserum (dilution factor is 1: 6) intradermal injection inject 4 points altogether, every some 0.1ml in Mus back sensitization.Carry out antigen after 48 hours and attack, intravenous injection 1ml0.5% azovan blue solution includes ovalbumin 1mg.It is an amount of that each dosage group of external preparation was smeared the levo-cetirizine hydrochloride external preparation at the sensitization skin part in preceding 30 minutes in attack.Irritate the stomach matched group and irritated stomach 1.2mg/kg in preceding 30 minutes in attack.Attack sacrificed by decapitation animal after 30 minutes, collect blood sample 2ml in the test tube of heparinization.Centrifugal, the accurate plasma sample 0.5ml that draws places 10ml tool plug centrifuge tube, adds pH 5.5 sodium citrate buffer 0.5ml and ethyl acetate 5ml, vortex vibration 2min, the centrifugal 5min of 3500r/min.Divide and to get ethyl acetate layer 4ml, place another 10ml tool plug centrifuge tube, add 1.7% phosphoric acid solution 100 μ l is counter and carry, behind the centrifugal 5min of 3500r/min, draw phosphoric acid solution 50 μ l, analyze, measure the blood drug level of levo-cetirizine hydrochloride with the high performance liquid chromatograph sample introduction.Skin basket speckle cut place in vitro, add 1mol/L KOH 1ml, 37 ℃ of digestion 15 hours adds phosphoric acid acetone mixed liquor 3.75ml then, after concussion is extracted, centrifugal 10 minutes of 2500r/min, get supernatant with spectrophotometer in 640nm place mensuration trap.
Calculate PCA with following formula and suppress percentage rate:
Suppress percentage rate=(model group trap value-each medication group trap value)/model group trap value
Respectively organize the difference (seeing Table 1) of blood drug level.
The external preparation of table 1 levo-cetirizine hydrochloride and gastric infusion compare rat passive cutaneous anaphylaxis, PCA inhibitory action of the same race and blood drug level.
*Compare P＜0.05 with each group of external preparation of levo-cetirizine hydrochloride;
#Compare P＜0.05 with the high dose group of cetirizine;
﹠amp;Compare P＜0.05 with the low dose group of cetirizine.
To annotate. the high dose concentration of each external preparation is 10mg/ml, and low dosage concentration is 3mg/ml.
Experimental result shows, the liniment of levo-cetirizine hydrochloride and ointment have significant inhibitory effect to rat passive cutaneous anaphylaxis, PCA of the same race, its effect significantly is better than irritating the stomach matched group, being better than the cetirizine matched group, and its blood drug level significantly is lower than filling stomach matched group.
2. levo-cetirizine hydrochloride external preparation xylol causes the influence of mouse ear inflammation
Get 60 of body weight 26-30g male mices, be divided into model control group, liniment high dose group, liniment low dose group, ointment high dose group, ointment low dose group at random and irritate stomach matched group, 10 every group.Dimethylbenzene 0.03-0.05ml dripped in the Mus auris dextra cause inflammation, left ear in contrast.Each group of external preparation is causing scorching back 30 minutes and is smearing corresponding external preparation an amount of respectively, irritates the stomach matched group and is causing scorching 30 minutes after irritate stomach and give and levo-cetirizine hydrochloride 1.5mg/kg.After 2 hours the mice dislocation is put to death, cut two ears, lay round auricle at the same position of left and right ear respectively, weigh, ask the poor of left and right auricle weight with the card punch of diameter 8mm along the auricle baseline, as the swelling degree, comparable group differences significance (seeing Table 2).
The comparison of the mouse ear inhibition of inflammation due to table 2 levo-cetirizine hydrochloride external preparation and the gastric infusion xylol.
*Compare P＜0.01 with model control group
*Compare P＜0.05 with model control group
To annotate. the high dose concentration of each external preparation is 10mg/ml, and low dosage concentration is 3mg/ml.
Experimental result shows, the mouse ear inflammation due to the liniment of levo-cetirizine hydrochloride and the ointment xylol has the good restraining effect, and gastric infusion is not seen this inhibitory action.
3. the levo-cetirizine hydrochloride external preparation influences the inductive mice delayed hypersensitivity of dinitrofluorobenzene (PTH)
Get 60 of body weight 18-22g mices, be divided into model control group, liniment high dose group, liniment low dose group, ointment high dose group, ointment low dose group at random and irritate stomach matched group, 10 every group by body weight.Cut off the mice ventral seta, abdominal part is smeared 1% dinitrofluorobenzene (DNFB), 50 μ l sensitization, and the 5th day every mice left side auricle smeared 1%DNFB5 μ l and sent out quick after the sensitization.Each dosage group of external preparation respectively send out quick to smear corresponding levo-cetirizine hydrochloride external preparation in back 30 minutes an amount of, irritate the stomach matched group sending out quick 30 minutes after irritate stomach to and levo-cetirizine hydrochloride 1.5mg/kg.Behind the 24h mice dislocation is put to death, cut two ears, lay round auricle at the same position of left and right ear respectively, weigh, ask the poor of left and right auricle weight with the card punch of diameter 8mm along the auricle baseline, as the swelling degree, comparable group differences significance (seeing Table 3).
Table 3 levo-cetirizine hydrochloride external preparation and gastric infusion are to the inhibiting comparison of the inductive mouse ear delayed hypersensitivity of dinitrofluorobenzene.
*Compare P＜0.01 with model control group
*Compare P＜0.05 with model control group
To annotate. the high dose concentration of each external preparation is 10mg/ml, and low dosage concentration is 3mg/ml.
Experimental result shows that the liniment of levocetirizine and ointment have the good restraining effect to the inductive mouse ear delayed hypersensitivity of dinitrofluorobenzene, and gastric infusion is not seen this inhibitory action.
Discuss
We are by adopting rat passive cutaneous anaphylaxis, PCA of the same race (PCA), three kinds of models of the inductive mice delayed hypersensitivity of mice caused by dimethylbenzene xylene otitis disease and dinitrofluorobenzene (PTH) have carried out experimentation to the pharmacodynamics of levo-cetirizine hydrochloride external preparation, the external preparation of finding levo-cetirizine hydrochloride not only has powerful antagonism to the inductive skin allergy of histamine, and to being that the skin delayed hypersensitivity that the chemical substance of representative causes also has quite ideal effect with the dinitrofluorobenzene, mouse ear acute inflammation effect due to the xylol is also quite desirable, and in drug systemic administration route, without any sign can point out levo-cetirizine hydrochloride to have this kind pharmacological activity.The external administration mode of levo-cetirizine hydrochloride can have the good curing effect to the delayed hypersensitivity of skin, this means that the levo-cetirizine hydrochloride external preparation has good application prospects to the chronic skin inflammation that clinical common various chemical substances cause, having solved does not clinically for many years have the problem of ideal treatment medicine to scytitis, meets the interests of extensive patients.And the discovery of the new pharmacologically active of this levo-cetirizine hydrochloride also has important enlightenment meaning for the pharmacological mechanism research of levo-cetirizine hydrochloride.Nearest basic research shows, the skin keratin cell is being played the part of important role in skin hypersensitivity reaction and scytitis process, but the levo-cetirizine hydrochloride of oral route administration can't touch the horn cell of skin, our result of study prompting, the levo-cetirizine hydrochloride of high dose may be inhibited to the horn cell activation; The inductive mice delayed hypersensitivity of dinitrofluorobenzene (PTH) is mainly cell-mediated by Th1, this time result of study is pointed out us, cell-mediated immunoreation may have important regulatory role to the levo-cetirizine hydrochloride of local high dose to Th1 in the skin, is worth further studying.This pharmacologically active and mechanism of drug action to histamine receptor antagonists such as further investigation levo-cetirizine hydrochlorides has important inspired significance.Our experimental studies results is indicating that the levo-cetirizine hydrochloride external preparation has good therapeutic effect to the chronic skin inflammation based on delayed hypersensitivity, has good potential applicability in clinical practice.
2. the preparation of levo-cetirizine hydrochloride external preparation
Embodiment 1
The levo-cetirizine hydrochloride liniment
Levo-cetirizine hydrochloride 20g
Ethanol 35ml
Propylene glycol 100ml
Phosphate buffer (PBS) adds to 1000ml
Preparation technology:
Earlier levo-cetirizine hydrochloride is dissolved in an amount of phosphate buffer (PBS), adds the ethanol and the propylene glycol of recipe quantity, reuse phosphate buffer (PBS) adds to 1000ml and gets final product.
Embodiment 2
The levo-cetirizine hydrochloride liniment
Levo-cetirizine hydrochloride 10g
Ethanol 200ml
Propylene glycol 300ml
Distilled water adds to 1000ml
Preparation technology:
Earlier levo-cetirizine hydrochloride is dissolved in an amount of distilled water, adds the ethanol and the propylene glycol of recipe quantity, the reuse distilled water adds to 1000ml and gets final product.
Embodiment 1 and embodiment 2 prepared liniments are packed in the specific container (aerosol apparatus or nebulizer), can be used as spray and use.
Embodiment 3
The ointment of levo-cetirizine hydrochloride
Levo-cetirizine hydrochloride 8g
Carboxymethyl cellulose 40g
Glycerol 400g
Lauryl alcohol 15g
Ethyl hydroxybenzoate 2g
Distilled water adds to 1000g
Preparation technology:
With carboxymethyl cellulose and glycerol mixing, add an amount of hot distilled water then, after placement is waited to be swelled into gel, add the aqueous solution that contains levo-cetirizine hydrochloride, lauryl alcohol, ethyl hydroxybenzoate again, add water to capacity and get final product.
Embodiment 4
The ointment of levo-cetirizine hydrochloride
Levo-cetirizine hydrochloride 5g
Acritamer 940 1g
Glycerol 60g
Tween 80 2g
Ethyl hydroxybenzoate 0.5g
Triethanolamine 4g
Distilled water adds to 1000g
Preparation technology:
The carbomer of recipe quantity is joined in the aqueous solution that contains levo-cetirizine hydrochloride, form low viscous acid solution, behind glycerol, Tween 80 and the ethyl hydroxybenzoate of adding recipe quantity, regulate pH value to 7.0 with triethanolamine and get final product.
Embodiment 5
The ointment of levo-cetirizine hydrochloride
Levo-cetirizine hydrochloride 3g
Carboxymethyl cellulose 60g
Glycerol 200g
Ethyl hydroxybenzoate 5g
Carbamide 10g
Distilled water adds to 1000g
Preparation technology:
With carboxymethyl cellulose and glycerol mixing, add an amount of hot distilled water then, after placement is waited to be swelled into gel, add the aqueous solution that contains levo-cetirizine hydrochloride, carbamide and ethyl hydroxybenzoate again, add water to capacity and get final product.
Embodiment 6
The aerosol of levo-cetirizine hydrochloride
Levo-cetirizine hydrochloride 10g
Ethanol 30ml
Carbamide 30g
Dichlorodifluoromethane 150g
Vitamin C 7.5g
Sterile distilled water adds to 1000ml
Preparation technology:
Levo-cetirizine hydrochloride, carbamide, the vitamin C of recipe quantity are dissolved in the sterile distilled water, add ethanol, add sterile distilled water to 1000ml after sand core funnel filters, the divided dose fill, sealing-in dosage valve system, dichlorodifluoromethane is injected in pressurization more respectively, promptly.
Embodiment 7
The spray of levo-cetirizine hydrochloride
Levo-cetirizine hydrochloride 15g
Ethanol 36ml
Dimethyl sulfoxide 15ml
Vitamin C 7.5g
Sterile distilled water adds to 1000ml
Preparation technology:
Levo-cetirizine hydrochloride, dimethyl sulfoxide, the vitamin C of recipe quantity are dissolved in the sterile distilled water, add ethanol after sand core funnel filters, add sterile distilled water to 1000ml, the divided dose embedding is in spray manual pump system, promptly.
Embodiment 8
The transdermal patch of levo-cetirizine hydrochloride
Levo-cetirizine hydrochloride 5g
Ethanol 30ml
Carbamide 15g
Vitamin C 7.5g
Acrylate pressure-sensitive adhesive is an amount of
Preparation technology:
Levo-cetirizine hydrochloride, vitamin C and carbamide heating are dissolved in the ethanol, under agitation pour into and be stirred in the acrylate pressure-sensitive adhesive evenly, put to room temperature, film, the heated volatile organic solvent covers polyolefin film by lining then, the cutting component, promptly.
Embodiment 9
The gel of levo-cetirizine hydrochloride
Levo-cetirizine hydrochloride 20g
Glycerol 30ml
Laurocapram 4g
Carbomer-940 16g
Triethanolamine is an amount of
Distilled water adds to 1000g
Preparation technology:
Get glycerol, carbomer-940, laurocapram and put in the mortar and grind well, and add an amount of distilled water, slowly drip triethanolamine and regulate about PH to 7.0, the limit edged stirs, and makes into gel, adds the levo-cetirizine hydrochloride mix homogeneously, adds distilled water, stirs evenly, and packing promptly.
Claims (4)
1. a pharmaceutical composition that contains levo-cetirizine hydrochloride is characterized in that it is a kind of local topical preparation that is used for skin allergic disease or the treatment of skin chronic inflammatory disease.
2. the pharmaceutical composition of levo-cetirizine hydrochloride according to claim 1 is characterized in that it is liniment, ointment, gel, spray, aerosol, transdermal patch.
3. as the pharmaceutical composition of levo-cetirizine hydrochloride as described in the claim 2, it is characterized in that ointment contains carboxymethyl cellulose, glycerol and ethyl hydroxybenzoate.
4. as the pharmaceutical composition of levo-cetirizine hydrochloride as described in the claim 2, it is characterized in that ointment contains carbomer-940, glycerol, ethyl hydroxybenzoate, Tween 80 and triethanolamine.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200610145385A CN100589805C (en) | 2005-11-29 | 2006-11-28 | External preparation of Levocetirizine hydrochloric acid |
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN200510129203.1 | 2005-11-29 | ||
| CN 200510129203 CN1813743A (en) | 2005-11-29 | 2005-11-29 | External-use formulation of levocetirizine hydrochloride |
| CN200610145385A CN100589805C (en) | 2005-11-29 | 2006-11-28 | External preparation of Levocetirizine hydrochloric acid |
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| Publication Number | Publication Date |
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| CN1957942A CN1957942A (en) | 2007-05-09 |
| CN100589805C true CN100589805C (en) | 2010-02-17 |
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| Publication number | Priority date | Publication date | Assignee | Title |
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| EP2465503A4 (en) * | 2009-08-12 | 2013-04-17 | Lunan Better Pharmaceutical Co Ltd | Pharmaceutical solution of cetirizine hydrochloride |
| CN101669913B (en) * | 2009-09-25 | 2012-09-05 | 海南康芝药业股份有限公司 | Levocetirizine dihydrochloride granule and preparation and detection methods thereof |
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