CN104069497A - Medicine composition for lowering drug tolerance, method and application thereof - Google Patents
Medicine composition for lowering drug tolerance, method and application thereof Download PDFInfo
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- CN104069497A CN104069497A CN201410298409.6A CN201410298409A CN104069497A CN 104069497 A CN104069497 A CN 104069497A CN 201410298409 A CN201410298409 A CN 201410298409A CN 104069497 A CN104069497 A CN 104069497A
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Abstract
The invention relates to a medicine composition for lowering drug tolerance and an application thereof. The main active components of the medicine composition comprise effective dose of a beta2 receptor stimulant or salt thereof acceptable in pharmacy, wherein the purity of excess value of a sinistrogyration (R) enantiomer of the beta2 receptor stimulant is over 90%. The invention also provides a method for lowering the drug tolerance. The medicine composition can effectively lower the drug tolerance, and also can reduce the side effects of the existing medicines for treating respiratory disease.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, particularly relate to a kind of pharmaceutical composition that reduces Drug tolerance.Further, the present invention relates to the application of this pharmaceutical composition in treatment respiratory disease.Especially, the invention still further relates to a kind of method that reduces Drug tolerance.
Background technology
Asthma claims again bronchial asthma, is one of common chronic respiratory tract disease, and prevalence is in recent years significantly to rise in the whole world, becomes gradually the chronic respiratory system diseases of serious threat human health.Asthma and concurrent inflammatory reaction thereof; can cause airway hyperreactivity; conventionally there will be extensively changeable reversible airflow limitation; and cause the symptoms such as the panting of repeated relapsing, out of breath, uncomfortable in chest or cough; be everlasting and show effect in night and (or) early morning, aggravate, most of patients can be alleviated after treatment.Asthmatic children in the early stage as not in time treatment is easy to develop into Adults Asthma and endangers all the life, so early diagnosis, early treatment are very crucial for Control of asthma.
At present, β
2receptor stimulating agent is still the effectively medicine of a class in Control of asthma symptom.According to the time length of its generation effect, now generally acknowledge and be divided into two types: quick-acting β
2receptor stimulating agent (SABA) and long-acting beta
2receptor stimulating agent (LABA).Especially at some new β
2receptor selective agonists, as after salbutamol, terbutaline, Airum etc. come out, the advantage such as long, oral effectively because its selectivity is high, effect strong, effect is held time, untoward reaction is light, becomes the symptomatic treatment medicine of asthma first-selection.But it is one of main clinical problem of this class medicine that medicine produces toleration, has greatly limited the use of this class medicine.
Drug tolerance, while referring to the continuous or a kind of medicine of life-time service of patient, patient's body is to this medicaments insensitive, and treatment effectively, becomes this medicine is produced to tolerance, causes the therapeutic effect of medicine to reduce.This is called the toleration of medicine.Drug tolerance causes drug action to decline gradually, and necessary escalated dose, could produce due drug effect, and even escalated dose can not increase curative effect sometimes, and medicine has lost the therapeutical effect to this patient.Generally believe, sb.'s illness took a turn for the worse and mortality rate increases relevant with asthma in the generation of Drug tolerance.How reducing Drug tolerance is a difficult problem for clinical medicine and pharmacopedics.
β
2receptor stimulating agent terbutaline is asthma common drug.During being used, clinical this medicine can produce comparatively significantly Drug tolerance.Conventional evaluation index is that the peak effect after repeated drug taking reduces and shorten action time.The conventional β that sucks
2receptor stimulating agent easily causes tachyphylaxis.Weber
[1]deng first, allow 13 routine asthmatic patients divide 4 times, each interval 20 minutes sucks the terbutaline of 1000 μ g, and detects after administration each time point FEV in 4 hours
1, peak effect and the action time of recording terbutaline.Then, allow every patient's routine suck terbutaline, dosage is 500 μ g, once a day, and totally 12 weeks.Every two weeks to checking peak effect and the action time of terbutaline.As a result, routine administration is after 14 days, and peak effect and the action time of terbutaline obviously shorten, and illustrate and have produced toleration.At O ' connor
[2]in research Deng one that carries out random, double blinding, cross-over design, 12 routine asthmatic patients suck terbutaline (dosage is 500 μ g, every day 4 times) or placebo, continuous 7 days.Result shows, the protective effect that the terbutaline airway reactivity that agent causes to airway contraction increases obviously declines.Experiment in vitro also confirms, gives for a long time β
2receptor stimulating agent cultured cell, can cause β
2the mRNA of receptor lowers
[3].
At present existing commercially available β
2receptor stimulating agent majority is chiral drug, and exists mainly with the form of racemic modification, contains left-handed (R) enantiomer of equivalent and the DL thing of dextrorotation (S) enantiomer.Commercially available terbutaline is also racemic drugs.What above-mentioned research also all adopted is raceme terbutaline.Because the different optical enantiomer of chiral drug exists different biological actions.Each isomer of chipal compounds is investigated respectively and just become quite important.Sedative Thalidomide such as the listing sixties, causes baby's teratogenesis and suspends sale of with regard to Zeng Yinwei.German Bonn university research person split Thalidomide afterwards, and confirmation is that (R) enantiomer has been brought into play sedation, and what bring teratogenesis is (S) enantiomer.
About the research of the d-isomer effect impact in cardio-pulmonary function in it that focuses mostly on.William
[4]research shows, with the Cavia porcellus of OVA sensitization, gives for a long time that dextrorotation (S) albuterol can cause serious air flue edema and to asthmogenic high response.Mazzoni
[5]adopted the guinea pig asthmatic model of anesthesia, in 1 hour, give d-isomer (as S-isoproterenol, S-albuterol, S-terbutaline) reactivity of rear detection animal to intravenous injection histamine, thus show that d-isomer has the effect of similarly short airway hyperreactivity.Levo form clinical treatment and toxic and side effects aspect whether be better than containing left-handed and racemic modification dextrorotation and still exist arguement.Whether should substitute outer (RS) raceme with left-handed (R) isomer clinically and also have dispute.The beta 2 receptor agonist using now both at home and abroad is still mainly raceme product.
Quantity research shows greatly, and left-handed (R) configuration is wherein active component, is the excellent body that reflects, its energy and β
2receptors bind, activates a series of downstream passages, thereby produces the pharmacologically actives such as diastole bronchus; Dextrorotation (S) configuration is the bad body that reflects without therapeutical effect.Yet, although bad, reflect body inefficacy, may produce or increase the weight of toxic and side effects.
Although prior art is studied in vitro and has been confirmed beta 2 receptor medicine dextrorotation (S) enantiomer, the direct toxicity of the reactivity that stimulate inflammatory reaction as dextrorotation (S) terbutaline and dextrorotation (S) albuterol have, increases trachea or air flue etc., in existing document, also do not relate to the bad body that reflects of dextrorotation (S) in racemic drugs for the impact producing aspect Drug tolerance.Whether existing document also relates to the bad body that reflects of dextrorotation (S) without any research can affect left-handed (R) excellent body Drug tolerance that reflects directly or indirectly.
The present invention is by Effect of Anti asthmatic medicament raceme β
2the impact of dextrorotation in receptor agonism agent medicine (S) enantiomer on Drug tolerance, and whether dextrorotation (S) enantiomer can affect left-handed (R) excellent body Drug tolerance that reflects directly or indirectly, thereby find the invention that reduces and avoid Drug tolerance, this is of great importance for the clinical treatment that improves asthma diseases related.
Summary of the invention
Main purpose of the present invention is, for widely used β clinically at present
2receptor stimulating agent easily produces the problem of anti-asthmatic medicament toleration, and a kind of compositions that can reduce and overcome Drug tolerance is provided, thereby is more suitable for practicality, and has the value in industry.
Another object of the present invention is, employing has clinical representational animal Tolerance Model, by rational experimental design and a large amount of objective experiments, in commercially available raceme, confirm that dextrorotation (S) enantiomer affects the relation of Drug tolerance, thereby change the clinical method that uses at present raceme beta 2 receptor agonist treatment asthma.
A further object of the present invention is, a kind of pharmaceutical composition that reduces Drug tolerance is provided, and described compositions is by β
2receptor stimulating agent or its officinal salt or form with pharmaceutically suitable carrier, wherein β
2the superfluous value of left-handed in receptor stimulating agent (R) body enantiomer purity is more than 90%, for reducing being widely used clinically β
2the anti-asthmatic medicament toleration that receptor stimulating agent produces.
The object of the invention to solve the technical problems realizes by the following technical solutions.A kind of compositions that reduces Drug tolerance proposing according to the present invention, it contains the β that treats effective dose
2receptor stimulating agent or its pharmaceutically acceptable salt, wherein said β
2the superfluous value of left-handed in receptor stimulating agent (R) enantiomer purity is more than 90%.
The object of the invention to solve the technical problems also can be applied to the following technical measures to achieve further.
Aforesaid a kind of pharmaceutical composition that reduces Drug tolerance, wherein said β
2receptor stimulating agent is β
2the superfluous value of left-handed in receptor stimulating agent (R) enantiomer purity is more than 95%.
Aforesaid a kind of pharmaceutical composition that reduces Drug tolerance, wherein said β
2receptor stimulating agent is β
2the superfluous value of left-handed in receptor stimulating agent (R) enantiomer purity is more than 99%.
Aforesaid a kind of pharmaceutical composition that reduces Drug tolerance, wherein said β
2terbutaline that receptor stimulating agent is selected from left-handed (R), left-handed (R) fenoterol, left-handed (R) orciprenaline, left-handed (R) Clenbuterol, left-handed (R) clorprenaline, left-handed (R) are than appropriate special sieve, left-handed (R) Rui meter Te Luo or left-handed (R) Mabuterol.
Aforesaid a kind of pharmaceutical composition that reduces Drug tolerance, wherein said β
2receptor stimulating agent pharmaceutically acceptable salt is selected from acylate, inorganic acid salt or its combination, described acylate or inorganic acid salt are selected from hydrochlorate, hydrobromate, sulfate or disulfate, dihydric phosphate, metilsulfate, Bromide, acetate, oxalates, maleate, fumarate, succinate, 2-naphthyl sulfate, gluconate, twist lemon hydrochlorate, tartrate, lactate, one or more of pyruvate, isethionate, benzene sulfonate and tosilate.
Aforesaid a kind of pharmaceutical composition that reduces Drug tolerance, it further contains pharmaceutically applicable carrier, and described carrier is selected from propellant, saccharide or the sugar alcohol that comprises fluorine hydrogen compound.
The object of the invention to solve the technical problems also adopts following technical scheme to realize.A kind of method that reduces Drug tolerance proposing according to the present invention, the method comprises to required patient takes the compositions described in claim 1-6, and take corticosteroid to required patient simultaneously, wherein said corticosteroid is selected from as budesonide, ciclesonide, beclomethasone, momestasone furoate, flunisolide, replaces Kazon propionic ester, hydrochloric acid triamcinolone acetonide, fluticasone and pharmaceutically acceptable salt or solvent.
The object of the invention to solve the technical problems also can be applied to the following technical measures to achieve further.
The method of aforesaid reduction Drug tolerance, wherein, β
2receptor stimulating agent is left-handed (R) terbutaline, and the molar ratio of itself and described corticosteroid is 1:1-1:60.
The object of the invention to solve the technical problems also adopts following technical scheme to realize.A kind of method that reduces Drug tolerance proposing according to the present invention, the method comprises to required patient takes the compositions described in claim 1-6, and take cholinergic receptor antagonist to required patient simultaneously, described cholinergic receptor antagonist is selected from as ipratropium bromide, for fertile tropine, trospium chloride, oxitropium bromide, reaches human relations tropine, atropine, melyltropeine, tropicamide, scopolamine, oxibutynin, tolterodine and pharmaceutically acceptable salt thereof.
The method of aforesaid reduction Drug tolerance, wherein, β
2receptor stimulating agent is left-handed (R) terbutaline, and the molar ratio that itself and described cholinergic receptor antagonist are used in combination is 1:0.1-1:2.
The object of the invention to solve the technical problems also adopts following technical scheme to realize.A kind of method that reduces Drug tolerance proposing according to the present invention, the method comprises to required patient takes the compositions described in claim 1-6, and uses nitric oxide to required patient simultaneously.
The object of the invention to solve the technical problems also adopts following technical scheme to realize.A kind of method that reduces Drug tolerance proposing according to the present invention, the method comprises to required patient takes the compositions described in claim 1-6, and use antiinflammatory or immunomodulator to required patient simultaneously, described antiinflammatory or immunomodulator are selected from interleukin receptor antagonist or agent interfering.
The dosage form of compositions provided by the invention is any in tablet, capsule, Foradil Aerolizer formoterol fumarate, atomized inhalation, aerosol, solvent or suspending agent.
The application in the medicine of preparation treatment asthma or other respiratory tract disease of compositions provided by the invention.
The present invention compared with prior art has obvious advantage and beneficial effect.The present invention proves by experiment, use separately left-handed (R) terbutaline, substitute the terbutaline (racemic modification) that contains left-handed (R) body and dextrorotation (S) body when using at present, can reduce significantly terbutaline left-handed (R) body continuously or the toleration causing during life-time service, the present invention is also to other similar β
2receptor agonism agent medicine is studied as albuterol, finds dextrorotation (S) albuterol or other β
2receptor stimulating agent dextrorotation (S) body medicine has the effect of similar increase Drug tolerance.
Above-mentioned left-handed (R) terbutaline should reach enough optical purities, and the superfluous value of its enantiomer should be at 90%-99%, and dextrorotation (S) terbutaline content should not surpass 5% by weight; More preferably in situation, should try one's best not containing the special terbutaline of dextrorotation (S), the superfluous value of the enantiomer of left-handed (R) terbutaline should be greater than 99%.For different inhalant prescription and different suction apparatus, to make active drug enter bronchus or pulmonary, reach same therapeutic effect, the amount of actual required left-handed (R) terbutaline may be different.Therefore,, when the different inhalant of preparation is write out a prescription, the consumption of left-handed (R) terbutaline should be adjusted according to actual needs.In addition, according to Cavia porcellus, suck the optimal dose of experiment, can, by body surface area or weight conversion method, draw the best inhalation dose that is suitable for patient; Also can extrapolate inhalation dose according to oral dose, above-mentioned dosage can also be according to patient's the state of an illness, age and therapeutic goal and adjust.
In technique scheme, in its pharmaceutical composition, the consumption of each composition is adjusted according to the therapeutic purposes of symptom, age and principal agent.
In sum, a kind of pharmaceutical composition and application thereof that reduces Drug tolerance that the present invention is special, it has above-mentioned many advantages and practical value, has large improvement technically, and has produced handy and practical effect.
The present invention has above-mentioned many advantages and practical value, at current medical domain, belongs to innovation.Above-mentioned explanation is only the main general introduction in technical solution of the present invention, in order to better understand technological means of the present invention and technique effect, below in conjunction with preferred embodiment as being described in detail.
The specific embodiment
For further setting forth the present invention, reach technological means and the effect that predetermined goal of the invention adopts, below in conjunction with preferred embodiment, a kind of its concrete embodiment of pharmaceutical composition, feature and effect that reduces drug resistance to proposing according to the present invention, is explained in detail.
Example 1: the Drug-resistant Journal of Sex Research that the Drug tolerance that the Drug tolerance that left-handed (R) terbutaline produces, dextrorotation terbutaline produce and racemic modification (RS) produce
(1) object of study
Choose Dunkin-Hartley Cavia porcellus, 250 ± 50g, male and female half and half, overnight fasting.Cavia porcellus is placed in 4L hermetic container, and constant speed atomization 0.6% histamine solution, sucks 15 seconds, observes Cavia porcellus from starting to suck histamine to the time of falling down.The Cavia porcellus that exceeds 120s discards, in 120s, fall for responsive Cavia porcellus, numbering, supports after 24h for next step experiment.
(2) method
Get qualified Cavia porcellus and be divided into 4 groups: dextrorotation terbutaline, left-handed terbutaline, racemization terbutaline and contrast normal saline group.By after Animal Anesthesia, the capable intrathoracic cannula of circulation of qi promoting cannula and intercostal.By measuring intrapleural pressure power, air-flow and tidal volume, can calculate airway resistance and pulmonary dynamic compliance.First suck and give 0.05% histamine normal saline solution (20s) and react in contrast.Then, suck and give dextrorotation (S) terbutaline or left-handed (R) terbutaline (being 4mg/ml) or racemic modification terbutaline (RS) or equivalent normal saline continuously respectively, 2min/ time, in 20min, give altogether 5 times, with the generation of induce drug toleration.Above-mentioned four groups of Mus are giving after different pharmaceutical continuously, same suction gives left-handed (R) terbutaline effective dose (1mg/ml2min), after 3min, again give equally same isoconcentration histamine normal saline solution and bring out asthma, the animal asthma reaction (airway resistance changes and pulmonary's compliance changes) that compares four medicine pretreated group, according to extent of reaction difference, judged whether that drug resistance produces and the order of severity.
(3) result of study
Table 1: left-handed (R) terbutaline is processed the asthma effect comparison in Cavia porcellus group at different pharmaceutical
*: compared utmost point significant difference (P<0.01%) with other each group
By known to table 1, giving continuously after normal saline, give left-handed (R) terbutaline, it has the effect that obvious antihistamine brings out asthma.Airway resistance and contrast ratio almost do not increase.And after giving continuously respectively dextrorotation (S) terbutaline, then giving left-handed (R) terbutaline, its effect that antihistamine is brought out to asthma obviously weakens.Showing as airway resistance significantly increases.Continuously dextrorotation (S) terbutaline is anticipated animal, and left-handed (R) terbutaline effect of not relievining asthma, illustrates the toleration having produced medicine.This shows dextrorotation (S) although body does not have asthma drug effect, can cause the obvious toleration of animal to left-handed (R) terbutaline.At racemization (RS) terbutaline treated animal, the generation of toleration is lower than dextrorotation (S) group (be about its 50%), and gives continuously left-handed (R) terbutaline, and the generation of toleration is significantly less than racemization (RS) terbutaline treated animal.During continuous several times administration, the degree that left-handed (R) terbutaline produces Drug tolerance is far smaller than its racemic modification (RS) (be about its 25%).
Embodiment 2
Left-handed in the present embodiment (R) terbutaline should reach enough optical purities, and the superfluous value of its enantiomer should be at 90%-99%, and content should not surpass 5% by weight; More preferably in situation, should try one's best not containing the special terbutaline of dextrorotation (S), the superfluous value of the enantiomer of left-handed (R) terbutaline should be greater than 99%.For different inhalant prescription and different suction apparatus, to make active drug enter bronchus or pulmonary, reach same therapeutic effect, the amount of actual required left-handed (R) terbutaline may be different.Therefore,, when the different inhalant of preparation is write out a prescription, the consumption of left-handed (R) terbutaline should be adjusted according to actual needs.In addition, according to Cavia porcellus, suck the optimal dose of experiment, can, by body surface area or weight conversion method, draw the best inhalation dose that is suitable for patient; Also can extrapolate inhalation dose according to oral dose, above-mentioned dosage can also be according to patient's the state of an illness, age and therapeutic goal and adjust.
Left-handed in the present embodiment (R) terbutaline itself or its pharmaceutically acceptable salt comprise salt or its combination forming with common pharmaceutically acceptable organic or inorganic acid.Comprise hydrochlorate, hydrobromate, sulfate or disulfate, dihydric phosphate, metilsulfate, Bromide, acetate, oxalates, maleate, fumarate, succinate, 2-naphthyl sulfate, gluconate, twist lemon hydrochlorate, tartrate, lactate etc., pyruvate, isethionate, benzene sulfonate, tosilate etc.
Embodiment 3
In the present embodiment, left-handed (R) terbutaline or its pharmaceutically acceptable salt, can be a kind of can combination by atomizing inhalant, such as, formed solvent or dispersant (suspending agent) or a kind of solution that can be atomized are squeezed in left-handed (R) terbutaline and a kind of impelling, such as left-handed (R) terbutaline is water-soluble, the combination of organic solvent or water/ORGANIC SOLVENT MIXTURES.Applicable propellant comprises fluorine hydrogen compound, particularly 1,1,2,2-tetrafluoroethane and 1,1,1,2,3,3,3-seven amyl fluorides or both mixing, left-handed (R) terbutaline of active drug composition or its pharmaceutically acceptable salt, disperse with special form at above-mentioned propellant, or form suspending agent.
In the prescription of above-mentioned aerosol, also can contain lubricant and surfactant, specifically with any can be with selecting in existing commercially available kind.In the prescription of another kind of aerosol applicatory, do not contain or contain few surfactant.In the prescription of aerosol, active drug left-handed (R) terbutaline, by weight, accounts for the ratio below 5% of propellant, as 0.002-5%, and 0.01-3%; 0.015-2%, 0.1-2%; 0.5-2% or 0.5 to 1%.And lubricant and surface-active contents by weight, can be 0.5-5%.Aerosol prescription also can contain cosolvent as ethanol especially for quantitative pressure aerosol device, and by weight, its content can reach 30%.
Example 4
In the present embodiment, left-handed (R) terbutaline and pharmaceutically acceptable salt thereof also can with various carrier combinations, make Foradil Aerolizer formoterol fumarate.Can be used as comprising of carrier: saccharide, as monosaccharide, disaccharidase and polysaccharide; Sugar alcohol: as arabinose, glucose, fructose, ribose, mannose, sucrose, trehalose, lactose, maltose, starch, glucosan or mannitol.A kind of particularly preferred carrier is lactose.Foradil Aerolizer formoterol fumarate can be put into the capsule of gel or duroplasts, or in aluminium foil medicated bag, then suck by powder inhaler.In addition, Foradil Aerolizer formoterol fumarate is also applicable to the powder inhaler of the drug storage boxlike of multiple dose.The active ingredient of inhalant can be also that left-handed (R) terbutaline and other medicines are as the combination compound recipe of corticosteroid hormone, anti-acetylcholine medicine etc.The inhalant preparation method that the inhalant preparation method of said medicine combination is used separately with left-handed (R) terbutaline is in principle identical.
Embodiment 5
(R) terbutaline left-handed in the present embodiment and their pharmaceutically acceptable salts, can use with all kinds of corticosteroids, combination in varing proportions, make above-mentioned all kinds of aerosol, Foradil Aerolizer formoterol fumarate, atomized inhalation or spray, per os or snuffing enter bronchus or pulmonary, are used for the treatment of asthma or other respiratory tract disease.The present invention uses combination compound recipe aerosol can improve therapeutic index, and performance is added or collaborative therapeutic effect.Above-mentioned corticosteroid comprises: as budesonide, ciclesonide, beclomethasone, momestasone furoate, flunisolide, for Kazon propionic ester, hydrochloric acid triamcinolone acetonide, fluticasone etc. and the upper acceptable salt of their physiology or solvent.Routine in molar ratio, left-handed (R) terbutaline and corticosteroid consumption are 1:1-1:60; Preferred ratio is 1:2-1:10; Preferred ratio is 1:2-1:4.Every day, corticosteroid amount ranges can be adjusted according to symptom and age, as FLUTICASONE PROPIONATE 50-2000 μ g; Beclometasone 100-2000 μ g; Budesonide 50-4000 μ g etc.
The prescription of the compound recipe of left-handed (R) terbutaline and above-mentioned glucocorticoid can be solution or the dispersed suspending agent of propellant or the atomization preparation that can suck, and comprising: the medicine that is dissolved in the mixture of water, organic appearance agent or water organic solvent; Or micronized dry powder, the capsule that can be used for various suction apparatus of making after mixing with lactose.Above-mentioned suction preparation can by the present invention above described method prepared.
Embodiment 6
In the present embodiment, also comprise being used in combination of a kind of new medicine.Use left-handed (R) terbutaline and their pharmaceutically acceptable salts of therapeutic dose, be used in combination with cholinolytic or cholinergic receptor antagonist, be prepared into and suck preparation suction bronchus or pulmonary, be used for the treatment of asthma or other respiratory tract disease.As combination therapy, this Drug combination can be simultaneously, continuous or divide other.This combination inhalation aerosol Therapeutic Method of the present invention can suppress bronchus cholinergic receptor, thereby produce addition or collaborative bronchiectatic activity when bronchus activates beta 2 receptor.Spendable cholinolytic thing comprises: as ipratropium bromide, for irrigating tropine, trospium chloride, oxitropium bromide, reaching human relations tropine, atropine, melyltropeine, tropicamide, scopolamine, oxibutynin, tolterodine etc. and their salt.Routine in molar ratio, the usage ratio that (R) terbutaline and cholinolytic thing are used in combination is 1:0.1-1:2; The ratio of more optimizing is: 1:0.5.
Cholinolytic thing amount ranges can be adjusted according to the therapeutic goal of symptom and age and principal agent, (R) prescription of the compound recipe of terbutaline and above-mentioned cholinolytic thing can be solution or the dispersant of propellant or the atomization preparation that can suck, and comprising: the mixture medicines that is dissolved in water, organic appearance agent or water organic solvent; Or micronized dry powder, the capsule that can be used for various suction apparatus of making after mixing with lactose.Above-mentioned suction preparation can by the present invention above described method prepared.
Embodiment 7
In the present embodiment, also comprise (R) terbutaline and remove fugitive β2agonists or other medicines being newly used in combination as nitric oxide (NO) of cholinolytic beyond the region of objective existence.Left-handed (R) terbutaline and nitric oxide (NO) can be prepared into suction preparation and be used in combination, and suck bronchus or pulmonary, are used for the treatment of asthma or other respiratory tract disease; Can improve therapeutic index and performance addition or collaborative therapeutic effect in treatment.The amount ranges of above-mentioned bronchodilator can be adjusted according to the therapeutic goal of symptom and age and principal agent.
The prescription of left-handed (R) terbutaline and above-mentioned nitric oxide production compound recipe can be solution or the dispersant of propellant or the atomization preparation that can suck, and comprising: the medicine that is dissolved in the mixture of water, organic appearance agent or water organic solvent; Or micronized dry powder, the capsule that can be used for various suction apparatus of making after mixing with lactose.Above-mentioned suction preparation can by the present invention above described method prepared.
Another example of the present invention also comprises being used in combination of a kind of brand-new medicine.Use left-handed (R) terbutaline and their pharmaceutically acceptable salts and antiinflammatory or the immunomodulator of therapeutic dose, as interleukin receptor antagonist, interferon and integrin etc. are used in combination, be prepared into and suck preparation suction bronchus or pulmonary, be used for the treatment of asthma or other respiratory tract disease.This combined therapy can be by simultaneously, continuous pass through or minute other administering mode, thereby improve therapeutic index or play the forward synergism of medicine.The amount ranges of above-mentioned anti-inflammatory agents can be adjusted according to the therapeutic goal of symptom and age and principal agent.Left-handed (R) terbutaline and said medicine combination suck preparation, can be solution or the dispersant of propellant or the atomization preparation that can suck, and comprising: the medicine that is dissolved in the mixture of water, organic appearance agent or water organic solvent; Or micronized dry powder, the capsule that can be used for various suction apparatus of making after mixing with lactose.Above-mentioned suction preparation can by the present invention above described method prepared.
It can also be to be prepared into solid preparation that said medicine is used in combination, as Tablet and Capsula agent.Interleukin receptor antagonist, as Meng Teluka etc., is used for the treatment of asthma or other respiratory tract disease.
Said medicine combined amount is adjusted according to the therapeutic goal of symptom and age and principal agent, and combined therapy can be by simultaneously, continuous pass through or minute other administering mode, thereby improves therapeutic index or play the forward synergism of medicine.
The above, it is only preferred embodiment of the present invention, not the present invention is done to any pro forma restriction, although the present invention preferred embodiment discloses as above, yet not in order to limit the present invention, any those skilled in the art, in not departing from the scope of the present invention, any simple modification, equivalent variations and the modification above embodiment done according to technical spirit of the present invention, all belong in the scope of technical solution of the present invention.
List of references:
[1]Richard?W.Weber,JosephA.Smith,Harold?S.Nelson.Aerosolized?terbutaline?in?asthmatics:development?of?subsensitivity?with?long-term?administration.Journal?of?Allergy?and?Clinical?Immunology,1982；70(6):417-422.
[2]Brian?J.O’Connor,Sarah?L.Aikman,Peter?J.Barnes.Tolerance?of?the?nonbronchodilator?effects?of?inhaled?β2-agonists?in?asthma,The?New?England?Journal?of?Medicine,1992；327(17):1204-1208
[3]Vasiliy?Goral,Yan?Jin,Haiyan?Sun?et?al.Agonist-directed?desensitization?of?the?β2-adernergic?receptor.PLoS?ONE,2011,6(4):1-8
[4].William?R.,Ena?Ray?Banerjee,Emil?Y.Chi.Differential?effects?of?S-and?R-enantiomers?of?albuterol?in?a?mouse?asthma?model.J?Allergy?Clin?Immunol,2005；116:332-340.
[5].Mazzoni.L,Naef.R,Chapman.I.D.,Morley.J.Hyperresponsiveness?of?the?airways?to?histamine?following?exposure?of?guinea-pigs?to?racemic?mixtures?and?distomers?of?beta2-selective?sympathomimetics.Pulm?Pharmacol.1994,7:367-376.
Claims (14)
1. reduce a compositions for Drug tolerance, it contains the β that treats effective dose
2receptor stimulating agent or its pharmaceutically acceptable salt, wherein said β
2the superfluous value of left-handed in receptor stimulating agent (R) enantiomer purity is more than 90%.
2. pharmaceutical composition according to claim 1, wherein said β
2receptor stimulating agent is β
2the superfluous value of left-handed in receptor stimulating agent (R) enantiomer purity is more than 95%.
3. pharmaceutical composition according to claim 2, wherein said β
2receptor stimulating agent is β
2the superfluous value of left-handed in receptor stimulating agent (R) enantiomer purity is more than 99%.
4. according to the compositions described in arbitrary claim in claim 1-3, wherein said β
2terbutaline that receptor stimulating agent is selected from left-handed (R), left-handed (R) fenoterol, left-handed (R) orciprenaline, left-handed (R) Clenbuterol, left-handed (R) clorprenaline, left-handed (R) are than appropriate special sieve, left-handed (R) Rui meter Te Luo or left-handed (R) Mabuterol.
5. compositions according to claim 1, wherein said β
2receptor stimulating agent pharmaceutically acceptable salt is selected from acylate, inorganic acid salt or its combination, described acylate or inorganic acid salt are selected from hydrochlorate, hydrobromate, sulfate or disulfate, dihydric phosphate, metilsulfate, Bromide, acetate, oxalates, maleate, fumarate, succinate, 2-naphthyl sulfate, gluconate, twist lemon hydrochlorate, tartrate, lactate, one or more of pyruvate, isethionate, benzene sulfonate and tosilate.
6. compositions according to claim 1, it further contains pharmaceutically applicable carrier, and described carrier is selected from propellant, saccharide or the sugar alcohol that comprises fluorine hydrogen compound.
7. according to the compositions described in the arbitrary claim of claim 1-6, the dosage form of described compositions is any in tablet, capsule, Foradil Aerolizer formoterol fumarate, atomized inhalation, aerosol, solvent or suspending agent.
8. a method that reduces Drug tolerance, the method comprises to required patient takes the compositions described in arbitrary claim in claim 1-6, and take corticosteroid to required patient simultaneously, wherein said corticosteroid is selected from as budesonide, ciclesonide, beclomethasone, momestasone furoate, flunisolide, replaces Kazon propionic ester, hydrochloric acid triamcinolone acetonide, fluticasone and pharmaceutically acceptable salt or solvent.
9. the method for reduction Drug tolerance according to claim 8, wherein β
2receptor stimulating agent is left-handed (R) terbutaline, and the molar ratio of itself and described corticosteroid is 1:1-1:60.
10. a method that reduces Drug tolerance, the method comprises to required patient takes the compositions described in arbitrary claim in claim 1-6, and take cholinergic receptor antagonist to required patient simultaneously, described cholinergic receptor antagonist is selected from as ipratropium bromide, for fertile tropine, trospium chloride, oxitropium bromide, reaches human relations tropine, atropine, melyltropeine, tropicamide, scopolamine, oxibutynin, tolterodine and pharmaceutically acceptable salt thereof.
The method of 11. reduction Drug tolerances according to claim 10, wherein β
2receptor stimulating agent is left-handed (R) terbutaline, and the molar ratio that itself and described cholinergic receptor antagonist are used in combination is 1:0.1-1:2.
12. 1 kinds of methods that reduce Drug tolerance, the method comprises to required patient takes the compositions described in arbitrary claim in claim 1-6, and uses nitric oxide to required patient simultaneously.
13. 1 kinds of methods that reduce Drug tolerance, the method comprises to required patient takes the compositions described in arbitrary claim in claim 1-6, and use antiinflammatory or immunomodulator to required patient simultaneously, described antiinflammatory or immunomodulator are selected from interleukin receptor antagonist or agent interfering.
The application of compositions described in the arbitrary claim of 14. claim 1-6 in the medicine of preparation treatment asthma or other respiratory tract disease.
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| CN115210210A (en) * | 2020-03-02 | 2022-10-18 | 谭文 | Crystalline form of (R) -terbutaline hydrochloride |
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