CN101234108A - Pharmaceutical composition containing (3S, 2'R)-3-(2'-hydroxy-2'-cyclopentyl-2'-phenylethoxy) quinuclidine hydrochloride and uses thereof - Google Patents
Pharmaceutical composition containing (3S, 2'R)-3-(2'-hydroxy-2'-cyclopentyl-2'-phenylethoxy) quinuclidine hydrochloride and uses thereof Download PDFInfo
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- CN101234108A CN101234108A CNA2007100483562A CN200710048356A CN101234108A CN 101234108 A CN101234108 A CN 101234108A CN A2007100483562 A CNA2007100483562 A CN A2007100483562A CN 200710048356 A CN200710048356 A CN 200710048356A CN 101234108 A CN101234108 A CN 101234108A
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Abstract
The invention discloses medical composition containing active component of (3S, 2'R)-3-(2'-hydroxyl-2'-cyclopentyl-2'-phenylethoxy) quinine quinuclidine chloride and application of the medical composition in preparing drugs for treating chronic obstructive lung disease, incontinentia urinae, diversified shock diseases and preparing adjuvant drugs used before anaesthesia. The active component of the medical composition of the invention has high optical purity, strong stereoselectivity in vivo process, definite curative effects and high pertinency to the disease, thus effectively avoiding generation of toxic and side effects.
Description
Technical field
The present invention relates to a kind of pharmaceutical composition, concrete, the present invention relates to contain (3S, 2 ' R)-pharmaceutical composition of 3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride, and said composition application in the adjuvant drug medicine before preparation treatment chronic obstructive pulmonary disease, urinary incontinence treatment, shock disease and anesthesia.
Background technology
Synthetic and the research of chiral drug has become the emphasis and the focus in 21 century study of pharmacy field, and chiral drug has been familiar with the history in existing more than 150 year, and clinical research is inchoate nearest decades.Important change trend of pharmacy circle is exactly to focus on the single optical isomer that uses high-optical-purity as specific drug at present, and most of from now on chirality original new drugs will concentrate on single enantiomer.
In the world in the Chang Yong synthetic drug, have 40% to be chiral drug approximately, but great majority all are with the form administration of racemic modification, and often have following drawback with the racemic modification form administration:
(1) only wherein a kind of enantiomer has activity in the raceme, the very low or non-activity of other enantiomer activity, and perhaps the enantiomer activity has the difference of matter, can not react the concentration of the enantiomer of performance effect truly as the total blood concentration of racemic modification;
(2) a certain specific toxicity of some drugs is mainly owing to a kind of enantiomer wherein;
(3) there is interactional probability between the enantiomer;
(4) has identical pharmacologically active between enantiomer.
Amyl ethyl quin ether hydrochloride, English name: Penehyclidine Hydrochloride, chemical name: 3-(2-cyclopenta-2-hydroxyl-2-phenyl ethoxy) quinuclidine hydrochloride, molecular formula: C
20H
29NO
2HCl, molecular weight: 351.92.
Comprise 2 chiral carbon atoies in the amyl ethyl quin ether hydrochloride molecular structure of compounds, 2 pairs of racemic modifications, 4 optical isomers, the space structure formula of its four chipal compounds is as follows respectively:
(1), (3R, 2 ' S)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride
(2), (3R, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride
(3), (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride
(4), (3S, 2 ' S)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride
At present, the relevant research that is used for pharmaceutical composition with 4 chipal compounds of amyl ethyl quin ether hydrochloride did not also appear in the newspapers.
Summary of the invention
The object of the present invention is to provide the pharmaceutical composition of a kind of containing (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride, and said composition is liquid preparation, solid preparation, spray agent by excipient.
Active component optical purity height in the pharmaceutical composition of the present invention, the physiological disposition stereo selectivity is strong, curative effect is determined, with strong points to disease, thus effectively avoided the generation of toxic and side effects.
Another object of the present invention is to provide the application in the adjuvant drug medicine before preparation treatment chronic obstructive pulmonary disease, urinary incontinence treatment, shock disease and anesthesia of this pharmaceutical composition.
For achieving the above object, the technical solution used in the present invention is as follows:
Contain (3S, 2 ' R)-pharmaceutical composition of 3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride, it is characterized in that: it is with (3S, 2 ' R)-and 3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride is an active component, adds pharmaceutically other auxiliary elements of acceptable and makes; Wherein, the weight proportion that contains described active component in each minimum preparation unit (every, every, every or every bottle) is: 0.1～10mg.
Other auxiliary elements of the present invention comprise acid-base modifier, solid filler, binding agent, lubricant, and the excipient that plays the excipient effect.
Described acid-base modifier is selected from any in hydrochloric acid, sulphuric acid or the phosphoric acid.
Described solid filler is selected from any in starch, dextrin, Icing Sugar, mannitol, microcrystalline Cellulose, the calcium sulfate.
Described binding agent is selected from any in hypromellose, polyvidone, dextrin, cellulosic other derivants.
Described lubricant is selected from any in stearic acid, calcium stearate, magnesium stearate, Polyethylene Glycol, Stepanol MG, sodium lauryl sulphate, the micropowder silica gel.
The excipient that plays the excipient effect of the present invention comprises water, dehydrated alcohol or above-mentioned solid filler, binding agent, lubricant, or plays the dichlorodifluoromethan hydrocarbon and the Compressed Gas of impelling effect.
Described fluorochloroparaffins is selected from any among fluorine Lyons, the HFC-134a.
Described Hydrocarbon is selected from any in ethanol, propane, normal butane, the iso-butane.
Described Compressed Gas is selected from any in carbon dioxide, nitrogen, the nitric oxide.
Pharmaceutical composition of the present invention, but concrete excipient is a liquid preparation, and the pH value of this liquid preparation is 3.5～6.5; The concentration range of wherein said (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride in this liquid preparation is: 0.1mg/ml～10mg/ml.
Liquid preparation of the present invention comprises oral liquid, injecting fluid preparation, spraying liquid preparation, aerosol liquid preparation, wherein:
Oral formulations, the every preparation unit of injection contain (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride 0.1～10mg.
Spraying liquid preparation, the every preparation unit of aerosol liquid preparation contain (3S, 2 ' R)-3-(2 '-hydroxyl 2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride 0.1～1mg.
Liquid preparation of the present invention can subcutaneous injection, intramuscular injection, the administration of intravenous injection mode, also can be oral, by breathing the mode administration that sucks.
Pharmaceutical composition of the present invention, but concrete excipient is a solid preparation, this solid preparation comprises tablet, capsule, the weight proportion of wherein said (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride in tablet or capsule is respectively 0.1～1mg/ sheet, 0.1～1mg/ grain.Other adjuvants are starch, dextrin, Icing Sugar, mannitol, microcrystalline Cellulose, calcium sulfate, hypromellose, polyvidone, cellulosic other derivants, stearic acid, calcium stearate, magnesium stearate, Polyethylene Glycol, Stepanol MG, sodium lauryl sulphate or micropowder silica gel.
The main uses of pharmaceutical composition in pharmacy of of the present invention containing (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride is:
1, the application in preparation treatment chronic obstructive pulmonary disease thing;
2, the application in preparation treatment urinary incontinence treatment medicine;
3, the application in preparation treatment shock disease medicament;
4, the application in the adjuvant drug medicine before preparation anesthesia.
Below by the experiment of pharmacology and pharmacokinetics, the drug action of pharmaceutical composition of the present invention is described further.
Pharmacological experiment: 4 optical isomers of amyl ethyl quin ether hydrochloride are as follows to QNB and the bonded competitive inhibition result of m receptor:
| Chemical compound | IC 50(M) |
| (3R, 2 ' S)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride | 3.3×10 -7 |
| (3R, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride | 0.8×10 9 |
| (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride | 5.4×10 -8 |
| (3S, 2 ' S)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride | 2.1×10 -6 |
From above data as can be seen: the different optical isomer of amyl ethyl quin ether hydrochloride has marked difference to m receptor in conjunction with activity.
Pharmacokinetic experiment: the different optical isomer pharmacokinetic parameter of amyl ethyl quin ether hydrochloride is as follows:
| Project | (3R，2’S) | (3R，2’R) | (3S，2’R) | (3S，2’S) | Amyl ethyl quin ether hydrochloride |
| T 1/2β(h) | 14.2±0.7 | 11.6±2.83 | 7.83±2.57 | 8.49±1.67 | 8.4±2.79 |
| T max(h) | 0.081±0.02 | 0.085±0.027 | 0.065±0.049 | 0.043±0.088 | 0.068±0.032 |
| C max | 23.5±9.54 | 15.8±3.15 | 19.3±8.46 | 14.6±4.72 | 30.2±6.10 |
| AUC | 23.5±9.54 | 15.8±3.15 | 19.3±8.46 | 14.6±4.72 | 10.7±26.30 |
Above result shows: different its pharmacokinetic difference of optical isomer of amyl ethyl quin ether hydrochloride is remarkable.
The invention has the advantages that: pharmaceutical composition active component optical purity height of the present invention, the physiological disposition stereo selectivity is strong, curative effect is determined, with strong points to disease, thus effectively avoided the generation of toxic and side effects.
The specific embodiment
Embodiment 1
The ejection preparation of a kind of containing (3S, 2 ' R)-3-(2 '-hydroxyl 2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride is characterized in that constituent and weight proportion are:
Prescription (one)
(3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 0.1g
Purified water: 1L
Hydrochloric acid (3mol/L): 10ml
Be prepared into 1000, the concentration 0.1mg/ml of unit.
Prescription (two)
(3S, 2 ' R)-3-(2 '-hydroxyl 2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 1g
Purified water: 1L
Hydrochloric acid (3mol/L): 10ml
Be prepared into 1000, the concentration 1mg/ml of unit.
Prescription (three)
(3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 10g
Purified water: 1L
Hydrochloric acid (3mol/L): 10ml
Be prepared into 1000 bottles, the concentration 10mg/ml of unit.
Be used for the treatment of chronic obstructive pulmonary disease, shock disease, urinary incontinence treatment and the preceding adjuvant drug of anesthesia.
Embodiment 2
The tablet of a kind of containing (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride is characterized in that constituent and weight proportion are:
Prescription (four)
(3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 0.1g
Lactose: 68g
Carboxymethyl starch sodium: 10g
Magnesium stearate: 0.35g
Be prepared into 1000, unit content 0.1mg/ sheet, oral, each 1, every day 1 time.
Prescription (five)
(3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 1g
Lactose: 68g
Carboxymethyl starch sodium: 10g
Magnesium stearate: 0.35g
Be prepared into 1000, unit content 1mg/ sheet, oral, each 1, every day 1 time.
Prescription (six)
(3S, 2 ' R)-3-(2 '-hydroxyl 2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 0.1g
Lactose: 520g
Carboxymethyl starch sodium: 10g
Magnesium stearate: 0.35g
Be prepared into 1000, unit content 0.1mg/ grain, oral, each 1, every day 1 time.
Prescription (seven)
(3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 1g
Lactose: 520g
Carboxymethyl starch sodium: 10g
Magnesium stearate: 0.35g
Be prepared into 1000, unit content 1mg/ grain, oral, each 1, every day 1 time.
Be used for the treatment of the preceding adjuvant drug of chronic obstructive pulmonary disease, various shock disease, urinary incontinence treatment and anesthesia.
Embodiment 3
Aerosol, the spray of a kind of containing (3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride is characterized in that constituent and weight proportion are:
Prescription (eight)
(3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 10g
Dehydrated alcohol: 1000ml
HFC-134a：11.2kg
Be prepared into 1000 bottles, the concentration 10mg/ of unit bottle.
Be used for the treatment of chronic obstructive pulmonary disease, various shock disease.
Prescription (nine)
(3S, 2 ' R)-3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride: 10g
Purified water: 1000ml
Be prepared into 1000 bottles, the concentration 10mg/ of unit bottle.
Be used for the treatment of chronic obstructive pulmonary disease, various shock disease.
Claims (8)
1. contain (3S, 2 ' R)-pharmaceutical composition of 3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride, it is characterized in that: it is with (3S, 2 ' R)-and 3-(2 '-hydroxyl-2 '-cyclopenta-2 '-phenyl ethoxy) quinuclidine hydrochloride is an active component, adds pharmaceutically other auxiliary elements of acceptable and makes; Wherein, the weight proportion that contains described active component in each minimum preparation unit is 0.1～10mg.
Described other auxiliary elements comprise acid-base modifier, solid filler, binding agent, lubricant, and the excipient that plays the excipient effect.
2. pharmaceutical composition as claimed in claim 1 is characterized in that: described acid-base modifier is selected from any in hydrochloric acid, sulphuric acid or the phosphoric acid.
3. pharmaceutical composition as claimed in claim 1 is characterized in that: described solid filler is selected from any in starch, dextrin, Icing Sugar, mannitol, microcrystalline Cellulose, the calcium sulfate.
4. pharmaceutical composition as claimed in claim 1 is characterized in that: described binding agent is selected from any in hypromellose, polyvidone, dextrin, cellulosic other derivants.
5. pharmaceutical composition as claimed in claim 1 is characterized in that: described lubricant is selected from any in stearic acid, calcium stearate, magnesium stearate, Polyethylene Glycol, Stepanol MG, sodium lauryl sulphate, the micropowder silica gel.
6. pharmaceutical composition as claimed in claim 1, it is characterized in that: the described excipient that plays the excipient effect comprises water, dehydrated alcohol, solid filler, binding agent, lubricant, or plays the dichlorodifluoromethan hydrocarbon of impelling effect, in the Compressed Gas any.
7. pharmaceutical composition as claimed in claim 1 is characterized in that: described pharmaceutical composition, be specially liquid preparation, and the pH value of this liquid preparation is 3.5～6.5; Wherein said active component shared weight proportion in liquid preparation is: 0.1mg～10mg/ml.
8. pharmaceutical composition as claimed in claim 1 is the application in the adjuvant drug medicine before preparation treatment chronic obstructive pulmonary disease, shock disease, urinary incontinence treatment and anesthesia.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100483562A CN101234108A (en) | 2007-01-30 | 2007-01-30 | Pharmaceutical composition containing (3S, 2'R)-3-(2'-hydroxy-2'-cyclopentyl-2'-phenylethoxy) quinuclidine hydrochloride and uses thereof |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CNA2007100483562A CN101234108A (en) | 2007-01-30 | 2007-01-30 | Pharmaceutical composition containing (3S, 2'R)-3-(2'-hydroxy-2'-cyclopentyl-2'-phenylethoxy) quinuclidine hydrochloride and uses thereof |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN101234108A true CN101234108A (en) | 2008-08-06 |
Family
ID=39918175
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| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2007100483562A Pending CN101234108A (en) | 2007-01-30 | 2007-01-30 | Pharmaceutical composition containing (3S, 2'R)-3-(2'-hydroxy-2'-cyclopentyl-2'-phenylethoxy) quinuclidine hydrochloride and uses thereof |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN101234108A (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN102896315A (en) * | 2012-09-15 | 2013-01-30 | 安徽省怀远县尚冠模具科技有限公司 | Method for manufacturing top board of die |
| CN103271872A (en) * | 2013-05-14 | 2013-09-04 | 成都自豪药业有限公司 | Industrial production method of penehyclidine hydrochloride injection |
| CN103284943A (en) * | 2012-02-29 | 2013-09-11 | 黄绍渊 | Novel method for preparing penehyclidine hydrochloride injection |
| CN107638383A (en) * | 2016-07-21 | 2018-01-30 | 王琴 | The preparation technology of penehyclidine hydrochloride injection |
-
2007
- 2007-01-30 CN CNA2007100483562A patent/CN101234108A/en active Pending
Cited By (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN103284943A (en) * | 2012-02-29 | 2013-09-11 | 黄绍渊 | Novel method for preparing penehyclidine hydrochloride injection |
| CN103284943B (en) * | 2012-02-29 | 2017-02-08 | 黄绍渊 | Method for preparing penehyclidine hydrochloride injection |
| CN102896315A (en) * | 2012-09-15 | 2013-01-30 | 安徽省怀远县尚冠模具科技有限公司 | Method for manufacturing top board of die |
| CN102896315B (en) * | 2012-09-15 | 2015-04-01 | 安徽省怀远县尚冠模具科技有限公司 | Method for manufacturing top board of die |
| CN103271872A (en) * | 2013-05-14 | 2013-09-04 | 成都自豪药业有限公司 | Industrial production method of penehyclidine hydrochloride injection |
| CN103271872B (en) * | 2013-05-14 | 2016-05-11 | 成都自豪药业有限公司 | The industrialized preparing process of penehyclidine hydrochloride injection |
| CN107638383A (en) * | 2016-07-21 | 2018-01-30 | 王琴 | The preparation technology of penehyclidine hydrochloride injection |
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Open date: 20080806 |