CN104208044A - Tramadol hydrochloride inhalation preparation - Google Patents
Tramadol hydrochloride inhalation preparation Download PDFInfo
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- CN104208044A CN104208044A CN201310205422.8A CN201310205422A CN104208044A CN 104208044 A CN104208044 A CN 104208044A CN 201310205422 A CN201310205422 A CN 201310205422A CN 104208044 A CN104208044 A CN 104208044A
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- 238000002360 preparation method Methods 0.000 title abstract description 12
- PPKXEPBICJTCRU-XMZRARIVSA-N (R,R)-tramadol hydrochloride Chemical compound Cl.COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 PPKXEPBICJTCRU-XMZRARIVSA-N 0.000 title abstract description 9
- 229960003107 tramadol hydrochloride Drugs 0.000 title abstract description 9
- TVYLLZQTGLZFBW-ZBFHGGJFSA-N (R,R)-tramadol Chemical compound COC1=CC=CC([C@]2(O)[C@H](CCCC2)CN(C)C)=C1 TVYLLZQTGLZFBW-ZBFHGGJFSA-N 0.000 claims abstract description 17
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Landscapes
- Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
- Medicinal Preparation (AREA)
Abstract
A tramadol hydrochloride inhalation preparation contains an active component namely tramadol or pharmaceutical salts thereof and one or more pharmaceutical auxiliary materials suitable for inhalation drug delivery.
Description
Technical field:
The present invention relates to and suck preparation containing tramadol hydrochloride
Background technology:
Tramadol (tramadol), a kind of novel) be the central action analgesic researched and developed by Glan Thailand (Grunentha1) company, often use tramadol hydrochloride (chemical name: (±)-2-(dimethyl aminomethyl)-1-(m-anisyl)-cyclohexanol HCI) clinically, be used for the treatment of various urgency, Chronic Moderate is to time severe pain, (" pharmacological characteristic of tramadol and the dependency investigation thereof such as Liu Zhimin, adverse effect magazine, volume the 2nd phase April the 9th in 2007, 117-120 points out, very weak due to its affinity be combined with opiate receptor, be about 1/6000 of morphine, its analgesic effect realizes mainly through non-opium mechanism of action, therefore be widely used.But due to the active metabolite M1((1-O-demethyl tramadol of tramadol in human body) stronger with the affinity of opiate receptor, be about the 160-300 of the former medicine of tramadol doubly, be 20-40 times of codeine, if therefore abuse and excessive use, also drug dependence can occur.Reduce by the blood medicine reducing its M1 the possibility that tramadol produces drug dependence, become problems of the prior art.
Summary of the invention:
The discovery that we are surprised, when tramadol is prepared into become suck preparation time, the blood medicine of its active metabolite M1 obviously reduces, and relative to other administering modes, significantly can reduce it and produce the probability of drug dependence.
The invention provides a kind of Inhaled pharmaceutical composition, it is characterized in that containing the tramadol as active component or its pharmaceutically useful salt, and one or more are applicable to the pharmaceutic adjuvant of inhalation.
Described pharmaceutical composition, is characterized in that described tramadol or its pharmaceutically useful salt are tramadol hydrochloride.
Described pharmaceutical composition is Foradil Aerolizer formoterol fumarate or aerosol.
The D90 particle diameter of described active component is 1 ~ 10 μm, is preferably 1-7 μm, is more preferably 3 ~ 6 μm.
Described pharmaceutical composition, when being prepared into Foradil Aerolizer formoterol fumarate, described pharmaceutic adjuvant comprises one or more in carrier, additives.
Described carrier is one or more in saccharide, aminoacid, lecithin, phosphatidylcholine.Described aminoacid is one or more in glycine, valine, leucine.
Described saccharide is monosaccharide, disaccharide, derived carbohydrate, monosaccharide is mannitol, fructose, glucose, described disaccharide is maltose, trehalose, cellobiose, lactose, sucrose, and described derived carbohydrate is eight acetate fiber two sugar esters, sucrose octa-acetate, eight acetic acid lactose esters, five acetic acid glucose esters, six acetic acid Nitranitols and eight acetic acid Sargassum sugar esters.
Described carrier is one or both the combination in saccharide and lecithin, phosphatidylcholine.Be preferably lactose.
The mean diameter of described carrier is 20 ~ 80 μm.Be preferably 30 ~ 40 μm.
Described Foradil Aerolizer formoterol fumarate, described additives contain one or more in surfactant, lubricant, antistatic additive.
Described surfactant is poloxamer.
Described lubricant is one or more in magnesium stearate, micropowder silica gel, Pulvis Talci.
Described Foradil Aerolizer formoterol fumarate, is characterized in that the summation of described active component and the weight ratio of carrier are 1:1 ~ 1000.Be preferably 1:1 ~ 200.
Described Foradil Aerolizer formoterol fumarate, is packed as capsule with the form of single or multiple dosage.
The mean diameter of described carrier is 20 ~ 80 μm.Be preferably 30 ~ 40 μm.
Described pharmaceutical composition is aerosol, and described pharmaceutic adjuvant comprises the pharmaceutically useful propellant and other optional additives that are applicable to aerosol.
Described propellant is one or more in hydrofluoroalkane compounds.Be preferably HFA 134a (HFA134a), one or both in 1,1,1.2,3,3,3-heptafluoro-propane (HFA 227).Be more preferably HFA 134a (HFA134a).
Comprise solvent in described additives, be selected from glycerol, propylene glycol, Polyethylene Glycol, ethanol or oleic acid.
Described solvent is one or more in ethanol, propylene glycol.
Described pharmaceutical composition, be aerosol, formula is: the ethanol weight percent content as solvent is 5-20%, and the propellant of surplus.
The preparation method of described aerosol is: the active component micropowder adding recipe quantity in aerosol bottle, opens the valve on bottle, is imported by the mixture of the propellant of premixing and optional additives, valve-off, obtain required aerosol by valve.Optional ultra sonic bath is carried out with solubilising to aerosol bottle.
Or following preparation method can be adopted: be distributed in additives by micronized active component, then add in the propellant after pre-cooling and mix, then be dispensed in aerosol bottle.
Should be appreciated that because known reason, as the retention of active component in suction apparatus, the amount of often kind of active component that patient sucks can be different from the amount of metering.Therefore the applicating ratio between active component can be different from the ratio of metering.The ratio preferably used is in the described metered proportions indicated.
Described aerosol bottle and valve system can select disclosed aerosol bottle and valve system in Chinese patent CN98805261.X.
In this patent, the dosage of said medicine is in tramadol,
Particle diameter in the present invention is equivalent volume footpath, is the diameter of the ball identical with actual particle volume.It is generally acknowledged that the diameter that laser method is surveyed is equivalent volume footpath.
Particle diameter corresponding when D90 particle diameter refers to that the cumulative particle sizes distribution number of a sample reaches 90%.Its physical significance be particle diameter be less than it amounts of particles account for 90%, this numerical value can be detected by laser particle instrument.
Mean diameter refers to meso-position radius, can detect with laser particle analyzer.
Detailed description of the invention
Micronization of the present invention can use known mechanical crushing method or spray drying method.Mechanical crushing method refers to and utilizes the method for fluid energy mill (using Nanjing Univ. Instrument Factory QM-3A) respectively medicine and/or carrier powder to be broken into required particle diameter.Spray drying method refers to and medicine and/or carrier is dissolved in organic solvent entirely as in ethanol, through spray dryer (as Buli Minispray, 190 types, Germany or QW-500, Xishan city Lin Zhou drying machine factory), solid material is made required particle diameter.Use during spray drying method and can also add surfactant as poloxamer etc.The process conditions of spray drying method can be: inlet temperature is 105 DEG C, and outlet temperature is 68 DEG C, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 50mL/h.
Powder spray adopts No. 3 plant capsules (sino-america joint-venture Suzhou Capsule Co., Ltd produces, trade name: Vcaps), and each embodiment feeds intake according to 1000 capsules.The capsule loading bubble-cap type of powder spray is aluminum-plastic packaged, takes out, load powder spray inhaler (Shanghai balance pharmaceutical factory) and use during use.
Medicine mist (dripping) the grain abundance measured in embodiment below detects according to the method in 2010 editions pharmacopeia annex XH.
In an embodiment, μ g/ unit refers to administration unit minimum in medicine, and as Foradil Aerolizer formoterol fumarate refers to that μ g/ grain (capsule-type) or μ g/ inhale (multiple dose), aerosol refers to that μ g/ sprays.D90 particle diameter refers to as a sample, particle diameter corresponding when its cumulative particle sizes distribution number reaches 90%, its physical significance be particle diameter be less than it granule account for 90%.。
Embodiment 1
According to following table, active component 1 is mixed with active component 2 with after fluid energy mill micronization, Lactis Anhydrous 10g fluid energy mill is micronized to mean diameter 42 μm, after mixing, be divided in 1000 No. 3 capsules after crossing 3 mixings of 200 mesh sieve, the active component in every capsules sees the following form.
The preparation of aerosol, active component used is the weight of 1000 administration units, and HFA-134a is HFA 134a, and HFA-227 is HFC-227ea.
Embodiment 2
Active component
Ethanol 100g
HFA-134a?900g
Preparation technology: the ethanol 1000 times of every for active component in following table spray amount being added recipe quantity, stirs, divided dose fill, sealing-in dose valve system, and HFA-134a is injected in pressurization more respectively, to obtain final product.
Embodiment 3
Active component
Ethanol 50g
HFA-227?950g
Preparation technology: the ethanol 1000 times of every for active component in following table spray amount being added recipe quantity, stirs, divided dose fill, sealing-in dose valve system, and HFA-227 is injected in pressurization more respectively, to obtain final product.
Embodiment 4
Active component
Ethanol 300g
HFA-227?600g
HFA-134a?600g
Preparation technology: the ethanol 1000 times of every for active component in following table spray amount being added recipe quantity, stirs, divided dose fill, sealing-in dose valve system, HFA-134a and HFA-227 is injected in pressurization more respectively, to obtain final product.
Embodiment 5
Active component is dissolved in ethanol, after filtration, filtrate adopts spraying dry, D90 particle diameter sees the following form, inhalant adjuvant micronization, ratio of adjuvant, mean diameter see the following form, by active component 1,2 and adjuvant mixing, be dispensed in 1000 No. 3 capsules after crossing 3 mixings of 200 mesh sieve, the active component in every capsules sees the following form.
Process conditions are: inlet temperature is 100 DEG C, and outlet temperature is 68 DEG C, throughput 90%, and jet expansion internal diameter is 0.1cm, nozzle air flow velocity 800ml/min, sample introduction speed 30mL/h.
Pharmacological Examples 1 acetic acid twisting analgesic effect is tested
Adopt male mice in kunming, body weight 20 ± 2g, often organize 10, matched group 1 gives the administration of tramadol hydrochloride injection tail vein injection, and matched group 2 gives tramadol hydrochloride powder gavage.Experimental group gives the medicine inhalation of the embodiment of the present invention respectively, and laboratory animal is after administration 10min, and every mouse peritoneal injects 0.7% glacial acetic acid 0.2ml, and mouse writhing number of times in record 10min, grouping and dosage and experimental result situation are as following table
Shown by above-mentioned experiment, the suction preparation inhalation adopting the embodiment of the present invention to provide, can improve the analgesic effect of tramadol hydrochloride significantly, and can reduce the consumption of medicine accordingly.
Pharmacological Examples 2 drug metabolism is tested
For the laboratory animal of Pharmacological Examples 1, upon administration 5,10,20,30min gets the blood drug level that tramadol and its active metabolite M1 are surveyed in blood examination respectively, and calculates the ratio M of the blood drug level of blood drug level/its active metabolite M1 of tramadol.Result is as follows
As can be seen from experimental result, compare with oral way with the injection of routine, after employing inhalation, M1 production concentration in experimental animals obviously reduces, illustrate when adopt different modes of administration time impact is created on the drug metabolism mode of tramadol, make the further metabolism of M1 faster than other conventional administration modes, because the binding ability of M1 and opiate receptor is better than the former medicine of tramadol far away, it is the main matter causing potential additive harm, so, low M1 concentration, can reduce tramadol and produce addicted probability.
Claims (10)
1. an Inhaled pharmaceutical composition, it is characterized in that containing the tramadol as active component or its pharmaceutically useful salt, and one or more is applicable to the pharmaceutic adjuvant of inhalation.
2. pharmaceutical composition as claimed in claim 1 or 2, is characterized in that described pharmaceutical composition is Foradil Aerolizer formoterol fumarate or aerosol.
3. pharmaceutical composition as claimed in claim 3, is characterized in that the D90 particle diameter of described active component is 1 ~ 10 μm.
4. pharmaceutical composition as claimed in claim 4, when it is characterized in that being prepared into Foradil Aerolizer formoterol fumarate, described pharmaceutic adjuvant comprises one or more in carrier, additives.
5. pharmaceutical composition as claimed in claim 5, is characterized in that described carrier is one or more in saccharide, aminoacid, lecithin, phosphatidylcholine.
6. pharmaceutical composition as claimed in claim 4, is characterized in that the mean diameter of described carrier is 20 ~ 80 μm.
7. pharmaceutical composition as claimed in claim 4, it is characterized in that described Foradil Aerolizer formoterol fumarate, described additives contain one or more in surfactant, lubricant, antistatic additive.
8. pharmaceutical composition as claimed in claim 4, it is characterized in that described Foradil Aerolizer formoterol fumarate, the summation of described active component and the weight ratio of carrier are 1:1 ~ 1000.
9. pharmaceutical composition as claimed in claim 1, it is characterized in that described pharmaceutical composition, is aerosol, and described pharmaceutic adjuvant comprises the pharmaceutically useful propellant and other optional additives that are applicable to aerosol.
10. pharmaceutical composition as claimed in claim 9, is characterized in that described propellant is for one or more in hydrofluoroalkane compounds.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310205422.8A CN104208044A (en) | 2013-05-29 | 2013-05-29 | Tramadol hydrochloride inhalation preparation |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201310205422.8A CN104208044A (en) | 2013-05-29 | 2013-05-29 | Tramadol hydrochloride inhalation preparation |
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| CN104208044A true CN104208044A (en) | 2014-12-17 |
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Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201310205422.8A Pending CN104208044A (en) | 2013-05-29 | 2013-05-29 | Tramadol hydrochloride inhalation preparation |
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| Country | Link |
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| CN (1) | CN104208044A (en) |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997017948A1 (en) * | 1995-11-14 | 1997-05-22 | Euro-Celtique, S.A. | Formulation for respiratory tract administration |
| WO2002094231A1 (en) * | 2001-05-24 | 2002-11-28 | Alexza Molecular Delivery Corporation | Delivery of analgesics through an inhalation route |
| CN1736370A (en) * | 2004-08-17 | 2006-02-22 | 石家庄制药集团欧意药业有限公司 | Freeze dried powder injection of tramadol hydrochloride and its preparation process |
-
2013
- 2013-05-29 CN CN201310205422.8A patent/CN104208044A/en active Pending
Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| WO1997017948A1 (en) * | 1995-11-14 | 1997-05-22 | Euro-Celtique, S.A. | Formulation for respiratory tract administration |
| WO2002094231A1 (en) * | 2001-05-24 | 2002-11-28 | Alexza Molecular Delivery Corporation | Delivery of analgesics through an inhalation route |
| CN1736370A (en) * | 2004-08-17 | 2006-02-22 | 石家庄制药集团欧意药业有限公司 | Freeze dried powder injection of tramadol hydrochloride and its preparation process |
Non-Patent Citations (2)
| Title |
|---|
| 崔福德: "《药剂学》", 31 January 2006 * |
| 王学民: "《生物药物制剂技术》", 30 September 2010 * |
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Application publication date: 20141217 |