CN1972670A - Pharmaceutical composition - Google Patents
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- CN1972670A CN1972670A CNA2005800091635A CN200580009163A CN1972670A CN 1972670 A CN1972670 A CN 1972670A CN A2005800091635 A CNA2005800091635 A CN A2005800091635A CN 200580009163 A CN200580009163 A CN 200580009163A CN 1972670 A CN1972670 A CN 1972670A
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Abstract
A process for micronization of pharmaceutically active agents.
Description
The present invention relates to a kind of granule for preparing forms of pharmacologically active agents, for example particle mean size less than about 7 microns short grained method, relate to granule, and relate to and comprise described particulate pharmaceutical composition with the forms of pharmacologically active agents of described method preparation.
The particulate control production of forms of pharmacologically active agents with the definite granularity that is positioned at low-micron or sub-micron scope has the special technique difficulty.When organic medicinal compound and activating agent are handled, conventional fragmentation, mill and wet grinding and dry grinding method often with the order of severity or the high or low operational issue or the product quality of difference, this is owing to for example heavy metal pollution causes.
For example, grinding technique is used to reduce solid granularity in the industrial practice of being everlasting.Yet dry milling technique may cause the dust of defective level, and this need take complicated safety precaution in grinding operation.In addition, in many cases, the dry grinding method increases the amorphous content in the granular preparation of forms of pharmacologically active agents, its may be disadvantageous or bring weaken or even bad therapeutic effect.The dry grinding method often suffers significant product loss or suffers operational issue such as product caking or equipment stop up.In dry grinding equipment, handle adhesivity in routine, the cohesiveness powder is observed the latter often.The main limitation of wet milling techniques has because the heavy metal pollution that granule contacts with the direct physical of the medium of milling and the wall wearing and tearing are caused.Other technical problem of observing in the dry method of forms of pharmacologically active agents and waterproof pulverization has because the thermal degradation and chemical degradation, uneven product attribute and batch differences that cause of the localized hyperthermia of milling apparatus for example.
Spraying and Freeze Drying Technique or utilize the granule of supercritical fluid to form the selectable method be used as production micronize dry powder.Yet all these three kinds of technology are almost all undesirable aspect particle mean size.In addition, when the temperature that is exposed to rising (using in spray drying usually), thermally unstable molecule may be easy to decompose or degraded.Similarly, in spraying and lyophilization and utilizing during the granule of supercritical fluid forms, usually observing often is the increase of amorphous content in undesirable preparation.
Need provide a kind of can overcome these technical problems, be used for the difficulty that commercial production has the particle mean size of control and the particle size distribution of control (PSD) and pulverize the micron of forms of pharmacologically active agents or particulate, the firm and simple method of sub-micron.The invention provides a kind of method of avoiding or minimizing above technical problem.
On the one hand, the invention provides and a kind of forms of pharmacologically active agents is controlled micronized method, described forms of pharmacologically active agents for example have less than about 7 microns, for example about 0.1 or 0.5 to about 1,2,3,4,5,5.5,6 or 6.5 micron particle mean size, this method comprises that (a) is suspended in forms of pharmacologically active agents in Compressed Gas or the propellant, (b) by the high pressure homogenize handle this suspension and (c) decompression back obtain dry powder by this method.
On the other hand, the invention provides and a kind of forms of pharmacologically active agents is controlled micronized method, described forms of pharmacologically active agents for example have less than about 7 microns, for example about 0.1 or 0.5 to about 1,2,3,4,5,5.5,6 or 6.5 micron particle mean size, this method comprises that (a) is suspended in forms of pharmacologically active agents in the propellant, (b) handle this suspension and (c) obtain the suspension of micronized forms of pharmacologically active agents in propellant by the high pressure homogenize.
Forms of pharmacologically active agents can be suspended in Compressed Gas or the propellant, randomly can use one or more pharmaceutically useful excipient to form suspension medium.
Can implement the present invention with various forms of pharmacologically active agents.Medicine preferably exists with pure basically form.Granularity by method drug powder of the present invention is about 10 to 200 microns from particle mean size, preferably about 10 to 40 microns coarse raw materials is decreased to particle mean size less than about 7 microns, for example about 0.1 or 0.5 to about 1,2,3,4,5,5.5,6 or 6.5 micron, for example about 0.5 to about 5.0 microns.Method of the present invention can be preferred for the needle-like or the crystallization of pin sample of micronization high aspect ratio.The granule that shows this class form or similar form often causes serious operational issue in conventional milling apparatus.Particularly usually observing the equipment that causes owing to the bulk powder agglomates that forms compression in grinder stops up or mechanical breakdown.In addition, method of the present invention is particularly suitable for adhesivity or the strong medicine of cohesiveness that micronization often causes similar or other operational issue.
For purpose of the present invention, " forms of pharmacologically active agents " means all materials that produce drug effect or curative effect.The example of forms of pharmacologically active agents includes but not limited to activating agent poorly water-soluble and/or thermally labile or chemically unstable, for example phenytoin (5, the 5-diphenyl hydantoin), β
2Formula I chemical compound among-adrenoceptor agonists such as the WO 2000/075114 (free form or salt form or solvate form thereof), the chemical compound of chemical compound, the especially following formula of preferred embodiment and its officinal salt,
And the formula I chemical compound among the WO 2004/016601 (free form or salt form or solvate form thereof), chemical compound, the especially embodiment 1,3,4,5 of preferred embodiment and 79 chemical compound; Formula I chemical compound among corticosteroid such as the WO 2002/000679 (free form or salt form or solvate form thereof), chemical compound, the especially embodiment 3,11,14,17,19,26,34,37,39,51,60,67,72,73,90,99 of preferred embodiment and 101 chemical compound; Formula I chemical compound among Antimuscarinic antagonist such as the PCT/EP2004/004605 (salt form or zwitterionic form), chemical compound, the especially embodiment 17,34,52,54,71,76,96,114,138,159,170,190,209,221,242 of preferred embodiment and 244 chemical compound; The pimecrolimus (33-table chloro-33-deoxidation-ascosin) that description is arranged in EP 427680 for example; The N-benzoyl staurosporin that description is arranged in EP 296110 for example; Protein; Peptide; Vitamin; Steroid; Corticosteroid and bronchodilator.
Other forms of pharmacologically active agents can include but not limited to oxcarbazepine, carbamazepine, 1-(2,6-two fluoro-benzyls)-1H-[1,2,3] triazole-4-carboxylic acid amide; Pyrimidylaminobenzamderivatives (pyrimidyalaminobenzamide) is as the formula I chemical compound among the WO 04/005281, chemical compound, the especially chemical compound of embodiment 92 of preferred embodiment; The Cox-2 selective depressant for example in WO 99/11605 for example, have description 5-methyl-2-(2 '-chloro-6 '-fluoroanilino) phenylacetic acid; The camptothecin derivative that is called compd A with following structure:
Compd A can be free form or pharmaceutical acceptable salt, and can be prepared described in 457 as U.S. Patent No. 6,424.Compd A can be the form of its possible enantiomer, diastereomer and relative mixture, its officinal salt and its active metabolite.
Pharmaceutically useful excipient can be a surfactant.The surfactant that is fit to comprises acetylated monoglycerides, and is for example known and can be with trade name Myvacet
9-08 (Fiedler loc.cit., p1167) commercially available surfactant, perfluorinated substituted carboxylic acids (perfluorocarboxilic acid), Polyethylene Glycol (PEG) sterol ester PEG 200 for example, 300,400 or 600 (Fiedler loc.cit., p 1348), polyoxyethylene sorbitan fatty acid ester be Tween for example
20,40,60,65,80 or 85 (Fiedlerloc.cit.pp 1754), sorbitan ester be sorbitan mono-laurate, sorbitan monooleate, sorbitan trioleate or anhydrous sorbitol monopalmitate, propylene glycol and oleic acid for example.Randomly can use the combination of one or more surfactants.
In another aspect of this invention, excipient can be a carrier.Carrier can comprise one or more crystal sugars, for example one or more sugar alcohols or polyhydric alcohol.Preferably, can use lactose or glucose.
In another aspect of this invention, excipient can be antifriction additive (anti-friction agent) or antiplastering aid such as lubricant.The lubricant that is fit to comprises leucine, lecithin, magnesium stearate, stearic acid, sodium lauryl sulphate, sodium stearyl fumarate, octadecanol, sucrose palmitic acid ester (sucrosemono palinate), menthol, colloidal silica for example can be with trade name Aerosil
200 commercially available colloidal silica and sodium benzoate or their combinations.
On the other hand, excipient can comprise for example benzalkonium chloride, acidulant citric acid, antioxidant ascorbic acid, chelating agen EDTA disodium for example for example for example of antimicrobial.
Excipient can comprise the combination of one or more additives.
The details of the excipient that is fit to that is used for method of the present invention is at " the Lexikonder Hilfsstoffe " of Fiedler, the 5th edition, ECV Aulendorf 2002 and " Handbook ofPharmaceutical Excipients ", Rowe, Sheskey and Weller, the 4th edition, description is arranged in 2003, these documents are incorporated herein by reference.
In one embodiment of the invention, the powder of used forms of pharmacologically active agents is suspended in the Compressed Gas in the method for the present invention.Be suspended in the activating agent in the Compressed Gas amount can for 0.1% grams per liter (every volume 0.01%) to about 250 grams per liters (every volume 25%).
One class Compressed Gas comprises CO
2, ethane, propane, butane, dimethyl ether and nitrogen.Also can use the combination of Compressed Gas.Preferably, can use CO
2
Another kind of Compressed Gas is a propellant, comprises hydrofluoroalkane (HFA) for example 1,1,1,2-tetrafluoroethane (HFA 134a) and 1,1,1,2,3,3,3-heptafluoro-propane (HFA 227).HFA 134a and HFA 227 can be used for the people, and be different with chlorofluorocarbon (CFC) propellant, and they are to not consumption effect of ozone layer.Other example of hydrofluoroalkane propellant has perfluoro ethane, F-22 and Difluoroethane.Also can use the combination of propellant.
For purpose of the present invention, " suspension " means the binary system of being made up of the solid of the fine segmentation in the gas phase that is dispersed in successive for example compression.
Suspension can prepare by coarse raw materials being packed into stir in the pressure vessel.This container can be closed or robust sealed so that can under elevated pressure, operate, and can add Compressed Gas to form suspension.Operating pressure in the stirred vessel can be dependent on Compressed Gas.According to the present invention, common operating pressure at room temperature can be extremely about 300 crust of 1.5 to 2 crust, for example clinging to for about 10 to about 30 for some hydrofluoroalkanes, for example cling to for about 55 to about 60 for carbon dioxide, for example is that about 200 crust are to about 300 crust for nitrogen.If operative temperature significantly is lower than room temperature, for example about 0 to 5 ℃, under the situation of hydrofluoroalkane, operating pressure can for about 2 to about 5 the crust.For the method that is proposed, suitable operative temperature can be-30 ℃ to about 50 ℃ approximately.Entire method can be carried out in firm closure and sealing, withstand voltage equipment.
The high pressure homogenize is a kind of prior art that is used for preparing o/w, w/o, s/o/w or w/o/w Emulsion, solid lipid nanoparticle (solid-lipid nanoparticle), stable suspension and makes the solid decondensation that is dispersed in aqueous suspension.In the high pressure homogenize of routine, at first form solid or the liquid suspension in liquid, then it is handled in the homogenize unit under up to the elevated pressure of thousands of crust.
According to the present invention, the high pressure homogenize of Compressed Gas suspension can be a kind of be used for by particle mean size be about 10 to about 200 microns coarse raw materials produce micronized forms of pharmacologically active agents granule, for example have less than about 7 microns, for example about 1 or 2 to about 3,4,5,5.5,6 or 6.5 microns particulate effective technologies of fixed output quota thing granularity really.Can control the particle mean size and the particle size distribution of product effectively by the characteristic method parameter of the method for micronization that strict control proposed, described product can gathered in the crops decompression back, described unit with dry powder form or with Compressed Gas suspension form.Can come the strict control product quality with the selection of homogenization pressures, suspension density and solid concentration, operative temperature, interaction geometry (geometries) with through the total pass (it is equivalent to total processing time to a great extent) of equipment or the combination of these main operating parameters.Method of the present invention can be used for producing and is positioned at less than 7 microns, about 1 or 2 narrow particle size distribution to about 3,4,5,5.5,6 or 6.5 microns magnitude range for example.About 1 to about 5 microns magnitude range may be particularly suitable for sucking in the preparation in treatment, for example application in Diskus (DPI) or in metered-dose inhaler (MDI) or pressure metered-dose inhaler (pMDI).
On the other hand, the invention provides a kind of being used for the micronized device of forms of pharmacologically active agents, it comprises that one or two stirs pressure vessel, high-pressure homogenizer and be connected described one or two stirring pressure vessel and the unitary fluid conduit systems of high pressure homogenize.The stirring pressure vessel that is used to prepare the raw material suspension can be connected with the pipeline of a supply capacity Compressed Gas, and this pipeline itself can soak pipe (dip-tube) or air tank (gas cylinder) with one or several or the compensator that contains gas-pressurized is connected.Can add Compressed Gas by pump and set and control required operating pressure until reaching set point.High pressure homogenize unit can comprise booster pump (intensifier pump) and one or more interactions chamber (interaction chamber), owing to granule-granule and granule-wall collision, shearing force and fluid cavitation (fluid cavitation) reducing or micronization of granularity is taken place in the interaction chamber.The pipeline that pressure vessel and the unitary booster pump of high pressure homogenize are stirred in booster pump, connection can be cooled to avoid the compressible gas bubble to accumulate at the intake section of booster pump.High pressure homogenize unit can comprise an other booster pump.The high pressure opening (gap) that can be by will crossing over static geometry or the pressure drop of determining of valve be adjusted into less than 1500 crust for example, for example be adjusted into 200,500,750,1000 or 1500 crust realizes homogenize.Can use the dynamic high-pressure current.This valve has overcome some major defects of static interaction geometry, as the obstruction under the solid concentration that raises.If block, valve is opened, and can manually or use the pressure control equipment that is fit to readjust required pressure drop automatically.
The interaction chamber can provide logistics diverter (stream splitter) and bump chamber (impactionchamber).The air-flow of Compressed Gas, the non-solvent that contains solid particle and optional pharmaceutically useful excipient can be divided into two tributaries in the logistics diverter, and these two logistics can combination again in the bump chamber.Cause solid particle micronized main power in high-pressure homogenizer to have shearing force, turbulent flow, acceleration and rapid change on flowing to; Impact force comprises the collision of solid-state components of processed granule and homogenizer and the collision between the processed granule; With cavitation power (cavitationforce), comprise with pressure and reduce the speed increase variation that variation is accompanied, and turbulent flow.Other power has friction, and what promptly friction caused mills.
If micronization be by discharge to cross over determine opening for example the pressure of high pressure valve realize, then cause micronized main power to have cavitation, shearing force, turbulent flow, impact force (comprising the collision of solid-state components of processed granule and homogenizer and the collision between the processed granule) and rub.
In one embodiment of the invention, this method can be carried out in comprising a stirring pressure vessel and the unitary device of high pressure homogenize.The outlet of homogenizer can be connected with the stirring pressure vessel that contains suspension.Processed suspension is introduced again to be contained in the container of undressed suspension.Can be with the particulate particle mean size of controlling total processing time in grain products or the Compressed Gas suspension.Can after in pressure vessel, having formed the suspension of activating agent in Compressed Gas, begin the operation of high-pressure homogenizer.Homogenizer can followingly be operated: the homogenizer with entrance and exit depends on and is designed for the high-pressure pump of supplying required pressure with the constant speed for the product logistics.This pump is sent product by the indoor definite fixed geometirc structure microchannel that interacts under constant pressure.The homogenize of the suspension that reduces and form in stirring pressure vessel before of granularity is all in the indoor generation that interacts.Ejection-type (jet) interaction chamber component utilizes three kinds of different power: shearing force, bump and cavitation.The high pressure homogenize provides the suitable uniform grain sizes of forms of pharmacologically active agents to reduce for example micronization and decondensation.
In another embodiment of the invention (with reference to figure 1), described device can comprise that two are stirred pressure vessel (10) and high pressure homogenize unit (12), and described stirring pressure vessel has agitator (16).The entrance and exit of homogenizer (12) can pass through high-voltage tube (15) and stir pressure vessels (10) and is connected with two, and all connections all can be closed respectively by manual or automatic operate high pressure three-way valve (11) or high pressure valve (17).The suspension of raw material can form in two of stirring in the pressure vessel, can begin homogenize then.The outlet of homogenizer can be that second empty pressure vessel is connected when initial.If first stirs pressure vessel be empty and second stir the suspension that pressure vessel is equipped with homogenize, then can carry out operational example as so that readjust second direction that stirs the content of pressure vessel by homogenizer of the suspension that closes homogenize, and stir the suspension of collecting twice homogenize in pressure vessel at first to valve.The advantage of this embodiment of the present invention is more effectively to control particle mean size by the control time of staying, and the control of the described time of staying is to control by the pass through equipment.In this embodiment, particle mean size is by controlling through total pass of homogenizer, in fact common pass be about 3 to 25 times be less than about 7 microns, for example about 0.1 or 0.5 to about 1,2,3,4,5,5.5,6 or 6.5 micron particle mean size.If reached the total pass through homogenizer, then suspension can be stored in the storage tank (14).In this embodiment of the present invention, both can use static interaction geometry also can use dynamic high-pressure graduated release valve (relaxationvalve) to carry out homogenize.
With static state interaction geometry is that the high-pressure homogenizer of feature can be for example a closed-system, for example Microfluidics Model M-110Y Microfluidizer
Microfluidizer
Device and operational approach in U.S. Patent No. 4,533,254 and U.S. Patent No. 4,908,154 in further description is arranged, these two pieces of documents are incorporated herein by reference.Also can replace original high-pressure piston pump and Microfluidics M-110Y Microfluidizer with membrane pump
The interaction geometry is connected.
The dynamic high-pressure homogenizer can be for example one comprise for example LEWA LDE/1VM211S barrier film dosing pump (membrane dosage pump) and have the system of the high pressure valve that is fit to of adjustable valve port or opening of high-pressure booster, and valve seat and valve body preferably by anti-cavitation material for example the material of zirconium oxide, tungsten carbide or similarity make.The material of needle or plunger can preferably be made by the material harder than valve seat.The dynamic high-pressure valve can manual operation or by using suitable downstream pressure control means to operate automatically.
In another aspect of this invention, method of the present invention provides by having that system decompression is obtained less than about 7 microns, about 1 or 2 micron dried granule to the forms of pharmacologically active agents that does not contain solvent and moisture of about 3,4,5,5.5,6 or 6.5 microns particle mean size for example.The about 1 forms of pharmacologically active agents powder particle to about 5 microns sizes can be used for Diskus (DPI) preparation without any further processing.
In another aspect of this invention, described method provide fine dispersion in can be used for people's propellant to form the having of suspension less than about 7 microns, about 0.1 or 0.5 micron granule for example to the forms of pharmacologically active agents of about 1,2,3,4,5,5.5,6 or 6.5 micron particle mean size.Comprise about 0.5 particulate suspension and can be filled directly in the suitable suction apparatus, be used in metered-dose inhaler (MDI) or pressure metered-dose inhaler (pMDI) preparation without any further processing then to about 5 microns sizes.
An advantage of the invention is: the suspension of forms of pharmacologically active agents in propellant or Compressed Gas can be by micronization in a single stage method, step after the other processing.To promptly obtain the dry powder of forms of pharmacologically active agents after Compressed Gas or the propellant decompression, it can be used to suck preparation without any further processing.This method be easy to use and gentleness with inert condition under carry out.Method of the present invention has been avoided increase, pollution and the wearing and tearing of many technical problems as using a large amount of solvents, amorphous content.
On the other hand, the invention provides a kind of comprising with the micronized forms of pharmacologically active agents granule of method acquisition of the present invention and the pharmaceutical composition of pharmaceutically acceptable excipient.Above-mentioned pharmaceutically acceptable excipient comprises surfactant, carrier and/or lubricant, and can be used for producing pharmaceutical composition, for example the pharmaceutical composition of solid dosage form such as capsule, tablet or sachet form.
On the other hand, the invention provides the micronized forms of pharmacologically active agents granule that can in ointment or eye drop, use.
On the other hand, the invention provides the micronized forms of pharmacologically active agents granule that can in parenteral formulation, use.
On the other hand, the invention provides the micronized forms of pharmacologically active agents granule that can in oral formulations, use.
On the other hand, the invention provides the micronized forms of pharmacologically active agents granule that can in topical formulations, use.
On the other hand, the invention provides a kind of packaging kit, it comprises compositions of the present invention and operation instructions.
With reference to the non-limitative illustration and the accompanying drawing of following a plurality of embodiments of the present invention, it is more apparent that structure of the present invention and advantage will become.
It below is the non-limitative illustration of way of example.
Pimecrolimus is suspended among the propellant HFA227 (1,1,1,2,3,3, the 3-heptafluoro-propane) and at Microfluidics Microfluidizer M-110Y
TMMiddle homogenize.Use a pressure vessel, total processing time is 60 minutes.Operating pressure in the stirred vessel is about 3 crust, and maximum homogenization pressures is about 500 crust.Inlet temperature is 0 ℃, and outlet temperature is about 30 ℃.Handle after 60 minutes,, dry labor thing powder is analyzed with standard off-line analysis instrument with the pressure vessel decompression.
Pimecrolimus is suspended among the propellant HFA227 (1,1,1,2,3,3, the 3-heptafluoro-propane) and at Microfluidics Microfluidizer M-110Y
TMMiddle homogenize.Use two pressure vessels, with the particle mean size of controlling product through the pass of equipment.Operating pressure is about 3 crust, and maximum homogenization pressures is about 500 crust.Inlet temperature is about 0 ℃, and outlet temperature is about 30 ℃.After the 10th time,, dry labor thing powder is analyzed with standard off-line analysis instrument with system decompression.
Embodiment 3
Be suspended in pimecrolimus among the propellant HFA134 (1,1, the 1-HFC-143a) and under the pressure drop of strict control, cross over high pressure valve and carry out homogenize.Use a pressure vessel, total processing time is 180 minutes.Operating pressure is about 10 crust, and maximum homogenization pressures is about 750 crust, therefore uses the pressure drop of about 740 crust of crossing over graduated release valve.Inlet temperature is about 0 ℃, and outlet temperature is about 30 ℃.Handle after 180 minutes,, dry labor thing powder is analyzed with standard off-line analysis instrument with the pressure vessel decompression.
The pimecrolimus granule that will obtain in embodiment 1,2 and 3 is dispersed in the water that contains the 0.1%Tween 20 that has an appointment again to form suspension, and supersound process was handled 60 seconds usually then, measures granularity with Sympatec Helos laser diffraction granularity analyser afterwards.The result of granulometry is as shown in table 1.Described in service at embodiment 1, the processing time is 60 minutes, handles the particle mean size (X of by volume in a continuous manner
50) be 2.7 microns, X
90It is 11.4 microns.Described in service at embodiment 2, sample is handled with batch mode, report the result after 10 times.In this case, X
50Be 5.3 (5.5) microns, X
90It is 19.2 (20.6) microns.
Table 1
| Operation number/measure number | Processing mode | ?X 10[μm] | ?X 50[μm] | ?X 90[μm] |
| 1/1 | 60 minutes | ?0.9 | ?2.7 | ?11.4 |
| 1/2 | 60 minutes | ?0.9 | ?2.7 | ?11.7 |
| 2/1 | 10 times | ?1.1 | ?5.5 | ?20.6 |
| 2/2 | 10 times | ?1.0 | ?5.3 | ?19.2 |
| 3/1 | 180 minutes | ?0.89 | ?2.13 | ?6.07 |
Embodiment 4
Be suspended in phenytoin (5, the 5-diphenyl hydantoin) among the propellant HFA134 (1,1, the 1-HFC-143a) and under the pressure drop of strict control, cross over high pressure valve and carry out homogenize.Use a pressure vessel, total processing time is 240 minutes.Operating pressure is about 10 crust, and maximum homogenization pressures is about 750 crust.Inlet temperature is about 0 ℃, and outlet temperature is about 30 ℃.Handle after 240 minutes,, dry labor thing powder is analyzed with standard off-line analysis instrument with the pressure vessel decompression.The particle size distribution of the phenytoin microgranule that embodiment 4 is produced as shown in Figure 2.
Be suspended in phenytoin (5, the 5-diphenyl hydantoin) in the carbon dioxide and under the pressure drop of strict control, cross over high pressure valve and carry out homogenize.Use a pressure vessel, total processing time is 240 minutes.Operating pressure is about 57 crust, and maximum homogenization pressures is about 800 crust.Inlet temperature is about 0 ℃, and outlet temperature is about 30 ℃.Handle after 240 minutes,, dry labor thing powder is analyzed with standard off-line analysis instrument with the pressure vessel decompression.The particle size distribution of the phenytoin microgranule that embodiment 5 is produced as shown in Figure 3.
The phenytoin granule that will obtain in embodiment 4 and 5 is dispersed in the water that contains the 0.1%Tween20 that has an appointment again to form suspension, and supersound process was handled 60 seconds usually then, measures granularity with SympatecHelos laser diffraction granularity analyser afterwards.The result of granulometry is as shown in table 2.At embodiment 4 and 5 described in service, the processing time is 240 minutes, handles the particle mean size (X of by volume in a continuous manner
50) be respectively 1.48 and 1.46 microns, X
90Be respectively 3.57 and 3.02 microns.
Table 2
| Operation number/measure number | Processing mode | ?X 10[μm] | ?X 50[μm] | ?X 90[μm] |
| 4 | 240 minutes | ?0.72 | ?1.48 | ?3.57 |
| 5 | 240 minutes | ?0.73 | ?1.46 | ?3.02 |
Brief Description Of Drawings
Fig. 1 is two the successive loops schematic representation of apparatus that stir the closure of pressure vessel that comprise of the present invention.This device comprises that two are stirred pressure vessel (10), high pressure homogenize unit (12) and storage tank (14), and described stirring pressure vessel has agitator (16).The entrance and exit of homogenizer (12) stirs pressure vessels (10) and is connected with two by high-voltage tube (15), and all connections all can be closed respectively by manual or automatic operate high pressure three-way valve (11) or high pressure valve (17).
Fig. 2 is to use the example of the phenytoin microgranule of method production of the present invention.In embodiment 4, the particle size distribution of measuring with Sympatec Helos laser diffraction granularity analyser is as follows: X
10=0.72 micron, X
50=1.48 microns, X
90=3.57 microns.
Fig. 3 is to use the example of the phenytoin microgranule of method production of the present invention.In embodiment 5, the particle size distribution of measuring with Sympatec Helos laser diffraction granularity analyser is as follows: X
10=0.73 micron, X
50=1.46 microns, X
90=3.02 microns.
Claims (22)
1. with the micronized method of forms of pharmacologically active agents, it comprises that (a) is suspended in forms of pharmacologically active agents in propellant or the Compressed Gas, (b) by the high pressure homogenize handle this suspension and (c) decompression back obtain dry powder.
2. with the micronized method of forms of pharmacologically active agents, it comprises that (a) is suspended in forms of pharmacologically active agents in the propellant, (b) handles this suspension and (c) obtains the suspension of micronized forms of pharmacologically active agents in propellant by the high pressure homogenize.
3. method according to claim 1 and 2 is wherein had about 0.1 to about 7.0 microns particle mean size by the micronized forms of pharmacologically active agents of described method.
4. according to above any described method of claim, wherein had about 0.5 to about 5.0 microns particle mean size by the micronized forms of pharmacologically active agents of described method.
5. according to above any described method of claim, wherein the suspension that is formed by forms of pharmacologically active agents and Compressed Gas or propellant comprises one or more pharmaceutically useful excipient.
6. according to above any described method of claim, wherein forms of pharmacologically active agents poorly soluble and/or chemical or thermally labile in water.
7. according to above any described method of claim; wherein forms of pharmacologically active agents is selected from pimecrolimus (33-table chloro-33-deoxidation-ascosin); 5-[(R)-2-(5; 6-diethyl-indane-2-base is amino)-1-hydroxyl-ethyl]-the 8-hydroxyl-(1H)-quinoline-2-one-; 3 methyl thiophene-2-carboxylic acid (6S; 9R; 10S, 11S, 13S; 16R; 17R)-and 9-chloro-6-fluoro-11-hydroxyl-17-methoxycarbonyl-10,13,16-trimethyl-3-oxo-6; 7; 8,9,10; 11; 12,13,14; 15; 16,17-ten dihydros-3H-cyclopenta [α] phenanthrene-17-base ester; N-benzoyl staurosporin; oxcarbazepine; carbamazepine; 1-(2,6-two fluoro-benzyls)-1H-[1; 2,3] triazole-4-carboxylic acid amide; the cox-2 inhibitor; pyrimidylaminobenzamderivatives; camptothecin derivative; protein; peptide; vitamin; steroid; at least a in the bronchodilator.
8. according to above any described method of claim, wherein Compressed Gas is selected from least a in carbon dioxide, nitrogen, dimethyl ether, ethane, propane and the butane.
9. according to above any described method of claim, wherein Compressed Gas is the HFA propellant that can be used for the people.
10. according to above any described method of claim, wherein Compressed Gas is selected from least a among HFA134a and the HFA227.
11. method according to claim 5, wherein pharmaceutically useful excipient are selected from least a in surfactant, carrier and the lubricant.
12. method according to claim 11, wherein surfactant is selected from least a in acetylated monoglycerides, perfluorinated substituted carboxylic acids, Polyethylene Glycol (PEG) sterol ester, polyoxyethylene sorbitan fatty acid ester, sorbitan ester, sorbitan mono-laurate, sorbitan monooleate, sorbitan trioleate, anhydrous sorbitol monopalmitate, propylene glycol and the oleic acid.
13. according to above any described method of claim, wherein the suspension of forms of pharmacologically active agents in propellant or Compressed Gas handled by homogenize with static geometry.
14. according to above any described method of claim, wherein the suspension of forms of pharmacologically active agents in propellant or Compressed Gas handled by homogenize with dynamic valve.
15. according to above any described method of claim, wherein the suspension of forms of pharmacologically active agents and Compressed Gas or propellant forms in first stirred vessel and is stored in after micronization process in second stirred vessel.
16. the micronized forms of pharmacologically active agents that obtains in order to the method for last any claim.
17. a pharmaceutical composition, it comprises micronized forms of pharmacologically active agents and pharmaceutically useful excipient with the method acquisition of claim 16.
18. a packaging kit, it comprises the compositions and the operation instructions of claim 17.
19. according to any described method in the claim 1 to 15, wherein said micronized forms of pharmacologically active agents is in the suction apparatus made acid-stable in situ.
20. the purposes of micronized forms of pharmacologically active agents in sucking preparation that obtains with the method for claim 1 to 15.
21. the purposes of micronized forms of pharmacologically active agents in parenteral formulation with method acquisition any in the claim 1 to 15.
22. be used for the micronized device of forms of pharmacologically active agents, it comprises
Two are stirred pressure vessel,
High-pressure homogenizer,
Connect the fluid conduit systems that stirs pressure vessel and high-pressure homogenizer.
Applications Claiming Priority (5)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB0406515.7 | 2004-03-23 | ||
| GB0406515A GB0406515D0 (en) | 2004-03-23 | 2004-03-23 | Organic compounds |
| GB0424727A GB0424727D0 (en) | 2004-11-09 | 2004-11-09 | Organic compounds |
| GB0424727.6 | 2004-11-09 | ||
| PCT/EP2005/003062 WO2005089718A2 (en) | 2004-03-23 | 2005-03-22 | Pharmaceutical compositions |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1972670A true CN1972670A (en) | 2007-05-30 |
| CN1972670B CN1972670B (en) | 2010-12-08 |
Family
ID=32188539
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN2005800091635A Expired - Fee Related CN1972670B (en) | 2004-03-23 | 2005-03-22 | Pharmaceutical composition |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN1972670B (en) |
| GB (1) | GB0406515D0 (en) |
Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101618023B (en) * | 2008-06-30 | 2011-11-30 | 江苏先声药物研究有限公司 | Method for preparing micronized protein |
| CN102639538A (en) * | 2009-11-30 | 2012-08-15 | 诺瓦提斯公司 | Polymorphous forms III and IV of n-benzoyl staurosporine |
| CN105055311A (en) * | 2009-12-03 | 2015-11-18 | 诺华股份有限公司 | Circulation of components during homogenization /microfluidisation of emulsions |
| USRE46906E1 (en) | 2009-12-03 | 2018-06-26 | Novartis Ag | Methods for producing vaccine adjuvants |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6135628A (en) * | 1995-10-13 | 2000-10-24 | Boehringer Ingelheim Pharmceuticals, Inc. | Method and apparatus for homogenizing aerosol formulations |
| DE19616573C2 (en) * | 1996-04-25 | 1999-03-04 | Pari Gmbh | Use of subcritical blowing agent mixtures and aerosols for the micronization of drugs with the help of dense gases |
| EP1089714B1 (en) * | 1998-06-19 | 2003-03-05 | Skyepharma Canada Inc. | Processes to generate particles of water-insoluble compounds of up to 2000 nm in size |
| IT1303692B1 (en) * | 1998-11-03 | 2001-02-23 | Chiesi Farma Spa | PROCEDURE FOR THE PREPARATION OF SUSPENSIONS OF PARTICLES OF DRUGS TO BE ADMINISTERED BY INHALATION. |
-
2004
- 2004-03-23 GB GB0406515A patent/GB0406515D0/en not_active Ceased
-
2005
- 2005-03-22 CN CN2005800091635A patent/CN1972670B/en not_active Expired - Fee Related
Cited By (8)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN101618023B (en) * | 2008-06-30 | 2011-11-30 | 江苏先声药物研究有限公司 | Method for preparing micronized protein |
| CN102639538A (en) * | 2009-11-30 | 2012-08-15 | 诺瓦提斯公司 | Polymorphous forms III and IV of n-benzoyl staurosporine |
| CN104211717A (en) * | 2009-11-30 | 2014-12-17 | 诺华股份有限公司 | Polymorphous Forms III And IV Of N-Benzoyl - Staurosporine |
| CN105055311A (en) * | 2009-12-03 | 2015-11-18 | 诺华股份有限公司 | Circulation of components during homogenization /microfluidisation of emulsions |
| US9750690B2 (en) | 2009-12-03 | 2017-09-05 | Novartis Ag | Circulation of components during microfluidization and/or homogenization of emulsions |
| USRE46906E1 (en) | 2009-12-03 | 2018-06-26 | Novartis Ag | Methods for producing vaccine adjuvants |
| US10463615B2 (en) | 2009-12-03 | 2019-11-05 | Novartis Ag | Circulation of components during microfluidization and/or homogenization of emulsions |
| US11141376B2 (en) | 2009-12-03 | 2021-10-12 | Novartis Ag | Circulation of components during microfluidization and/or homogenization of emulsions |
Also Published As
| Publication number | Publication date |
|---|---|
| CN1972670B (en) | 2010-12-08 |
| GB0406515D0 (en) | 2004-04-28 |
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