CN102485225B - Be used for the treatment of the pharmaceutical composition of bacteriological infection - Google Patents
Be used for the treatment of the pharmaceutical composition of bacteriological infection Download PDFInfo
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Abstract
The invention provides the pharmaceutical composition being used for the treatment of bacteriological infection.Particularly, the invention provides drug microparticles and the method for making thereof of micronized formula II compound.Present invention also offers the pharmaceutical composition containing described drug microparticles.Method of micronization of the present invention not only greatly reduces bonding, clogging in pulverizing, also can significantly improve the dissolubility of micronized medicine, yield and crush efficiency.Pharmaceutical composition prepared by the present invention can improve dissolution in vitro and the body absorption of medicine, can be used as single medicament or is used for the treatment of bacteriological infection with other therapeutic combination.
Description
Technical field
The present invention relates to drug world, relate more specifically to the pharmaceutical composition being used for the treatment of bacteriological infection.The invention still further relates to the method and micronized pharmaceutical composition of preparing Wei Fenization oxazolidinone medicine.Method of micronization of the present invention greatly can reduce bonding, clogging in pulverizing, improves the dissolubility of micronized medicine, yield and crush efficiency.The compositions of preparation can improve vitro Drug dissolution and body absorption.
Background technology
Due to increasing gradually of antimicrobial drug drug resistance, the treatment of bacteriological infection needs the novel antibacterial medicine with novel binding mode forwardly.That the up-to-date anti-various pathogens that has of a class infects and comprises the synthesis compounds of drug-fast bacteria infection at newer antibacterials Zhong ， oxazolidinone compounds.
Formula (I) ortho-fluorophenyl oxazolidinones compound Shi Mengke medical science company limited (MicuRxPharmaceuticals, Inc.) the class full Xin oxazolidinone compounds developed, and applied for global PCT patent (number of patent application: PCT/US2008/009441; Chinese Patent Application No.: 200880020610.0).In formula, each group definition is see PCT/US2008/009441.
Formula (I) compound
In the series compound of formula (I), compound MRX-I is one of good candidate compound of drug effect and safety.
Compound MRX-I
The chemical name of compound MRX-I is (5S)-5-[(isoxazole-3-is amino) methyl]-3-[(the fluoro-4-of 2,3,5-tri-(4-oxo-2,3-dihydropyridine-1-base) phenyl]-oxazolidine-2-ketone.
The route of administration of compound first-selection is oral.Oral administration is clinical most popular application method.Compound being prepared into new pharmaceutical compositions is used for oral, can improve the clinical compliance of medicine to greatest extent.The index weighing oral formulations effectiveness be oral after bioavailability.Bioavailability after oral affects by multiple factor, as the gastrointestinal tract permeability of medicine itself, the dissolubility etc. of medicine.
But compound MRX-I is poorly water soluble drugs, the saturation solubility in 37 DEG C of water is only about 0.2mg/ml, and dissolubility is lower.
For insoluble drug, usually affect its body absorption due to its dissolution difference, and then affect bioavailability.Solid drugs dissolution and its granule surface area size have direct relation, and particle diameter is less, and dissolution rate is faster.By carrying out micronization to insoluble drug, to reduce drug particles particle diameter, there is very important meaning to raising bioavailability.
Drug micronization has multiple method, comprising comminution by gas stream, ball-milling method, ultrasonic method, spray drying method etc.
Certain methods needs to add liquid medium (as water, ethanol etc.) and dissolves or dispersion medicine, to reduce the cementation produced when the electrostatic interaction of drug powder, Van der Waals force or drug particles clash into mutually.But the micronized medicine of this wet-layer preparation needs to be removed by liquid medium by the mode such as spraying dry or vacuum drying usually, just can obtain solid drugs.But this process also exists that drug particle size is wayward, drug particle coalescent, the shortcoming such as medicine is unstable, difficulty is produced in medicine crystal phase transition, organic solvent residual, amplification, energy consumption is large and efficiency is low again.Especially for the method adding liquid medium, also need to slough liquid medium, therefore cause the operating time long and complicated.
Therefore, do not add any liquid medium, directly carrying out micronization to solid pharmaceutical powder is a kind of simple and quick method.But a lot of medical solid powder is directly pulverized and also had problems, such as: with comminution by gas stream directly pulverizing can there is the shortcomings such as coalescent, blocking tract, efficiency is low; And with ball-milling method directly pulverizing can there is the shortcomings such as adhesion, molding, weak effect.These shortcomings all can cause drug powder metallization processes can not scale and industrialization, even all cannot carry out at laboratory.
For oxazolidinone compounds shown in formula (I), take MRX-I as representative, it all shows height antibacterial activity in vivo with in in-vitro antibacterial model, biomembrane permeability is good, but it is insoluble drug in water, BCS II class medicine is belonged to by Biopharmaceutics Classification system (Biopharmaceutics Classification System, BCS).For BCS II class oral drugs, manage to improve drug-eluting speed to improve bioavailability in medicine body.Carrying out micronization to reduce solid drugs particle size to this kind of medicine is improve the practicable method of one of drug-eluting speed.
When directly carrying out micronization pulverizing with the pressed powder of comminution by gas stream to Nan Rong oxazolidinone compounds such as MRX-I, find that medicine is very easily bonded in pulverizing chamber, very hard, short time will block pulverizing chamber and high pressure draught passage, have a strong impact on crush efficiency, even make crushed work have to stop.Jet mill is taken apart to carry out clean be the process of a complicated and time consumption, the medicine of bonding is difficult to remove, and needs to go cleaning with water or organic solvent, and then dries.Thoroughly the clean rear micronization that continues is pulverized, and there is felt jam problem equally.Therefore, the gratifying pressed powder to Nan Rong oxazolidinone compounds such as MRX-I is not still had to carry out micronized method at present.
Therefore, the method for micronization being applicable to the Nan Rong oxazolidinone compounds such as MRX-I that this area is easy in the urgent need to development technology, efficiency is high.In addition, this area in the urgent need to exploitation for the new pharmaceutical dosage form of the Nan Rong oxazolidinone compounds such as MRX-I so that improve mammal oral after stripping, absorption and exposure level, namely improve the bioavailability after preparation oral.
Summary of the invention
Object of the present invention is just to provide a kind of simple process, the method for micronization being applicable to the difficult molten property oxazolidinone compounds such as MRX-I that efficiency is high.
Another object of the present invention is to provide a kind of new pharmaceutical dosage form, thus improve mammal oral after bioavailability.
In a first aspect of the present invention, provide a kind of drug microparticles, described drug microparticles contains (i) formula II compound or its pharmaceutically acceptable salt, hydrate or solvate
Chemistry (5S)-5-by name [(isoxazole-3-is amino) methyl]-3-[(the fluoro-4-of 2,3,5-tri-(4-oxo-2,3-dihydropyridine-1-base) phenyl]-oxazolidine-2-ketone; With
(ii) micronize auxiliary agent;
Further, the particle diameter D (90) of described drug microparticles is less than or equal to 10 microns,
Further, described drug microparticles compound of formula H and the weight ratio of micronize auxiliary agent are 100: 20-100: 0.5.
In another preference, the dissolution of described drug microparticles in water exceeds at least 50% than not micronized compound.
In another preference, the particle diameter D (90) of described drug microparticles is 1-8 micron.
In another preference, described micronize auxiliary agent is selected from lower group: lactose, microcrystalline Cellulose, fructose, sucrose, mannitol, sorbitol, xylitol, maltose alcohol, maltodextrin, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, sodium lauryl sulphate, poloxamer, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, silicon dioxide, Pulvis Talci, Polyethylene Glycol, sodium stearyl fumarate, Rikemal B 200 or its combination.
In a second aspect of the present invention, provide a kind of pharmaceutical composition, it contains the drug microparticles described in first aspect present invention as active component and pharmaceutically acceptable carrier.
In another preference, the ratio of formula II compound in pharmaceutical composition is 1% ~ 99% (w/w).
In another preference, the dosage form of described pharmaceutical composition is selected from lower group: tablet, capsule, powder, pill, granule, dry suspension, suspensoid, and the liquid preparation that arbitrary previous formulations and water or other pharmaceutically acceptable solvent are mixed.
In another preference, described pharmaceutically acceptable carrier is selected from lower group: filler or diluent, binding agent, wetting agent or solubilizing agent, disintegrating agent, lubricant or fluidizer or its combination.
In a third aspect of the present invention, provide a kind of method preparing the pharmaceutical composition described in second aspect present invention, comprise step:
A drug microparticles described in first aspect present invention mixes with pharmaceutically acceptable carrier by (), thus form pharmaceutical composition.
In another preference, described step (a) also comprises: after the drug microparticles described in mixing and pharmaceutically acceptable carrier, carry out sieving, granulate, tabletting, thus forms tablet; Or carry out filled capsules, thus form capsule.
In a fourth aspect of the present invention, provide a kind of method of pharmaceutical compositions, comprise step:
A () is by the formula II compound of solid-state form
Mix by weight 100: 20-100: 0.5 with solid-state micronization auxiliary agent, form solid mixt;
B () carries out micronization pulverizing to the solid mixt described in step (a), thus form the drug microparticles that particle diameter D (90) is less than or equal to 10 microns;
C drug microparticles described in step (b) mixes with pharmaceutically acceptable carrier by (), thus form pharmaceutical composition.
In another preference, in step (b), carry out micronization pulverizing with comminution by gas stream, ball-milling method.
In another preference, described pharmaceutically acceptable carrier is selected from lower group: filler or diluent, binding agent, wetting agent or solubilizing agent, disintegrating agent, lubricant or fluidizer or its combination.
In another preference, representational filler or diluent comprise (but being not limited to): lactose, microcrystalline Cellulose, starch, dextrin, fructose, sucrose, mannitol, sorbitol, xylitol, maltose alcohol or its combination.
In another preference, representational binding agent comprises (but being not limited to): polyvinylpyrrolidone, hydroxypropyl emthylcellulose, carboxymethyl cellulose (sodium), hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, arabic gum, guar gum, xanthan gum, dextrin, starch or its combination.
In another preference, representational wetting agent or solubilizing agent comprise (but being not limited to): sodium lauryl sulphate, poloxamer, beta-schardinger dextrin-, hydroxypropylβ-cyclodextrin, hydroxyethylβcyclodextrin, alpha-cyclodextrin, Polysorbate, Polyethylene Glycol, polyvinylpyrrolidone or its combination.
In another preference, representational disintegrating agent comprises (but being not limited to): polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose or its combination.
In another preference, representational lubricant or fluidizer comprise (but being not limited to): magnesium stearate, calcium stearate, stearic acid, silicon dioxide, Pulvis Talci, Polyethylene Glycol, sodium stearyl fumarate or its combination.
Broadly, in a fifth aspect of the present invention, provide a kind of drug microparticles, described drug microparticles containing (i) formula I or its pharmaceutically acceptable salt and (ii) micronize auxiliary agent,
Formula (I)
In formula,
R
1cH
2nHC (=O) R
6, CONHR
6, CHR
6oH, CH
2nHC (=S) R
6, CH
2nHC (=NCN) R
6, CH
2nH-Het
1, CH
2o-Het
1, CH
2s-Het
1, Het
2, or CN; And R
6h, NH
2, NHC
1-4alkyl, C
1-4alkyl, C
3-6cycloalkyl, C
2-4thiazolinyl, C
2-4alkynyl, C
1-4assorted alkyl, Het
1, Het
2, (CH
2)
mc (=O) C
1-4alkyl, OC
1-4alkyl, SC
1-4alkyl, (CH
2)
mc
3-6cycloalkyl, (CH
2)
mc (=O)-aryl, or (CH
2)
mc (=O)-Het
1;
R
2h or F;
R
3and R
4be H, F, Cl, CN independently, or OH; And
R
5cONHR
6, C
3-6cycloalkyl, aryl, biaryl (biaryl), Het
1, Het
2, 4 yuan to 7 yuan heterocyclic groups; And wherein m is 0,1, or 2;
Het
1be five yuan or the hexa-member heterocycle that C-connects, comprise dicyclo;
Het
2be five yuan or hexa-member heterocycle there is 1-4 nitrogen-atoms, optionally there is the N-of an oxygen or sulphur atom connection, comprise dicyclo;
Wherein, the particle diameter D (90) of described drug microparticles is less than or equal to 10 microns,
And described drug microparticles compounds of formula I and the weight ratio of micronize auxiliary agent are 100: 20-100: 0.5.
In another preference, described formula I has following additional conditions:
Additional conditions get rid of following compound: R in formula
1cH
2nHC (=O) R
6, and R
6c
1-6alkyl, OC
1-4alkyl, or NHC
1-6alkyl; And R
2h; And R
3and R
4all F; And R
5be
wherein X is CH or N; And Y is O or S (O)
n; Or X is N and Y is HOCH
2(C=O) N; And n is 0,1, or 2.
In another preference, representational Het
1example includes but not limited to: 3-isoxazolyl, 4-isoxazolyl, 5-isoxazolyl, furan, pyridine, pyrimidine, 2-pyridine radicals, 4-pyrimidine radicals etc.
In another preference, representational Het
2example includes but not limited to: imidazole radicals, pyrazolyl, isoxazole alkyl ketone group, 1,2,3-triazoles base etc.
In another preference, the dissolution of described drug microparticles in water exceeds at least 50% than not micronized formula I.General not micronized formula I refers to the formula I of particle diameter D (90) >=300 micron, and measuring method is mixed with water by compound, measures dissolution after 1 hour.
In another preference, described formula I is
Chemistry (5S)-5-by name [(isoxazole-3-is amino) methyl]-3-[(the fluoro-4-of 2,3,5-tri-(4-oxo-2,3-dihydropyridine-1-base) phenyl]-oxazolidine-2-ketone.
In another preference, the particle diameter D (90) of described drug microparticles is 1-8 micron.
In another preference, the particle diameter D (50) of described drug microparticles is 1-5 micron.
In another preference, described micronize auxiliary agent is selected from lower group: lactose, microcrystalline Cellulose, fructose, sucrose, mannitol, sorbitol, xylitol, maltose alcohol, maltodextrin, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, sodium lauryl sulphate, poloxamer, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, silicon dioxide, Pulvis Talci, Polyethylene Glycol, sodium stearyl fumarate, Rikemal B 200 or its combination.
Broadly, in a sixth aspect of the present invention, provide and a kind of micronized method carried out to formula I Suo Shu oxazolidinone compounds or its pharmaceutically acceptable salt,
Formula (I)
In formula,
R
1cH
2nHC (=O) R
6, CONHR
6, CHR
6oH, CH
2nHC (=S) R
6, CH
2nHC (=NCN) R
6, CH
2nH-Het
1, CH
2o-Het
1, CH
2s-Het
1, Het
2, or CN; And R
6h, NH
2, NHC
1-4alkyl, C
1-4alkyl, C
3-6cycloalkyl, C
2-4thiazolinyl, C
2-4alkynyl, C
1-4assorted alkyl, Het
1, Het
2, (CH
2)
mc (=O) C
1-4alkyl, OC
1-4alkyl, SC
1-4alkyl, (CH
2)
mc
3-6cycloalkyl, (CH
2)
mc (=O)-aryl, or (CH
2)
mc (=O)-Het
1;
R
2h or F;
R
3and R
4be H, F, Cl, CN independently, or OH; And
R
5cONHR
6, C
3-6cycloalkyl, aryl, biaryl (biary1), Het
1, Het
2, 4 yuan to 7 yuan heterocyclic groups; And wherein m is 0,1, or 2;
Het
1be five yuan or the hexa-member heterocycle that C-connects, comprise dicyclo;
Het
2be five yuan or hexa-member heterocycle there is 1-4 nitrogen-atoms, optionally there is the N-of an oxygen or sulphur atom connection, comprise dicyclo;
Additional conditions get rid of following compound: R in formula
1cH
2nHC (=O) R
6, and R
6c
1-6alkyl, OC
1-4alkyl, or NHC
1-6alkyl; And R
2h; And R
3and R
4all F; And R
5be
wherein X is CH or N; And Y is O or S (O)
n; Or X is N and Y is HOCH
2(C=O) N; And n is 0,1, or 2;
The method comprising the steps of:
A the formula I of solid-state form mixes by weight 100: 20-100: 0.5 with solid-state micronization auxiliary agent by (), form solid mixt; With
B () carries out micronization pulverizing to the solid mixt described in step (a), thus form the drug microparticles that particle diameter D (90) is less than or equal to 10 microns.
In another preference, described formula I is
Its chemistry (5S)-5-by name [(isoxazole-3-is amino) methyl]-3-[(the fluoro-4-of 2,3,5-tri-(4-oxo-2,3-dihydropyridine-1-base) phenyl]-oxazolidine-2-ketone.
In another preference, in step (b), carry out micronization pulverizing with comminution by gas stream, ball-milling method.
In another preference, described micronize auxiliary agent is selected from lower group: lactose, microcrystalline Cellulose, fructose, sucrose, mannitol, sorbitol, xylitol, maltose alcohol, maltodextrin, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, sodium lauryl sulphate, poloxamer, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, silicon dioxide, Pulvis Talci, Polyethylene Glycol, sodium stearyl fumarate, Rikemal B 200 or its combination.
In another preference, described micronization auxiliary agent is selected from lower group: sodium lauryl sulphate, magnesium stearate, silicon dioxide, Pulvis Talci, Rikemal B 200 or its combination.
Broadly, in a seventh aspect of the present invention, provide a kind of pharmaceutical composition, it contains the drug microparticles described in fifth aspect present invention as active component and pharmaceutically acceptable carrier.
In another preference, the dosage form of described pharmaceutical composition is selected from lower group: tablet, capsule, powder, pill, granule, dry suspension or suspensoid.
In another preference, in pharmaceutical composition, the content of described drug microparticles is 10%-99% (w/w).
Broadly; in a eighth aspect of the present invention; provide a kind of method of disease therapy, comprise step: the mammal treated to needs uses (comprising people) the present invention first of safe and effective amount or the drug microparticles described in the 5th aspect or the present invention second or the pharmaceutical composition described in the 7th aspect.
In another preference, described disease comprises courses of infection.
Should be understood that within the scope of the present invention, above-mentioned each technical characteristic of the present invention and in below (eg embodiment) specifically described each technical characteristic can combine mutually, thus form new or preferred technical scheme.As space is limited, tiredly no longer one by one to state at this.
Accompanying drawing explanation
Fig. 1 shows the grain size distribution of the medicine MRX-I before micronization.
Fig. 2 shows in the present invention's example, the grain size distribution of the medicine MRX-I microgranule after micronization.
Fig. 3 shows in the present invention's example, the dissolution in vitro of MRX-I micronization composition tablet of the present invention and MRX-I capsule in contrast.
Fig. 4 shows in the present invention's example, MRX-I micronization composition tablet of the present invention and the blood concentration-time curve of MRX-I capsule in contrast after Beagle dog is oral.
Fig. 5 shows in the present invention's example, and diameter of aspirin particle is on the impact of preparation dissolution.
Fig. 6 shows in the present invention's example, and in tablet, sodium lauryl sulphate different amounts is on the impact of stripping curve.
Detailed description of the invention
The present inventor is through extensive and deep research, be surprised to find that in the micromill process of oxazolidinone compounds MRX-I, by adding a certain amount of micronization auxiliary agent, effectively can prevent the shortcoming such as pipeline obstruction in comminution by gas stream, drug loss is little, and obtained particle diameter D (90) is less than or equal to the drug microparticles of 10 microns (even 5 microns).Complete the present invention on this basis.
Active component
In the present invention, sensu lato (medicine) active component refers to slightly solubility oxazolidinone compounds, is especially disclosed in formula (I) compound in PCT patent application PCT/US2008/009441 or its pharmaceutically acceptable salt (document introduces the application in full with way of reference).
Formula (I) compound
In formula, the definition of each group as mentioned above or can see PCT/US2008/009441.
Should be understood that active component of the present invention not only comprises above-claimed cpd, also comprise and refer to its salt, hydrate, solvate or its combination.
The particularly preferred active component of one class is compound MRX-I.As used herein, term " compound MRX-I " refers to following formula: compound,
Its chemical name is (5S)-5-[(isoxazole-3-amino) methyl]-3-[(the fluoro-4-of 2,3,5-tri-(4-oxo-2,3-dihydropyridine-1-base) phenyl]-oxazolidine-2-ketone.
MRX-I all shows height antibacterial activity in vivo with in in-vitro antibacterial model, its antimicrobial spectrum mainly covers aerobic gram positive bacteria, comprising resistant clinical isolates such as methicillin-resistant Staphylococci (MRSA and MRSE etc.), the insensitive streptococcus pneumoniae of penicillin (PISP and PRSP) and Vancomycin-resistant Enterococcus (VRE).In the long term toxicity evaluation test of rat and Canis familiaris L., the bone marrow depression toxicity of MRX-I compound is significantly lower than Linezolid.MRX-I compound can be used as the antibacterials for the treatment of of infection, comprising but be not limited to: skin infection, respiratory tract infection, soft tissue infection, bacteremia, urinary system infection, infection of bone and eye infections.
As used herein, term " bacteriological infection " comprises, but be not limited to the microbial infection of aerobic Grain-positive, comprising microbial infection of drug resistance such as methicillin-resistant Staphylococci (MRSA and MRSE etc.), the insensitive streptococcus pneumoniae of penicillin (PISP and PRSP) and Vancomycin-resistant Enterococcus (VRE).
Micronization auxiliary agent
As used herein, term " micronization auxiliary agent " refers to that association helps the micronization of oxazolidinone compounds (especially compound MRX-I), plays the reagent preventing from blocking pulverizing chamber and gas channel when comminution by gas stream process.
In the present invention, representational micronization auxiliary agent example comprises (but being not limited to): lactose, microcrystalline Cellulose, fructose, sucrose, mannitol, sorbitol, xylitol, maltose alcohol, maltodextrin, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, sodium lauryl sulphate, poloxamer, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, silicon dioxide, Pulvis Talci, Polyethylene Glycol, sodium stearyl fumarate, the combination of one or more in Rikemal B 200 etc.
One class preferred micronization auxiliary agent is the micronization just can assisting active constituents of medicine when consumption is less, thus forms the reagent of drug microparticles.These preferred micronization auxiliary agents comprise: sodium lauryl sulphate, magnesium stearate, calcium stearate, silicon dioxide (comprising micropowder silica gel), Pulvis Talci, sodium stearyl fumarate, Polyethylene Glycol, stearic acid, Rikemal B 200 or its combination.
Certainly, according to the needs produced, a large amount of micronization auxiliary agents can also be used, such as lactose, microcrystalline Cellulose etc.Select the micronization auxiliary agent such as lactose, microcrystalline Cellulose and MRX-I co-micronised, the larger bonding phenomenon that could reduce in pulverizing of the amount ratio of these micronization auxiliary agents.Certainly, micronization auxiliary dosage greatly not only can increase micronized time and energy consumption, thus increases cost, also can affect the selection space of other adjuvant in follow-up formulation study, increases the difficulty of preparation process.
In the present invention, the complexity prepared according to other supplementary product consumption scope and preparation in micronized effect and efficiency, preparation prescription is determined by the consumption of micronization auxiliary agent.In preference, the weight ratio of the consumption of medicine and these micronization auxiliary agents can be 100: 20-100: 0.5, is preferably 100: 10-100: 0.75, is more preferably 100: 5-100: 1.The present inventor is surprised to find that, even if when using the micronization auxiliary agent of low consumption like this, just significantly can improve obstruction, the bonding phenomenon in micronization process, reaching good micronization effect.When the consumption of micronization auxiliary agent can increase micronized time and energy consumption in limited time higher than the upper of above-mentioned scope, and cause active component content in drug microparticles to decline, be unfavorable for the research and development of later stage preparation.When the consumption of micronization auxiliary agent is prescribed a time limit lower than the lower of above-mentioned scope, micronized effect can decline to some extent.
Method of micronization
In the present invention, the micronization of active constituents of medicine should adopt the method for micronization of not adding liquid medium, comprising (but being not limited to): comminution by gas stream, ball-milling method, ultrasonic method, spray drying method etc.Preferably comminution by gas stream.
Comminution by gas stream (jet mill) utilizes the energy of high velocity air to make granule produce impact, collision and friction each other, thus cause a kind of superfine technique of breakage of particles refinement.Being different from mechanical activation comminution relies on blade or tup etc. to the impact comminution of material, and for a kind of low temperature is pulverized without medium, production process clean environment firendly, is particularly suitable for the pulverizing of thermal sensitivity, low melting point, sugary part and volatile material.
Be applicable to airflow pulverization method of the present invention and device is not particularly limited, commercially available air flow crushing device can be adopted, and carry out comminution by gas stream according to conditioned disjunction parameter recommended by the manufacturer.
A kind of preferred airflow pulverization method is micronization breaking method provided by the invention, by medicine (as compound MRX-I) pressed powder and above-mentioned micronization auxiliary agent by 100: 20-100: 0.5 (preferably 100: 10-100: 0.75, be more preferably 100: 5-100: 1) after ratio fully mixes, direct comminution by gas stream carries out dry pulverization process to pressed powder after mixing, does not need to add any liquid medium during pulverizing.
Certainly, it is also feasible for adopting ball-milling method to replace comminution by gas stream.
Drug microparticles
In the present invention, by improving micromill process, not only also there will not be clogging in continuous pulverizing, but also provide a kind of drug micronization microgranule of Xin Ying oxazolidinone compounds, or referred to as drug microparticles.
As used herein, term " drug micronization microgranule ", " drug microparticles " or " active component microgranule " are used interchangeably, and refer to active component of the present invention together with the micronization auxiliary agent of interpolation by microgranule that micromill process is formed.
In drug microparticles of the present invention, the weight ratio of the consumption of medicine and micronization auxiliary agent is generally 100: 20-100: 0.5, is preferably 100: 10-100: 0.75, is more preferably 100: 5-100: 1.
Though with without micronization processes or through micronization processes but compared with the situation of not adding micronization auxiliary agent, the particle of the drug microparticles of the oxazolidinone compounds of Ben Faming is less.After measured, its D (90) can reach less than 10 μm or 5 μm.
Use drug microparticles of the present invention, Gai Shan oxazolidinone compounds (as the compound MRX-I) dissolution in water (or aqueous medium) can be shown by Xian, thus significantly improve its bioavailability.Usually, compared with the formula I of not micronized particle diameter D (90) >=300 micron, the dissolution of drug microparticles of the present invention in water exceeds at least 50% than not micronized formula I, more preferably exceed at least 100%, wherein, described measuring method is mixed with water by compound, measures dissolution after 1 hour.
Pharmaceutical composition and preparation method
Present invention also offers the pharmaceutical composition of the active component containing said medicine particulate form.This pharmaceutical composition contains described drug microparticles and pharmaceutically acceptable carrier.
Adopt micronized MRX-I micronization process pharmaceutical composition of the present invention, bioavailability in the dissolution in vitro of active component and body can be improved.
Usually, the ratio of micronized drug microparticles of the present invention in pharmaceutical composition is 10%-99% (w/w), and surplus is pharmaceutically acceptable carrier.
Can be used for the pharmaceutically acceptable carrier of pharmaceutical composition of the present invention, its representative example comprises (but being not limited to): lactose, microcrystalline Cellulose, starch, dextrin, fructose, sucrose, mannitol, sorbitol, xylitol, maltose alcohol, maltodextrin, polyvinylpyrrolidone, hydroxypropyl emthylcellulose, carboxymethyl cellulose (sodium), hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, arabic gum, guar gum, xanthan gum, sodium lauryl sulphate, poloxamer, beta-schardinger dextrin-, hydroxypropylβ-cyclodextrin, hydroxyethylβcyclodextrin, alpha-cyclodextrin, Polysorbate, Polyethylene Glycol, polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, titanium dioxide, magnesium stearate, calcium stearate, stearic acid, silicon dioxide, Pulvis Talci, Polyethylene Glycol, sodium stearyl fumarate, the combination of one or more in Rikemal B 200 etc.
The dosage form of pharmaceutical composition of the present invention is not particularly limited, and can be the dosage form of various routine, and representational dosage form comprises (but being not limited to): tablet, capsule, powder, pill, granule, dry suspension, suspensoid.Should be understood that the liquid preparation that pharmaceutical composition of the present invention also comprises arbitrary previous formulations and water or other solvent and is mixed, the liquid preparation namely after reconstruct.
In preference of the present invention, provide the pharmaceutical composition of contained II compound and pharmaceutically acceptable carrier.
In another preference, described pharmaceutically acceptable carrier is selected from lower group: filler or diluent, binding agent, wetting agent or solubilizing agent, disintegrating agent, lubricant or fluidizer or its combination
In another preference, representational filler or diluent comprise (but being not limited to): lactose, microcrystalline Cellulose, starch, dextrin, fructose, sucrose, mannitol, sorbitol, xylitol, maltose alcohol or its combination.
In another preference, representational binding agent comprises (but being not limited to): polyvinylpyrrolidone, hydroxypropyl emthylcellulose, carboxymethyl cellulose (sodium), hydroxypropyl cellulose, hydroxyethyl-cellulose, gelatin, arabic gum, guar gum, xanthan gum, dextrin, starch or its combination.
In another preference, representational wetting agent or solubilizing agent comprise (but being not limited to): sodium lauryl sulphate, poloxamer, beta-schardinger dextrin-, hydroxypropylβ-cyclodextrin, hydroxyethylβcyclodextrin, alpha-cyclodextrin, Polysorbate, Polyethylene Glycol, polyvinylpyrrolidone or its combination.
In another preference, representational disintegrating agent comprises (but being not limited to): polyvinylpolypyrrolidone, cross-linking sodium carboxymethyl cellulose, carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, microcrystalline Cellulose or its combination.
In another preference, representational lubricant or fluidizer comprise (but being not limited to): magnesium stearate, calcium stearate, stearic acid, silicon dioxide, Pulvis Talci, Polyethylene Glycol, sodium stearyl fumarate or its combination.
The dosage form of pharmaceutical composition of the present invention is not particularly limited, representational example comprises (but being not limited to): tablet, capsule, powder, pill, granule, dry suspension, and the liquid preparation that arbitrary previous formulations and water or other solvent are mixed.
An important feature of the present invention is by pulverizing the formula II compound in pharmaceutical composition or grind, and reduces the size of drug particle, can improve the dissolution of medicine.In one embodiment of the invention, after formula II compound superfine grinding, particle size distribution D (90) is less than 10 μm, and the dissolution of its tablet is obviously faster than the tablet prepared after formula II compound only mistake 60 mesh sieves.
Another important feature of the present invention is the compositions prepared by above-mentioned preparation method, formula II compounds content account for compositions proportion very high time, still can obtain the preparation that tablet formability, disintegrative and dissolution are satisfied.In one embodiment of the invention, when formula II compounds content accounts for about 70% (w/w) of composition weight, prepared mobility of particle tablet hardness that is good, compacting is large, Dissolution of Tablet is high.
Application process
The drug microparticles of formula I of the present invention and the new pharmaceutical compositions containing described drug microparticles, can be used for treating bacteriological infection.Preferably, pharmaceutical composition of the present invention should by the oral patient or the object that give bacteriological infection, to obtain pharmacology and the pharmacodynamic action of expectation.
In the present invention, described patient or object are the mammal of bacteriological infection, comprise people.
The total amount of the active component (formula I) using pharmaceutical composition of the present invention to give via oral route is generally and is about 0.1mg/kg every day to about 200mg/kg body weight.The effective dose of pharmaceutical composition of the present invention can easily be determined by those skilled in the art.The dosage given can change to a great extent according to following Consideration: the dosage form adopted, medication and time, treatment phase, age of patient for the treatment of, sex and general status, the nature and extent of disease for the treatment of, drug metabolism and the speed of excretion, possible drug regimen and drug interaction etc.
Pharmaceutical composition of the present invention can be used as single medicament or treats coupling with one or more other.
Major advantage of the present invention comprises:
A () micronisation process of the present invention effectively can reduce the phenomenon such as bonding, blocking of pressed powder in directly pulverizing of oxazolidinone compounds such as MRX-I Deng.
B () micromill process of the present invention is simple, crush efficiency is high, loss is few.
(c) drug microparticles of the present invention due to the micronization auxiliary dosage added little, therefore do not affect the formulation and technology research of preparation, for formulation development provides very large space.
D () with the pharmaceutical composition of micronization process of the present invention, drug dissolution is high, and body absorption is good.
Below in conjunction with specific embodiment, set forth the present invention further.Should be understood that these embodiments are only not used in for illustration of the present invention to limit the scope of the invention.The experimental technique of unreceipted actual conditions in the following example, usually conveniently condition, or according to the condition that manufacturer advises.Unless otherwise indicated, otherwise number and percentages.
Comparative example 1
Directly comminution by gas stream is carried out to compound MRX-I
After MRX-I medicine is crossed 60 mesh sieves, do not add any medium (micronization auxiliary agent), directly with jet mill (the miniature jet mill of CH-6828 of JEPT Pharma, and the MX-50 type experiment jet mill of Yixing cumulative research of super-pine crush equipment company) carry out the pulverizing of dry method micronization, pulverize pressure and be about 4-8bar.
Found that, medicine MRX-I very easily sticks in pulverizing chamber, and the short time will block pulverizing chamber and high pressure draught passage, has a strong impact on crush efficiency, even makes crushed work have to stop.
Jet mill is taken apart, with water cleaning, and then dries.Thoroughly the clean rear micronization that continues is pulverized, and there is felt jam problem equally.
Embodiment 1: with sodium lauryl sulphate and the co-micronised pulverizing of MRX-I (small lot)
By 38.9g MRX-I crude drug (D (50)=78 micron, D (90)=307 micron) to mix with 1.9g sodium lauryl sulphate (medicine is about 100: 5 with auxiliary material proportion) and to cross 30 mesh sieve 3 times, micronization is carried out with jet mill (the JGM-H100 type jet mill of Huali Co., Ltd), pulverize pressure and be about 8bar, feed rate is about 15g/min, and micronization processes once.After micronization has been pulverized, receive to obtain micronized medicine 40.0g, yield is 98.0%.
Measure the particle size distribution of micronizing materials with Malvern Particle Size Analyzer, result shows, and D (50) is 2.3 μm, and D (90) is 5.0 μm.
By medicine and sodium lauryl sulphate co-micronised, medicine yield is high, and micronization is effective, has no clogging.
Embodiment 2: with sodium lauryl sulphate and the co-micronised pulverizing of MRX-I (more in enormous quantities)
By 422.4g MRX-I crude drug (D (50)=20 micron, D (90)=185 micron) mix homogeneously with 21.1g sodium lauryl sulphate (medicine is about 100: 5 with auxiliary material proportion), cross 16 mesh sieve 3 times, then jet mill (the JGM-H200 type jet mill of Huali Co., Ltd) is used to carry out micronization, pulverize pressure 8 ± 0.5bar, feed rate is 75 ± 25g/min about, micronization processes 2 times.After pulverizing completes, reclaim and obtain micronizing materials 436.5g altogether, loss is few, and the response rate reaches 98.4%.
Measure the particle size distribution of micronizing materials with Malvern Particle Size Analyzer, D (50) is 2.9 μm, and D (90) is 6.2 μm.
After continuous micronization 2 more large batch of mixed materials, in jet mill tract, have no bonding or clogging.Medicine does not almost lose.Micronized drug particle size all meets the granularity requirements of expection.Illustrate that this micromill process can carry out amplification and produce.
Embodiment 3: with silicon dioxide and the co-micronised pulverizing of MRX-I
By 40.1g compound MRX-I (D (50)=78 micron, D (90)=307 micron) mix homogeneously with 0.3g silicon dioxide (medicine is about 100: 0.75 with auxiliary material proportion), and cross 30 mesh sieve 3 times, micronization is carried out with jet mill (the JGM-H100 type jet mill of Huali Co., Ltd), pulverize pressure and be about 8bar, feed rate is about 15g/min, and micronization processes once.After micronization has been pulverized, receive to obtain micronized medicine 38.5g, yield is 95.3%.
Measure the particle size distribution of micronizing materials with Malvern Particle Size Analyzer, result shows, and D (50) is 3.8 μm, and D (90) is 8.3 μm.In jet mill tract, bonding phenomenon is had no after micronization.
Embodiment 4:MRX-I and microcrystalline Cellulose and lactose co-micronised
After according to the form below 1, in prescription e, f, g and h, the MRX-I of phase application quantity fully mixes with adjuvant, cross 50-60 mesh sieve, carry out micronization with jet mill (the MX-50 type experiment jet mill of Yixing cumulative research of super-pine crush equipment company), pulverizing pressure is 4-5bar.After micronization completes, collect micronizing materials, calculated yield, the results are shown in Table 1.
As seen from the table, independent MRX-I carries out micronization, or only adds microcrystalline Cellulose or lactose, and micronization yield is all lower, but after adding a small amount of sodium lauryl sulphate, micronization yield is significantly increased, and the yield of such as prescription h is apparently higher than prescription g.Also can be observed in micronization process, containing sodium lauryl sulphate or silicon dioxide prescription micronization process smoothly, bonding phenomenon is very light, and prescription e, f and g are all shown in bonding phenomenon in various degree.
Table 1.MRX-I micronization prescription composition
Embodiment 5: containing the pharmaceutical composition of micronized drug microparticles
After being mixed in 100: 5 ratios with sodium lauryl sulphate by medicine MRX-I, carry out micronization processes 2 times with comminution by gas stream, pulverize pressure 8 ± 0.5bar, feed rate 75 ± 25g/min.Before micronization, the particle size distribution D (90) of MRX-I crude drug is 322 μm.
The yield of micronizing materials (i.e. drug microparticles) is greater than 99wt%, after measured particle size distribution D (90)≤10 μm, is 8.0 μm.(see Fig. 1 and Fig. 2)
By the drug microparticles formed after micronization, by the prescription composition pharmaceutical compositions of table 2.Concrete technology following (a step comminution granulation):
Polyvidone is dissolved in appropriate pure water, as binder solution, by micronized medicine active component microgranule, microcrystalline Cellulose, polyvinylpolypyrrolidone and cross-linking sodium carboxymethyl cellulose mix homogeneously, be placed in fluid bed, with binder solution with the pelletize of top spray mode hydrojet, continue dry after hydrojet completes in fluid bed.Dried particles is mixed with magnesium stearate and silicon dioxide and crosses 30 mesh sieves.Tabletting, every sheet is containing MRX-I compound 100mg.In said preparation compositions, medicine accounting reaches 2/3, belongs to the solid preparation of high medicament contg.
The prescription composition of table 2.MRX-I powder compounds feed composition
Control sample: the capsule (100mg/ capsule) of the direct fill of not micronized compound MRX-I raw material.The particle size distribution D (90) of crude drug is at 322 μm.
The medicinal composition tablets of above-mentioned preparation is carried out dissolution with the capsule control sample (100mg/ capsule) of the direct fill of not micronized raw material and bioavailability compares.
Dissolution Rate Testing condition is: paddle method, rotating speed 75rpm, and medium is the pH 1 hydrochloric acid solution 900ml containing 0.02% (w/v) sodium lauryl sulphate.The animal of two groups of preparation bioavailability study is often organizes 6 adult Beagle dogs, male and female half and half.Every bar dog qf oral administration dosage is 100mg.According to the area under the drug-time curve (AUC of oral tablet and capsule
0-∞) calculate the relative bioavailability of oral tablet relative to capsule.
Result as shown in Figure 3 and Figure 4.
Result shows, by the dissolution of the medicinal composition tablets of MRX-I and the co-micronised micronization process of micronization auxiliary agent obviously faster than capsule.Tablet is 221% to the relative bioavailability of capsule, and tablet bioavailability adds one times, illustrate medicine and adjuvant co-micronised and prepare its compositions, significantly can improve bioavailability in the dissolution in vitro of medicine and body.
The above results is pointed out, and is mixed by oxazolidinone compounds such as MRX-I Deng and jointly carries out micronization in solid form, can realize suitability for industrialized production with micronization auxiliary agent.In addition, compared with the pharmaceutical preparation of the identical active component without micronization processes, the drug combination preparation of the active component containing drug microparticles form of the present invention, can have higher dissolution and bioavailability after oral administration in human body.
Embodiment 6: the dissolution of different dosage form and prescription compares
The prescription of drug microparticles compositions is composed as follows:
The prescription composition of table 3.MRX-I drug microparticles compositions
The preparation of drug microparticles composition tablet: be scattered in appropriate pure water by the polyvidone of recipe quantity, is stirred to formation settled solution, as binder solution.By micronized MRX-I drug microparticles (D90 is about 8 μm), microcrystalline Cellulose, polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose mix homogeneously, add binder solution, fully stir and make into wet granular, cross 30 mesh sieves, 60 DEG C of oven dryings.Dried particles crosses 20 mesh sieve granulate, mixs homogeneously with magnesium stearate and silicon dioxide, tabletting.Every sheet is containing MRX-I compound 100mg.
The preparation of non-micronized medicine composition tablet: prescription composition is identical with table 3, and difference is that sodium lauryl sulphate does not form drug microparticles as micronization auxiliary agent and MRX-I compound.The polyvidone of recipe quantity is scattered in appropriate pure water, 0.5g sodium lauryl sulphate is added and heating in water bath, be stirred to formation settled solution, as binder solution.Non-micronization is crossed the MRX-I compound (D90 is about 300 μm) of 60 mesh sieves, microcrystalline Cellulose, polyvinylpolypyrrolidone and low-substituted hydroxypropyl cellulose mix homogeneously, add binder solution, abundant stirring makes into wet granular, crosses 30 mesh sieves, 60 DEG C of oven dryings.Dried particles crosses 20 mesh sieve granulate, mixs homogeneously with magnesium stearate and silicon dioxide, tabletting.Every sheet is containing MRX-I compound 100mg.
The preparation of MRX-I capsule before and after micronization: micronized drug microparticles and non-micronization are crossed the medicine material of 60 mesh sieves and be directly filled into respectively in capsule, does not add other adjuvants.Each capsule is containing MRX-I compound 100mg.
Be that dissolution medium carries out dissolution determination to the Tablet and Capsula of above-mentioned preparation with water.Stripping curve is shown in Fig. 5.
Dissolution experiments result shows, no matter is capsule or tablet, uses micronized drug microparticles all can significantly improve drug dissolution, illustrates to reduce diameter of aspirin particle by micronization, can improve the dissolution rate of medicine.Can see, after the medicine of same particle sizes is prepared into composition tablet, the capsule of all direct than the medicine fill of dissolution rate is significantly increased, and illustrates that the formulation and technology of this composition tablet also can further improve the dissolution of medicine simultaneously.
The above results is pointed out, and the tablet of the oral present composition, can improve the absorption in patient body and bioavailability.
The composition tablet of embodiment 7 wetting agent sodium lauryl sulphate different amounts
Repeat embodiment 6, difference is: substitute low-substituted hydroxypropyl cellulose with cross-linking sodium carboxymethyl cellulose, and with in embodiment 3 prepare MRX-I and silicon dioxide micronized drug microparticles substitution table 3 in micronized drug microparticles.In addition, add the sodium lauryl sulphate (SLS) as wetting agent in formula, make SLS content in tablets be respectively 0.0%, 1.7% and 3.3%, other prescription composition and preparation method are with the tablet in embodiment 6.Be that dissolution medium carries out dissolution determination with water, stripping curve the results are shown in Figure 6.
The data display of dissolution, uses micronized drug microparticles can significantly improve drug dissolution to about 65%.In addition, add the sodium lauryl sulphate (SLS) as wetting agent in tablets, drug dissolution can be significantly improved further to about 75%.
The all documents mentioned in the present invention are quoted as a reference all in this application, are just quoted separately as a reference as each section of document.In addition should be understood that those skilled in the art can make various changes or modifications the present invention after having read above-mentioned teachings of the present invention, these equivalent form of values fall within the application's appended claims limited range equally.
Claims (9)
1. a drug microparticles, is characterized in that, described drug microparticles contains (i) formula II compound or its pharmaceutically acceptable salt,
Chemistry (5S)-5-by name [(isoxazole-3-is amino) methyl]-3-[(the fluoro-4-of 2,3,5-tri-(4-oxo-2,3-dihydropyridine-1-base) phenyl]-oxazolidine-2-ketone; With
(ii) micronize auxiliary agent;
Further, the particle diameter D of described drug microparticles
90be less than or equal to 10 microns,
Further, described drug microparticles compound of formula H and the weight ratio of micronize auxiliary agent are 100:20-100:0.5;
Further, described micronize auxiliary agent is sodium lauryl sulphate.
2. drug microparticles as claimed in claim 1, it is characterized in that, the dissolution of described drug microparticles in water exceeds at least 50% than not micronized compound.
3. drug microparticles as claimed in claim 1, is characterized in that, the particle diameter D of described drug microparticles
90for 1-8 micron.
4. a pharmaceutical composition, is characterized in that, it contains drug microparticles according to claim 1 as active component and pharmaceutically acceptable carrier.
5. pharmaceutical composition as claimed in claim 4, it is characterized in that, the ratio of formula II compound in pharmaceutical composition is 1% ~ 99% (w/w).
6. pharmaceutical composition as claimed in claim 4, it is characterized in that, the dosage form of described pharmaceutical composition is selected from lower group: tablet, capsule, powder, pill, granule, suspensoid, and the liquid preparation that arbitrary previous formulations and water or other pharmaceutically acceptable solvent are mixed.
7. pharmaceutical composition as claimed in claim 4, it is characterized in that, described pharmaceutically acceptable carrier is selected from lower group: filler or diluent, binding agent, wetting agent or solubilizing agent, disintegrating agent, lubricant or fluidizer or its combination.
8. prepare a method for pharmaceutical composition according to claim 4, it is characterized in that, comprise step:
A drug microparticles according to claim 1 mixes with pharmaceutically acceptable carrier by (), thus form pharmaceutical composition.
9. a method for pharmaceutical compositions, is characterized in that, comprises step:
A () is by the formula II compound of solid-state form
Mix by weight 100:20-100:0.5 with solid-state micronization auxiliary agent, form solid mixt, wherein, described micronize auxiliary agent is sodium lauryl sulphate;
B () carries out micronization pulverizing to the solid mixt described in step (a), thus form particle diameter D
90be less than or equal to the drug microparticles of 10 microns;
C drug microparticles described in step (b) mixes with pharmaceutically acceptable carrier by (), thus form pharmaceutical composition.
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| CN101720325A (en) * | 2007-08-06 | 2010-06-02 | 盟科医药技术公司 | Antimicrobial ortho-fluorophenyl oxazolidinones for treatment of bacterial infections |
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| 微粉化及包合技术对格列本脲溶出度的影响;罗昕 等;《中国药学杂志》;20030331;第38卷(第3期);第193-196页 * |
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