CN1954803A - Spray-dried granules containing pranlukast and processes for the preparation thereof - Google Patents
Spray-dried granules containing pranlukast and processes for the preparation thereof Download PDFInfo
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- CN1954803A CN1954803A CNA2006101410742A CN200610141074A CN1954803A CN 1954803 A CN1954803 A CN 1954803A CN A2006101410742 A CNA2006101410742 A CN A2006101410742A CN 200610141074 A CN200610141074 A CN 200610141074A CN 1954803 A CN1954803 A CN 1954803A
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1605—Excipients; Inactive ingredients
- A61K9/1629—Organic macromolecular compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
- A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
- A61K9/1682—Processes
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
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Abstract
The invention provides a spray-dried granule comprising pranlukast, a water-soluble polymer and a surfactant, and a method for producing the granule. The average particle size of the pranlukast in the granule is 0.5-20 um. Thereby, not only adhesion cohesiveness and solubility of the pranlukast but also elution rate and bioavailability thereof can be improved even without coating the pranlukast with saccharides such as lactose. As a result, the dose can remarkably be reduced from that of conventional formulations. Furthermore, since the formulation can be produced without using an organic solvent, the formulation is suitable for mass-production on an industrial scale.
Description
Invention field
The present invention relates to a kind of spray-dried granules of pranlukast and method of preparation thereof of comprising.
Background technology
Pranlukast (chemical name: 4-oxa--8-[4-(4-benzene butoxy) benzamido]-2-(tetrazolium-5-yl)-4H-1-benzo give a tongue-lashing the semihydrate of muttering), it is antagonism leukotrienes C4 and leukotriene D4 effectively, is used to treat bronchial asthma and allergic rhinitis.
At present commercially available pranlukast be capsule (the Onon capsule, pranlukast 112.5mg/ grain is taken two capsules at every turn, Donga Pharmaceutical Co., Ltd.).
Yet pranlukast is a kind of have very strong viscosity and relatively poor medicine of water solublity.Therefore, when pranlukast was mixed with tablet or capsule, it adhered to above stamping machine, the mould etc., thereby made continuous production become difficult.In addition, based on its low bioavailability, 200mg or bigger therapeutic dose are used in suggestion usually.
In view of there being these problems, people have carried out the physical characteristic that various researchs improve pranlukast.For example, US patent 5,876,760 discloses a kind of pure water suspension preparation dried granules by spray drying sugar, water-soluble polymer and surfactant.Surfactant is used for improving the wettability and the dispersibility of suspension pranlukast, and exists with the form that the pranlukast of sugar (for example, lactose) bag quilt can solid crystal.(Donga Pharmaceutical Co. Ltd.) is a kind of commercially available spray-dried granules agent to disclosed Onon capsule in the US patent 5,876,760.
Disclosed spray-dried granules agent has improved the viscosity of pranlukast effectively in the US patent 5,876,760, but because its low-down dissolution rate still demonstrates low bioavailability.That is, the rate of dissolution of Onon capsule in buffer solution (pH6.8,37 ℃) is lower than 5%.
The open WO01/89574 (corresponding to early stage disclosed Korean Patent No.2001-106006) of PCT discloses a kind of pranlukast and (hydroxypropyl) methylcellulose or (hydroxypropyl) cellulosic solid dispersion of containing.Pranlukast is present in the rate of dissolution that increases pranlukast in the solid dispersion with noncrystalline attitude form.
Yet in the PCT open source literature, the preparation of solid dispersion relates to pranlukast and (hydroxypropyl) methylcellulose or (hydroxypropyl) cellulose dissolution at organic solvent (promptly, the mixed solvent of dichloromethane and methanol) in, therefore may cause the problems such as genotoxic potential of environmental pollution and organic solvent residual.In addition, owing to needing to use a large amount of organic solvents dissolve pranlukast fully, feasible dry (for example, spray drying) is complicated and needs long time, and these have caused suitability for industrialized production to become difficult.
In addition, Int.J.Pharm 172 (1998), 179-188/173 (1998), 243-251 and Pharmaceutical Research 11 (1998), reported the example of the compositions that contains pranlukast among the 1748-1759, it discloses the powder aerosol that contains pranlukast; Japan Patent alerting bulletin No.Hei.8-73353 discloses a kind of liquid preparation that contains polyethylene polypyrrole alkane ketone or beta-schardinger dextrin-as the dissolving adjuvant, such as eye drop, and nose drop, or injection; The open WO99/004790 of PCT discloses a kind of fluid composition that contains pranlukast, wherein also comprises surfactant, water-soluble cellulose derivative, water-soluble ethylene based polyalcohol.
Yet people still need to develop a kind of compositions that comprises pranlukast, and said composition has improved dissolubility and viscosity and increased rate of dissolution and bioavailability, and can solve the problem of utilizing organic solvent to produce.
Summary of the invention
When exploring the solution of the problems referred to above; the inventor finds; pass through water-soluble polymer; when the pranlukast microgranule that is included in surfactant particlesization and modification (or bag by) in the spray-dried granules as active component; even without using sugar such as newborn glycolyx, the dissolving of pranlukast also is significantly improved.
Consider US patent 5,876,760 not openly the physical characteristic (dissolubility and viscosity) of pranlukast change with the granularity of pranlukast, these discoveries are very surprising.The granularity that US patent 5,876,760 discloses spray-dried granules may be 20-1000nm, but does not mention the granularity of pranlukast in the granule.
Above-mentioned discovery is different from US patent 5 equally, 876, the feature of disclosed spray-dried granules in 760, the coated glucide of pranlukast wherein, thereby and the wettability and the dispersibility that utilize surfactant to improve pranlukast make pranlukast complete by glycolyx.In addition, very surprisingly when micronize pranlukast particle is comprised in the spray-dried granules, can only utilizes surfactant and do not need saccharide just can improve the physical characteristic (for example, dissolution rate) of pranlukast effectively.
In addition, spray-dried granules of the present invention is different from and disclosedly among the WO99/004790 comprises the rate of dissolution that noncrystalline shape pranlukast solid dispersion improves pranlukast.Do not use the necessary organic solvent of preparation solid dispersion in the preparation of spray-dried granules of the present invention.
Therefore, the purpose of this invention is to provide a kind of spray-dried granules that contains pranlukast.
In addition, another object of the present invention provides a kind of preparation method of spray-dried granules.
In one embodiment of the invention, provide the spray-dried granules that comprises pranlukast, water-soluble polymer and surfactant, wherein the particle mean size of pranlukast is 0.5-20 μ m in the granule, and preferred 5-18 μ m.
Contain in the spray-dried granules of pranlukast in the present invention, the pranlukast particle is by micronize (that is 20 μ m or littler) and use surfactant and water-soluble polymer finishing (or bag quilt).Therefore, the viscosity of pranlukast has reduced, and the dissolving of pranlukast increases significantly in the while preparation.Therefore, even without utilizing for the requisite sugar of spray-dried granules in the US patent 5,876,760, also can prepare viscosity and the dissolubility that significantly increases and the spray-dried granules of rate of dissolution that comprises pranlukast and have improvement.
Usually, the general knowledge in the pharmaceutics is when having the particle size reduction of full-bodied medicine, viscosity between its drug particles increase and therefore the dissolubility of medicine reduce.Therefore; surprisingly find when micronized medication (being pranlukast) is used surfactant and water-soluble polymer finishing (or coated); the viscosity of pranlukast can be improved effectively, and even the dissolubility and the rate of dissolution of pranlukast can be increased.
The spray-dried granules that the present invention contains pranlukast comprises pranlukast, as the water-soluble polymer of binding agent and be coated on the lip-deep surfactant of pranlukast.The particle mean size of pranlukast can be 0.5-20 μ m in the granule, preferred 5-18 μ m, and preferred 7-13 μ m.The particle mean size of pranlukast can be adjusted according to different process for preparing medicine.For example, spray-dried granules of the present invention can be prepared by the suspension that following method obtains by spray drying: pranlukast is added in the aqueous solution that comprises water-soluble polymer and surfactant, disperse consumingly with agitator, homogenizer or the ultrasonic oscillator of for example being furnished with propeller simultaneously; Or by disperseing to comprise the suspension of pranlukast, water-soluble polymer and surfactant consumingly with agitator, homogenizer or the ultrasonic oscillator of for example being furnished with propeller, and spray drying dispersion liquid.Certainly, except above-mentioned method, spray-dried granules of the present invention also can utilize the method that adopts usually in the pharmaceuticals industry, and for example microjet machine or high-pressure homogenizer prepare.
The water-soluble polymer that is used as binding agent in the present invention contains the spray-dried granules of pranlukast can be the water-soluble polymer that adopts usually in the pharmaceuticals industry.For example, water-soluble polymer can be polyvinylpyrrolidone, (hydroxypropyl) methylcellulose, (hydroxypropyl) cellulose, Polyethylene Glycol, polyvinyl alcohol, gelatin, xanthan gum Radix Acaciae senegalis, alginic acid or its salt, acrylate copolymer (for example, Eudragit E), or the like.Wherein, water-soluble polymer can be selected from: polyvinylpyrrolidone, (hydroxypropyl) methylcellulose, (hydroxypropyl) cellulose, Polyethylene Glycol, polyvinyl alcohol, xanthan gum, and composition thereof.
The surfactant of bag quilt can be a normally used surfactant in the pharmaceuticals industry on the surface of the pranlukast molecule in the spray-dried granules of the present invention.For example, surfactant is optional from Polyethylene Glycol-15-stearic acid (hydroxystearate) (for example, Solutol
HS 15), the polyoxyethylene oxyacetate natural or hydrogenant Oleum Ricini (for example, Cremophor
RH 40, Cremophor
RH 60), polyoxyethylene-polyoxypropylene copolymer (Poloxame for example
407, Poloxame
118), sucrose fatty acid ester, synthetic vitamin e derivative (for example, vitamin E TPGS
), sorbitan ester, polyoxyethylene sorbitan aliphatic ester (for example, Polysorbate
80), (for example, Br0 52 for polyxyethylated ester
), (for example, myrj 52 for polyoxyethylene 8 stearate salt
), fatty acid polyethyleneglycol glyceride (for example, Gelucire44/14
), polyglycine fatty acid ester (for example, Plurol oleique
), bile acid (for example, taurocholic acid (Taurocholic acid)), sodium lauryl sulphate, lecithin, fatty acid glyceride (for example, glyceryl monostearate) or the like.Wherein, surfactant can be selected from: Polyethylene Glycol-15-stearic acid, polyoxyethylene oxyacetate natural or castor oil hydrogenated, polyoxyethylene-polyoxypropylene copolymer, synthetic vitamin e derivative, sorbitan ester, polyoxyethylene sorbitan fatty acid ester, and polyxyethylated ester.
The spray-dried granules that the present invention contains pranlukast can comprise the pranlukast based on the 40-80wt% of granule gross weight, the water-soluble polymer of 5-20wt%, and the surfactant of 10-50wt%.
The present invention also provides and has comprised the above-mentioned spray-dried granules of pranlukast and the pharmaceutical composition of pharmaceutical carrier of containing.
Pharmaceutical carrier comprises diluent, disintegrating agent, lubricant or the like.It is known in the art.Here the example of spendable diluent comprises mannitol, maltose alcohol, sucrose, lactose, silicon dioxide, dextrin, dextrate, microcrystalline Cellulose, cellulose, glucose, poly-dextrin, starch, gelatinized starch, corn starch, cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, sodium starch glycolate, and composition thereof, the example of disintegrating agent comprises sodium starch glycolate, cross-linked carboxymethyl cellulose sodium and polyvinylpolypyrrolidone, and the example of lubricant comprises sodium stearyl fumarate and hard ester acid enzyme.
Pharmaceutical carrier can use based on 30 to 70wt% amounts of the gross weight of pharmaceutical composition.Pharmaceutical carrier can suitably be selected according to final preparation.
Pharmaceutical composition of the present invention can be selected from different dosage forms, comprises granule, tablet, capsule or dry syrup.These dosage forms can prepare according to the normally used method of pharmaceuticals industry.For example, can be by stirring above-mentioned spray-dried granules and diluent, disintegrating agent, lubricant etc. and the mixture tabletting prepared tablet, and can be by preparing capsule with the mixture filled capsules.In addition, also dosage form can be used for film-coating or casing-coating and improve stability, drug compliance, outward appearance or the like.
The present invention also provides a kind of preparation to contain the method for the spray-dried granules of pranlukast.Also be, as mentioned above, can obtain suspension by pranlukast is added in the aqueous solution that contains water-soluble polymer and surfactant by spraying-drying, disperse to prepare spray-dried granules consumingly with agitator, homogenizer or the ultrasonic oscillator of for example being furnished with propeller simultaneously; Or by disperseing to comprise the suspension of pranlukast, water-soluble polymer and surfactant consumingly with agitator, homogenizer or the ultrasonic oscillator of for example being furnished with propeller, and spray drying dispersion liquid.Preferably, by using homogenizer with 10,000 to 22,000rpm stirs and disperses.
Therefore, the invention provides the method that a kind of preparation contains the spray-dried granules of pranlukast, it comprises water-soluble polymer and surfactant dissolves are produced aqueous solution in water; 10,000 to 22,000rpm stirs down pranlukast to be added into and produces suspension in the solution; And spray drying suspension.
The method that the present invention also provides a kind of preparation to contain the spray-dried granules of pranlukast, it comprises water-soluble polymer and surfactant dissolves in water and pranlukast is added in the solution of generation and produces suspension; And with 10,000 to 22,000rpm stirred suspension 5 to 30 minutes, preferred 10 to 20 minutes; Spray drying then.
In said method, can utilize general comminutor to carry out spray drying, for example, fluidized bed comminutor, cylindrical comminutor, or high speed rotating comminutor.
From following embodiment and experimental example as can be seen, when the oral the present invention of using contained the spray-dried granules of pranlukast, the comparable commercial preparation of the bioavailability of pranlukast (Onon capsule) was high two to three times.
Even the spray-dried granules that contains pranlukast is with than commercially available pranlukast preparation (the Onon capsule: two capsules once that contains, the pranlukast of 225mg) low dosage (100mg or pranlukast still less) administration, they also demonstrate and are equivalent to or greater than the commercially available drug effect that contains the preparation of pranlukast.
Description of drawings
Accompanying drawing 1A, 1B, 1C, 1D and 1E have shown the comparative result by the solubility test of the tablet of spray-dried granules preparation of the present invention and marketed drugs;
Accompanying drawing 2 has shown the comparative result by the solubility test of the capsule of spray-dried granules preparation of the present invention and marketed drugs;
Accompanying drawing 3 is the curve charts that show the pharmacokinetics result in rat, and
Accompanying drawing 4 is the curve charts that show the pharmacokinetics result in human body.
Hereinafter, the present invention will more specifically be described in conjunction with following embodiment.The following example is used for exemplary purpose and is not to be used for limiting purpose of the present invention.
The specific embodiment
Embodiment 1: the preparation of spray-dried granules
With the polyvinylpyrrolidone (PVP) of 20g, the Solutol of 12g
The Poloxamer of HS 15 (BASF) and 28g
407 (BASF) are dissolved in the pure water of 500ml.Utilize homogenizer under the 18000-20000rpm rotating speed stirs, the 100g pranlukast to be joined in the solution of generation then and produce suspension.
Under the condition of internal temperature 120-130 ℃ and external temperature 80-90 ℃, utilize mini spray dryer (Buchi 190) that suspension is carried out spray drying and produce spray-dried granules.Utilize optical particle sizer AccuSizer 780A (ParticleSizing Systems.Inc.Santa Barbara, Calif., U.S.A) particle mean size of pranlukast in the mensuration spray-dried granules according to the power light scattering technique.As a result, the particle mean size of pranlukast is 9.79 μ m in the spray-dried granules.
Embodiment 2-10: the preparation of spray-dried granules
With with embodiment 1 in same way as, prepare spray-dried granules according to component in the following table 1 and content.Every 1g pranlukast uses the pure water of 5ml.
Table 1
| Embodiment | Composition (g) | Granularity (*) (μ m) | ||||
| Pranlukast | PVP | Solutol
| Cremophor RH 40 | Poloxamer 407 | ||
| 2 | 100 | 20 | - | 12 | 28 | 11.52 |
| 3 | 100 | 20 | 15 | - | 35 | 10.84 |
| 4 | 100 | 20 | 21.6 | - | 38.4 | 9.30 |
| 5 | 75 | 15 | 16.2 | - | 28.8 | 9.35 |
| 6 | 75 | 15 | 11.25 | - | 26.25 | 12.29 |
| 7 | 100 | 20 | - | 10 | 50 | 7.94 |
| 8 | 100 | 20 | - | 15 | 60 | 8.97 |
| 9 | 100 | 10 | - | 20 | 50 | 7.16 |
| 10 | 100 | 10 | - | - | 70 | 15.92 |
PVP: polyvinylpyrrolidone
(*): the particle mean size of pranlukast in the granule
Embodiment 11: the preparation of spray-dried granules
With the polyvinylpyrrolidone of 10g, the Cremophor of 15g
The Poloxamer of RH 40 (BASF) and 37.5g
407 (BASF) are dissolved in the pure water of 500ml.Under magnetic stirrer stirs, the pranlukast of 100g is added in the solution of generation and produce suspension thus.Then, with homogenizer 18,000-20, the homogenize suspension is 10 minutes under the 000rpm rotating speed, and produces spray-dried granules with fluidized bed pelletizer (Glatt) spray drying under the condition of internal temperature 110-130 ℃ and 1.0-2.0bar atomisation pressure.With with embodiment 1 in identical method measure the particle mean size of pranlukast in the spray-dried granules.As a result, the particle mean size of pranlukast is 11.30 μ m in the spray-dried granules.
Embodiment 12-20: the preparation of spray-dried granules
With with embodiment 1 in same way as, prepare spray-dried granules according to component in the following table 2 and content.Every 1g pranlukast uses the pure water of 5ml.
Table 2
| Ex. | Component (g) | PS (μm) | ||||||||||
| Pranlukast | PVP | HP MC | Xanthan gum | Solutol HS 15 | Taurocholic acid | Cremo- phor RH 40 | Poloxa -mer 188 | Vitamin E TPGS | Poly- Sorbate 80 | Brij 52 | ||
| 12 | 100 | 10 | - | - | - | - | 20 | 50 | - | - | - | 12.57 |
| 13 | 100 | - | 20 | - | - | - | - | 28 | - | - | - | 15.49 |
| 14 | 100 | - | 20 | - | - | - | - | - | 18 | 32 | - | 11.75 |
| 15 | 100 | - | - | 20 | - | 50 | - | - | - | - | - | 14.13 |
| 16 | 100 | 20 | - | - | 12 | - | - | 28 | - | - | - | 10.97 |
| 17 | 100 | 20 | - | - | - | - | 10 | 50 | - | - | - | 8.63 |
| 18 | 100 | 20 | - | - | - | - | - | 60 | - | 15 | - | 10.14 |
| 19 | 100 | - | 20 | - | - | 12 | - | - | - | - | 28 | 17.29 |
| 20 | 100 | - | - | 10 | 28 | - | - | - | - | - | 12 | 16.32 |
PVP: polyvinylpyrrolidone
The HPMC:(hydroxypropyl) methylcellulose
PS: the particle mean size of pranlukast in the granule
Embodiment 21-26: the preparation of spray-dried granules
With with embodiment 11 in same way as, prepare spray-dried granules according to component in the following table 3 and content.Every 1g pranlukast uses the pure water of 10ml.
Table 3
| Ex. | Component (g) | Granularity (*) (μ m) | ||||||
| Pranlukast | PVP | HPC | HPMC | Solutol
| Vitamin E TPGS | Lecithin | ||
| 21 | 100 | 20 | - | - | 12 | - | 28 | 14.43 |
| 22 | 100 | - | 20 | - | - | 12 | 28 | 12.75 |
| 23 | 100 | - | - | 20 | 12 | - | 35 | 15.63 |
| 24 | 100 | 20 | - | - | - | 10 | 50 | 11.82 |
| 25 | 100 | 20 | - | - | - | 15 | 60 | 10.07 |
| 26 | 100 | 10 | - | - | - | 20 | 50 | 9.54 |
PVP: polyvinylpyrrolidone
The HPC:(hydroxypropyl) methylcellulose
The HPMC:(hydroxypropyl) methylcellulose
(*): the particle mean size of pranlukast in the granule
Embodiment 27-29: the preparation of spray-dried granules
With the polyvinylpyrrolidone of 15g, the Solutolr of 16.2g
The Poloxamer of HS 15 (BASF) and 28.8g
407 (BASF) are dissolved in the pure water of 750ml.Under magnetic stirrer stirs, the pranlukast of 75g is added in the solution of generation and produce suspension thus.Then, with homogenizer with 18,000-20,000rpm homogenize suspension 8 minutes, and use with embodiment 1 in identical mode spray drying produce spray-dried granules (embodiment 27).
Spray-dried granules also can prepare with above-mentioned identical method, and just the time of homogenizer homogenize suspension under the 18000-20000rpm rotating speed is respectively 4 minutes (embodiment 28) and 2 minutes (embodiment 29).
Measure the particle mean size of pranlukast in the spray-dried granules of embodiment 27-29 preparation with the method identical, the results are shown in the following table 4 with embodiment 1.
Table 4
| Embodiment | Component (g) | Granularity (*) (μ m) | |||
| Pranlukast | Polyvinyl pyrrolidone | Solutol HS 15 | Poloxamer 407 | ||
| 27 | 75 | 15 | 16.2 | 28.2 | 18.03 |
| 28 | 75 | 15 | 16.2 | 28.2 | 25.70 |
| 29 | 75 | 15 | 16.2 | 28.2 | 44.97 |
(*): the particle mean size of pranlukast in the granule
Embodiment 30: utilize spray-dried granules to prepare tablet
With the spray-dried granules of preparation among the 150g embodiment 1, the 42.19g corn starch, the 98.44g lactose, the 14.06g polyvinylpolypyrrolidone, the aerosil of 4.69g, and the magnesium stearate of 9.38g is mixed and made into tablet.(OY-C-7000AWhite, Colorcon) peridium patch agent produce 800 tablets of tablets that contain the 100mg pranlukast respectively thus with the Opadry of 8g.
Embodiment 31-35: utilize spray-dired preparation of granules tablet
According to component of enumerating in the following table 5 and content, utilize embodiment 2,3, the spray-dried granules of preparation prepares tablet (every piece of tablet contains the 100mg pranlukast respectively) by the method identical with embodiment 30 in 7,8 and 9.
Table 5
| Component | Embodiment | |||||||
| 31 | 32 | 33 | 34 | 35 | ||||
| Sheet | Spray-dried | Embodiment | 2 | 160 | - | - | - | - |
| Agent nuclear | Embodiment 3 | - | 170 | - | - | - | ||
| Embodiment 7 | - | - | 180 | - | - | |||
| Embodiment 8 | - | - | - | 195 | - | |||
| Embodiment 9 | - | - | - | - | 180 | |||
| Diluent/disintegrating agent | Microcrystalline Cellulose | - | - | 94 | 102 | 94 | ||
| Lactose | 140 | 175 | 94 | 102 | 94 | |||
| | 60 | 75 | - | - | - | |||
| Primellose | 13 | 9 | 10 | 15 | 10 | |||
| Polyvinylpolypyrrolidone | - | 12 | 13 | 7 | 13 | |||
| | 4 | 5 | 5 | 6 | 5 | |||
| Lubricant | Magnesium stearate | 3 | 4 | 14 | 4 | 4 | ||
| | Opadry | 10 | 14 | 12 | 12 | 12 | ||
| Gross weight | 390 | 464 | 412 | 428 | 412 | |||
Embodiment 36 and 37: utilize spray-dired preparation of granules tablet
According to component of enumerating in the following table 6 and content, the spray-dried granules that utilizes among the embodiment 4 and 5 preparation prepares tablet (every piece of tablet contains the pranlukast (embodiment 36) of 100mg and the pranlukast (embodiment 37) of 75mg respectively) by the method identical with embodiment 30.
Table 6
| Component (g) | Embodiment | ||||
| 36 | 37 | ||||
| Tablet core | Spray-dried | Embodiment | 4 | 180 | - |
| Embodiment 5 | - | 135 | |||
| Diluent/disintegrating agent | Microcrystalline Cellulose | 114 | 85.5 | ||
| Lactose | 114 | 85.5 | |||
| Cross-linking | 10 | 9.5 | |||
| Polyvinylpolypyrrolidone | 15 | 11.5 | |||
| Aerosil | 5 | 4 | |||
| | Magnesium stearate | 12 | 9 | ||
| Coating | Opadry (Opadry) | 14 | 10 | ||
| Gross weight | 464 | 350 | |||
Embodiment 38-44: utilize spray-dried granules to prepare tablet
According to component of enumerating in the following table 7 and content, the spray-dried granules that utilizes among the embodiment 21,22 preparation prepares tablet (every piece of tablet contains the pranlukast of 100mg respectively) by the method identical with embodiment 30.
Table 7
| Component (g) | Embodiment | ||||||||
| 38 | 39 | 40 | 41 | 42 | 43 | 44 | |||
| Tablet core | Spray-dried granules | Embodiment 21 | 160 | - | - | - | - | - | - |
| Embodiment 22 | - | 160 | - | - | - | - | - | ||
| Embodiment 23 | - | - | 170 | - | - | - | - | ||
| Embodiment 24 | - | - | - | 180 | - | - | - | ||
| Embodiment 25 | - | - | - | - | 195 | - | - | ||
| Embodiment 26 | - | - | - | - | - | 180 | - | ||
| The pranlukast powder | - | - | - | - | - | - | 112.5 | ||
| Diluent | Microcrystalline Cellulose | - | - | - | 70 | 80 | 94 | 120 | |
| Lactose | 140 | 140 | 175 | 70 | 80 | 94 | 120 | ||
| | 60 | 60 | 75 | - | - | - | - | ||
| Cross-linking | 16 | 16 | 18 | 16 | 14 | 19 | 18.5 | ||
| Aerosil | 3 | 3 | 4 | 4 | 3 | 4 | 7 | ||
| Lubricant | Magnesium stearate | 6 | 6 | 8 | 10 | 8 | 9 | 12 | |
| Coating | Opadry (Opadry) | 10 | 10 | 13 | 10 | 10 | 12 | 10 | |
| Gross weight | 395 | 395 | 463 | 360 | 390 | 412 | 400 | ||
Embodiment 45: utilize spray-dired preparation of granules capsule
With the spray-dried granules of 128g of preparation among the embodiment 2, the microcrystalline Cellulose of 59.2g, the lactose of 59.2g, the polyvinylpolypyrrolidone of 5.2g, the aerosil of 1.6g, and the magnesium stearate of 2.8g mixes, and be filled in the No.1 capsule and prepare capsule.Each components contents of every capsules (mg) is as shown in table 8.
Table 8
| Component | Content in each capsule (mg) |
| | 100 |
| | 20 |
| Solutol HS 15 | 12 |
| Poloxamer 407 | 28 |
| Microcrystalline Cellulose | 74 |
| Lactose | 74 |
| Polyvinylpolypyrrolidone | 6.5 |
| Aerosil | 2 |
| Magnesium stearate | 3.5 |
| Amount to | 320 |
Embodiment 46-49: utilize spray-dired preparation of granules capsule
Utilize the spray-dried granules for preparing among embodiment 5 and the 27-29 to prepare capsule by the method identical with embodiment 45.
Embodiment 50: utilize spray-dried granules to prepare dry syrup
Spray-dried granules with preparation among the embodiment 4 of 126g, 1.4g xanthan gum, 0.7g titanium oxide, 3.5g the strawberry essence powder, 5.6g silicon dioxide and the maltodextrin of 105g mix, further to the sucrose that wherein adds 457.8, prepare the particulate dry syrup that contains the 100mg pranlukast in every gram granule thus then.Each components contents is as shown in table 9 in the 1 gram dry syrup granule.
Table 9
| Component | Content in the 1g granule (mg) |
| | 100 |
| | 20 |
| Solutol HS 15 | 21.6 |
| Poloxamer 407 | 38.4 |
| Maltodextrin | 150 |
| Sucrose | 654 |
| | 2 |
| | 1 |
| The | 5 |
| | 8 |
| Amount to | 1,000 |
Experimental example 1: solubility test
In pure water, first solution (pH 1.2) and second solution (pH 6.8), measure the spray-dried granules dissolubility for preparing among the embodiment 7-9.Respectively in pure water, first solution and second solution that pranlukast powder for preparing among the embodiment 7-9 with 1g and spray-dried granules add 50ml to, and in 25 ℃ of water-baths, firmly stirred 6 hours with agitator.Getting above-mentioned solution also filters with 0.45 μ m microfilter.Utilize high performance liquid chromatography (HPLC) to measure the concentration of pranlukast, the result is as shown in table 10.
Table 10
| Sample | Dissolubility (μ g/ml) | ||
| Purified water | pH 1.2 | pH 6.8 | |
| The pranlukast powder | 1.6 | x | 0.2 |
| Embodiment 7 | 672.87 | 111.83 | 835.23 |
| | 637.75 | 568.40 | 1206.89 |
| Embodiment 9 | 684.09 | 483.45 | 1274.53 |
X: be lower than detectability
As shown in table 10, the dissolubility of spray-dried granules of the present invention has all increased in all solvent environment.In particular, the dissolubility improvement effect in first solution (pH 12) is significant.
Experimental example 2: fluidity test
(every capsules contains the pranlukast of 112.5mg, Donga Pharmaceutical Co., granule Ltd.) (with reference to granule), and the spray-dried granules of preparation in embodiment 4,5,8 and 9 is measured flowability to estimate pranlukast powder, Onon capsule.The results are shown in the following table 11.
Table 11
| Sample | ρo | ρt | Compressibility (%) | Mobile |
| The pranlukast powder | 0.17 | 0.30 | 43.33 | Very |
| With reference to granule | 0.62 | 0.73 | 15.07 | |
| Embodiment | ||||
| 4 | 0.40 | 0.48 | 16.67 | |
| Embodiment | ||||
| 5 | 0.42 | 0.48 | 12.50 | |
| Embodiment | ||||
| 8 | 0.44 | 0.51 | 13.73 | Excellent |
| Embodiment 9 | 0.42 | 0.49 | 14.29 | Excellent |
ρ o: volume density
ρ t: tap density
Compressibility (%)=(ρ o-ρ t)/pt*100
As shown in table 11, the pranlukast with very strong viscosity demonstrates 40% or bigger compressibility.Therefore, the pranlukast powder has very weak weak mobile as can be seen.On the other hand, spray-dried granules of the present invention demonstrates excellent flowability.
Experimental example 3: slaking test
Measure the disintegration time of the tablet of embodiment 38-44 preparation according to the slaking test described in the Pharmacopoeia Coreana.Under 37 ± 0.5 ℃, utilize auxiliary microwell plate up-down adjustment purifying waste water as test(ing) medium.Time cycle when observing some soft or turbid materials when mensuration does not observe the sample residue or in glass tubing, the results are shown in the table 12.
Table 12
| Sample | Disintegration time (min) |
| Embodiment 38 | 12-14 |
| Embodiment 39 | 15-16 |
| | 13-15 |
| Embodiment 41 | 20-22 |
| Embodiment 42 | 20-23 |
| Embodiment 43 | 19-21 |
| Embodiment 44 | 360 or more |
As shown in table 12, all tablets that contain spray-dried granules of the present invention decomposed in 30 minutes.On the other hand, in the tablet that contains pranlukast powder (embodiment 44), produce powder agglomerates, cause decomposing delay thus with strong viscosity.
Experimental example 4: solubility test
Mensuration is from the rate of dissolution of the pranlukast in the tablet for preparing among the embodiment 30-35.Second kind of solution (pH 6.8) of 900ml is placed the resolution measurement device, and go up maintenance 45 minutes at 37 ± 0.5 ℃.Between glass tubing that the diagonal of the glass tubing that contains sample is placed and beaker, get the 10ml aliquot sample, filter with 0.45 μ m microfilter.First filtrate of 5ml is abandoned, next get 2ml filtrate, utilize HPLC to analyze.The result is as shown in table 13.(every capsules contains the pranlukast of 112.5mg to the Onon capsule, and DongaPharmaceutical Co. Ltd.) is used as with reference to preparation.
Table 13
| Sample | Rate of dissolution (%) |
| With reference to preparation | 7.81 |
| | 35.71 |
| Embodiment 31 | 27.50 |
| Embodiment 32 | 32.83 |
| Embodiment 33 | 55.17 |
| Embodiment 34 | 98.37 |
| Embodiment 35 | 67.37 |
Table 13 shows that the rate of dissolution of the pranlukast of the tablet that free spray-dried granules of the present invention is made compares with reference to the high 4-12 of preparation Onon capsule doubly.
Experimental example 5: compare solubility test
With the tablet of preparation in embodiment 36 and 37, commercially available preparation, (pranlukast 112.5mg/ grain, Donga Pharmaceutical Co. Ltd.) are used for the comparison dissolution experiment to the Onon capsule.Method 2 (paddle method) according to the Pharmacopoeia Coreana regulation compares solubility test.
With purifying waste water of 900ml, first solution (pH 1.2), buffer solution (pH 4.0), second solution (pH 6.8), place the dissolving determinator with 0.2% second solution (pH 6.8) that contains polysorbate 80, under 37 ± 0.5 ℃, 100rpm stir,, the dissolve medium of 3ml is taken in the pipe of silicon-Bao quilt with the rate of dissolution of preset time measuring space with respect to the time, filter with 0.45 μ m injection filter, and analyze with UV.The results are shown among the accompanying drawing 1A to 1E.Accompanying drawing 1A, 1B, 1C, 1D and 1E have shown respectively and are purifying waste water, second solution (pH 6.8), first solution (pH 1.2), buffer solution (pH 4.0) and contain solubility test result in second solution (pH 6.8) of 0.2% polysorbate 80.With respect to the Onon capsule, the rate of dissolution of pranlukast in first solution (pH 1.2) and buffering solution (pH 4.0) drops under the detectability.
Shown in accompanying drawing 1A to 1E, the tablet of being made by spray-dried granules of the present invention demonstrates excellent dissolution mode in all solvent conditions.
Experimental example 6: with respect to the comparison solubility test of pranlukast granularity in the granule
The capsule of the embodiment 4649 that will be made by the spray-dried granules of embodiment 5 and 27-29 preparation, with commercially available preparation, (pranlukast 112.5mg/ grain, DongaPharmaceutical Co. Ltd.), are used for the comparison dissolution experiment to the Onon capsule.Method 2 (paddle method) according to the Pharmacopoeia Coreana regulation compares solubility test.
Second solution that contains 0.2% polysorbate 80 (pH 6.8) of 900ml is placed the dissolving analyzer, and stir down mensuration with respect to the medicine dissolution speed of time at 37 ± 0.5 ℃, 100rpm.With preset time at interval, the dissolve medium of 3ml is taken in the pipe of silicon-Bao quilt,, and analyzes with UV with the filtration of 0.45 μ m injection filter.The results are shown in the accompanying drawing 2.
As shown in Figure 2, for being the capsule that the spray-dried granules of 20 μ m or littler pranlukast is made by containing particle mean size, the peak dissolution rates of pranlukast is up to 90% or more.On the other hand, about being the capsule that the spray-dried granules of the pranlukast of 25.70 μ m and 44.97 μ m is made by containing particle mean size, the peak dissolution rates of pranlukast is respectively 78.76% and 56.53%.Especially, by containing the capsule that particle mean size is the spray-dried granules preparation of 20 μ m or littler pranlukast, demonstrated about 80% or bigger rate of dissolution in back 15 minutes in the dissolving beginning.According to the oral drugs of korean foods and drug administration (KFDA) dissolving standard guidelines, reach 85% or stop solubility test more for a long time in dissolving when medicine.Therefore, the mensuration particle mean size is difficult greater than the dissolving termination time of the pranlukast of 20 μ m.
Experimental example 7: the pharmacokinetics evaluation in rat
Utilize tablet prepared in accordance with the present invention and be included in granule (with reference to granule) in the commercial preparation, (pranlukast 112.5mg/ grain, Donga Pharmaceutical Co. Ltd.) carry out pharmacokinetics evaluation in rat to the Onon capsule.
With Sprague-Dawley rat (body weight: 200-250g) be divided into three groups (n=5).With irritating the tablet (first group) of stomach pin with preparation among the embodiment 37 of 11.25mg/kg, 15
The tablet (second group) of preparation among the embodiment 37 of mg/kg, and 33.75mg/kg's is Orally administered to rat on an empty stomach with reference to granule (the 3rd group).In oral back 0.5,1,1.5,2,2.5,3,4,5,6 and 8 hours, by polyethylene tube being inserted the blood sample that carotid artery is collected about 300 μ l, and 10, under the rotating speed of 000rpm, took separated plasma in centrifugal 1 minute.The blood plasma of getting 100 μ l is stored in-20 ℃ for use in quantitative analysis.Utilize the pranlukast in the LC/MS mensuration blood plasma, experimental result is seen accompanying drawing 3.
With reference to the accompanying drawings 3, administration after 8 hours plasma concentration and the zone below the time curve (AUC) corresponding to first group be 442.71ngh/ml and corresponding to second group for 628.36ngh/ml, it is similar to or to compare the 3rd group 453.27ngh/ml high 1.4 times.These results show that spray-dried granules of the present invention demonstrates higher bioavailability, like this, have both made them even have had identical drug effect with the dosage of commercially available medicament about 1/3 with commercially available medicament.
Experimental example 8: the pharmacokinetics evaluation in human body
Tablet that utilization is made by spray-dried granules of the present invention (embodiment 36) and commercially available preparation Onon capsule in human body, carry out the pharmacokinetics evaluation (pranlukast 112.5mg/ grain, Donga Pharmaceutical Co., Ltd.).
The normal adults in 8 30-40 years is divided into two groups (n=4).Intersect on an empty stomach administration with the tablet (pranlukast of 100mg) (first group) of preparation among the embodiment 36 and with reference to preparation (two Onon capsules, the pranlukast of 225mg) (second group), use the 200ml water delivery service.Before administration and administration 1,2,3,4,4.5,5,5.5,6, after 7,8,10 and 24 hours by median cubital vein blood sampling (3.0ml).Blood sample places the vacuum tube that contains heparin, mixes 5 minutes with cylinder, changes the eppendorf pipe over to, 3, and under the rotating speed of 000rpm, centrifugal 5 minutes.Get blood plasma, insert in the eppendorf pipe of sterilization ,-70 ℃ are stored to analysis.Utilize the pranlukast in the LC/MS mensuration blood plasma, experimental result is seen accompanying drawing 4.
4, the first groups AUC (after the administration 24 hours) is 2386.8ngh/ml with reference to the accompanying drawings, and it is than second group (1978.2ngh/ml) high 20% or more.These results show that the tablet of being made by spray-dried granules of the present invention demonstrates higher bioavailability, like this, even the dosage of pranlukast is 80mg or still less, they have identical drug effect with commercially available medicament.
Spray-dried granules of the present invention can improve the viscosity and the dissolubility of pranlukast, and can increase the rate of dissolution and the bioavailability of pranlukast, even pranlukast does not wrap by sugar such as lactose, like this, can significantly reduce dosage with respect to conventional dose and use.In addition, spray-dried granules of the present invention can be produced thus on a large scale not preparing under with an organic solvent the situation.
Claims (8)
1, a kind of spray-dried granules that comprises pranlukast, water-soluble polymer and surfactant, wherein the particle mean size of pranlukast is 0.5-20 μ m in the granule.
2, according to the spray-dried granules of claim 1, wherein the particle mean size of pranlukast is 5-18 μ m in the granule.
3, according to the spray-dried granules of claim 1, wherein water-soluble polymer is selected from and comprises polyvinylpyrrolidone, (hydroxypropyl) methylcellulose, (hydroxypropyl) cellulose, Polyethylene Glycol, polyvinyl alcohol, xanthan gum, and composition thereof group.
4, according to the spray-dried granules of claim 1, wherein surfactant be selected from comprise Polyethylene Glycol-15-stearic acid, the polyoxyethylene oxyacetate is natural or castor oil hydrogenated, polyoxyethylene-polyoxypropylene copolymer, synthetic vitamin e derivative, sorbitan ester, polyoxyethylene sorbitan fatty acid ester, and the group of polyxyethylated ester.
5, a kind of pharmaceutical composition that comprises arbitrary spray-dried granules of claim 1-4 and pharmaceutical carrier.
6, according to the pharmaceutical composition of claim 5, it is the form of granule, tablet, capsule or dry syrup.
7, a kind of method for preparing the arbitrary spray-dried granules of claim 1-4, it comprises:
With water-soluble polymer and the surfactant aqueous solution that produces soluble in water;
10,000 to 22, under the rotating speed of 000rpm, stir following pranlukast is added to and produce suspension in the aqueous solution; With
The spray drying suspension.
8, a kind of method for preparing the arbitrary spray-dried granules of claim 1-4, it comprises:
With water-soluble polymer with surfactant is soluble in water and pranlukast is added in the solution of generation and produce suspension; With
10,000 to 22, under the rotating speed of 000rpm, stirred suspension 5 to 30 minutes is spray drying then.
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| WO2023010762A1 (en) * | 2021-08-03 | 2023-02-09 | 湖南复瑞生物医药技术有限责任公司 | Preparation method for high-purity, small-particle-size pranlukast |
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| KR100981750B1 (en) | 2005-10-28 | 2010-09-10 | 주식회사유한양행 | Spray-dried granules and processes for the preparation thereof |
| JP2008162966A (en) * | 2006-12-28 | 2008-07-17 | Taisho Pharm Ind Ltd | Method for decreasing attaching and coherent property of pranlukast hydrate |
| JP2011500647A (en) * | 2007-10-19 | 2011-01-06 | アボット ゲーエムベーハー ウント カンパニー カーゲー | Solid dispersion product containing N-arylurea compounds |
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| JPH0776516A (en) * | 1993-09-06 | 1995-03-20 | Toyobo Co Ltd | Production of slightly soluble medicine-containing preparation |
| JP2958863B2 (en) * | 1995-06-12 | 1999-10-06 | 小野薬品工業株式会社 | Granulated product containing pranlukast, method for producing the same, and method for improving adhesion and cohesion of pranlukast |
| EP0834314B1 (en) | 1995-06-12 | 2003-01-15 | Ono Pharmaceutical Co., Ltd. | Granules containing pranlukast, process for producing the granules, and method of lowering cohesiveness of pranlukast |
| AU1939797A (en) * | 1996-03-14 | 1997-10-01 | Shionogi & Co., Ltd. | Rapid-release microdispersible ecadotril preparation |
| TW546151B (en) | 1997-07-23 | 2003-08-11 | Senju Pharma Co | Aqueous liquid pharmaceutical composition containing as main component benzopyran derivative |
| ZA991922B (en) * | 1998-03-11 | 1999-09-13 | Smithkline Beecham Corp | Novel compositions of eprosartan. |
| GB9920148D0 (en) * | 1999-08-25 | 1999-10-27 | Smithkline Beecham Plc | Novel composition |
| KR100381834B1 (en) | 2000-05-20 | 2003-04-26 | 이상득 | Solid dispersion system of pranlukast with improved dissolution, and the method thereof |
| JP2004175795A (en) * | 2002-11-13 | 2004-06-24 | Takeda Chem Ind Ltd | Medicinal composition excellent in releasability of medicament |
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