WO2010072105A1 - 一种度洛西汀肠溶制剂及其芯材和制备方法 - Google Patents
一种度洛西汀肠溶制剂及其芯材和制备方法 Download PDFInfo
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- WO2010072105A1 WO2010072105A1 PCT/CN2009/074786 CN2009074786W WO2010072105A1 WO 2010072105 A1 WO2010072105 A1 WO 2010072105A1 CN 2009074786 W CN2009074786 W CN 2009074786W WO 2010072105 A1 WO2010072105 A1 WO 2010072105A1
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- duloxetine
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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
- A61K31/38—Heterocyclic compounds having sulfur as a ring hetero atom
- A61K31/381—Heterocyclic compounds having sulfur as a ring hetero atom having five-membered rings
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/284—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone
- A61K9/2846—Poly(meth)acrylates
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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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2806—Coating materials
- A61K9/2833—Organic macromolecular compounds
- A61K9/286—Polysaccharides, e.g. gums; Cyclodextrin
- A61K9/2866—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- 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
- A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
- A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5089—Processes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
Definitions
- the invention belongs to the field of pharmaceutical preparations, and in particular relates to a duloxetine enteric preparation and a core material thereof and a preparation method thereof.
- Duloxetine is a selective serotonin and norepinephrine reuptake inhibitor (SNRIs), a safe and effective antidepressant, chemically named (S)-(+)-N-A
- the base-3-(1-naphthyloxy)-3-(2-thienyl)-propylamine is usually used in the form of the hydrochloride. Due to the instability and prone to degradation of duloxetine in an acidic environment, it is suitable to use duloxetine or a salt thereof as an enteric preparation to resist the destruction of the drug by gastric juice.
- US 5,508,276 relates to an enteric pellet of duloxetine comprising a) a core composed of duloxetine and a pharmaceutically acceptable excipient; b) a dispensable barrier; c) a hydroxyl acetate An enteric coating layer of propylcellulose succinate (HPMCAS) and a pharmaceutically acceptable excipient; d) a dispensable modifying layer. Sucrose in the barrier layer mitigates migration and interaction of the enteric coating material with duloxetine to improve acid resistance and stability.
- HPMCAS propylcellulose succinate
- Z1200410067160.4 relates to a duloxetine enteric coated tablet and a preparation method thereof, wherein duloxetine hydrochloride, a water-soluble solid dispersion carrier and a diluent are dissolved in an aqueous ethanol solution, and sieved by a method known in the art.
- the method uses a solid dispersion technique to increase the solubility of the main drug and increase the final release amount, thereby increasing the bioavailability of duloxetine.
- duloxetine is more susceptible to degradation and other reactions, and the water accelerates or catalyzes in the reaction.
- the disclosed duloxetine hydrochloride enteric preparation is prepared into a duloxetine hydrochloride solution or suspension in the preparation process of duloxetine hydrochloride core material, or a wetting agent or a binder is added. Exposure to water and some organic solvents such as ethanol, thereby affecting the stability of duloxetine hydrochloride; And organic solvents not only costly and costly, but also increase the instability, and if you use organic solvents, it will also pollute the environment.
- the technical problem to be solved by the present invention is that the existing duloxetine enteric preparation core material is exposed to water or an organic solvent during the preparation process, and the instability factor of the drug active ingredient duloxetine and the shortage of the solvent residue are increased.
- the duloxetine core material is not exposed to any water and an organic solvent during the preparation process, and the degradation of the drug active ingredient duloxetine is small, High stability, high content of active pharmaceutical ingredients, and good dissolution.
- the present inventors attempted to prepare a duloxetine hydrochloride core material without adding a solvent such as water, but since the duloxetine hydrochloride has a small specific gravity and poor flowability, it cannot be uniformly mixed with other auxiliary materials, and it is difficult to carry out a method of directly pressing the core material by powder; Duloxetine hydrochloride is loose in the dry state, has poor viscosity and is not easy to be mixed, and has poor molding and low yield by dry extrusion granulation.
- the hot melt method can mix the medicine and the auxiliary material without using water or an organic solvent, and the hot melt method not only makes the mixing effect of the medicine and the auxiliary material good, but also completes the core material molding at the same time. Therefore, the present inventors prepared a duloxetine core material and an enteric preparation thereof by a hot melt method, and the obtained duloxetine enteric preparation completely achieved the object of the present invention by an effect test, thereby completing the present invention.
- a core material of a duloxetine enteric preparation which is composed of a pharmaceutically active ingredient duloxetine or a salt thereof and a pharmaceutically acceptable auxiliary material.
- the pharmaceutically acceptable excipient contains a water-soluble hot melt material, and the content of the water-soluble hot melt material is 10% to 40%, and the content of the pharmaceutically active ingredient duloxetine or a salt thereof is 15 to 60%, and the rest
- the percentage is the percentage by mass of the total core material.
- the water-soluble hot melt material is a solid in an environment of 18 to 26 ° C, heating a pharmaceutically acceptable water-soluble material which can be softened or melted.
- the softening or melting temperature of the water-soluble hot melt material is preferably from 40 to 65 °C.
- the water-soluble hot melt material of the present invention has a special softening or melting temperature on the one hand, and produces a bonding force after melting, and is solid at room temperature, thereby satisfying the need for melt granulation. On the other hand, its water solubility can achieve the release of the main drug from the core. Put it.
- the water soluble hot melt material is preferably selected from one or more of polyethylene glycol (PEG), poloxamer and polyoxyl (40) ester stearate.
- the polyethylene glycol is preferably any one or more selected from the group consisting of polyethylene glycols 4000 to 10000.
- the content of the water-soluble hot melt material is preferably 5% to 40%, more preferably 10% to 25%, and the percentage is the mass percentage of the water-soluble hot melt material to the total amount of the core material.
- the duloxetine salt is preferably duloxetine hydrochloride.
- the content of the duloxetine or a salt thereof is preferably from 15 to 60%, and the percentage is the mass percentage of duloxetine or a salt thereof to the total amount of the core material.
- the average particle size of the duloxetine or a salt thereof is preferably less than 100 ⁇ m.
- the other pharmaceutically acceptable excipient is preferably any one or more selected from the group consisting of a filler, a disintegrant, a lubricant, and a surfactant.
- the filler is preferably selected from the group consisting of sucrose, mannitol, xylitol, glucose, maltitol, sorbitol, hydroxypropyl beta-cyclodextrin, starch, microcrystalline cellulose, pregelatinized starch, magnesium oxide.
- Studies by the present invention have shown that some sugars and sugar alcohols not only facilitate the release of the main drug from the core material, but also contribute to the stability of the main drug, particularly sucrose, mannitol, xylitol and maltitol.
- Lactose is the main filler, which affects the stability of the preparation, so lactose is not a preferred filler.
- the content of the filler may be from 0% to 65%, preferably from 10% to 65%, more preferably from 20% to 50%, based on the mass of the core material.
- the disintegrant is preferably selected from the group consisting of sodium carboxymethyl starch, hydroxypropyl cellulose, crospovidone and croscarmellose sodium. More preferably, it is selected from sodium carboxymethyl starch, crospovidone and croscarmellose sodium.
- the content of the disintegrant may be from 0% to 18%, preferably from 1% to 18%, more preferably from 2% to 10%, based on the mass of the core material.
- the lubricant may be selected from conventional materials in pharmaceutical preparations, preferably any one or more selected from the group consisting of magnesium stearate, micronized silica gel, sodium stearate and sodium talc.
- the content of the lubricant may be from 0% to 3% by mass of the core material, preferably from 0.1% to 3%, more preferably from 0.5% to 1.5%.
- the surfactant may be selected from conventional materials in pharmaceutical preparations, preferably selected from the group consisting of Tween-80, polyoxyethylene castor oil, and sodium dodecyl sulfate.
- the content may be from 0% to 3% by mass of the core material, preferably from 0.1 to 1.5% by mass of the core material.
- the second technical solution adopted by the present invention to solve the above technical problems is: a method for preparing a core material of a duloxetine enteric preparation as described above, comprising the following steps: dissolving duloxetine or a salt thereof, and water-soluble
- the hot melt material is mixed with a pharmaceutically acceptable auxiliary material, and then heated until the water-soluble hot melt material is softened or melted, granulated in a softened or molten state of the water-soluble hot melt material, and then cooled, that is, obtained.
- the granulation is preferably hot melt agitation granulation, hot melt fluid granulation or hot melt extrusion granulation.
- the hot-melt agitation granulation is to place the material in a jacketed heating granulation container, open the three-way stirring blade to rotate at a certain speed, and heat the material to a desired temperature through the granulation container heating jacket, heat After the molten material is melted, the adhesive material is formed, so that the material forms a soft material, and the material is turned in the container to rotate along the wall, the high-speed rotating scraper breaks the block, the friction between the powder and the container wall, and the aggregation friction between the powder particles, and finally Forming particles.
- the hot melt fluidized granulation is operated in a fluidized bed granulator, and the hot air heats the material to a desired temperature.
- the adhesive force generated by the melting of the hot melt material causes the powder to be aggregated.
- the knot forms a particle nucleus around it, and the particle nucleus and the particle nucleus, the particle nucleus and the particle continue to combine with each other to form a larger particle.
- the hot-melt extrusion granulation is an extruder which mixes materials and heats and holds the jacket, and the hot-melt material is melted to form a wet material, and the wet material is extruded through a sieve with a certain diameter by spiral propulsion. The plate, extruded into a cylindrical strip of extrudate, was immediately cut into pellets.
- the amount of the hot-melt material, the stirring time during granulation, the jacket temperature, and the material temperature have a large influence on the characterization of the granules and the quality of the granules.
- the stirring time during granulation can be controlled according to the composition and amount of the hot melt material, and the preferred stirring time is controlled within 10 minutes after reaching the melting temperature of the hot melt material.
- the jacket temperature is generally 60 to 90 °C, and the jacket temperature can be controlled to exceed the melting temperature of the hot melt material by 15 to 25 °C depending on the composition of the hot melt material.
- a duloxetine enteric preparation comprising a core material, a release layer and an enteric layer, wherein the core material is a core material as described above .
- the duloxetine enteric preparation is preferably an enteric tablet, an enteric granule or an enteric microcapsule capsule.
- the enteric tablet or the enteric granule is coated with a release layer and an enteric layer in this order outside the core material of the present invention.
- the enteric microchip capsule is in a conventional hard gel The capsule is filled with the above-mentioned core material of the present invention coated with an enteric microchip prepared by a barrier layer and an enteric layer.
- the barrier layer may comprise various barrier materials conventional in the art, preferably one selected from the group consisting of hypromellose, hydroxypropylcellulose, and methylcellulose.
- barrier materials preferably one selected from the group consisting of hypromellose, hydroxypropylcellulose, and methylcellulose.
- a sugar and a sugar alcohol may be further included to increase the stability of the duloxetine or its salt enteric preparation;
- the barrier layer may further comprise a filler selected from the group consisting of a filler Other medicinal excipients such as sunscreens, plasticizers and anti-adherents.
- the enteric layer may comprise enteric materials commonly used in the pharmaceutical formulation art.
- the enteric material is preferably selected from the group consisting of acrylic resin, polyvinyl alcohol phthalate, hydroxypropyl methylcellulose acetate succinate (HPMCAS) and hydroxypropyl methylcellulose phthalate (HPMCP).
- HPMCAS hydroxypropyl methylcellulose acetate succinate
- HPMCP hydroxypropyl methylcellulose phthalate
- the enteric layer further comprises a plasticizer.
- the plasticizer is preferably selected from one or more of triethyl citrate, diethyl benzoate, methyl silicone oil, castor oil and polyethylene glycol.
- the enteric layer may further contain other medicinal excipients including anti-adhesive agents, lubricants, surfactants and the like.
- the enteric layer may also include a modifying layer, but is not required.
- the selection of an appropriate modification layer can increase the moisture resistance of the enteric preparation during storage, and the appearance is more complete and smooth.
- the modifying layer may comprise one or more selected from the group consisting of a film forming material such as hypromellose, a talc powder, silica, titanium dioxide, polyethylene glycol or wax.
- a method for preparing a duloxetine enteric preparation as described above comprising the following steps:
- the enteric layer is coated by a conventional manufacturing process in the art.
- the preparation method of the duloxetine enteric preparation further comprises the steps of: 3) coating the modified layer.
- the present invention adopts a hot melt process to prepare a core material of an enteric preparation of duloxetine or a salt thereof, thereby avoiding introduction of moisture or an organic solvent in the preparation process, and reducing Solvent residue also reduces the degradation of duloxetine, improves the stability of the preparation during preparation and storage; no need to add binder, particles do not need to be dried, greatly simplify the operation steps, and less loss, thus reducing Preparation cost; hot melt material of the invention, such as polyethylene glycol, Polo The sam and stearic acid polyoxyl (40) lipids are water-soluble, achieving release of the main drug from the core, good dissolution, and improved bioavailability of the drug; the duloxetine of the present invention or The enteric preparation of the salt has a high content of the active ingredient of the drug.
- Figure 1 shows that the duloxetine hydrochloride core prepared by conventional wet granulation is sealed in a high-density polyethylene bottle and placed at a temperature of 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5% for six months. Relevant substance determination map.
- FIG. 2 is a view showing the preparation of the core of duloxetine hydrochloride in the high-density polyethylene bottle according to the embodiment 5 of the present invention, which is placed at a temperature of 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5% for six months. Material determination map.
- the softening temperature of polyethylene glycol 4000 ⁇ 10000 is 48 ⁇ 63 °C
- the melting temperature of poloxamer is 49 ⁇ 57 °C
- the melting temperature of polyoxyl (40) ester of stearic acid is 46 ⁇ 51 °C.
- Example 1 Enteric-coated tablets (converted to 1.2 kg)
- duloxetine hydrochloride sucrose, microcrystalline cellulose, 70% amount of crospovidone and PEG6000 uniformly, and placing the granulator agitator in a quick mixer with a temperature of 80-85 °C. After the temperature of the material reached 60 ° C, stirring was continued for 6 minutes, discharged, cooled, and sieved with a 24-mesh sieve. Add the remaining amount of crospovidone and magnesium stearate, mix well, and compress to obtain the core.
- This embodiment is prepared as a duloxetine enteric-coated tablet, and the coating preparation process is as follows: Dispersing hypromellose with 70 ° C hot water, stirring with water, adding homogenized talcum powder and titanium dioxide. A layer solution having a solid content of about 15% by weight. The core was placed in a coating pan, and the inlet air temperature was adjusted so that the bed temperature was 30 to 40 ° C, the atomization pressure was 4.0 kg/cm 2 , and the pot rotation speed was 12 rpm, and the core was coated with a separator.
- Jacques MP was prepared as a 20 wt% solids aqueous dispersion, and methyl methacrylate with a weight of 0.5 wt% of Jacós was added and stirred for 20 minutes.
- the inlet air temperature was adjusted so that the bed temperature was 28 to 32 ° C, the atomization pressure was 2.0 kg/cm 2 , and the pot rotation speed was 12 rpm, and the core was coated with an enteric layer.
- Titanium dioxide 1.6mg
- Acrylic resin aqueous dispersion 35.8mg
- duloxetine hydrochloride sucrose, 70% crospovidone and PEG6000 uniformly, and setting the jacket temperature to 80 ⁇ 85 °C in a fast mixer, open the granulator agitator, when the material temperature reaches 60 Stirring was continued for 8 minutes at ° C, discharged, cooled, and sieved through a 24-mesh sieve. Add the remaining amount of cross-linked povidone and magnesium stearate, mix well, and tablet to obtain the core.
- This embodiment is prepared as a duloxetine enteric-coated tablet, and the coating preparation process is as follows: Dispersing hypromellose with 70 ° C hot water, stirring with water, adding homogenized talcum powder and titanium dioxide. A layer solution having a solid content of about 15% by weight. The core is placed in a coating pan, and the inlet air temperature is adjusted so that the bed temperature is 35 to 40 ° C, the atomization pressure is 2.0 kg/cm 2 , and the pot rotation speed is 20 rpm, and the core is coated with a separator.
- Enteric layer operation Add triethyl citrate and talc to water, homogenize for 5 ⁇ 10 minutes with high shear homogenizer, add to the aqueous dispersion of acrylic resin, stir slowly for 30 minutes. An 80 mesh sieve was used to prepare an enteric layer solution having a solid content of about 20% by weight. The core of the barrier layer is placed in a coating pan for coating with an enteric layer.
- duloxetine hydrochloride, maltitol, hydroxypropylcellulose, arginine and PEG6000 were uniformly mixed, prepared into granules according to Example 2, and added with micro-silica gel and magnesium stearate, uniformly mixed, and tableted to obtain a tablet core. .
- the isolation layer operates the same as in Example 2.
- Hypromellose 5. lmg
- duloxetine hydrochloride, sucrose, pregelatinized starch, sodium hydrogencarbonate and PEG6000 were uniformly mixed, prepared into granules according to Example 2, and added with micro-silica gel, magnesium stearate and crospovidone, uniformly mixed, and compressed. , that is, the core.
- the isolation layer operates the same as in Example 2.
- HPMCP-55S to a mixture of ethanol and methylene chloride, and stir while mixing until the mixture is even; add talc to water, stir well, slowly add to the above ethanol and dichloromethane In the mixture solution of hydrazine, stirring was continued to completely dissolve, and a suspension of 5 wt% of HPMCP-55S was sieved through 60 mesh. The core is coated with an enteric layer.
- the granulation operation, the barrier layer and the enteric layer operation were the same as in Example 2.
- Duloxetine hydrochloride, mannitol, pregelatinized starch, PEG4000, PEG 8000 and 70% amount of crospovidone were uniformly mixed, prepared into granules according to Example 2, and the remaining amount of crospovidone and the remaining amount were added.
- Isolation layer operation Disperse Opadry 03K19229 (OPADRY CLEAR 03K19229) evenly into water of about 80 °C, shear at high speed for 10 minutes, continue stirring for 45 minutes, and prepare a solution with a solid content of 10wt% to isolate the core. Layer coating.
- the enteric layer was operated as in Example 1.
- Acrylic resin aqueous dispersion 35.8mg
- Titanium dioxide 1.6mg Preparation process:
- duloxetine hydrochloride, mannitol, sodium carboxymethyl starch, poloxamer and PEG 8000 were uniformly mixed, prepared into granules according to Example 2, and added crospovidone, micro-silica gel and magnesium stearate, and uniformly mixed. , tableting, that is, the core.
- the barrier layer and the enteric layer were operated in the same manner as in Example 2.
- the modification layer The operation of the modification layer: the hypromellose was dispersed with 70 ° C hot water, stirred with water, and the homogenized talc powder and titanium dioxide were added to prepare a separator solution having a solid content of about 15% by weight.
- the core is placed in a coating pan for a modified layer coating.
- Titanium dioxide 1.6mg
- Acrylic resin aqueous dispersion 35.8mg
- Duloxetine hydrochloride, maltitol, hydroxypropyl beta-cyclodextrin, polyoxyl (40) ester magnesium carbonate stearate and PEG 8000 were uniformly mixed, prepared into granules according to Example 2, and crospovidone was added. And magnesium stearate, evenly mixed, tablet, that is, the core.
- the barrier layer and the enteric layer were operated in the same manner as in Example 2.
- Example 7 The modification layer operation is referred to in Example 7.
- Example 9 Enteric-coated tablets (fluidized granulation)
- Granulation operation Mix duloxetine hydrochloride, sucrose, microcrystalline cellulose, sodium carbonate, PEG6000 and 70% crospovidone uniformly, open the fluidized bed granulator, set the fan wind rate to 12 ⁇ 15Hz, to the material temperature of 60 ⁇ 65 ° C discharge, cooling, using a 24 mesh sieve to complete the grain. Add the remaining amount of crospovidone and magnesium stearate, mix well, and compress to obtain the core.
- the barrier operation and the enteric layer operation were the same as in Example 1.
- Duloxetine hydrochloride, sucrose, microcrystalline cellulose, 70% amount of crospovidone and PEG6000 were uniformly mixed, prepared into granules according to Example 2, and the remaining amount of crospovidone, microsilica gel and hard were added. Magnesium oleate, evenly mixed, tableted, that is, the core is obtained.
- the separator was the same as in Example 6; the enteric layer was operated in the same manner as in Example 2.
- Example 12 Enteric coated tablets
- the granulation operation, the barrier layer and the enteric layer operation were the same as in Example 2.
- Titanium dioxide 0.9mg
- the croscarmellose sodium and talc powder were added, mixed uniformly, and pressed into 25 mg of microchips to obtain a tablet core.
- Example 3 The separator was referred to Example 3; the enteric layer was operated as in Example 2.
- microcapsules containing the enteric layer are placed in a hard capsule, which is obtained.
- Example 16 Enteric granules (extrusion granulation)
- Granulation operation Mix duloxetine hydrochloride, microcrystalline cellulose, PEG6000, poloxamer, crospovidone, sodium decyl sulfate and talc, and heat the jacket to 75 ⁇ 85°.
- the wet material is extruded through a sieve plate of 1 mm aperture by screwing, extruded into a cylindrical strip extrudate, cut off immediately, cooled to form granules, and sieved to a fine powder with a 30 mesh sieve. grain.
- the barrier layer was prepared as in Example 1 and the barrier layer was coated in a bottom jet fluidization coater.
- Enteric layer operation The enteric layer solution was prepared as in Example 3, and an enteric layer was coated in a bottom jet fluidized coating machine.
- the granulation operation, the barrier layer and the enteric layer operation were the same as in Example 2.
- Hypromellose 4.18mg talc 2.5mg mannitol 3mg enteric layer
- the enteric layer was operated as in Example 3.
- Acrylic resin aqueous dispersion 17mg Triethyl citrate 0.6mg
- the selected ones of the present invention are water-soluble hot melt materials, the dissolution and release of the main drug can be accelerated. Improve the bioavailability of the drug.
- the hot-melt granulation process selected for the present invention has a better release rate of the duloxetine hydrochloride enteric-coated tablet prepared by the conventional wet granulation process, the inventors separately press the two lists of the prescription materials in the following table.
- the duloxetine hydrochloride enteric-coated tablets were prepared by a hot melt granulation process and a conventional wet granulation process, and the release of the two samples was compared.
- Hot-melt pellet core Mix duloxetine hydrochloride, sucrose, lactose, povidone K30 and PEG6000 into a rapid mixer with a temperature of 80-85 ° C, and open the granulator agitator. After the temperature of the material reached 60 ° C, stirring was continued for 6 minutes, discharging, cooling, and granulating with a 24-mesh sieve. Add magnesium stearate, mix well, and compress to obtain the core.
- Example 2 The operation of the separator and the enteric layer of the above core was carried out separately as in Example 2. Two drops of duloxetine enteric-coated tablets were placed in high-density polyethylene plastic bottles, sealed, placed in an accelerated test chamber, and compared at a temperature of 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%. Stability study (release data).
- the release rate of two batches of samples was determined by using 900 ml of phosphate buffer (pH 6.8) as the release medium and the rotation speed was 100 rpm.
- the results are as follows:
- the invention adopts a hot melt process to prepare a core material of an enteric preparation of duloxetine or a salt thereof, the introduction of moisture or an organic solvent in the preparation process is avoided, solvent residue is reduced, and degradation of duloxetine is also reduced, and the degradation is improved.
- the present inventors compared the stability of the enteric coated tablet prepared in Example 5 of the present invention with the enteric coated tablet prepared in the conventional wet granulation process in Test Example 1. Two drops of duloxetine enteric-coated tablets were placed in high-density polyethylene plastic bottles, sealed, placed in an accelerated test chamber, and placed at a temperature of 40 ° C ⁇ 2 ° C and a relative humidity of 75% ⁇ 5%. For six months, compare stability (total impurities).
- the phosphate buffer (pH 5.8) - acetonitrile (63: 37) was used as the mobile phase, and the detection wavelength was 230 nm. Precisely take the above two sample solutions into the liquid chromatograph and record the chromatogram to twice the retention time of the main component peak.
- the total impurity data are as follows.
- the HPLC measurement spectra are shown in Figure 1 and Figure 2, respectively.
- sugars and sugar alcohols facilitate the release of the main drug from the core material, especially sucrose, mannitol, xylitol and maltitol.
- Lactose is the main filler, which affects the stability of the preparation, so lactose is not a preferred filler.
- a tablet core was prepared in accordance with Example 5 of the present invention, and a tablet core was prepared in addition to the sucrose in Example 5 of the present invention, and the separator and the enteric layer coating were carried out in the same manner as in Example 5 of the present invention.
- duloxetine enteric-coated tablets Two drops of duloxetine enteric-coated tablets were placed in high-density polyethylene plastic bottles, sealed, placed in an accelerated test chamber, and placed at a temperature of 40 °C ⁇ 2 °C and a relative humidity of 75% ⁇ 5%. After six months, the stability, ie the degree of release and the total amount of impurities, were examined.
- the total amount of impurities was determined by the same method, and the data is as follows:
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Description
一种度洛西汀肠溶制剂及其芯材和制备方法
技术领域
本发明属于药物制剂领域,特别涉及一种度洛西汀肠溶制剂及其芯材和 制备方法。
背景技术
度洛西汀是一种选择性的 5-羟色胺与去甲肾上腺素再摄取抑制剂 ( SNRIs) , 是一种安全有效的抗抑郁药物, 化学名为 (S)-(+)-N-甲基 -3- ( 1- 萘氧基) -3- (2-噻吩基) -丙胺, 通常以盐酸盐的形式被使用。 因度洛西汀 在酸性环境中不稳定和容易发生降解,故适宜将度洛西汀或其盐制成肠溶制 剂以抵御胃液对药物的破坏。
US5508276涉及一种度洛西汀的肠溶微丸,其中包括 a)由度洛西汀和可 药用赋型剂组成的药芯; b ) 可有可无的隔离层; c )含有醋酸羟丙甲纤维素 琥珀酸酯 (HPMCAS ) 和可药用的赋形剂的肠溶衣层; d) 可有可无的修饰 层。 在隔离层中蔗糖减轻肠溶衣材料与度洛西汀的迁移和相互作用, 以改善 耐酸性和稳定性。
Z1200410067160.4涉及一种度洛西汀肠溶包衣片剂及其制备方法, 将盐 酸度洛西汀、 水溶性固体分散载体和稀释剂溶解于乙醇水溶液, 采用本领域 公知的方法, 过筛制粒、 烘干、 整粒, 加入润滑剂后压片; 并在片芯外包裹 隔离层和在隔离层外包裹肠溶层。 该方法采用固体分散技术, 增加主药溶解 度, 提高最终释放量, 从而提高度洛西汀生物利用度。
度洛西汀较易发生降解等反应, 在反应中水分起到了加速或催化作用。 已公开的盐酸度洛西汀肠溶制剂,在盐酸度洛西汀芯材的制备过程中都先配 制成盐酸度洛西汀溶液或混悬液, 或者加入润湿剂或粘合剂, 都接触了水和 一些如乙醇等的有机溶剂, 从而影响盐酸度洛西汀的稳定性; 而且在去除水
和有机溶剂时不但费时费工增加成本, 还会增加不稳定的因素, 如果使用有 机溶剂还会污染环境。
发明内容
因此, 本发明要解决的技术问题就是针对现有的度洛西汀肠溶制剂芯材 在制备过程中接触了水或有机溶剂, 增加药物活性成分度洛西汀不稳定因素 以及溶剂残留的不足,提供一种新的度洛西汀芯材、肠溶制剂及其制备方法, 该度洛西汀芯材在制备过程中不接触任何水和有机溶剂, 药物活性成分度洛 西汀降解小, 稳定性高, 药物活性成分含量高, 溶出度好。
本发明人尝试不添加水等溶剂制备盐酸度洛西汀芯材,但是由于盐酸度 洛西汀比重小、 流动性能差, 不能与其他辅料混合均匀而难以实施粉末直接 压制芯材的方法; 由于盐酸度洛西汀在干燥状态下松散、粘性差、不易混合, 采用干挤制粒方法成型差和收率低。热熔法可以不使用水或有机溶剂进行药 物和辅料的混合, 并且热熔法不但使药物和辅料的混合效果好, 又在同时完 成了芯材成型。因此,本发明人采用热熔法制备度洛西汀芯材及其肠溶制剂, 经效果试验, 所得的度洛西汀肠溶制剂完全达到了本发明的目的, 从而完成 了本发明。
因此,本发明解决上述技术问题所采用的技术方案之一是:一种度洛西 汀肠溶制剂的芯材, 由药物活性成分度洛西汀或其盐和药学上可接受的辅料 组成, 其中, 药学上可接受的辅料中含有水溶性热熔材料, 并且水溶性热熔 材料的含量为 10%〜40%,药物活性成分度洛西汀或其盐的含量为 15〜60%, 其余为其他的药学上可接受的辅料,所述的百分比为其占芯材总量的质量百 分比。
根据本发明,其中,所述的水溶性热熔材料是在 18〜26°C的环境中为固 体, 加热可软化或熔融的药学上可接受的水溶性的材料。 所述的水溶性热熔 材料的软化或熔融温度较佳的为 40〜65°C。本发明的水溶性热熔材料一方面 具有特殊的软化或熔融温度, 在熔融后产生了黏合力, 常温下又为固体, 从 而满足了熔融制粒的需要。 另一方面其水溶性则可以实现主药从片芯中释
放。 所述的水溶性热熔材料较佳的选自聚乙二醇 (PEG)、 泊洛沙姆和硬脂 酸聚烃氧(40 )酯中的一种或多种。 所述的聚乙二醇较佳的为选自聚乙二醇 4000〜10000中的任何一种或几种。 所述的水溶性热熔材料的含量较佳的为 5%〜40%, 更佳的为 10%〜25%, 所述的百分比为水溶性热熔材料占芯材总 量的质量百分比。
根据本发明, 所述的度洛西汀盐较佳的为盐酸度洛西汀。所述的度洛西 汀或其盐的含量较佳的为 15〜60%,所述的百分比为度洛西汀或其盐占芯材 总量的质量百分比。所述的度洛西汀或其盐的平均粒径较佳的小于 100微米。
根据本发明, 所述的其他的药学上可接受的辅料较佳的为选自填充剂、 崩解剂、 润滑剂和表面活性剂中的任何一种或几种。所述的填充剂较佳的选 自蔗糖、 甘露醇、 木糖醇、 葡萄糖、 麦芽糖醇、 山梨醇、 羟丙基倍他环糊精、 淀粉、 微晶纤维素、 预胶化淀粉、 氧化镁、 精氨酸、 碳酸镁、 碳酸钠、 碳酸 氢钠和磷酸氢钙二水合物中的任何一种或几种, 更佳的选自蔗糖、 甘露醇、 木糖醇、麦芽糖醇、羟丙基倍他环糊精、微晶纤维素、预胶化淀粉、氧化镁、 精氨酸、 碳酸钠、 碳酸氢钠和碳酸镁中的任何一种或几种。 通过本发明研究 表明一些糖和糖醇不但有利于主药从芯材中释放, 而且有利于主药稳定, 尤 其是蔗糖、 甘露醇、 木糖醇和麦芽糖醇。 而以乳糖为主要填充剂会影响制剂 的稳定性, 所以乳糖不是优选的填充剂。 所述的填充剂的含量可以为占芯材 质量的 0%〜65%, 较佳的为 10%〜65%, 更佳的 20%〜50%。
根据本发明, 所述的崩解剂较佳的选自羧甲淀粉钠、 羟丙纤维素、 交联 聚维酮和交联羧甲纤维素钠。 更佳的选自羧甲淀粉钠、 交联聚维酮和交联羧 甲纤维素钠。 所述的崩解剂的含量可以为占芯材质量的 0%〜18%, 较佳的 为 1 %〜 18%, 更佳的 2%〜 10%。
根据本发明, 所述的润滑剂可选自药物制剂中的常规材料, 较佳的为选 自硬脂酸镁、 微粉硅胶、 硬脂酸富马酸钠和滑石粉中的任何一种或几种。 所 述的润滑剂的含量可以为占芯材质量的 0%〜3%, 较佳的为 0.1%〜3%, 更 佳的 0.5%〜1.5%。 所述的表面活性剂可选自药物制剂中常规材料, 较佳的 选自吐温 -80、 聚氧乙烯蓖麻油和十二垸基硫酸钠等。 所述的表面活性剂的
含量可以为占芯材质量的 0%〜3%, 较佳的为占芯材质量的 0.1〜1.5%。 本发明解决上述技术问题所采用的技术方案之二是: 一种如上所述的度 洛西汀肠溶制剂的芯材的制备方法, 包括以下歩骤: 将度洛西汀或其盐、 水 溶性热熔材料和药学上可接受的辅料混合, 之后加热至水溶性热熔材料软化 或熔融, 在水溶性热熔材料软化或熔融状态下制粒, 然后冷却, 即得。
根据本发明, 所述的制粒较佳的为热熔搅拌制粒、 热熔流化制粒或热熔 挤压制粒。 其中, 所述的热熔搅拌制粒是将物料置夹套加热的制粒容器中, 开启三向搅拌叶以一定的速度转动,通过制粒容器加热夹套将物料加热至所 需温度, 热熔材料熔融后产生黏合作用, 使物料形成软材, 在容器中翻动沿 壁旋转, 高速旋转的刮刀打碎块状物, 通过粉粒与容器壁的摩擦, 以及粉粒 间的聚集摩擦, 最后形成颗粒。所述的热熔流化制粒是在流化床制粒机中操 作, 热空气将物料加热至所需温度, 在物料的流化过程中, 热熔材料熔融后 产生的黏合力使粉末聚结在其周围形成粒子核, 粒子核与粒子核之间、 粒子 核与粒子之间相互继续结合, 形成较大的颗粒。所述的热熔挤压制粒是将物 料混合, 置夹套加热保温的挤压机内, 热熔材料熔融后使物料形成湿料, 经 螺旋推进将湿料挤压通过具一定孔径的筛板, 挤压成圆柱形条状挤出物, 立 即切断后制成颗粒。
根据本发明, 所述的热熔搅拌制粒中, 热熔材料的用量、 制粒时的搅拌 时间、 夹套温度以及物料温度对颗粒的性状成型和颗粒的质量有较大影响。 可以根据调节热熔材料组分和用量, 来控制制粒时的搅拌时间, 较佳的搅拌 时间控制在达到热熔材料熔融温度后的 10分钟以内。 夹套温度一般为 60〜 90 °C , 可根据热熔材料组分的不同, 将夹套温度控制在超出热熔材料熔融温 度 15〜25°C。 这些都有利于制备出可压性好和流动性好的颗粒。
本发明解决上述技术问题所采用的技术方案之三是: 一种度洛西汀肠溶 制剂, 包括芯材、 隔离层和肠溶层, 其中, 所述的芯材为如上所述的芯材。
根据本发明, 所述的度洛西汀肠溶制剂较佳的为肠溶片剂、 肠溶颗粒剂 或肠溶微片装胶囊剂。 其中, 所述的肠溶片剂或肠溶颗粒剂在上述本发明的 芯材外依次包被有隔离层和肠溶层。所述肠溶微片装胶囊剂为在常规的硬胶
囊中装有上述本发明的芯材包被了隔离层和肠溶层所制备的肠溶微片。
同本领域常规的肠溶制剂一样,所述的隔离层可以包括本领域常规的各 种隔离层材料, 较佳的选自羟丙甲纤维素、 羟丙纤维素和甲基纤维素中的一 种或几种; 在隔离层中还可进一歩包括糖和糖醇, 可增加度洛西汀或其盐肠 溶制剂的稳定性; 隔离层中还可以进一歩包括选自填充型赋形剂、 遮光剂、 增塑剂和抗粘剂等其他药用辅料。 同本领域常规的肠溶制剂一样, 所述的肠 溶层可包含药物制剂领域常用的肠溶材料。 肠溶材料较佳的选自丙烯酸树 脂、 邻苯二甲酸聚乙烯醇酯、 羟丙基甲基纤维素醋酸琥珀酸酯 (HPMCAS ) 和羟丙基甲基纤维素邻苯二甲酸酯 (HPMCP) 中的一种或几种。 所述的肠 溶层较佳的还可进一歩包含增塑剂。 该增塑剂较佳的选自柠檬酸三乙酯、 苯 二甲酸二乙酯、 甲基硅油、 蓖麻油和聚乙二醇中的一种或几种。 肠溶层中还 可进一歩包含抗粘剂、 润滑剂、 表面活性剂等其他药用辅料。 所述的肠溶层 外还可以包括修饰层, 但并不是必需的。 在一些处方中, 选择适当的修饰层 可以增加肠溶制剂在贮存期内的抗湿能力, 外观更完整光洁。 较佳的, 所述 的修饰层可包括选自羟丙甲纤维素等成膜材料、 滑石粉、 二氧化硅、 二氧化 钛、 聚乙二醇或者蜡等疏水性材料中的一种或几种。
本发明解决上述技术问题所采用的技术方案之四是: 一种如上所述的度 洛西汀肠溶制剂的制备方法, 包括以下歩骤:
1 ) 采用本领域常规的制备工艺, 对如上所述的芯材包被隔离层;
2) 采用本领域常规的制备工艺包被肠溶层。
根据本发明, 所述的度洛西汀肠溶制剂的制备方法, 还包括歩骤: 3)包 被修饰层。
本发明所用的原料或试剂除特别说明之外, 均市售可得。
相比于现有技术, 本发明的有益效果如下: 本发明采用热熔工艺制备度 洛西汀或其盐的肠溶制剂的芯材, 避免了制备过程中水分或有机溶剂的引 入, 减少了溶剂残留, 也减少度洛西汀的降解, 提高了制剂在制备和贮存过 程中的稳定性; 不需加入黏合剂、 颗粒不需进行干燥, 大大简化操作歩骤, 另外损耗也少, 从而降低制备成本; 本发明的热熔材料, 如聚乙二醇、 泊洛
沙姆和硬脂酸聚烃氧(40) 脂是水溶性的, 实现了主药从片芯中的释放, 溶 出度好, 提高了药物的生物利用度; 本发明的度洛西汀或其盐的肠溶制剂药 物活性成分含量高。
附图说明
以下结合附图说明本发明的特征和有益效果。
图 1是按常规湿法制粒制备的盐酸度洛西汀片芯在高密度聚乙烯瓶中密 封, 于温度 40°C ±2°C,相对湿度 75%± 5%条件下放置六个月的有关物质测 定图谱。
图 2是本发明实施例 5制备盐酸度洛西汀片芯在高密度聚乙烯瓶中密 封, 于温度 40°C ±2°C,相对湿度 75%± 5%条件下放置六个月的有关物质测 定图谱。
具体实施方式
下面用实施例来进一歩说明本发明, 但本发明并不受其限制。 下列实施 例中未注明具体条件的实验方法, 通常按照常规条件, 或按照制造厂商所建 议的条件。其中, 聚乙二醇 4000〜10000的软化温度为 48〜63 °C、泊洛沙姆 的熔融温度为 49〜57°C, 硬脂酸聚烃氧 (40) 酯的熔融温度为 46〜51 °C。
实施例 1 肠溶片 (折算到 1.2公斤)
所用材料清单:
滑石粉 15.6g
蔗糖 40.0g
二氧化钛 6.3g
肠溶层
雅克宜 MP 74.9g
甲基硅油 0.37g 制备工艺:
将盐酸度洛西汀、蔗糖、微晶纤维素、 70%量的交联聚维酮的和 PEG6000 混合均匀, 置夹套温度 80〜85°C的快速搅拌机内, 开启制粒机搅拌器, 当物 料温度达到 60°C后继续搅拌 6分钟, 出料, 冷却, 用 24目筛整粒。 加入剩 余量的交联聚维酮和硬脂酸镁, 混合均匀, 压片, 即得片芯。
本实施例制备成盐酸度洛西汀肠溶片, 其包衣制备过程为: 将羟丙甲纤 维素用 70°C热水分散后加水搅拌溶解,加入匀化好的滑石粉和二氧化钛,制 成固含量约 15wt%的隔离层溶液。将片芯置包衣锅中, 调节进风温度使片床 温度为 30〜40°C、 雾化压力为 4.0kg/ cm2, 锅体转速为 12rpm, 对片芯进行 隔离层包衣。
将雅克宜 MP配制为 20wt%固含量的水分散体, 加入对雅克宜 MP量 为 0.5wt%的甲基硅油,搅拌 20分钟。调节进风温度使片床温度为 28〜32°C、 雾化压力为 2.0kg/ cm2, 锅体转速为 12 rpm, 对片芯进行肠溶层包衣。
实施例 2 肠溶片
所用材料清单:
隔离层
羟丙甲纤维素 8.1mg
滑石粉 8mg
蔗糖 4.1mg
二氧化钛 1.6mg
肠溶层
丙烯酸树脂水分散体 35.8mg
(L30D-55 )
柠檬酸三乙酯 1.2mg
滑石粉 1.2mg 制备工艺:
将盐酸度洛西汀、 蔗糖、 70%量的交联聚维酮的和 PEG6000混合均匀, 置夹套温度 80〜85°C的快速搅拌机内,开启制粒机搅拌器, 当物料温度达到 60°C后继续搅拌 8分钟, 出料, 冷却, 用 24目筛整粒。 加入剩余量的交联 聚维酮和硬脂酸镁, 混合均匀, 压片, 即得片芯。
本实施例制备成盐酸度洛西汀肠溶片, 其包衣制备过程为: 将羟丙甲纤 维素用 70°C热水分散后加水搅拌溶解,加入匀化好的滑石粉和二氧化钛,制 成固含量约 15wt%的隔离层溶液。将片芯置包衣锅中, 调节进风温度使片床 温度为 35〜40°C、 雾化压力为 2.0kg/ cm2, 锅体转速为 20rpm, 对片芯进行 隔离层包衣。
肠溶层操作: 将柠檬酸三乙酯和滑石粉加入到水中, 用高剪切匀浆机充 分匀化 5〜10分钟后, 加入到丙烯酸树脂水分散体中, 慢速搅拌 30分钟, 过 80目筛, 制成固含量约 20wt%的肠溶层溶液。 将包好隔离层的片芯置包 衣锅中进行肠溶层包衣。
实施例 3 肠溶片
所用材料清单:
片心
盐酸度洛西汀 33.6mg
麦芽糖醇 99.6mg
PEG6000 34.3mg
羟丙纤维素 17.7mg
精氨酸 10 mg
交联聚维酮 3.6mg
微粉硅胶 0.3mg
硬脂酸镁 lmg
隔离层
羟丙甲纤维素 5.1mg
滑石粉 lOmg
二氧化钛 lmg
肠溶层
HPMCAS-LF 13.7mg
柠檬酸三乙酯 3.83mg
滑石粉 4. lmg
十二垸基硫酸钠 0.4mg
制备工艺:
将盐酸度洛西汀、 麦芽糖醇、 羟丙纤维素、 精氨酸和 PEG6000混合均 匀, 按实施例 2制备成颗粒, 加入微粉硅胶和硬脂酸镁, 混合均匀, 压片, 即得片芯。
隔离层操作同实施例 2。
肠溶层操作:
首先将柠檬酸三乙酯溶解于水, 溶液冷却至 10°C, 小心缓慢加入 HPMCAS-LF,十二垸基硫酸钠和滑石粉,制备成 75%(W/V) 的 HPMCAS-LF 的悬浮液。 将片芯置包衣锅中进行肠溶层包衣。
实施例 4 肠溶片
所用材料清单:
片心
盐酸度洛西汀 33.6mg
蔗糖 99.6mg
PEG6000 34.3mg
预胶化淀粉 15.7mg
碳酸氢钠 12 mg
交联聚维酮 3.6mg
微粉硅胶 lmg
硬脂酸镁 lmg
隔离层
羟丙甲纤维素 5. lmg
滑石粉 lOmg
二氧化钛 lmg
肠溶层
HPMCP-55S 14.3mg
滑石粉 4.29 mg
二氯甲垸 107 mg
乙醇 133.6 mg
水 26.9mg 制备工艺:
将盐酸度洛西汀、 蔗糖、 预胶化淀粉、 碳酸氢钠和 PEG6000混合均匀, 按实施例 2制备成颗粒,加入微粉硅胶、硬脂酸镁和交联聚维酮,混合均匀, 压片, 即得片芯。
隔离层操作同实施例 2。
肠溶层操作:
将 HPMCP-55S加入到乙醇和二氯甲垸的混合液中, 边加边搅拌, 至混 合均匀; 将滑石粉加入到水中, 搅拌均匀后, 缓慢加入到上述乙醇和二氯甲
垸的混合液溶液中, 继续搅拌使完全溶解, 5 wt %的 HPMCP-55S的悬浮液, 60目过筛。 对片芯进行肠溶层包衣。
实施例 5 肠溶片
所用材料清单:
制备工艺:
制粒操作、 隔离层和肠溶层操作同实施例 2。
实施例 6 肠溶片
所用材料清单:
硬脂酸镁 1.5mg
隔离层
欧巴代 03K19229 8mg
肠溶层
雅克宜 MP 12mg
甲基硅油 0.06 mg 制备工艺:
将盐酸度洛西汀、 甘露醇、 预胶化淀粉、 PEG4000、 PEG8000和 70%量 的交联聚维酮, 混合均匀, 按实施例 2制备成颗粒, 加入剩余量的交联聚维 酮和硬脂酸镁, 混合均匀, 压片, 即得片芯。
隔离层操作: 将欧巴代 03K19229 (OPADRY CLEAR 03K19229 ) 均匀 分散至约 80°C的水中, 高速剪切 10分钟, 继续搅拌 45分钟, 配成固含量为 10wt%的溶液, 对片芯进行隔离层包衣。
肠溶层操作同实施例 1。
实施例 7 肠溶片
所用材料清单:
(L30D-55 )
柠檬酸三乙酯 1.2mg
滑石粉 1.2mg 羟丙甲纤维素 4.6mg
滑石粉 1.5mg
二氧化钛 1.6mg 制备工艺:
将盐酸度洛西汀、 甘露醇、 羧擧甲淀粉钠、 泊洛沙姆和 PEG8000混合均 匀, 按实施例 2制备成颗粒, 加入交联聚维酮、 微粉硅胶和硬脂酸镁, 混合 均匀, 压片, 即得片芯。
隔离层和肠溶层操作同实施例 2。
修饰层操作:将羟丙甲纤维素用 70°C热水分散后加水搅拌溶解,加入匀 化好的滑石粉和二氧化钛, 制成固含量约 15wt%的隔离层溶液。将片芯置包 衣锅中进行修饰层包衣。
实施例 8 肠溶片
所用材料清单:
肠溶层
丙烯酸树脂水分散体 35.8mg
(L30D-55 )
柠檬酸三乙酯 1.2mg
滑石粉 1.2mg 羟丙甲纤维素 4.6mg
滑石粉 1.5mg 制备工艺: 擧
将盐酸度洛西汀、 麦芽糖醇、羟丙基倍他环糊精、硬脂酸聚烃氧 (40)酯 碳酸镁和 PEG8000混合均匀, 按实施例 2制备成颗粒, 加入交联聚维酮和 硬脂酸镁, 混合均匀, 压片, 即得片芯。
隔离层和肠溶层操作同实施例 2。
修饰层操作参照实施例 7。
实施例 9 肠溶片 (流化制粒)
所用材料清单:
制粒操作: 将盐酸度洛西汀、 蔗糖、 微晶纤维素、 碳酸钠、 PEG6000和 70%量的交联聚维酮混合均匀, 开启流化床制粒机, 设定风机风率为 12〜 15Hz, 至物料温度为 60〜65°C出料, 冷却, 用 24目筛整粒。 加入剩余量的 交联聚维酮和硬脂酸镁, 混合均匀, 压片, 即得片芯。
隔离层操作和肠溶层操作同实施例 1。
实施例 10 肠溶片
所用材料清单:
制备工艺:
将盐酸度洛西汀、 蔗糖、 微晶纤维素、 70%量的交联聚维酮和 PEG6000 混合均匀, 按实施例 2制备成颗粒, 加入剩余量的交联聚维酮、 微粉硅胶和 硬脂酸镁, 混合均匀, 压片, 即得片芯。
隔离层同实施例 6; 肠溶层操作同实施例 2。
实施例 11 肠溶片
所用材料清单:
片心 盐酸度洛西汀 33.6mg 蔗糖 35.2mg
PEG6000 8.0mg 交联聚维酮 6.1mg 微粉硅胶 0.2mg 硬脂酸镁 0.8mg 隔离层
羟丙甲纤维素 3.6mg 滑石粉 3.2mg 二氧化钛 0.72mg 肠溶层
丙烯酸树脂水分散体 21.3mg (L30D-55 )
柠檬酸三乙酯 0.7mg 滑石粉 0.7mg 制备工艺:
制粒操作、 隔离层和肠溶层操作同实施例 2。 实施例 12 肠溶片
所用材料清单:
(L30D-55 )
柠檬酸三乙酯 1.2mg 滑石粉 1.3mg 制备工艺:
制粒操作和
实施例 13 肠溶
所用材料清单:
制备工艺:
制粒操作、 隔离层和肠溶层操作同实施例 2。
实施例 14 肠溶微片装胶囊剂
所用材料清单:
片心
盐酸度洛西汀 33.6mg 微晶纤维素 40.2mg
PEG4000 20. lmg
PEG8000 19.4mg
木糖醇 13.7mg
交联羧甲纤维素钠 2.9mg
硬脂酸镁 0.5mg
滑石粉 2.1mg
隔离层
羟丙甲纤维素 4.2mg
滑石粉 8.4mg
二氧化钛 0.9mg
肠溶层
丙烯酸树脂水分散体 42.5mg
(L30D-55 )
柠檬酸三乙酯 1.3mg
滑石粉 1.3mg 制备工艺:
将盐酸度洛西汀、 微晶纤维素、 PEG4000、 PEG8000、 和木糖醇混合均 匀, 置夹套温度 80〜85°C的快速搅拌机内, 开启制粒机搅拌器, 当物料温度 达到 60°C后继续搅拌 6分钟, 出料, 冷却, 用 24目筛整粒。 加入交联羧甲 纤维素钠和滑石粉, 混合均匀, 压成 25mg的微片, 即得片芯。
隔离层参照实施例 3 ; 肠溶层操作同实施例 2。
将包好肠溶层的微片装入硬胶囊中, 即得。
实施例 15 肠溶片
所用材料清单:
隔离层
羟丙甲纤维素 3.4mg
滑石粉 7.3mg 二氧化钛 0.7mg
肠溶层
丙烯酸树脂水分散体 35.0mg
(L30D-55 )
柠檬酸三乙酯 l .lmg
滑石粉 1.2mg 制备工艺:
制粒操作和隔离层参照实施例 1 ; 肠溶层操作同实施例 2。 实施例 16 肠溶颗粒 (挤压制粒)
所用材料清单:
制粒操作: 将盐酸度洛西汀、 微晶纤维素、 PEG6000、 泊洛沙姆、 交联 聚维酮、十二垸基硫酸钠和滑石粉混合均匀,置夹套加热保温 75〜85°C的挤 压机内, 经螺旋推进将湿料挤压通过 lmm孔径的筛板, 挤压成圆柱形条状 挤出物, 立即切断, 冷却后制成颗粒, 并用 30目筛筛去细粉粒。
隔离层操作: 隔离层液按实施例 1配制, 在底喷流化包衣机中包制隔离 层。
肠溶层操作: 肠溶层液按实施例 3配制, 在底喷流化包衣机中包制肠溶 层。
实施例 17 肠溶片
所用材料清单:
制备工艺:
制粒操作、 隔离层和肠溶层操作同实施例 2。
实施例 18 肠溶片
所用材料清单:
片心 盐酸度洛西汀 56mg
PEG6000 22.4mg 蔗糖 30mg 交联聚维酮 2.24mg 硬脂酸镁 l .lmg 隔离层
羟丙甲纤维素 4.18mg 滑石粉 2.5mg 甘露醇 3mg 肠溶层
HPMCAS-LF 9.5mg 柠檬酸三乙酯 2.6mg 滑石粉 2.8mg 十二垸基硫酸钠 0.25 mg 制备工艺:
制粒操作和隔离层操作同实施例 2。
肠溶层操作同实施例 3。
实施例 19肠溶片
所用材料清单:
滑石粉 0.6mg 制备工艺:
制粒操作、 隔离和肠溶层操作同实施例 2。
实施例 20肠溶片
所用材料清单:
制备工艺:
制粒操作、 隔离和肠溶层操作同实施例 2。
下面通过试验实施例来进一歩说明本发明的有益效果。
试验实施例 1:
由于本发明所选用的均为水溶性热熔材料, 能加快主药的溶出和释放,
提高药物的生物利用度。为验证本发明所选用的热熔制粒工艺比常规湿法制 粒工艺制备的盐酸度洛西汀肠溶片的释放度好,本发明人照下表中两份处方 材料基本一致的清单分别按热熔制粒工艺和常规湿法制粒工艺制备盐酸度 洛西汀肠溶片, 比较两份样品的释放度。
片芯对比处方材料清单:
隔离层以及肠溶层材料清单:
热熔制粒片芯的制备: 将盐酸度洛西汀、 蔗糖、 乳糖、 聚维酮 K30 和 PEG6000混合, 置夹套温度 80〜85°C的快速搅拌机内, 开启制粒机搅拌器, 当物料温度达到 60°C后继续搅拌 6分钟, 出料, 冷却, 用 24目筛整粒。 加 入硬脂酸镁, 混合均匀, 压片, 即得片芯。
常规湿法制粒片芯的制备: 将聚维酮 K30溶解于 60%(wt:>乙醇液中, 加 入盐酸度洛西汀, 使其溶解后加入蔗糖和乳糖, 在槽形混合机中搅拌制成软
材。 用摇摆颗粒机 (装 20 目尼龙网) 制成湿粒。 湿粒在在热风循环烘箱中 50〜60°C干燥后冷却, 用 20 目筛整粒, 加入硬脂酸镁混合均匀。 压片, 即 得片芯。
上述片芯的隔离层和肠溶层操作按实施例 2分别进行。将两份盐酸度洛 西汀肠溶片分别置高密度聚乙烯塑料瓶中, 密封, 放入加速考察箱中, 于温 度 40°C ±2°C, 相对湿度 75%± 5%条件进行对比稳定性考察(释放度数据)。
根据中国药典 2005年二部附录的肠溶制剂释放度测定方法,以磷酸盐缓 冲液(pH6.8 ) 900ml为释放介质, 转速为每分钟 100转, 测定两批样品的释 放度, 结果如下:
试验实施例 2
由于本发明采用热熔工艺制备度洛西汀或其盐的肠溶制剂的芯材,避免 了制备过程中水分或有机溶剂的引入, 减少了溶剂残留, 也减少度洛西汀的 降解, 提高了其制剂在制备和贮存过程中的稳定性。 本发明人将本发明实施 例 5制备的肠溶片与试验实施例 1中用常规湿法制粒工艺制备的肠溶片进行 稳定性比较。 将两份盐酸度洛西汀肠溶片分别置高密度聚乙烯塑料瓶中, 密 封, 放入加速考察箱中, 于温度 40°C ±2°C, 相对湿度 75%± 5%条件下放置 六个月, 对比考察稳定性 (杂质总量)。
测定方法: 以磷酸盐缓冲液 (pH值 5.8 ) —乙腈 (63 : 37 ) 为流动相, 检测波长为 230nm。精密量取上述两份样品溶液注入液相色谱仪, 记录色谱 图至主成分峰保留时间的 2倍, 杂质总量数据如下, HPLC测定图谱分别见 图 1和图 2。
试验实施例 3
本发明人认为糖和糖醇有利于主药从芯材中释放,尤其是蔗糖、甘露醇、 木糖醇和麦芽糖醇。 而以乳糖为主要填充剂会影响制剂的稳定性, 所以乳糖 不是优选的填充剂。
按照本发明实施例 5制备片芯, 另外制备除将本发明实施例 5中蔗糖更 换为乳糖同法制备片芯,并按本发明实施例 5同法进行隔离层和肠溶层包衣。
将两份盐酸度洛西汀肠溶片分别置高密度聚乙烯塑料瓶中, 密封, 放入 加速考察箱中,于温度 40 °C ±2°C,相对湿度 75%± 5%条件下放置六个月后, 对比考察稳定性, 即释放度和杂质总量。
对比处方:
根据上述试验实施例 2同法测定释放度, 数据如下:
实施例 5制备的盐酸度洛
对比样品的杂质总量 西汀肠溶片的杂质总量
0个月 0.08% 0.11% 加速试验 3个月 0.14% 0.45% 加速试验 6个月 0.30% 1.21%
Claims
1、 一种度洛西汀肠溶制剂的芯材, 由药物活性成分度洛西汀或其盐和 药学上可接受的辅料组成, 其特征在于, 所述的药学上可接受的辅料中含有 水溶性热熔材料, 并且水溶性热熔材料的含量为 10%〜40%, 药物活性成分 度洛西汀或其盐的含量为 15〜60%, 其余为其他的药学上可接受的辅料, 所 述的百分比为其占芯材总量的质量百分比。
2、 根据权利要求 1所述的芯材, 其特征在于, 所述的水溶性热熔材料 的软化或熔融温度为 40〜65°C。
3、 根据权利要求 1所述的芯材, 其特征在于, 所述的水溶性热熔材料 为选自聚乙二醇、 泊洛沙姆和硬脂酸聚烃氧 (40) 酯中的一种或多种。
4、 根据权利要求 3所述的芯材, 其特征在于, 所述的聚乙二醇为选自 聚乙二醇 4000〜10000中的任何一种或几种。
5、 根据权利要求 1所述的芯材, 其特征在于, 所述的度洛西汀盐为盐 酸度洛西汀。
6、 根据权利要求 1所述的芯材, 其特征在于, 所述的其他的药学上可 接受的辅料为选自填充剂、 崩解剂、 润滑剂和表面活性剂中的任何一种或几 种。
7、 根据权利要求 6所述的芯材, 其特征在于, 所述的填充剂选自蔗糖、 甘露醇、木糖醇、麦芽糖醇、羟丙基倍他环糊精、微晶纤维素、预胶化淀粉、 氧化镁、 精氨酸、 碳酸钠、 碳酸氢钠和碳酸镁中的任何一种或几种, 所述的 填充剂的含量为占芯材质量的 10%〜65%。
8、 根据权利要求 6所述的芯材, 其特征在于, 所述的崩解剂选自羧甲 淀粉钠、 羟丙纤维素、 交联聚维酮和交联羧甲纤维素钠, 所述的崩解剂的含 量为占芯材质量的 1%〜18%。
9、 根据权利要求 6所述的芯材, 其特征在于, 所述的润滑剂选自硬脂 酸镁、 微粉硅胶、 硬脂酸富马酸钠和滑石粉中的任何一种或几种, 所述的润
滑剂的含量为占芯材质量的 0.1%〜3%。
10、 根据权利要求 6所述的芯材, 其特征在于, 所述的表面活性剂选自 吐温 -80、 聚氧乙烯蓖麻油和十二垸基硫酸钠, 所述的表面活性剂的含量为 占芯材质量的 0.1%〜1.5%。
11、 一种如权利要求 1〜10任一项所述的度洛西汀肠溶制剂的芯材的制 备方法, 其特征在于, 包括以下歩骤: 将度洛西汀或其盐、 水溶性热熔材料 和药学上可接受的辅料混合, 之后加热至水溶性热熔材料软化或熔融, 在水 溶性热熔材料软化或熔融状态下制粒, 然后冷却, 即得。
12、 根据权利要求 11 所述的制备方法, 其特征在于, 所述的制粒为热 熔搅拌制粒、 热熔流化制粒或热熔挤压制粒。
13、一种度洛西汀肠溶制剂, 包括芯材、 隔离层和肠溶层, 其特征在于, 所述的芯材为如权利要求 1〜10任一项所述的芯材。
14、 根据权利要求 13所述的度洛西汀肠溶制剂, 其特征在于, 所述的 度洛西汀肠溶制剂为肠溶片剂、 肠溶颗粒剂或肠溶微片装胶囊剂。
15、 根据权利要求 13所述的度洛西汀肠溶制剂, 其特征在于, 所述的 肠溶层外还可以包括修饰层。
16、 一种如权利要求 13所述的度洛西汀肠溶制剂的制备方法, 其特征 在于, 包括以下歩骤:
1 ) 采用本领域常规的制备工艺, 对如权利要求 1〜10任一项所述的芯 材包被隔离层;
2 ) 采用本领域常规的制备工艺包被肠溶层。
17、 根据权利要求 16所述的制备方法, 其特征在于, 还包括歩骤: 3) 包被修饰层。
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EP09834058.1A EP2380563B1 (en) | 2008-12-26 | 2009-11-04 | A enteric formulation of duloxetine and its core and prepration method |
US13/142,116 US8980314B2 (en) | 2008-12-26 | 2009-11-04 | Enteric formulation of duloxetine and its core and preparation method |
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CN200810207877.2 | 2008-12-26 |
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CN102579403B (zh) * | 2011-12-26 | 2013-08-21 | 天津市嵩锐医药科技有限公司 | 盐酸度洛西汀药物组合物 |
CN102988181B (zh) * | 2012-12-31 | 2015-01-14 | 广州白云山天心制药股份有限公司 | 一种口服固体制剂的制粒方法 |
CN103127023B (zh) * | 2013-03-01 | 2014-08-27 | 河北天成药业股份有限公司 | 一种盐酸度洛西汀肠溶片及其制备方法 |
GR1008228B (el) * | 2013-04-23 | 2014-06-16 | "Φαρματεν Α.Β.Ε.Ε.", | Φαρμακευτικο σκευασμα περιεχον ενα διπλο αναστολεα επαναπροσληψης και μεθοδος για την παρασκευη αυτου |
WO2014194872A1 (en) * | 2013-06-04 | 2014-12-11 | Zentiva, K.S. | Taste masking of water soluble drugs using poloxamers |
PL224543B1 (pl) * | 2013-08-21 | 2017-01-31 | Pabianickie Zakłady Farm Polfa Spółka Akcyjna | Dojelitowa tabletka duloksetyny |
CN106176659B (zh) * | 2015-05-05 | 2019-07-12 | 四川科瑞德制药股份有限公司 | 一种坦度螺酮肠溶片及其制备方法 |
US20160331689A1 (en) | 2015-05-12 | 2016-11-17 | SE Tylose USA, Inc. | Aqueous enteric coating composition |
CN105520920B (zh) * | 2016-01-04 | 2018-09-07 | 浙江美华鼎昌医药科技有限公司 | 盐酸度洛西汀胶囊及其制备方法 |
CN105534949A (zh) * | 2016-01-06 | 2016-05-04 | 北京修正创新药物研究院有限公司 | 一种盐酸度洛西汀的肠溶微丸制剂 |
CN105534940B (zh) * | 2016-02-19 | 2018-12-07 | 国药集团致君(深圳)坪山制药有限公司 | 一种双氯芬酸钠缓释片组合物及其制备方法 |
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WO2007034503A2 (en) * | 2005-06-20 | 2007-03-29 | Cadila Healthcare Limited | Controlled release dosage formulation of duloxetine |
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EP2380563A4 (en) | 2012-07-25 |
CN101756960A (zh) | 2010-06-30 |
US20110274750A1 (en) | 2011-11-10 |
EP2380563B1 (en) | 2016-04-27 |
CN101756960B (zh) | 2012-06-27 |
US8980314B2 (en) | 2015-03-17 |
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