CN113116848A - Duloxetine hydrochloride enteric-coated tablet and preparation method thereof - Google Patents

Duloxetine hydrochloride enteric-coated tablet and preparation method thereof Download PDF

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Publication number
CN113116848A
CN113116848A CN201911389104.5A CN201911389104A CN113116848A CN 113116848 A CN113116848 A CN 113116848A CN 201911389104 A CN201911389104 A CN 201911389104A CN 113116848 A CN113116848 A CN 113116848A
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enteric
layer
tablet
duloxetine hydrochloride
tablet core
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Inventor
綦宁姣
徐豪
石海芹
丁祎馨
傅麟勇
周敏
丁云晖
王菲
李星旺
王永
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Shanghai Zhongxi Pharmaceutical Group Co ltd
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Shanghai Zhongxi Pharmaceutical Group Co ltd
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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
    • A61K9/2886—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
    • 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
    • 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
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/22—Anxiolytics
    • 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

Abstract

The invention discloses a duloxetine hydrochloride enteric-coated tablet and a preparation method thereof. The enteric coated tablet comprises: tablet core: the tablet core comprises duloxetine hydrochloride, lactose, a lubricant and a non-lactose filler, the mass percentages in the tablet core are respectively 7.7% -22.3%, 31.8% -56.7%, 0.3% -1.5% and the balance is up to 100%; isolation layer: the isolating layer comprises 20.0-50.0% of adhesive, 20.0-50.0% of sucrose and 10.0-50.0% of anti-sticking agent by mass percent respectively; enteric layer: the enteric layer comprises enteric material, antisticking agent and plasticizer, the mass percentage in the enteric layer is 60.0% -85.7%, 5.4% -30.0% and 5.0% -25% respectively; the weight of the coating of the isolating layer is 4 to 12 percent, and the weight of the coating of the enteric layer is 5.4 to 12 percent. The enteric coated tablet has better dissolution rate in buffer solution.

Description

Duloxetine hydrochloride enteric-coated tablet and preparation method thereof
Technical Field
The invention relates to a duloxetine hydrochloride enteric-coated tablet and a preparation method thereof.
Background
Duloxetine hydrochloride (API) is a potent dual absorption inhibitor of 5-hydroxytryptamine and norepinephrine used to treat depression, chemically known as: s- (+) -N-methyl-3- (1-naphthyloxy) -3- (2-thienyl) -propylamine hydrochloride having the formula:
Figure BDA0002344431730000011
duloxetine hydrochloride is white or white-like crystalline powder, is dissolved in ethanol, has certain solubility in water, is unstable under acidic conditions, and is easy to degrade, so that the duloxetine hydrochloride is suitable for being prepared into an enteric preparation to resist the damage of gastric juice to the medicine.
Originally, the enteric-coated pellets are prepared by adopting a fluidized bed and filled into gelatin capsule capsules. In the united states, the first approval was for the treatment of Major Depressive Disorder (MDD), the 2-month approval was for Generalized Anxiety Disorder (GAD) in 2007, and the subsequent approvals were also sequential for the treatment of Diabetic Peripheral Neuralgia (DPNP), Fibromyalgia (FM), and chronic musculoskeletal pain. In addition, it is approved in the european union for the treatment of severe Stress Urinary Incontinence (SUI) in women. At present, the traditional Chinese medicine is only used for treating Major Depressive Disorder (MDD) and Generalized Anxiety Disorder (GAD).
Original patent CN1106191C discloses a duloxetine hydrochloride enteric-coated pill, but the preparation of the pill is difficult and the production period is long. As known to those skilled in the art, the preparation of the tablet is relatively easy, and the production period is short, so if the enteric-coated tablet with bioequivalence consistent with the original research can be prepared, the defects of the pill preparation can be overcome, and the production efficiency can be greatly improved. Patent document CN106619556A discloses a duloxetine hydrochloride enteric tablet, which removes the separating layer and causes the increase of related substances. Patent document CN100362997C discloses a duloxetine enteric coated tablet and a preparation method thereof, which adopts solid dispersion, so that a large amount of ethanol solution is needed to dissolve the materials, granulation is difficult in large-scale production process, and the operable space is small. Patent document CN101756960B discloses a duloxetine enteric preparation and a preparation method thereof, which adopts a hot melting technology, and uses a large amount of hot melting materials such as PEG, which causes the problem of easy sticking during mass production.
Patent document CN101756960A, published japanese 2010.06.30, paragraph [0165] thereof, paragraph [0177], discloses a duloxetine hydrochloride enteric tablet prepared by conventional wet granulation. However, the dissolution rate of the enteric coated tablet in phosphate buffer solution with pH6.8 was 85% at 0 month of accelerated test. The dissolution rate needs to be further improved, and therefore, the finding of a duloxetine hydrochloride enteric-coated tablet with better dissolution rate in a phosphate buffer solution with a pH value of 6.8 and a preparation method thereof is a technical problem to be solved at present.
Disclosure of Invention
The invention aims to solve the technical problem of overcoming the defect that the duloxetine hydrochloride enteric-coated tablet in the prior art has poor dissolution rate in a phosphate buffer solution with the pH value of 6.8, and provides the duloxetine hydrochloride enteric-coated tablet and a preparation method thereof.
The invention solves the technical problems through the following technical scheme:
one of the technical schemes of the invention is as follows:
the invention provides a duloxetine hydrochloride enteric-coated tablet, which comprises:
(1) tablet core: the tablet core comprises duloxetine hydrochloride, lactose, a lubricant and a non-lactose filler, wherein the mass percentages of the duloxetine hydrochloride, the lactose, the lubricant and the non-lactose filler in the tablet core are respectively 7.7% -22.3%, 31.8% -56.7%, 0.3% -1.5% and the balance is up to 100%;
(2) an isolation layer wrapped on the tablet core: the isolating layer comprises a binder, cane sugar and an anti-sticking agent, the mass percentages of the binder, the cane sugar and the anti-sticking agent in the isolating layer are respectively 20.0-50.0%, 20.0-50.0% and 10.0-50.0%, and the sum of the components in the isolating layer is 100%; wherein the adhesive is hydroxypropyl methyl cellulose and/or hydroxypropyl cellulose;
and (3) an enteric layer coated on the isolating layer: the enteric layer comprises an enteric material, an anti-sticking agent and a plasticizer, the mass percentages of the enteric material, the anti-sticking agent and the plasticizer in the enteric layer are respectively 60.0% -85.7%, 5.4% -30.0% and 5.0% -25%, the sum of the components in the enteric layer is 100%, and the enteric material is one or more of a hydroxypropyl methyl cellulose derivative, acrylic resin and an acrylic resin derivative;
wherein the coating weight of the isolating layer is 4-12%, and the coating weight of the enteric layer is 5.4-12%.
Compared with the duloxetine hydrochloride enteric-coated tablet prepared by conventional wet granulation disclosed in paragraph [0165] of patent document CN101756960A [0177], the duloxetine hydrochloride enteric-coated tablet in the technical scheme has the advantage that the dissolution rate in a phosphate buffer solution with the pH value of 6.8 can be further improved.
(1) With regard to the tablet core:
the mass percentage of duloxetine hydrochloride in the tablet core is preferably 7.8% -10.2%, more preferably 7.9% -9.3%.
The mass percentage of lactose in the tablet core is preferably 34.3-52.6%, more preferably 33.3-39.2%, e.g. 35.1%.
In the preparation of the core, the pH of the lactose in the core material may be conventional in the art, and may for example be in the range 4 to 7, e.g. 4.03 to 6.98, 5.03 to 6.5, 5.3 to 6 or 5.5 to 5.98, preferably 6.74 to 6.9. The inventor of the invention researches and discovers that the pH value of lactose in a tablet core raw material is 6.74-6.9, so that the content of related substances in the obtained duloxetine hydrochloride enteric-coated tablet can be further reduced.
The lubricant in the core may be a lubricant conventional in the art, such as one or more of stearic acid, calcium stearate, sodium stearyl fumarate, aerosil and magnesium stearate, preferably aerosil and/or magnesium stearate.
The mass percentage of lubricant in the core is preferably 0.3% to 1.0%, more preferably 0.5% to 0.9%, for example 0.8%.
The non-lactose filler in the core may be a filler other than lactose conventionally used in the art, preferably one or more of mannitol, starch, pregelatinized starch, microcrystalline cellulose and sucrose, more preferably microcrystalline cellulose and/or sucrose.
The mass percentage of non-lactose filler in the tablet core is preferably 20-54.9%, for example 35.1-54.5%, 48.7-54.1% or 52.6%.
The tablet core may further comprise a binder. The binder is preferably one or more of povidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose, more preferably povidone.
Wherein the model of the povidone is preferably povidone K30.
Wherein the pH of the povidone is conventional in the art, preferably 3.2-4.32, more preferably 4-4.2.
Wherein the hydroxypropylmethylcellulose preferably has a viscosity of 3 to 50 mPas, for example 5 mPas.
Wherein the hydroxypropyl cellulose preferably has a viscosity of 3 to 50 mPa.s, for example 5 mPa.s.
Wherein the mass percentage of the adhesive in the tablet core is preferably 2.6-3.5%.
The tablet core may also include a disintegrant.
The disintegrant is preferably low-substituted hydroxypropyl cellulose and/or crospovidone, and more preferably crospovidone.
Wherein the mass percentage of the disintegrating agent in the tablet core is preferably 0.8-1.4%, more preferably 0.9-1.0%.
(2) With respect to the spacer layer:
the binder in the release layer is preferably hydroxypropyl methylcellulose.
The viscosity of the adhesive in the separating layer is preferably 3 to 50mPa · s, for example 5mPa · s.
The mass percentage of the adhesive in the isolation layer is preferably 25.0% to 45.5%, more preferably 31.4% to 32.6%.
The mass percentage of sucrose in the isolation layer is preferably 22.7% to 43.5%, more preferably 25.0% to 39.2%, and even more preferably 31.4% to 36.4%.
The anti-tack agent in the barrier layer may be an anti-tack agent conventional in the art, such as one or more of talc, aerosil, glyceryl monostearate and glyceryl distearate. The anti-sticking agent is preferably talc.
The mass percentage of the anti-sticking agent in the isolation layer is preferably 15% to 50.0%, more preferably 17.4% to 29.4%, and even more preferably 22.7% to 25%.
The isolating layer may also contain an opacifier.
Wherein the opacifier is preferably titanium dioxide.
Wherein, the mass percentage of the opacifier in the isolation layer is preferably 4.5% -10%, more preferably 6% -9.1%, and even more preferably 6.5% -7%.
(3) For enteric layer
The hydroxypropyl methylcellulose derivative in the enteric layer can be one or more of cellulose acetate phthalate, hydroxypropyl methylcellulose titanate and hydroxypropyl methylcellulose acetate succinate, preferably hydroxypropyl methylcellulose acetate succinate and/or cellulose acetate phthalate, more preferably hydroxypropyl methylcellulose acetate succinate.
Wherein the hydroxypropyl methyl cellulose acetate succinate is preferably one or more of AS-LG, AS-LF, 716G and 716F.
Wherein the type of the phthalic acid cellulose acetate is preferably HP55 and/or HP55 s.
The derivative of acrylic resin in the enteric layer is preferably methacrylic acid-ethyl acrylate copolymer, more preferably 30% dry matter of an aqueous dispersion of methacrylic acid-ethyl acrylate (1:1) copolymer.
The mass percentage of the enteric material in the enteric layer is preferably 60.6% to 80.4%, more preferably 60.9% to 79.1%, and even more preferably 61.0% to 63.2%, for example 61.4%.
The anti-adherent in the enteric layer may be an anti-adherent conventional in the art, such as one or more of talc, glyceryl monostearate and glyceryl distearate. The anti-sticking agent is preferably talc.
The mass percentage of the anti-sticking agent in the enteric layer is preferably 12.5% to 29.9%, more preferably 13.2% to 29.5%, and further more preferably 13.3% to 15.9%, for example 15.8%.
The plasticizer in the enteric layer may be a plasticizer conventional in the art, such as one or more of triethyl citrate, polyethylene glycol, triacetin, glycerol, and propylene glycol. The plasticizer is preferably triethyl citrate.
The mass percentage of the plasticizer in the enteric layer is preferably 7.1% to 23.3%, more preferably 7.7% to 22.7%, even more preferably 8.9% to 21.1%, and even more preferably 9.1% to 10%.
The enteric layer may also contain a pigment.
Wherein, the pigment in the enteric layer can be lemon yellow, for example.
The mass percentage of the pigment in the enteric layer in the duloxetine hydrochloride enteric-coated tablet can be conventional in the art, and is preferably less than 5%, and is not 0, for example 3.3%.
(3) Relating to decorative layers
The duloxetine hydrochloride enteric-coated tablet can further comprise a modification layer coated on the enteric layer, the coating weight of the modification layer can be less than 6% and is not 0, wherein the coating weight of the modification layer refers to the ratio of the mass of the modification layer to the sum of the mass of the tablet core, the isolation layer and the enteric layer.
(4) Coating weight gain for isolation and enteric layers
The coating weight gain of the isolation layer refers to the ratio of the mass of the isolation layer to the mass of the tablet core. The coating weight gain of the isolation layer is preferably 7.7% to 10%, more preferably 7.9% to 9.3%, even more preferably 8% to 9.1%, 8.3% to 9%, or 8.4% to 8.9%.
The coating weight gain of the enteric layer refers to the ratio of the mass of the enteric layer to the sum of the mass of the tablet core and the isolating layer. The coating weight gain of the enteric layer is preferably 6-12%, 7-11%, 7.2-7.7% or 7.3%, more preferably 8-10%. The inventor of the invention finds that the dissolution rate of the duloxetine hydrochloride enteric-coated tablet can be further improved when the weight increase of the coating of the enteric layer is 8% -10%.
In a preferred embodiment of the invention, the mass percentage of duloxetine hydrochloride in the tablet core is 7.8% -22.3%, the mass percent of lactose in the tablet core is 39.2-56.7%, the mass percent of lubricant in the tablet core is 0.5-1.0%, the mass percent of the adhesive in the isolating layer is 25.0-32.6%, the mass percent of the cane sugar in the isolating layer is 25.0-43.5%, the mass percentage of the anti-adhesion agent in the isolating layer is 17.4-50.0%, the mass percentage of the enteric material in the enteric layer is 60.6-79.1%, the mass percent of the anti-adhesion agent in the enteric layer is 13.2-30.3%, the mass percent of the plasticizer in the enteric layer is 7.7-9.1%, the coating weight of the isolating layer is 8-10%, and the coating weight of the enteric layer is 7.3-10%. In vivo data (namely bioequivalence) of the duloxetine hydrochloride enteric-coated tablet in the technical scheme can reach a level equivalent to that of the original research (namely, the production of Lily of 20 mg).
In a more preferred embodiment of the present invention, the non-lactose filler in the tablet core is microcrystalline cellulose, the lubricant in the tablet core is magnesium stearate, the binder in the isolation layer is hydroxypropyl methylcellulose, the anti-sticking agent in the isolation layer is talc, the enteric material is hydroxypropyl methylcellulose acetate succinate, the anti-sticking agent in the enteric layer is talc, and the plasticizer in the enteric layer is triethyl citrate. Compared with the duloxetine hydrochloride enteric-coated tablet prepared by conventional wet granulation disclosed in paragraph [0165] of patent document CN101756960B [0177], the duloxetine hydrochloride enteric-coated tablet in the technical scheme has the advantage that the dissolution rate in a phosphate buffer solution with the pH value of 6.8 is further improved; meanwhile, the in vivo data (namely, bioequivalence) can reach the level equivalent to that of the original research (namely, the Lily production of Xinbaida (20 mg)).
The second technical scheme of the invention is as follows:
the invention also provides a preparation method of the duloxetine hydrochloride enteric-coated tablet, which comprises the following steps:
(1) preparation of the tablet core: sequentially carrying out wet granulation, drying and granule finishing on the uniformly mixed tablet core raw materials, adding a lubricant, mixing and tabletting to obtain a tablet core;
(2) coating the tablet core with a coating solution of an isolation layer to obtain a coated tablet;
(3) and coating the coated tablet with an enteric-coated layer coating solution to obtain the duloxetine hydrochloride enteric-coated tablet.
In step (1), preferably, the drying is stopped when the moisture content of the tablet core is less than 1.0 wt%.
In the step (1), preferably, the drying temperature is 40-50 ℃, for example, 45 ℃.
In the step (2), the temperature of the wrapping is preferably 38-44 ℃.
In the step (3), the temperature of the wrapping is preferably 33-39 ℃.
In a preferred embodiment of the invention, in the step (1), the pH of lactose in the core raw material is 6.74-6.9; in the step (1), the drying is stopped when the water content of the tablet core is less than 1.0 wt%; in the step (1), the drying temperature is 40-50 ℃; in the step (2), the temperature of the package is 38-44 ℃; in the step (3), the temperature of the package is 33-39 ℃. The inventor of the invention finds that in the technical scheme, the content of related substances in the obtained duloxetine hydrochloride enteric-coated tablet can be greatly reduced.
The above preferred conditions can be arbitrarily combined to obtain preferred embodiments of the present invention without departing from the common general knowledge in the art.
The reagents and starting materials used in the present invention are commercially available.
The positive progress effects of the invention are as follows: the duloxetine hydrochloride enteric-coated tablet has better dissolution rate in phosphate buffer solution with pH of 6.8.
Detailed Description
The invention is further illustrated by the following examples, which are not intended to limit the scope of the invention. The experimental methods without specifying specific conditions in the following examples were selected according to the conventional methods and conditions, or according to the commercial instructions.
In the following examples, the prepared duloxetine hydrochloride enteric-coated tablets have a specification of 20mg (in terms of duloxetine), and each duloxetine hydrochloride enteric-coated tablet contains 22.4mg of duloxetine hydrochloride; hydroxypropyl methylcellulose has a viscosity of 5 mPas as represented by the type E5; hydroxypropyl cellulose, type E5, represents a viscosity of 5 mPas; the povidone is K30.
Examples 1-3 duloxetine hydrochloride enteric coated tablets were finally prepared as follows:
Figure BDA0002344431730000081
Figure BDA0002344431730000091
example 1
The duloxetine hydrochloride enteric-coated tablet is prepared from the raw materials according to the table, and the preparation method comprises the following steps:
(1) preparation of the tablet core: the active ingredients and the filler are manually premixed and then sieved by a 40-mesh sieve, the sieved mixture is poured into a rapid stirring granulator, and a stirring paddle is opened for premixing for 5 minutes. And then opening a fly cutter at a low speed, adding purified water, wherein the mass ratio of the purified water to the core raw material is 1:5, opening the fly cutter at a high speed after the purified water is added, continuously granulating for about 3-8 minutes, stopping stirring, discharging to an oven at 50 ℃ for drying, and stopping drying when the water content is less than 1.0 wt%. Installing a stainless steel sieve ring with the specification of 1.2 mm-2.0 mm for size stabilization, then adding a lubricant, mixing for 5 minutes, tabletting, and controlling the hardness to be 4-10kg, the friability to be less than 0.8 percent and the weight difference to be +/-5 percent.
(2) Coating an isolation layer: firstly, preparing a coating solution: placing purified water into a stirring barrel, starting stirring, dissolving the adhesive in the purified water, adding the filler, finally adding the anti-sticking agent, continuously stirring for at least 30 minutes, and sieving by a 60-mesh sieve to obtain the isolating layer coating liquid with the solid content of 20 wt%. Controlling the temperature of the slice bed to be 38-44 ℃ for coating the isolation layer, closing heating after spraying the coating liquid, continuing air cooling until the air outlet temperature is less than 40 ℃, and discharging.
(3) Coating with an enteric layer: firstly, preparing a coating solution: weighing 80% (V/V) ethanol water solution, placing the ethanol water solution into a stirring barrel, starting stirring, slowly adding the enteric-coated material into the ethanol water solution, adding the plasticizer, adding the anti-sticking agent after the enteric-coated material is completely dissolved, continuously stirring for at least 30 minutes, and sieving by a 60-mesh sieve to obtain the enteric-coated layer coating solution with the solid content of 7 wt%. Secondly, controlling the temperature of the slice bed to be 33-39 ℃ for coating the isolation layer, closing and heating after the coating liquid is sprayed, and continuously performing air cooling until the air outlet temperature is lower than 36 ℃ for discharging.
Examples 2 to 3
The duloxetine hydrochloride enteric-coated tablet is prepared from the raw materials according to the table, and the preparation method comprises the following steps:
(1) preparation of the tablet core: pretreatment: pulverizing sucrose, sieving with 40 mesh sieve, and sieving the rest materials with 40 mesh sieve. And (3) wet granulation: preparation of a binding agent: dissolving the adhesive in 70% (w/w) ethanol water solution, wherein the mass ratio of the ethanol water solution to the tablet core raw material is 1: 18. Secondly, adding the active ingredients and the filling agent into a trough type mixing machine, mixing for 10 minutes, uniformly pouring the adhesive, continuously stirring for 3-5 minutes after pouring, preparing a soft material, and closing stirring. And thirdly, a nylon net with 20 meshes is arranged on the swinging granulator, the soft material is added into the feed hopper in several times for granulation operation, the prepared wet particles are collected into a stainless steel basin and evenly and properly paved on a stainless steel baking pan padded with clean baking cloth, and the surface of the wet particles in the baking pan needs to be finished and leveled. And (3) post-treatment: setting a drying temperature of 42 ℃, monitoring moisture, and stopping drying when the moisture is less than 1.0 wt%; adopting a granulating machine to carry out granulating work, and installing a stainless steel sieve ring with the specification of 1.5 mm-2.5 mm for granulating; performing total mixing operation by adopting a mixer, adding the lubricant, the disintegrant and the granules after finishing granules into a pot body of the mixer, tightly covering, and discharging after total mixing for 5 minutes; tabletting, controlling the hardness to be 4-10kg, the friability to be less than 0.8 percent and the weight difference to be +/-5 percent.
(2) Coating an isolation layer: firstly, preparing a coating solution: and (3) placing the purified water into a stirring barrel, starting stirring, dissolving the adhesive into the purified water, adding the rest isolation layer auxiliary materials, continuously stirring for at least 30 minutes, and sieving by using a 60-mesh sieve to obtain the isolation layer coating solution with the solid content of 15 wt%. Controlling the temperature of the slice bed to be 38-44 ℃ for coating the isolation layer, closing heating after spraying the coating liquid, continuing air cooling until the air outlet temperature is less than 40 ℃, and discharging.
(3) Coating with an enteric layer: firstly, preparing a coating solution: placing purified water in a stirring barrel, stirring, adding enteric material (30% ethyl methacrylate-ethyl acrylate (1:1) copolymer water dispersion), adding plasticizer and antisticking agent, stirring for at least 30 min, and sieving with 60 mesh sieve to obtain enteric coating solution with solid content of 20 wt%. Secondly, controlling the temperature of the slice bed to be 33-39 ℃ for coating the isolation layer, closing and heating after the coating liquid is sprayed, and continuously performing air cooling until the air outlet temperature is lower than 36 ℃ for discharging.
Examples 4 to 7
The starting materials for duloxetine hydrochloride enteric tablets were prepared as described in the following table, and prepared in the same manner as in example 1.
Figure BDA0002344431730000101
Figure BDA0002344431730000111
Examples 8 and 9
The duloxetine hydrochloride enteric tablet is prepared as shown in the following table, and its preparation method is the same as example 2, except that no disintegrant is added during the preparation of the tablet core.
Figure BDA0002344431730000112
Examples 10 to 18
The duloxetine hydrochloride enteric-coated tablet is prepared from the following raw materials in the following preparation method:
(1) the tablet core was prepared as in example 1, except that purified water was replaced with a binder, and the binder was formulated as in example 2;
(2) the preparation of the tablet cores was followed by the coating of the barrier layer and the coating of the enteric layer as in example 2.
Figure BDA0002344431730000113
Figure BDA0002344431730000121
Examples 19 to 22
The duloxetine hydrochloride enteric-coated tablet is prepared from the following raw materials in the following preparation method:
(1) the tablet core and the coating of the separating layer were prepared as in example 2;
(2) coating with an enteric layer: the only difference from example 2 is that the plasticizer, the antiblocking agent and the pigment are added together;
(3) coating the modification layer: firstly, preparing a coating solution: and (3) placing the purified water into a stirring barrel, starting stirring, dissolving the adhesive into the purified water, adding the opacifier, finally adding the anti-sticking agent, continuously stirring for at least 30 minutes, and sieving by a 60-mesh sieve to obtain the modifying layer coating solution with the solid content of 20 wt%. Secondly, controlling the temperature of the slice bed to be 38-44 ℃ for coating by an isolation layer, closing and heating after the coating liquid is sprayed, and continuously performing air cooling until the air outlet temperature is lower than 40 ℃ for discharging.
Figure BDA0002344431730000122
Figure BDA0002344431730000131
Comparative examples 1 to 2
The starting materials for duloxetine hydrochloride enteric tablets were prepared as described in the following table, and prepared in the same manner as in example 1.
Figure BDA0002344431730000132
Effect example 1 stability examination
The stability of the above examples 1, 2 and 3 was examined according to the requirements of 9001 "guidelines for stability tests of raw materials and preparations" in the fourth part of the chinese pharmacopoeia 2015, and the content uniformity, dissolution rate and measurement method of related substances disclosed in duloxetine hydrochloride enteric-coated tablets (examination notes) were carried out, where the acid in the following table is 0.1 mol/hydrochloric acid, and the buffer solution is phosphate buffer solution with pH 6.8.
Figure BDA0002344431730000141
In the above table, D1 refers to duloxetine hydrochloride enteric coated tablet prepared by conventional wet granulation as disclosed in paragraph [0165] of patent document CN101756960A and paragraph [0177 ].
In the above table, the difference between examples 10-18 and example 8 is only that the pH of lactose and the pH of povidone used in the tablet core are different, and the dissolution rates of the two are not affected, so that the dissolution rates of the duloxetine hydrochloride enteric-coated tablets obtained in examples 10-18 in acid and phosphate buffer solution with pH of 6.8 are equivalent to that in example 8. Based on this, it can be seen from the above table that the dissolution rates of the above examples are all better than that of D1 in phosphate buffered saline at pH 6.8.
Comparing the data of the impurity contents of the examples 10 to 18, it can be seen that the pH of lactose in the core material is 6.74 to 6.9, which can further reduce the content of the related substances in the obtained duloxetine hydrochloride enteric tablet.
Figure BDA0002344431730000151
The acid in the table is 0.1 mol/hydrochloric acid, the buffer solution is a phosphate buffer solution with pH of 6.8, and the dissolution rate in the table is measured when the acceleration is 0 day; as can be seen from the above table, examples 4-7 were able to achieve better dissolution than D1 in phosphate buffer at pH 6.8; comparing examples 4-7, it can be seen that the dissolution rates of examples 5-6 are better than those of other examples, that is, when the weight of the coating of the enteric layer is increased to 8% -10%, the dissolution rate of the obtained duloxetine hydrochloride enteric tablet in the phosphate buffer solution with pH of 6.8 can be further improved.
From comparative examples 1-2, it can be seen that when the coating weight of the enteric layer is increased to 4%, even though other technical characteristics are the same as or similar to those of example 4, the dissolution rate of the obtained duloxetine hydrochloride enteric tablet in phosphate buffer solution with pH of 6.8 is much lower than that of the examples of the present application; when the coating weight of the enteric layer is increased to 14%, even if other technical characteristics are the same as or similar to those of example 4, the obtained duloxetine hydrochloride enteric-coated tablet has poorer dissolution rate in phosphate buffer solution with pH of 6.8 than the examples of the application.
Effect example 2 pharmacokinetic chronograph
The results shown in tables 1-2 were obtained for pharmacokinetics of healthy volunteers and bioequivalence between the two formulations by single oral administration of duloxetine hydrochloride enteric tablets (test formulation) prepared in examples 1 and 3 and synephrine (20mg) Lily as a positive control (reference formulation) under fasting and high-fat meal conditions, respectively.
The experimental method of the biological equivalence is as follows: the selected healthy subjects were randomly assigned to 2 groups, the first and second, using a single-center, randomized, open, two-cycle, two-sequence, double crossover, single fasting/postprandial drug design approach. The selected subjects entered the BE/phase I clinical trial study center the day before the trial and fasted for at least 10 hours before dosing (postprandial trial was a high-fat meal). The next morning after a blank blood sample was collected, 1 reference preparation or 1 test preparation was orally administered on an empty stomach/meal. The medicine is administered with 240mL warm water. In the fasting test, venous blood is collected at 20 time points of 0h (within 60min before administration) administration, 1h, 2h, 3h, 4h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 12h, 16h, 24h, 36h, 48h and 72h respectively; the postprandial test collects venous blood at 21 time points of 0h (within 60min before administration) and 1h, 2h, 3h, 4h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 9h, 10h, 12h, 14h, 16h, 24h, 36h, 48h and 72h respectively; about 4mL of blood was drawn each time into a vacutainer containing a sodium heparin anticoagulant, and all post-centrifugation plasma samples were divided into two. Centrifuging within 60min after blood sample collection, centrifuging within 120min, temporarily storing in a refrigerator at about-20 deg.C, transferring to a refrigerator at about-70 deg.C within 24h, or directly storing in a refrigerator at about-70 deg.C. And after blood samples of all the subjects are collected, transporting the plasma samples to an analysis testing center for blood concentration determination by adopting proper conditions, and determining the concentration of the duloxetine in the plasma by adopting an LC-MS/MS method. Pharmacokinetic parameters C for duloxetinemax、AUC(0-t)、AUC(0-∞)After logarithmic transformation, analysis of variance was performed, and bioequivalence evaluation was performed using a 90% confidence interval method.
TABLE 1
Figure BDA0002344431730000161
Figure BDA0002344431730000171
TABLE 2
Example 1 AUC(0-t) AUC(0-∞) Cmax
[1-2α]Interval(s) 88.6％～118.2％ 90.0％～115.4％ 87.4％～118.0％
Equivalence standard 80％～125％ 80％～125％ 80％～125％
T/R 102.3％ 101.9％ 101.5％
Conclusion Qualified Qualified Qualified
Example 3 AUC(0-t) AUC(0-∞) Cmax
[1-2α]Interval(s) 95.6％～108.8％ 96.0％～108.8％ 85.8％～107.1％
Equivalence standard 80％～125％ 80％～125％ 80％～125％
T/R 102.0％ 102.2％ 95.8％
Conclusion Qualified Qualified Qualified
In table 1, the in vivo bioequivalence data of the duloxetine hydrochloride enteric-coated tablets (test reagents) of examples 1 and 3 and the positive control drug (reference reagent) under fasting condition are shown.
Table 2 shows the in vivo bioequivalence data of the duloxetine hydrochloride enteric-coated tablets (test agent) of example 1 and example 3 and the positive control drug (reference agent) under high-fat meal conditions.
In tables 1-2, as known to those skilled in the art, T/R is the mean ratio of the self-prepared product and the positive control, and the closer the mean ratio is to 100%, the more the self-prepared product and the positive control have similar in vivo bioavailability, so the related results in the above table show that the duloxetine hydrochloride enteric tablet prepared by the present invention has similar in vivo bioavailability as the existing drugs.
While specific embodiments of the invention have been described above, it will be appreciated by those skilled in the art that this is by way of example only, and that the scope of the invention is defined by the appended claims. Various changes and modifications to these embodiments may be made by those skilled in the art without departing from the spirit and scope of the invention, and these changes and modifications are within the scope of the invention.

Claims (10)

1. A duloxetine hydrochloride enteric tablet, comprising:
(1) tablet core: the tablet core comprises duloxetine hydrochloride, lactose, a lubricant and a non-lactose filler, wherein the mass percentages of the duloxetine hydrochloride, the lactose, the lubricant and the non-lactose filler in the tablet core are respectively 7.7% -22.3%, 31.8% -56.7%, 0.3% -1.5% and the balance is up to 100%;
(2) an isolation layer wrapped on the tablet core: the isolating layer comprises a binder, cane sugar and an anti-sticking agent, the mass percentages of the binder, the cane sugar and the anti-sticking agent in the isolating layer are respectively 20.0-50.0%, 20.0-50.0% and 10.0-50.0%, and the sum of the components in the isolating layer is 100%; wherein the adhesive is hydroxypropyl methyl cellulose and/or hydroxypropyl cellulose;
and (3) an enteric layer coated on the isolating layer: the enteric layer comprises an enteric material, an anti-sticking agent and a plasticizer, the mass percentages of the enteric material, the anti-sticking agent and the plasticizer in the enteric layer are respectively 60.0% -85.7%, 5.4% -30.0% and 5.0% -25%, the sum of the components in the enteric layer is 100%, and the enteric material is one or more of a hydroxypropyl methyl cellulose derivative, acrylic resin and an acrylic resin derivative;
wherein the coating weight of the isolating layer is 4-12%, and the coating weight of the enteric layer is 5.4-12%.
2. The duloxetine hydrochloride enteric tablet of claim 1, wherein the mass percentage of duloxetine hydrochloride in the core is 7.8% -10.2%, preferably 7.9% -9.3%;
and/or the mass percentage of lactose in the tablet core is 34.3% -52.6%, preferably 33.3% -39.2%;
and/or, in the preparation of said core, the pH of the lactose in the core material is 4-7, preferably 6.74-6.9;
and/or the lubricant in the tablet core is one or more of stearic acid, calcium stearate, sodium stearyl fumarate, micro-powder silica gel and magnesium stearate, preferably micro-powder silica gel and/or magnesium stearate;
and/or the mass percentage of the lubricant in the tablet core is 0.3-1.0%, preferably 0.5-0.9%;
and/or the non-lactose filler in the tablet core is one or more of mannitol, starch, pregelatinized starch, microcrystalline cellulose and sucrose, preferably microcrystalline cellulose and/or sucrose;
and/or the mass percentage of the non-lactose filler in the tablet core is 20-54.9%;
and/or the tablet core further comprises a binder, wherein the binder is one or more of povidone, hydroxypropyl methylcellulose and hydroxypropyl cellulose, preferably povidone; wherein the pH of the povidone is preferably 3.2-4.32; the mass percentage of the adhesive in the tablet core is preferably 2.6-3.5%;
and/or, the tablet core further comprises a disintegrant; wherein, the disintegrating agent is preferably low-substituted hydroxypropyl cellulose and/or crospovidone, and more preferably crospovidone; the mass percentage of the disintegrant in the tablet core is preferably 0.8-1.4%.
3. The duloxetine hydrochloride enteric tablet of claim 1, wherein the binder in the separating layer is hydroxypropyl methylcellulose;
and/or the viscosity of the adhesive in the isolating layer is 3-50 mPa.s;
and/or the mass percentage of the adhesive in the isolating layer is 25.0-45.5%, preferably 31.4-32.6%;
and/or the mass percentage of the sucrose in the isolating layer is 22.7-43.5%, preferably 25.0-39.2%, more preferably 31.4-36.4%;
and/or the anti-sticking agent in the isolating layer is one or more of talcum powder, superfine silica gel powder, glyceryl monostearate and glyceryl distearate, preferably the talcum powder;
and/or the mass percentage of the antisticking agent in the isolating layer is 15-50.0%, preferably 17.4-29.4%, more preferably 22.7-25%;
and/or the isolating layer also contains an opacifier; wherein the opacifier is preferably titanium dioxide; the mass percentage of the opacifier in the isolation layer is preferably 4.5% to 10%, more preferably 6% to 9.1%, and even more preferably 6.5% to 7%.
4. Duloxetine hydrochloride enteric tablets according to claim 1, wherein the derivative of hydroxypropyl methylcellulose in the enteric layer is one or more of cellulose acetate phthalate, hydroxypropyl methylcellulose titanate and hydroxypropyl methylcellulose acetate succinate, preferably hydroxypropyl methylcellulose acetate succinate and/or cellulose acetate phthalate, more preferably hydroxypropyl methylcellulose acetate succinate;
and/or the derivative of acrylic resin in the enteric layer is methacrylic acid-ethyl acrylate copolymer, preferably dry matter in 30% methacrylic acid-ethyl acrylate (1:1) copolymer aqueous dispersion;
and/or, the mass percentage of the enteric material in the enteric layer is 60.6-80.4%, preferably 60.9-79.1%, more preferably 61.0-63.2%;
and/or the anti-sticking agent in the enteric layer is one or more of talcum powder, glyceryl monostearate and glyceryl distearate, preferably talcum powder;
and/or the mass percentage of the anti-sticking agent in the enteric layer is 12.5-29.9%, preferably 13.2-29.5%, more preferably 13.3-15.9%;
and/or the plasticizer in the enteric layer is one or more of triethyl citrate, polyethylene glycol, triacetin, glycerol and propylene glycol, preferably triethyl citrate;
and/or the mass percentage of the plasticizer in the enteric layer is 7.1% -23.3%, preferably 7.7% -22.7%, more preferably 8.9% -21.1%, and further more preferably 9.1% -10%;
and/or, the enteric layer also contains pigment; the pigment in the enteric layer is preferably lemon yellow, and the mass percentage of the pigment in the enteric layer in the duloxetine hydrochloride enteric-coated tablet is preferably less than 5% and is not 0.
5. The duloxetine hydrochloride enteric tablet of claim 1, further comprising a modification layer coated on the enteric layer, wherein the weight of the coating of the modification layer is less than 6% and is not 0.
6. The duloxetine hydrochloride enteric tablet of claim 1, wherein the coating weight gain of the separating layer is 7.7% to 10%, preferably 7.9% to 9.3%, more preferably 8% to 9.1%, 8.3% to 9% or 8.4% to 8.9%;
and/or the coating weight of the enteric layer is increased by 6 to 12 percent, preferably 8 to 10 percent.
7. The duloxetine hydrochloride enteric tablet of claim 1, wherein the mass percent of duloxetine hydrochloride in the tablet core is 7.8% -22.3%, the mass percent of lactose in the tablet core is 39.2% -56.7%, the mass percent of lubricant in the tablet core is 0.5% -1.0%, the mass percent of binder in the isolation layer is 25.0% -32.6%, the mass percent of sucrose in the isolation layer is 25.0% -43.5%, the mass percent of anti-sticking agent in the isolation layer is 17.4% -50.0%, the mass percent of enteric material in the enteric layer is 60.6% -79.1%, the mass percent of anti-sticking agent in the enteric layer is 13.2% -30.3%, the mass percent of plasticizer in the enteric layer is 7.7% -9.1%, and the coating weight of the isolation layer is 8% -10%, the weight of the coating of the enteric layer is increased by 7.3-10%.
8. The duloxetine hydrochloride enteric tablet of claim 7, wherein the non-lactose filler in the core is microcrystalline cellulose, the lubricant in the core is magnesium stearate, the binder in the isolation layer is hydroxypropyl methylcellulose, the anti-sticking agent in the isolation layer is talc, the enteric material is hydroxypropyl methylcellulose acetate succinate, the anti-sticking agent in the enteric layer is talc, and the plasticizer in the enteric layer is triethyl citrate.
9. A process for the preparation of duloxetine hydrochloride enteric tablets according to any of claims 1 to 8, wherein the process comprises the steps of:
(1) preparation of the tablet core: sequentially carrying out wet granulation, drying and granule finishing on the uniformly mixed tablet core raw materials, adding a lubricant, mixing and tabletting to obtain a tablet core;
(2) coating the tablet core with a coating solution of an isolation layer to obtain a coated tablet;
(3) coating an enteric-coated layer coating solution outside the coated tablet to obtain the duloxetine hydrochloride enteric-coated tablet;
in step (1), preferably, the drying is stopped when the moisture content of the tablet core is less than 1.0 wt%;
in the step (1), preferably, the drying temperature is 40-50 ℃;
in the step (2), the temperature of the package is preferably 38-44 ℃;
in the step (3), the temperature of the wrapping is preferably 33-39 ℃.
10. The method for preparing duloxetine hydrochloride enteric tablets of claim 9, wherein in step (1), the pH of lactose in the core material is 6.74-6.9; in the step (1), the drying is stopped when the water content of the tablet core is less than 1.0 wt%; in the step (1), the drying temperature is 40-50 ℃; in the step (2), the temperature of the package is 38-44 ℃; in the step (3), the temperature of the package is 33-39 ℃.
CN201911389104.5A 2019-12-30 2019-12-30 Duloxetine hydrochloride enteric-coated tablet and preparation method thereof Pending CN113116848A (en)

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