CN112972412A - Paroxetine hydrochloride sustained-release orally disintegrating tablet and preparation method thereof - Google Patents

Paroxetine hydrochloride sustained-release orally disintegrating tablet and preparation method thereof Download PDF

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Publication number
CN112972412A
CN112972412A CN201911295613.1A CN201911295613A CN112972412A CN 112972412 A CN112972412 A CN 112972412A CN 201911295613 A CN201911295613 A CN 201911295613A CN 112972412 A CN112972412 A CN 112972412A
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release
sustained
orally disintegrating
disintegrating tablet
paroxetine hydrochloride
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吴霞
王宇杰
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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Beijing Wanquan Dezhong Medical Biological Technology Co Ltd
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A61K31/4523—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems
    • A61K31/4525—Non condensed piperidines, e.g. piperocaine containing further heterocyclic ring systems containing a five-membered ring with oxygen as a ring hetero atom
    • 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
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
    • 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
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/24—Antidepressants

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  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Zoology (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Biomedical Technology (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

The invention relates to the technical field of medicines, in particular to a paroxetine hydrochloride-containing sustained-release orally disintegrating tablet and a preparation method thereof. The sustained-release orally disintegrating tablet is characterized by convenient taking, rapid disintegration of the sustained-release granules in the presence of saliva under the condition of no need of drinking water, rapid disintegration within 30s, good taste, and suitability for the old, children, coma patients and special patients with dysphagia; the medicine can be slowly released in vivo, the blood concentration is stable, the toxic and side effects are avoided, the half-life period is long, and the administration frequency can be reduced; and moreover, the powder direct pressing process is adopted, so that the method is simplified and easy to produce.

Description

Paroxetine hydrochloride sustained-release orally disintegrating tablet and preparation method thereof
Technical Field
The invention relates to the technical field of medicines, in particular to a paroxetine hydrochloride sustained-release orally disintegrating tablet and a preparation method thereof.
Background
Depression, also known as depressive disorder, is characterized clinically by a marked and persistent depression in the mood, the main type of mood disorder. The low mood is not matched with the situation in clinic, the depression of the mood can be from sultriness to sadness, and the self-declining depression and even the pessimism are taken away, and suicide attempts or behaviors can be caused; even the occurrence of stupor; in some cases, there is significant anxiety and motor agitation; in severe cases, psychotic symptoms such as hallucinations and delusions may occur. Each episode lasts for at least 2 weeks, most cases have a tendency to have recurrent episodes, most of which can be alleviated, and some of which can have residual symptoms or become chronic.
At present, paroxetine hydrochloride for treating depression-related symptoms in the market has the defects of low medicament release stability effect, large irritation to gastrointestinal tracts, low bioavailability, inconvenient package, transportation and storage, complex preparation method and the like.
Paroxetine hydrochloride (PX) is an antidepressant drug, is a strong and high-selectivity 5-hydroxytryptamine reuptake inhibitor, and can increase the concentration of 5-hydroxytryptamine in synaptic cleft and enhance the nerve function of central 5-hydroxytryptamine. Inhibit the reuptake of norepinephrine and dopamine only weakly, with little affinity for muscarinic 1, 2 receptors or adrenergic receptors, dopamine 2 receptor, 5-hydroxytryptamine 1, 2 receptor, and histamine H1 receptor. Compared with the traditional tricyclic and monoamine oxidase inhibitor antidepressant, the paroxetine hydrochloride has stronger selectivity and less adverse reactions, and the PX has good organism tolerance and high therapeutic index.
Paroxetine hydrochloride has the chemical name: (-) -trans-4R- (4-fluorophenyl) -3S- { [3 ', 4' - (methylenedioxy) phenoxy ] methyl } -piperidine hydrochloride hemihydrate; the English name is: pareoxetine Hydrochloride; the general abbreviation is PX or POTH in the field of pharmaceutical chemistry; the molecular formula is as follows: : C19H20FNO 3. HC 1. 1/2 HCl; molecular weight: 374.84, respectively; half-life: about 24 hours; the character is white opaque crystals.
The chemical structural formula is as follows:
Figure DEST_PATH_IMAGE002
at present, paroxetine hydrochloride for treating depression-related symptoms in the market has the defects of poor medicament release stabilizing effect, large irritation to gastrointestinal tracts, low bioavailability, inconvenient package, transportation and storage, complex preparation method and the like. Therefore, how to provide a paroxetine sustained-release orally disintegrating tablet, which has the advantages of simple production and preparation process, low cost of tablet core auxiliary materials and good thermal stability, can effectively control the drug release rate, enables the blood concentration curve to be stable, and reduces the fluctuation of the blood concentration, thereby increasing the safety, effectiveness and compliance of patients taking medicine, and has rapid disintegration and good taste, which is the technical problem to be solved urgently at present.
Disclosure of Invention
The invention provides paroxetine hydrochloride orally disintegrating tablets with stable release and a preparation method thereof.
The paroxetine hydrochloride sustained-release orally disintegrating tablet provided by the invention has a blank inert pill core, and a drug layer and a sustained-release layer which are sequentially wrapped on the blank inert pill core.
Further, the blank inert pellet core is a sucrose pellet core, a microcrystalline cellulose pellet core or a silicon dioxide pellet core, and is preferably a sucrose pellet core.
Further, the particle size of the blank inert pellet core is 500-1500 μm.
Further, the medicine layer contains paroxetine hydrochloride and can be obtained by applying medicine solution or suspension.
Furthermore, the drug layer also comprises pore-forming agent, such as some water-soluble substances such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP), salts, hydroxypropyl methylcellulose (HPMC), hydroxypropyl cellulose (HPC) and the like, or insoluble solid components such as talcum powder, magnesium stearate, silicon dioxide, titanium dioxide and the like, which are used for regulating the in-vivo and in-vitro release behaviors of the preparation.
Further, the slow release layer is a water-insoluble polymer, and the water-insoluble polymer is selected from one or more of ethyl cellulose or an aqueous dispersion thereof, cellulose acetate or an aqueous dispersion thereof or a methacrylic acid copolymer.
Further, a protective layer is arranged between the medicine layer and the slow release layer or/and on the slow release layer, and the protective layer is Opadry.
Further, mixing the coated granules with a disintegrating agent, a filling agent, a sweetening agent and a lubricating agent, and then performing powder direct compression; wherein the disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone; fillers include, but are not limited to, lactose, mannitol, microcrystalline cellulose; flavoring agents include, but are not limited to, aspartame, acesulfame potassium, menthol.
A preparation method of paroxetine hydrochloride sustained-release orally disintegrating tablets comprises the following steps:
(1) packaging a medicine layer: dissolving the raw materials of the drug layer in ethanol solution, placing the blank inert pellet core in a fluidized bed, coating the solution on the surface of the blank inert pellet core by bottom spraying, and controlling the temperature at 25-45 deg.C to form pellet core coated with the drug layer;
(2) coating a slow release layer: dispersing the raw materials of the sustained-release layer in water to obtain aqueous dispersion with solid content of 10-20%, stirring, placing the pill core coated with the medicinal layer in fluidized bed, coating the above solution on the surface of the pill core by bottom spraying, and controlling the temperature at 28-32 deg.C to obtain sustained-release pill core;
(3) and (3) drying: mixing the obtained sustained-release pill core with pulvis Talci, placing into oven of 45-55 deg.C, and drying for 2-3 hr;
(4) sieving with 40 mesh sieve, grading, adding filler, disintegrant, sweetener and lubricant, mixing, and directly pressing.
Further, when the protective layer is included, the wrapping method of the protective layer is as follows: dispersing Opadry in water to obtain coating solution with solid content of 6-12%, placing the pill core or sustained-release pill core coated with the medicinal layer into fluidized bed, and coating the solution on the surface of the pill core by bottom spraying at 38-42 deg.C.
The paroxetine hydrochloride sustained-release orally disintegrating tablet is determined according to a pharmacopoeia disintegration time limit determination method, and the disintegration time limit of the paroxetine hydrochloride sustained-release orally disintegrating tablet is less than 30s and meets the requirements of orally disintegrating tablets.
Detailed Description
To more clearly illustrate the advantages and features of the present invention, the following detailed description of the present invention is given by way of example only, and it should be understood by those skilled in the art that the following detailed description is given by way of illustration and not limitation, and the scope of the present invention should not be limited thereby.
In the examples, the disintegration time of orally disintegrating tablets was measured according to the disintegration time examination method of the four parts 0921 in "Chinese pharmacopoeia" 2015 edition.
Example 1
Figure DEST_PATH_IMAGE004
The preparation method comprises the following steps:
packaging a medicine layer: dissolving paroxetine hydrochloride and hydroxypropyl methylcellulose in appropriate amount of water, uniformly dispersing talcum powder in the above solution, placing microcrystalline cellulose pill core in fluidized bed, coating the above solution on the surface of pill core by bottom spraying, and controlling the material temperature at about 40 deg.C.
Coating a protective layer: dispersing Opadry in appropriate amount of water to obtain coating solution with solid content of 10%, placing the pill core containing medicine in fluidized bed, coating the pill core surface with the solution by bottom spraying, and controlling the material temperature at about 40 deg.C.
Coating a slow release layer: the Eudragit RS30D is dispersed in a proper amount of water to prepare aqueous dispersion with the solid content of 15 percent, and the aqueous dispersion is stirred evenly. Putting the pill core coated with the protective layer into a fluidized bed, coating the solution on the surface of the pill core by bottom spraying, and controlling the temperature of the material at about 30 ℃.
And (3) drying: drying the obtained sustained-release pill core in an oven at 45 deg.C for 3 hr;
sieving with 40 mesh sieve, grading, adding PVPP, microcrystalline cellulose, acesulfame potassium and pulvis Talci, mixing, and directly tabletting.
And (3) test results:
disintegration time period 23 s.
Example 2
Figure DEST_PATH_IMAGE006
The preparation method comprises the following steps:
packaging a medicine layer: dissolving paroxetine hydrochloride and hydroxypropyl cellulose in a proper amount of 50% ethanol solution, uniformly dispersing talcum powder in the solution, putting the sucrose pellet core into a fluidized bed, coating the solution on the surface of the pellet core by adopting a bottom spraying mode, and controlling the temperature of the materials to be about 30 ℃.
Coating a slow release layer: dispersing the Sulisi in a proper amount of water to prepare an aqueous dispersion with the solid content of 15%, dissolving PEG6000 in a proper amount of water, and uniformly stirring the aqueous dispersion and the PEG 6000. Placing the pill core with medicine in fluidized bed, coating the above solution on the surface of the pill core by bottom spraying, and controlling the material temperature at about 35 deg.C. Drying in fluidized bed at 55 deg.C for 30 min.
And (3) drying: drying the obtained sustained-release pill core in an oven at 50 deg.C for 2.5 hr;
sieving with 40 mesh sieve, grading, adding low-substituted hydroxypropyl cellulose, lactose, Mentholum and silicon dioxide, mixing, and directly tabletting.
And (3) test results:
the disintegration time was 22 s.
Example 3
Figure DEST_PATH_IMAGE008
The preparation method comprises the following steps:
packaging a medicine layer: dissolving paroxetine hydrochloride and hydroxypropyl methylcellulose in appropriate amount of water, uniformly dispersing talcum powder in the above solution, placing the silicon dioxide pellet core into a fluidized bed, coating the above solution on the surface of the pellet core by bottom spraying, and controlling the material temperature at about 45 deg.C.
Coating a protective layer: dispersing Opadry in appropriate amount of water to obtain coating solution with solid content of 12%, placing the pill core containing medicine in fluidized bed, coating the pill core surface with the solution by bottom spraying, and controlling the material temperature at about 40 deg.C.
Coating a slow release layer: the Eudragit NE30D is dispersed in a proper amount of water to prepare an aqueous dispersion with the solid content of 20 percent, and the aqueous dispersion is stirred uniformly. Putting the pill core coated with the protective layer into a fluidized bed, coating the solution on the surface of the pill core by bottom spraying, and controlling the temperature of the material at about 45 ℃.
Coating a protective layer: dispersing Opadry in appropriate amount of water to obtain coating solution with solid content of 6%, placing the pill core containing medicine in fluidized bed, coating the pill core surface with the solution by bottom spraying, and controlling the material temperature at about 40 deg.C.
And (3) drying: drying the obtained sustained-release pill core in an oven at 55 deg.C for 2 hr;
sieving with 40 mesh sieve, granulating, adding croscarmellose sodium, mannitol, aspartame and magnesium stearate, mixing, and directly tabletting.
And (3) test results:
the disintegration time was 28 s.
It should be understood that the above-mentioned embodiments of the present invention are only examples for clearly illustrating the present invention, and are not intended to limit the embodiments of the present invention, and it will be obvious to those skilled in the art that other variations or modifications may be made on the basis of the above description, and all embodiments may not be exhaustive, and all obvious variations or modifications may be included within the scope of the present invention.

Claims (9)

1. A paroxetine hydrochloride sustained-release orally disintegrating tablet is prepared from the following components in percentage by weight:
Figure DEST_PATH_IMAGE001
。
2. the paroxetine hydrochloride sustained-release orally disintegrating tablet of claim 1, which has a blank inert pellet core, and a drug layer and a sustained-release layer sequentially wrapped thereon.
3. The paroxetine hydrochloride sustained-release orally disintegrating tablet according to claim 1, wherein the blank inert pellet core is one of a sucrose pellet core, a microcrystalline cellulose pellet core and a silicon dioxide pellet core, and is preferably a sucrose pellet core.
4. The paroxetine hydrochloride sustained-release orally disintegrating tablet of claim 1, wherein the blank inert pellet core has a particle size of 500 μm to 1500 μm.
5. The paroxetine hydrochloride sustained-release orally disintegrating tablet of claim 4, wherein the drug layer further comprises a pore-forming agent.
6. The paroxetine hydrochloride sustained-release orally disintegrating tablet as claimed in claim 1, wherein the pore-forming agent is selected from one or more of polyethylene glycol, polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxypropyl cellulose, talc, magnesium stearate, silicon dioxide and titanium dioxide.
7. The paroxetine hydrochloride sustained-release orally disintegrating tablet of claim 1, wherein a protective layer is further provided between the drug layer and the sustained-release layer or/and on the sustained-release layer, and the protective layer is Opadry.
8. The paroxetine hydrochloride sustained-release orally disintegrating tablet according to claim 1, wherein the disintegrant is one or more of croscarmellose sodium, sodium carboxymethyl starch, low-substituted hydroxypropyl cellulose and crospovidone; wherein fillers include, but are not limited to, lactose, mannitol, microcrystalline cellulose; flavoring agents include, but are not limited to, aspartame, acesulfame potassium, menthol.
9. A process for the preparation of a paroxetine hydrochloride sustained release orally disintegrating tablet as claimed in claim 1, which comprises the steps of:
(1) packaging a medicine layer: dissolving the raw materials of the drug layer in ethanol solution, placing the blank inert pellet core in a fluidized bed, coating the solution on the surface of the blank inert pellet core by bottom spraying, and controlling the temperature at 25-45 deg.C to form pellet core coated with the drug layer;
(2) coating a slow release layer: dispersing the raw materials of the sustained-release layer in water to obtain aqueous dispersion with solid content of 10-20%, stirring, placing the pill core coated with the medicinal layer in fluidized bed, coating the above solution on the surface of the pill core by bottom spraying, and controlling the temperature at 28-32 deg.C to obtain sustained-release pill core;
(3) and (3) drying: mixing the obtained sustained-release pill core with pulvis Talci, placing into oven of 45-55 deg.C, and drying for 2-3 hr;
(4) sieving with 40 mesh sieve, granulating, adding disintegrating agent, filler, sweetener and lubricant, mixing, and directly tabletting.
CN201911295613.1A 2019-12-16 2019-12-16 Paroxetine hydrochloride sustained-release orally disintegrating tablet and preparation method thereof Pending CN112972412A (en)

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CN201911295613.1A CN112972412A (en) 2019-12-16 2019-12-16 Paroxetine hydrochloride sustained-release orally disintegrating tablet and preparation method thereof

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Application publication date: 20210618