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CN121003600A - Duloxetine enteric-coated microcapsules and compound preparations and their preparation methods - Google Patents

Duloxetine enteric-coated microcapsules and compound preparations and their preparation methods

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Publication number
CN121003600A
CN121003600A CN202510616385.2A CN202510616385A CN121003600A CN 121003600 A CN121003600 A CN 121003600A CN 202510616385 A CN202510616385 A CN 202510616385A CN 121003600 A CN121003600 A CN 121003600A
Authority
CN
China
Prior art keywords
enteric
duloxetine
layer
ethanol
hpmcp
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
CN202510616385.2A
Other languages
Chinese (zh)
Inventor
刘锋
黄俊龙
谭晓峰
梁文伟
王丽群
沈耀成
郭炜绵
吴念真
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
AC Pharmaceuticals Co Ltd
Original Assignee
AC Pharmaceuticals Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by AC Pharmaceuticals Co Ltd filed Critical AC Pharmaceuticals Co Ltd
Priority to PCT/CN2025/096173 priority Critical patent/WO2025242110A1/en
Publication of CN121003600A publication Critical patent/CN121003600A/en
Pending legal-status Critical Current

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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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • 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
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • 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
    • 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
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, 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
    • A61K9/48—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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • 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
    • A61K9/5005—Wall or coating material
    • A61K9/5021—Organic macromolecular compounds
    • A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • A61K9/5047—Cellulose ethers containing no ester groups, 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
    • A61K9/48—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/12—Antidiuretics, e.g. drugs for diabetes insipidus

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Epidemiology (AREA)
  • Diabetes (AREA)
  • General Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Neurology (AREA)
  • Neurosurgery (AREA)
  • Biomedical Technology (AREA)
  • Hematology (AREA)
  • Inorganic Chemistry (AREA)
  • Pain & Pain Management (AREA)
  • Psychiatry (AREA)
  • Emergency Medicine (AREA)
  • Endocrinology (AREA)
  • Obesity (AREA)
  • Medicinal Preparation (AREA)

Abstract

The application discloses a duloxetine enteric pellet, a compound preparation and a preparation method thereof, wherein the enteric pellet comprises a pellet-containing core, an enteric inner layer and an enteric outer layer, the enteric outer layer comprises hydroxypropyl methylcellulose phthalate (HPMCP), the mass ratio of the HPMCP to the enteric outer layer is 55.6-90.9%, and the HPMCP can be dissolved in a medium with the pH value of above 5.0 or above 5.5. The duloxetine enteric pellets and the compound preparation thereof have the advantages of combining the anti-ethanol dumping effect and the ideal dissolution speed by the optimization of the anti-ethanol dumping material type and the weight increment of the enteric layer, and having lower impurity content in the weakly acidic dissolution medium with the pH value of less than 5.0 for 2 hours.

Description

Duloxetine enteric micropill, compound preparation and preparation method
Technical Field
The invention belongs to the field of pharmaceutical preparations, and in particular relates to duloxetine enteric pellets, a compound preparation and a preparation method thereof.
Background
Dose dumping (dose dumping) refers to the act of releasing all or most of the drug in a short period of time. Dose dumping can present a significant risk to patients due to safety issues and/or reduced efficacy.
Duloxetine hydrochloride (Duloxetine hydrochloride, trade name Cymbalta) is an oral selective 5-hydroxytryptamine and norepinephrine reuptake inhibitor developed by Eli Lilly company, and is widely used clinically for the treatment of major depression, stress urinary incontinence, diabetic peripheral neuropathic pain, and the like. Since duloxetine is unstable in gastric acid, acid hydrolysis of its ether linkage produces thiophene alcohol and 1-naphthol. 1-naphthol is toxic and can cause cramps, abdominal pain, nausea and vomiting. Serious systemic effects include nephritis, cystitis, liver injury, convulsions and hemolysis in patients with acute intravascular erythrocyte glucose-6-phosphate deficiency. Thus, duloxetine is generally formulated into an enteric formulation. The enteric materials in general are readily soluble in ethanol and thus duloxetine enteric formulations in the presence of ethanol are particularly prone to dose dumping, a manifestation also known as "alcohol dumping" (or "ethanol dumping"). Which results in premature and/or excessive release of the pharmaceutically active ingredient from orally administered pharmaceutical compositions, may expose the patient to high risk levels of the active agent, possibly leading to adverse reactions and/or drug-induced toxicity. To solve the problem of duloxetine alcohol dumping, it is common to add an anti-alcohol dumping material to its enteric coating. The existing materials for resisting ethanol pouring are sodium alginate, cellulose Acetate Phthalate (CAP) and the like.
However, in practical formulation development, it is not sufficient to pay attention to only the anti-ethanol dumping effect. Some enteric-coated preparations cannot achieve both the anti-ethanol-dumping effect and the drug dissolution rate due to improper selection of the type of anti-ethanol-dumping material and the thickness of the enteric-coated layer. Still other ethanol pour resistant materials dissolve due to insufficient acid resistance, resulting in the release of API under meta-acidic conditions, which in turn react to produce impurities. Therefore, the problems of ethanol pouring resistance, medicine dissolution speed, impurities and the like of the preparation need to be comprehensively solved.
Duloxetine and gamma-aminobutyric acid (GABA) analogues such as pregabalin, gabapentin, melagatran and the like are existing medicines for treating neuropathic pain including diabetic peripheral neuropathy (DSPN), however, the single medicine treatment effect of the analogues is not ideal, and the preparation of the analogues into compound preparations has practical significance. In addition, the compound preparation has good application prospect in the aspect of treating neuropathic pains such as postherpetic neuralgia (PHN), trigeminal neuralgia, postoperative neuropathy, sciatica, post-stroke neuralgia and the like, and mixed pains such as pains caused by lumbar and dorsal nerve roots, cervical radiculopathy, cancer pains, carpal tunnel syndrome and the like with concurrent neuropathic pains and nociceptive pains.
Disclosure of Invention
The invention aims to provide duloxetine enteric pellets, a compound preparation and a preparation method thereof, which ensure that the duloxetine enteric pellets and the compound preparation thereof have both the anti-ethanol dumping effect and the ideal dissolving speed and have lower impurity content in a weakly acidic dissolving medium with the pH value of less than 5.0 for 2 hours through the optimization of the type of anti-ethanol dumping materials and the thickness of an enteric layer.
The invention aims at being realized by the following technical scheme:
a duloxetine enteric pellet comprises a core containing pill, an enteric inner layer and an enteric outer layer.
The enteric coating contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein the HPMCP accounts for 55.6-90.9% of the enteric coating by mass.
The dosage of the enteric coating accounts for 9-200% of the mass of the enteric coating inner pellet (hereinafter also referred to as weight increment), and the duloxetine enteric pellet can resist ethanol dumping and has a dissolution rate meeting the requirement.
A duloxetine enteric pellet comprises a core containing pill, an enteric inner layer and an enteric outer layer.
The enteric coating contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein the HPMCP accounts for 55.6-90.9% of the enteric coating by mass.
The HPMCP can be dissolved in a medium with the pH value of more than 5.0.
The HPMCP dissolved in the medium with the pH value of more than 5.0 is preferably HP-50, and the phthaloyl content of the HPMCP is 21.0-27.0%.
When the HPMCP can be dissolved in a medium with the pH value of above 5.0, the dosage of the enteric outer layer accounts for 9-200% of the mass of the enteric inner layer pellets (hereinafter also referred to as weight increment), the duloxetine enteric pellets under weight increment can resist 20% ethanol dumping, the dissolution rate meets the requirement, preferably, the weight increment of the enteric outer layer is 12-150%, and further preferably, the weight increment of the enteric outer layer is 12-100%;
particularly preferably, the weight of the enteric coating is 60-200%, and the duloxetine enteric pellets under the weight increase can resist 20-40% ethanol dumping and have a dissolution rate meeting the requirement.
A duloxetine enteric pellet comprises a core containing pill, an enteric inner layer and an enteric outer layer.
The enteric coating contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein the HPMCP accounts for 55.6-90.9% of the enteric coating by mass.
The HPMCP can be dissolved in a medium with the pH value of more than 5.5.
The HPMCP dissolved in the medium with the pH value of more than 5.5 is preferably HP-55 or HP-55S, and the phthaloyl content of the HPMCP is 27.0-35.0%. At 20 ℃, the viscosity of a 10% (W/W) methanol-dichloromethane (1:1) (W/W) solution prepared by HP-55 is 32-48 mPa.s, and the viscosity of a 10% (W/W) methanol-dichloromethane (1:1) (W/W) solution prepared by HP-55s is 136-204 mPa.s.
The HPMCP can be dissolved in a medium with the pH value of more than 5.5, the weight gain of the enteric coating is more than 9%, the duloxetine enteric pellets under the weight gain can resist 20% ethanol dumping, the weight gain of the enteric coating is preferably more than 50%, and the duloxetine enteric pellets under the weight gain can resist 20-40% ethanol dumping;
Further preferably, the weight of the enteric coating is 12-50%, and the duloxetine enteric pellets under weight increment can resist 20% ethanol dumping and have a dissolution rate meeting the requirement.
Preferably, the enteric outer layer contains HPMCP and more than one auxiliary agent.
Further preferably, the enteric outer layer comprises HPMCP, a plasticizer and an anti-adhesive agent.
Particularly preferably, the enteric outer layer contains the following components in percentage by mass:
HPMCP:55.6~90.9%
3.2 to 22.2 percent of plasticizer
3.7-32.3% Of anti-adhesion agent.
An isolating layer is arranged between the pill-containing core and the enteric-coated inner layer. The main function of the isolation layer is to isolate the pill-containing core from the enteric inner layer so as to prevent unnecessary interaction between the medicine and the enteric inner layer and keep the stability and activity of the medicine.
The duloxetine enteric pellets are characterized in that a protective layer is arranged outside an enteric outer layer. The protective layer has the functions of reducing static electricity of the pellets in the capsule filling process, preventing external environmental factors (such as humidity, oxygen, light and the like) from affecting the physical aspects, the chemical aspects and the like of the pellets, and can be colored to form certain appearance characteristics for distinguishing and identifying.
The enteric inner layer contains enteric materials or more than one auxiliary agent, and the mass of the enteric inner layer is 45.5-100%.
Preferably, the enteric inner layer comprises an enteric material, a plasticizer and an anti-adhesive agent.
The enteric material is at least one of hydroxypropyl methylcellulose acetate succinate (HPMCAS), methacrylic acid-ethyl acrylate copolymer and water dispersion thereof, methacrylic acid copolymer A type and polyvinyl acetate phthalate.
The dosage of the enteric inner layer accounts for 15-65% of the mass of the isolation layer pellets (or the pill-containing cores), and preferably 20-60%.
Preferably, the enteric inner layer comprises the following components in percentage by mass:
45.5-100% of enteric material
0 To 37.5% of anti-adhesion agent
0-37.5% Of plasticizer.
The pill-containing core comprises a blank pill core and a drug-containing layer, and is prepared by processes such as pill core drug loading, or a pill-containing core prepared by mixing duloxetine or salt thereof and an auxiliary agent, and can be prepared by processes such as centrifugal pill making or extrusion and spheronization.
When the pill core medicine-feeding process is adopted, the pill-containing core contains blank pill cores, duloxetine or salt thereof, film-forming materials and optional auxiliary agents.
The blank pill core is sucrose pill core, lactose pill core, starch pill core, microcrystalline cellulose pill core, mannitol pill core, silicon dioxide pill core or lactose-microcrystalline cellulose pill core.
The drug-containing layer contains duloxetine or salt thereof, a film-forming material and optional auxiliary agents.
The weight of the drug-containing layer is increased by 90-130% of the weight of the blank pill core.
Preferably, the drug-containing layer contains duloxetine or a salt thereof, a film-forming material and an anti-adhesive agent.
Particularly preferably, the medicine-containing layer contains the following components in percentage by mass:
65-80% of duloxetine or salt thereof
15-25% Of film forming material
5-10% Of an anti-adhesion agent.
When using a centrifugal pelleting or extrusion spheronization process, the pellet-containing core contains duloxetine or a salt thereof, and one or more auxiliary agents, preferably duloxetine or a salt thereof, a binder and a filler.
The isolation layer contains a film forming material or more than one auxiliary agent, and the film forming material accounts for 5-100%.
The concrete composition comprises the following components in percentage by mass:
5-100% of film forming material
0-80% Of pore-forming agent
0-50% Of an anti-adhesion agent.
The weight gain of the isolation layer accounts for 10-155% of the mass of the pill core.
The protective layer contains a film forming material or more than one auxiliary agent, and the film forming material accounts for 50-90%.
The concrete composition comprises the following components in percentage by mass:
50-90% of film forming material
0-30% Of opacifier
10-50% Of an anti-adhesion agent.
The protective layer accounts for 2-15% of the mass of the enteric outer-layer pellets.
The preparation method of the duloxetine enteric pellets comprises the following steps:
(1) Preparing a pill-containing core, namely preparing bulk drugs, a film-forming material, an auxiliary agent and water into a suspension coating liquid, using a fluidized bed to carry out bottom spraying coating, and atomizing and spraying the suspension coating liquid on a blank pill core to obtain the pill-containing core, or preparing the pill-containing core by using a centrifugal pill-making or extrusion and spheronization process;
(2) Preparing a film forming material, an auxiliary agent and water into an isolation layer coating liquid, using a fluidized bed to carry out bottom spraying coating, and spraying the isolation layer coating liquid on the drug-containing pellets to obtain isolation layer pellets;
(3) Enteric coating, namely preparing enteric material, auxiliary agent and solvent into enteric coating liquid, wherein the solvent is at least one of water and ethanol, using a fluidized bed to carry out bottom spray coating, and spraying the enteric coating liquid on the isolated layer pellets to obtain enteric coating pellets;
(4) Enteric coating, namely preparing HPMCP, auxiliary agent, ethanol and water into enteric coating liquid, using a fluidized bed to carry out bottom spray coating, and spraying the enteric coating liquid on the enteric inner pellet to obtain the enteric outer pellet;
(5) And (3) coating a protective layer, namely preparing a film forming material, an auxiliary agent and water into a protective layer coating liquid, using a fluidized bed to carry out bottom spraying coating, and spraying the coating liquid on the enteric-coated outer-layer pellets to obtain the duloxetine enteric-coated pellets.
A compound preparation contains the duloxetine enteric micropill.
The compound preparation contains duloxetine enteric pellets and gamma-aminobutyric acid analogues.
The compound preparation is obtained by filling duloxetine enteric pellets and gamma-aminobutyric acid analogues into capsule shells.
The gamma-aminobutyric acid analogue is in an immediate release form.
The gamma-aminobutyric acid analogue is pregabalin, gabapentin, melagatran or pregabalin besylate.
The quick-release part of the gamma-aminobutyric acid analogue comprises the gamma-aminobutyric acid analogue and more than one auxiliary agent, and comprises the following components in percentage by mass:
7-97% of gamma-aminobutyric acid analogue
3-85% Of anti-adhesion agent
0-85% Of disintegrating agent
0-90% Of filler.
The gamma-aminobutyric acid analogue is preferably pregabalin.
The pregabalin quick-release part comprises pregabalin and more than one auxiliary agent, wherein the pregabalin accounts for 10-97% of the quick-release part, and the pregabalin quick-release part comprises the following components in percentage by mass:
10-97% of pregabalin
3-85% Of anti-adhesion agent
0-85% Of disintegrating agent.
In the compound preparation, the mass ratio of pregabalin to duloxetine is (3.75-5.00) 1.
The compound preparation contains 150mg of pregabalin and 30-40 mg of duloxetine, or contains 75mg of pregabalin and 15-20 mg of duloxetine.
The administration method is to administer the compound preparation to a patient for 1-3 times a day, preferably for 2 times a day, wherein the mass ratio of pregabalin to duloxetine in the compound preparation is (3.75-5.00): 1.
Preferably, the compound preparation contains 150mg of pregabalin and 30-40 mg of duloxetine, and is administrated 2 times a day.
Preferably, the compound preparation contains 75mg of pregabalin and 15-20 mg of duloxetine, and is administrated 2 times a day.
The film forming material is more than one of hypromellose, hydroxypropyl cellulose, povidone, polyvinyl alcohol, acacia or methacrylic acid aminoalkyl ester copolymer.
The auxiliary agent is one or more of plasticizer, anti-adhesive, opacifier, pore-forming agent, disintegrating agent, adhesive or filler.
The plasticizer is one or more of triethyl citrate, tributyl citrate, polyethylene glycol, diethyl phthalate, dimethyl phthalate, dibutyl sebacate, cetyl alcohol, propylene glycol, glycerol, polyethylene glycol, castor oil, diacetyl monoglyceride, olive oil or succinic acid.
The anti-adhesion agent is inorganic powder, preferably talcum powder and/or silicon dioxide.
The opacifier is a lake, preferably more than one of titanium dioxide, ferric oxide, aluminum lake or ferric pyrophosphate.
The pore-forming agent is more than one of sucrose, lactose, mannitol, sodium chloride, potassium chloride or polyethylene glycol.
The disintegrating agent is more than one of crosslinked sodium carboxymethyl cellulose, crosslinked povidone, corn starch, potato starch, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose, pregelatinized starch, sodium carboxymethyl starch or microcrystalline cellulose.
The adhesive is one or more of corn starch, potato starch, pregelatinized starch, soluble starch, water-soluble starch, hydroxypropyl cellulose, hypromellose, povidone or dextrin.
The filler is one or more of microcrystalline cellulose, lactose monohydrate, lactose anhydrous, mannitol, anhydrous calcium hydrogen phosphate, calcium hydrogen phosphate dihydrate, corn starch, potato starch, sucrose, dextrin or calcium sulfate.
Compared with the prior art, the application has the following advantages and beneficial effects:
1. According to the application, through the optimization of the type of the anti-ethanol pouring material and the thickness of the enteric layer, HPMCP is selected as the enteric material (enteric outer layer) for resisting ethanol pouring, so that the duloxetine enteric pellets have both the anti-ethanol pouring effect and the ideal dissolution speed, and the impurity content generated by the duloxetine enteric pellets in a weakly acidic dissolution medium with the pH value of less than 5.0 for 2 hours is lower.
2. The product prepared by adopting sodium alginate as an ethanol-pouring-resistant material mainly uses the principle that polysaccharide is insoluble in ethanol, and can resist 40% ethanol dosage pouring but cannot resist 20% ethanol dosage pouring under the condition that the weight of a sodium alginate layer is increased by 50%. Under this weight gain, the resulting formulation does not have the ability to resist 20% ethanol dumping and the dissolution rate is too slow to be satisfactory, so there is no need to increase the weight gain so that the product resists 20% ethanol dumping, which results in slower dissolution rates.
3. The enteric-coated outer-layer coating liquid is adopted to prepare enteric-coated inner-layer pellets, and under the condition of 35% weight gain, although the in-vitro dissolution speed can meet the standard requirement by adjusting the weight gain of the enteric-coated inner-layer pellets, the preparation can resist 20% ethanol dumping, and in the in-vivo pharmacokinetics experiment of beagle dogs, C max and AUC 0-t are obviously lower than Cymbalta (duloxetine hydrochloride enteric-coated capsule original grinding medicine) and do not meet the requirement. Since C max and AUC 0-t were significantly lower in beagle experiments, continued increase in CAP gain only resulted in slower release of the formulation in beagle, and no increase in C max and AUC 0-t. Thus, while increasing CAP weight gain may potentially render it resistant to 40% ethanol dumping, there is no study to continue to increase CAP weight gain as the beagle experimental data has been significantly unexpected. Under the condition of 35% of enteric coating weight gain, the prepared compound preparation has the dissolution rate of 29% in 120min in the 20% ethanol dosage pouring resisting experiment, and is close to the limit, so that the study of lower CAP weight gain in the compound preparation is not necessary. Meanwhile, when CAP is used for coating, acetone is needed to be used as a coating solvent, the acetone has certain toxicity and is relatively not environment-friendly, and the acetone has high explosion-proof requirements on workshops and the preparation production environment is harsh.
4. The results of the original manufacturer's study of Cymbalta showed that the bioavailability of duloxetine decreased after night administration. The original research manufacturer considers that the delayed gastric emptying is caused by the night administration, and the coating film of the original research medicine cannot be kept unbroken in the time of delayed gastric emptying, so that duloxetine is degraded into naphthol, and the bioavailability of the product is reduced. The preparation of the invention is added with a layer of enteric coating film, which can obviously increase the acid resistance of the preparation. Therefore, the compound preparation provided by the invention is presumed that the degradation proportion of duloxetine is reduced after night administration, and the bioavailability is improved compared with that of the original product, thereby being beneficial to improving the curative effect and reducing the toxic and side effects.
5. The inventor surprisingly found that the ethanol pouring resistant preparation is prepared by adopting a scheme of a double-layer enteric layer (using HPMCAS and HPMCP as enteric materials of an inner layer and an outer layer respectively), the overall ethanol pouring resistant capability is reduced after pregabalin is added to prepare a compound preparation, and the inventor further optimizes the thickness of the enteric outer layer (HPMCP) so that the release amount of duloxetine in the ethanol-containing hydrochloric acid solution of the compound preparation can also meet the set limit.
6. The relevant substances produced by Cymbalta in a hydrochloric acid solution containing 20% ethanol are significantly higher than those produced in a hydrochloric acid solution containing 40% ethanol, indicating that duloxetine is more unstable in a hydrochloric acid solution containing 20% ethanol, and the product's resistance to 20% ethanol dumping is more important than that of 40% ethanol dumping. In the compound preparation provided by the invention, the release amount of duloxetine in a hydrochloric acid solution of 20% ethanol is obviously lower than that of Cymbalta.
Detailed Description
The present invention will be described in further detail with reference to examples, but embodiments of the present invention are not limited thereto.
Example 1
The duloxetine enteric pellet comprises a blank pellet core, a drug-containing layer, an isolation layer, an enteric inner layer and an enteric outer layer, wherein the dosage of the enteric outer layer accounts for 33% of the mass of the enteric inner layer pellet, and the compositions of the enteric inner layer and the enteric outer layer are shown in table 1:
table 1 composition of enteric inner and outer layers of enteric pellets of each prescription
The batch of the pellets is 800g, wherein the compositions of the blank pellet cores, the drug-containing layers and the isolation layers (the prescriptions 1-5 are the same) are shown in the following table 2:
TABLE 2 composition of pellet core, drug-containing layer and isolation layer (mg)
The preparation method of the duloxetine enteric pellets comprises the following steps:
(1) The preparation method of the pill core comprises preparing duloxetine hydrochloride, hypromellose, pulvis Talci and water into suspension coating liquid, and performing bottom spray coating with fluidized bed. Preheating sucrose pellet core before spraying, and keeping the temperature of target material above 40deg.C. After preheating, setting the air inlet temperature to be 45-75 ℃, setting the atomization pressure to be 1.5bar, spraying the liquid at the speed of less than or equal to 10g/min, and atomizing and spraying the suspended coating liquid on the sucrose pill core. And after spraying, setting the air inlet temperature to be 45-75 ℃ and drying for 10min to obtain the pill core.
(2) And (3) isolating coating, namely preparing hypromellose, sucrose, talcum powder and water into an isolating layer coating liquid, and using a fluidized bed for bottom spraying coating. Before spraying, preheating the pill-containing core, wherein the temperature of the target material is above 40 ℃. After the preheating is finished, the air inlet temperature is set to be 45-75 ℃, the atomization pressure is set to be 1.5bar, the liquid spraying speed is less than or equal to 10g/min, and the suspended coating liquid is atomized and sprayed on the pill-containing cores. And after spraying, setting the air inlet temperature to be 45-75 ℃ and drying for 10min to obtain the isolation layer pellets.
(3) Enteric inner coating:
Prescription 1, prescription 3 and prescription 4, HPMCAS, talcum powder (if any), triethyl citrate (if any), ethanol and water are prepared into enteric inner coating liquid, and the fluid bed is used for bottom spray coating. Before spraying, preheating the isolation layer pellets, wherein the temperature of the target material is above 40 ℃. After the preheating is finished, the air inlet temperature is set to be 40-65 ℃, the atomization pressure is 1.5bar, the liquid spraying speed is less than or equal to 10g/min, and the suspended coating liquid is atomized and sprayed on the isolation layer pellets. After spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 30min to obtain enteric inner-layer pellets;
Prescription 2 and prescription 5, the methacrylic acid-ethyl acrylate copolymer, talcum powder, triethyl citrate and ethanol are prepared into enteric inner layer coating liquid, the solvent is ethanol, and the fluidized bed is used for bottom spray coating. Before spraying, preheating the isolation layer pellets, wherein the temperature of the target material is above 35 ℃. And after the preheating is finished, setting the air inlet temperature to be 25-40 ℃, setting the atomization pressure to be 1.7bar, spraying the liquid at the speed of less than or equal to 10g/min, and atomizing and spraying the suspended coating liquid on the isolation layer pellets. After spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 30min to obtain enteric inner-layer pellets;
(4) Enteric coating, namely preparing HPMCP, plasticizer, talcum powder, ethanol and water into enteric coating liquid, and using a fluidized bed for bottom spray coating. Before spraying, the enteric-coated inner pellet is preheated, and the temperature of the target material is above 40 ℃. After the preheating is finished, the air inlet temperature is set to be 45-65 ℃, the atomization pressure is set to be 1.7bar, the spraying speed is less than or equal to 10g/min, and the suspended coating liquid is atomized and sprayed on the enteric-coated inner-layer pellets. And after spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 30min to obtain the duloxetine enteric pellets.
The release of duloxetine pellets prepared by each prescription in 750mL of 0.1mol/L hydrochloric acid solution containing 20% ethanol and 0.1mol/L hydrochloric acid solution containing 40% ethanol was measured by adopting a basket method of 100 revolutions per minute, and the influence of ethanol on duloxetine release was examined.
The release dose (%) of duloxetine in 20% ethanol medium for each formulation is shown in table 3.
The release dose (%) of duloxetine in 40% ethanol medium for each formulation is shown in table 4.
In the examples, prescription 3 (30) represents adjusting the weight gain of the enteric outer layer of prescription 3 to 30%, and so on.
Prescription 3-a represents the replacement of HP-50 in the enteric outer layer of prescription 3 with HP-55, with the weight gain of the enteric outer layer remaining unchanged, still 33%.
Prescription 3-B represents a replacement of HP-50 in the enteric outer layer of prescription 3 with HP-55S, with the weight gain of the enteric outer layer unchanged, still 33%.
Prescriptions 3-A (9) and 3-B (9) represent respectively adjusting the weight gain of the enteric coating of 3-A and 3-B to 9%, and so on.
Prescription 3' represents a prescription obtained by removing the enteric coating layer component from prescription 3.
The comparative example is Cymbalta (also referred to as reference formulation in the present invention), which is a raw product, and adopts a single enteric layer, and HPMCAS as an enteric material.
Prescription 3-sodium alginate (50) shows that sodium alginate is used as a material for resisting ethanol pouring on the basis of prescription 3 enteric-coated inner-layer pellets, the components of a sodium alginate coating layer are sodium alginate and polyethylene glycol (sodium alginate: polyethylene glycol=10:3), and the weight gain of the sodium alginate coating layer is 50%.
Prescription 3-CAP (35) means that CAP is used as a material for anti-ethanol dumping based on prescription 3 enteric inner pellets, the components of the CAP coating layer are CAP and diethyl phthalate (CAP: diethyl phthalate=3:1), the weight gain of the CAP coating layer is 35%, and the like.
When sodium alginate is used as a coating material for resisting ethanol dumping, the preparation method of the duloxetine pellets is as follows:
(1) The preparation method of the pill core comprises preparing duloxetine hydrochloride, hypromellose, pulvis Talci and water into suspension coating liquid, and performing bottom spray coating with fluidized bed. Preheating sucrose pellet core before spraying, and keeping the temperature of target material above 40deg.C. After preheating, setting the air inlet temperature to be 45-75 ℃, setting the atomization pressure to be 1.5bar, spraying the liquid at the speed of less than or equal to 10g/min, and atomizing and spraying the suspended coating liquid on the sucrose pill core. After spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 10min to obtain a pill-containing core;
(2) And (3) isolating coating, namely preparing hypromellose, sucrose, talcum powder and water into an isolating layer coating liquid, and using a fluidized bed for bottom spraying coating. Before spraying, preheating the pill-containing core, wherein the temperature of the target material is above 40 ℃. After the preheating is finished, the air inlet temperature is set to be 45-75 ℃, the atomization pressure is set to be 1.5bar, the liquid spraying speed is less than or equal to 10g/min, and the suspended coating liquid is atomized and sprayed on the pill-containing cores. After spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 10min to obtain isolation layer pellets;
(3) Enteric coating, namely preparing HPMCAS, talcum powder, triethyl citrate, ethanol and water into enteric inner layer coating liquid, and performing bottom spray coating by using a fluidized bed. Before spraying, preheating the isolation layer pellets, wherein the temperature of the target material is above 40 ℃. After the preheating is finished, the air inlet temperature is set to be 40-65 ℃, the atomization pressure is 1.5bar, the liquid spraying speed is less than or equal to 10g/min, and the suspended coating liquid is atomized and sprayed on the isolation layer pellets. After spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 30min to obtain enteric layer pellets;
(4) And (3) coating sodium alginate, namely preparing sodium alginate, polyethylene glycol and water into coating liquid, and performing bottom spray coating by using a fluidized bed. After the preheating is finished, the air inlet temperature is set to be 45-75 ℃, the atomization pressure is set to be 1.7bar, the liquid spraying speed is less than or equal to 10g/min, and the coating liquid is atomized and sprayed on the enteric coating pellets. And after spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 30min to obtain the sodium alginate coated pellets.
When CAP is used as an enteric coating material, the preparation method of the duloxetine enteric pellets is as follows:
(1) The preparation method of the pill core comprises preparing duloxetine hydrochloride, hypromellose, pulvis Talci and water into suspension coating liquid, and performing bottom spray coating with fluidized bed. Preheating sucrose pellet core before spraying, and keeping the temperature of target material above 40deg.C. After preheating, setting the air inlet temperature to be 45-75 ℃, setting the atomization pressure to be 1.5bar, spraying the liquid at the speed of less than or equal to 10g/min, and atomizing and spraying the suspended coating liquid on the sucrose pill core. After spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 10min to obtain a pill-containing core;
(2) And (3) isolating coating, namely preparing hypromellose, sucrose, talcum powder and water into an isolating layer coating liquid, and using a fluidized bed for bottom spraying coating. Before spraying, preheating the pill-containing core, wherein the temperature of the target material is above 40 ℃. After the preheating is finished, the air inlet temperature is set to be 45-75 ℃, the atomization pressure is set to be 1.5bar, the liquid spraying speed is less than or equal to 10g/min, and the suspended coating liquid is atomized and sprayed on the pill-containing cores. After spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 10min to obtain isolation layer pellets;
(3) Enteric inner coating, namely preparing HPMCAS, talcum powder, triethyl citrate, ethanol and water into enteric inner coating liquid, and performing bottom spray coating by using a fluidized bed. Before spraying, preheating the isolation layer pellets, wherein the temperature of the target material is above 40 ℃. After the preheating is finished, the air inlet temperature is set to be 40-65 ℃, the atomization pressure is 1.5bar, the liquid spraying speed is less than or equal to 10g/min, and the suspended coating liquid is atomized and sprayed on the isolation layer pellets. After spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 30min to obtain enteric inner-layer pellets;
(4) Enteric coating, namely preparing CAP, diethyl phthalate and acetone into enteric coating liquid, and using a fluidized bed for bottom spray coating. Before spraying, the enteric-coated inner pellet is preheated, and the temperature of the target material is above 35 ℃. After the preheating is finished, the air inlet temperature is set to be 40-60 ℃, the atomization pressure is 1.8bar, the liquid spraying speed is less than or equal to 10g/min, and the coating liquid is atomized and sprayed on the enteric inner-layer pellets. And after spraying, setting the air inlet temperature to be 45-75 ℃, and drying for 30min to obtain enteric-coated outer-layer pellets (duloxetine enteric pellets).
TABLE 3 Release of enteric pellets of each prescription in 20% ethanol medium (%)
Prescription of prescription 30min 45min 60min 90min 120min
1 0 0 0 0 0
2 0 0 0 0 0
3 0 0 0 0 0
4 0 0 0 0 0
5 0 0 0 0 0
3(30) 0 0 0 0 0
3(12) 0 0 0 3 9
3(9) 0 0 1 14 28
3-A 0 0 0 0 0
3-A(12) 0 0 0 2 8
3-A(9) 0 0 0 5 22
3-B 0 0 0 0 0
3-B(12) 0 0 0 2 7
3-B(9) 0 0 0 5 21
3’ 0 8 52 94 94
Comparative example 0 7 52 93 93
3-Sodium alginate (50) 0 1 24 52 70
3-CAP(35) 0 0 1 4 16
In the 2025 edition of the Chinese pharmacopoeia, the limit of the dissolution rate of duloxetine hydrochloride in hydrochloric acid is not more than 10% in 2 hours, and the limit of the dissolution rate of duloxetine hydrochloride in hydrochloric acid containing ethanol is not specified. In the present application, the ethanol pouring resistance up to the standard is a standard that the dissolution rate in 2 hours is not more than 30%, and under the limit, it can be considered that the safety of taking a preparation meeting the standard is significantly better than that of the comparative example even in the case of some drinking wines.
Comparative examples in both of 20% ethanol-containing hydrochloric acid (Table 3) and 40% ethanol-containing hydrochloric acid (Table 4), the 2-hour elution amounts exceeded 90%.
Formulations 1-5 and comparative examples did not release (0%) in 2 hours in 0.1mol/L hydrochloric acid solution without ethanol.
As can be seen from table 3, the formulations (comparative examples and formulation 3') without the enteric HPMCP outer layer did not have the ability to resist 20% ethanol dumping, and the 2-hour duloxetine elution amount was 90% or more, exceeding the standard that the 2-hour elution amount was not more than 30%.
At 33% weight gain, the enteric pellets of the dual enteric layer (inner HPMCAS+outer HPMCP (HP-50, HP-55 or HP-55S)) regimen of the present invention had very desirable anti-20% ethanol dumping effect. Therefore, the weight gain of the enteric coating can be regulated downwards, and the 20% ethanol pouring resisting effect still reaches the standard when the weight gain is 9%.
The effect of the sodium alginate coated pellets on 20% ethanol dumping at 50% weight gain is not up to standard. Because the prescription using sodium alginate as the enteric layer material dissolves significantly slower than the comparative example (see table 5) at a weight gain of 50%, it is not necessary to increase the weight gain to improve the ethanol dumping resistance.
Based on the prescription 3, HP-50 in the enteric coating is replaced by CAP, and the anti-20% ethanol dumping effect meets the anti-ethanol dumping requirement under the condition of 35% weight gain.
Table 4 Release of enteric pellets of each formulation in 40% ethanol medium (%)
The experiment shows that the dosage of the preparation (single-layer enteric layer) taking HPMCAS as the enteric layer material in the comparative example and the prescription 3' is poured at 40% ethanol, and the release amount reaches more than 90% in 2 hours.
At 33% weight gain, the anti-40% ethanol dumping effect of the double enteric layer (inner HPMCAS+outer HPMCP (HP-50, HP-55 or HP-55S)) formulation of the present invention was not ideal.
Further adjusting the weight gain of the enteric coating to meet the 40% ethanol dumping resistance, it was found that at least 60% of the weight gain of the enteric coating was required with HP-50 as the enteric material, and at least 55% and 50% of the weight gain of the enteric coating was required with HP-55 or HP-55S, respectively.
Prescription 3-sodium alginate (50) was resistant to 40% ethanol dose dumping and was better than 20% resistant to 40% ethanol dumping, probably due to sodium alginate being water soluble but not ethanol soluble.
The prescription 3-CAP (35) takes CAP as an enteric material, and the anti-40% ethanol pouring effect does not reach the standard when the weight of the enteric coating is increased by 35%. However, the dissolution of the formulation was already slower (see example 2, table 5) due to this weight gain, the increased weight dissolution tended to be slower, and the relevant animal experimental data showed (see example 3, table 6) that in the in vivo pharmacokinetic experiment in beagle dogs, the formulation schemes C max and AUC 0-t were significantly lower than Cymbalta (duloxetine hydrochloride enteric capsule prime). There has been no need to increase the coating weight gain to investigate resistance to 40% ethanol dumping.
Example 2
Referring to the dissolution requirement of each theory of duloxetine hydrochloride enteric capsule in the second part of the Chinese pharmacopoeia 2025, the dissolution and release degree measurement method (the first method enteric preparation method 1 of the general rule 0931 of the Chinese pharmacopoeia 2025) is adopted to measure the release curve of the duloxetine hydrochloride enteric pellets.
0-2 Hours, namely 0.1mol/L hydrochloric acid solution, 750mL;
After 2 hours, the medium is replaced, 250mL of 0.2mol/L sodium phosphate solution (pH value is adjusted to 6.8+/-0.05 by 2mol/L hydrochloric acid solution or 2mol/L sodium hydroxide solution if necessary) with the temperature of 37 ℃ plus or minus 0.5 ℃ is added into the acid solution, and the total volume is 1000mL;
the rotation speed is 100 rpm.
The results are shown in Table 5.
Table 5 enteric pellets of each prescription in hydrochloric acid dissolution in pH6.8 medium (%)
Table 5 shows that under the condition that the weight of the enteric coating is increased by 33%, the dissolution rate of HP-50 serving as a prescription of the enteric material is far higher than 75% after the hydrochloric acid is converted into pH6.8, the enteric coating meets the requirements (the theory of duloxetine hydrochloride enteric capsule version 2025 in Chinese pharmacopoeia) and the weight is increased to 200% continuously, and the dissolution still meets the requirements. The method shows that the dissolution requirement can be met when the weight of the enteric inner layer is increased by 20-65% and the weight of the enteric outer layer is increased by 200% at most.
The dissolution rate of HP-55 or HP-55S serving as the prescription of the enteric material is higher than 75% after the pH of hydrochloric acid is changed to 6.8 under the condition that the weight of the enteric coating is increased by 33%, the enteric coating meets the requirement, and the dissolution rate still meets the requirement after the weight is increased to 50%. It is explained that when HP-50 or HP-55S is used as the enteric coating material, the enteric coating layer is increased by 50% or less, and the dissolution of hydrochloric acid at pH6.8 can be satisfied.
The dissolution rate of the prescription 3-sodium alginate (50) is not satisfactory.
HP-50 in the enteric coating of the prescriptions 2, 3 and 5 is replaced by CAP, and the dissolution speed of the prescriptions 2-CAP (35) and 3-CAP (35) meets the requirement under the condition that the weight of the enteric coating is increased by 35 percent, but the dissolution speed of the 5-CAP (35) does not meet the requirement.
Example 3
Comparing with comparative example original grinding product Cymbalta (60 mg specification), 60mg specification (duloxetine micro-pill of table 2 is used for filling, and duloxetine hydrochloride enteric capsule containing duloxetine 60mg per capsule is used for performing beagle dog PK test to examine the pharmacokinetic condition of different prescriptions in beagle dogs) obtained by 5 prescriptions of 3 (150), 3-A (25), 3-B (25), 3-CAP (35) and 2-CAP (35). The blood sampling time points are 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 4h, 5h, 6h, 8h, 12h, 18h, 24h and 30h, and the measuring method is LC-MS/MS. The results are shown in Table 6:
Table 6 pharmacokinetic parameters of each of the prescribed enteric pellets
The enteric pellets obtained from the prescriptions 3-CAP (35) and 2-CAP (35) have significantly lower geometric means of C max and AUC (0-t) in beagle dogs than the reference formulation. The geometric mean values of the C max and the AUC (0-t) of the other 3 prescriptions are between 90% and 110% of the reference preparation, and are relatively close to the reference preparation.
Example 4
The stability of the duloxetine hydrochloride enteric capsule single formulation prepared in formulation 3 and the comparative example in 750mL of 0.1mol/L hydrochloric acid solution containing 20% ethanol was measured using basket method at 100 rpm, the investigation time was 2 hours, and the detection results of impurities are shown in table 7.
TABLE 7 detection results of impurities in a sample of 0.1mol/L hydrochloric acid solution containing 20% ethanol
From the experimental results, the level of the relevant substances detected by the prescription 3 is significantly lower than that of the comparative example at the same time. The concentration of 20% ethanol represents a cocktail, which means that the relevant substances produced when taking homemade samples are significantly lower than those produced when taking comparative examples in the case of drinking cocktails, and can improve the safety of the drug.
The stability of the duloxetine hydrochloride enteric capsule single formulation prepared in formulation 3 and the comparative example in 750mL of a 0.1mol/L hydrochloric acid solution containing 40% ethanol was measured using a basket method of 100 rpm, and the detection results of impurities are shown in table 8.
TABLE 8 detection results of impurities in a sample of 0.1mol/L hydrochloric acid solution containing 40% ethanol
From the experimental results, the level of the relevant substances detected by the prescription 3 is significantly lower than that of the comparative example at the same time. The concentration of 40% ethanol represents white spirit, which means that the medicine is taken under the condition of drinking white spirit, and related substances generated by taking self-made samples are obviously lower than those of the comparative example, so that the safety of the product can be improved.
Prescription 3 is more resistant to 20% ethanol than 40% ethanol, so that prescription 3 detects less of the relevant substances in a 0.1mol/L hydrochloric acid solution containing 20% ethanol than in a 0.1mol/L hydrochloric acid solution containing 40% ethanol.
The comparative examples were inferior in resistance to both 20% ethanol and 40% ethanol. The pH of the 0.1mol/L hydrochloric acid solution containing 20% ethanol was lower than that of the 0.1mol/L hydrochloric acid solution containing 40% ethanol, so that the substances of interest detected in the comparative example in the 0.1mol/L hydrochloric acid solution containing 20% ethanol were higher than those detected in the 0.1mol/L hydrochloric acid solution containing 40% ethanol at the same time. It is said that duloxetine is more unstable in a hydrochloric acid solution containing 20% ethanol, and the resistance of the product to 20% ethanol dumping is more important than the resistance to 40% ethanol dumping.
Example 5
Prescription 3 (outer HP-50) is based on prescription 3, the enteric inner layer is removed, and only the enteric outer layer is left;
The duloxetine enteric pellets obtained in formulas 3, 3 (external HP-50), 3-A and 3-B were placed in a medium having a pH of 5.0, and the impurity content was examined by the following method:
Taking 1 capsule, placing the dissolution device in 500mL sodium phosphate (pH 5.0) buffer solution at 37deg.C at 100rpm by spin basket method, and sampling and detecting related substances at 2 hr and 6 hr.
Octyl silane bonded silica gel is used as a filler (Zorbax SB C8,4.6mm multiplied by 150mm,3.5 mu m), phosphate buffer solution (3.4 g of monopotassium phosphate and 15mL of triethylamine are taken, 1000mL of water is added for dissolution, phosphoric acid is used for adjusting the pH value to 5.5+/-0.05) -methanol (60:40) is used as a mobile phase A, methanol is used as a mobile phase B, gradient elution is carried out, the flow rate is 1.5mL per minute, the column temperature is 45 ℃, the detection wavelength is 230nm, and the sample injection volume is 80 mu L.
The results are shown in the following table:
Table 9 content of impurities in enteric pellets of each prescription
As can be seen from Table 9, the duloxetine related substances content is very low under the double-layer enteric layer (inner HPMCAS+outer HPMCP) scheme (prescriptions 3, 3-A and 3-B), the total impurities in 2 hours are less than 0.05%, and the total impurities in 6 hours are 0.05% -0.07%.
In contrast, the regimen with HP-50 as the sole enteric layer (formulation 3 (outer HP-50)) produced significant impurities at both 2h and 6 h. This is due to the dissolution of HP-50 at pH5.0, resulting in drug release. Whereas duloxetine hydrochloride is relatively unstable at pH5.0 and degrades to produce impurities. If the enteric inner layer is contained, the medicine can be prevented from being released in advance at the pH of 5.0, so that the generation of impurities is reduced, and the risk of toxic and side effects of the medicine in vivo is reduced. This also highlights the necessity of using a double enteric layer scheme with HP-50 as the enteric material.
Example 6
A compound preparation comprises duloxetine enteric pellet and gamma-aminobutyric acid analogue quick release part;
The composition of the immediate release portion of the gamma-aminobutyric acid analog is shown in table 10:
TABLE 10 composition of immediate release portions of gamma-aminobutyric acid analogues
The preparation process of the prescription P1-P4 comprises the steps of adding gamma-aminobutyric acid analogues, talcum powder, corn starch, mannitol (if any) and microcrystalline cellulose (if any) into a laboratory hopper mixer for mixing for 25min, wherein the mixing speed is 15rpm, the mixing batch is 500g, and the mixing is finished.
And (3) filling the immediate-release part of the pregabalin prepared by the prescription P1 and duloxetine enteric pellets of different prescriptions into gelatin hard capsule shells to obtain a compound capsule preparation, wherein the filling weight of the duloxetine enteric pellets is adjusted downwards (the pellets used are unchanged), and each capsule contains 75mg of pregabalin and 17.5mg of duloxetine. And filling the part of gabapentin Ding Sushi prepared by the prescription P3 and duloxetine enteric pellets into gelatin hard capsule shells to obtain a compound capsule preparation, wherein the filling weight of the duloxetine enteric pellets is adjusted downwards (the pellets used are unchanged), and each capsule contains 225mg of gabapentin and 17.5mg of duloxetine. And (3) filling the quick-release part of the mezloballin prepared by the prescription P4 and the duloxetine enteric pellets into gelatin hard capsule shells to obtain a compound capsule preparation, wherein the filling weight of the duloxetine enteric pellets is adjusted downwards (the pellets used are unchanged), and each capsule contains 5mg of the mezloballin and 17.5mg of duloxetine. The following table:
Table 11 prescription composition of compound preparation
Adjusting the filling weight of the duloxetine enteric-coated pellets to ensure that 30-40 mg of duloxetine is contained in the duloxetine enteric-coated pellets, and then filling the immediate-release part of pregabalin prepared by a P2 prescription and the duloxetine enteric-coated pellets of different prescriptions into gelatin hard capsule shells to obtain a compound capsule preparation, wherein each capsule contains 150mg of pregabalin and 30-40 mg of duloxetine, and the following table shows:
prescription composition of Table 12 compound preparation
The duloxetine dissolution profile (detected by the method in reference example 2) in the compound capsules prepared in the prescription 6 and the prescriptions 8-14 was detected and was similar to the dissolution behavior exhibited by the corresponding duloxetine enteric pellets in example 2. The addition of the quick-release part of the gamma-aminobutyric acid analogue and the adjustment of the proportion of the gamma-aminobutyric acid analogue to the duloxetine are shown to have no obvious influence on the dissolution behavior of the duloxetine enteric pellets.
Referring to the method of example 1, the release condition of duloxetine enteric pellets in a compound prescription 6-9 and a prescription 12-18 in a hydrochloric acid solution containing 20% ethanol and 40% ethanol is detected, and the influence of pregabalin on the duloxetine enteric pellet amount dumping experiment is examined according to the dose dumping condition of the duloxetine enteric pellets correspondingly used in the compound prescription under a single condition.
Table 13 Release of duloxetine in 20% ethanol medium (%)
Table 14 release of duloxetine in 40% ethanol medium (%)
As can be seen from tables 13 and 14, the addition of the immediate release portion of pregabalin reduced the resistance to ethanol dumping.
Under the condition of 20% ethanol medium, the anti-ethanol pouring capacity of the compound preparation in two hours of 6-9, 12-15 and 17 of the prescription meets the standard, the prescription 16 (corresponding to 9% of weight gain of the enteric coating) can meet the anti-ethanol pouring capacity standard in two hours due to lower weight gain of the enteric coating, but the whole anti-ethanol pouring capacity of the product is poor after the pregabalin quick-release component is added, and the anti-ethanol pouring capacity of the compound preparation is not up to standard. After the weight gain of the enteric coating is adjusted, the ethanol pouring resistance of the compound preparation of the prescription 15 (corresponding to the weight gain of the enteric coating of 12%) also reaches the standard. The compound preparation prepared in the prescription 17 has the release amount of 29% in two hours under the medium of 20% ethanol, and is close to the limit, which shows that when CAP is adopted as an enteric coating layer, the prepared compound preparation can resist 20% ethanol dumping when the weight of the enteric coating layer is less than 35%, but if the weight of the enteric coating layer is further reduced, the release amount of the duloxetine in two hours is more than 30% (not in accordance with acceptable standards), and the prescription 18 basically has no ethanol dumping resistance because of no enteric coating layer, and the release amount of the compound preparation in one side and two hours is 94%.
In 40% ethanol medium, formula 7 (corresponding to 60% weight gain of the enteric coating layer) of the compound preparation can also meet the ethanol pouring resistance standard. The compound preparation of the double enteric layer scheme of the invention has good anti-ethanol dumping ability under the condition of lower concentration ethanol (20%), and needs to optimize the weight increment condition of an enteric outer layer (HPMCP) under the condition of high concentration ethanol (40%), thereby achieving the effect of anti-ethanol dumping.
The reason why the addition of pregabalin affects the anti-dose dumping effect of duloxetine pellets is presumed to be that after pregabalin is dissolved in ethanol-containing hydrochloric acid medium, the ion concentration of the medium is increased, resulting in an increase in the dissolution rate of enteric materials. Gabapentin, mevalonate and pregabalin have partially similar compound structures, and therefore it is speculated that gabapentin or mevalonate also affects the ability of duloxetine enteric pellets to resist ethanol dumping.
The above examples are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the spirit and principle of the present invention should be made in the equivalent manner, and the embodiments are included in the protection scope of the present invention.

Claims (15)

1.一种度洛西汀肠溶微丸，其特征在于含有含药丸芯、肠溶内层和肠溶外层；1. A duloxetine enteric-coated microcapsule, characterized in that it comprises a drug-containing core, an inner enteric layer, and an outer enteric layer; 所述的肠溶外层含有羟丙甲纤维素邻苯二甲酸酯(HPMCP)，其中HPMCP占肠溶外层的质量比为55.6～90.9％；The enteric outer layer contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein HPMCP accounts for 55.6% to 90.9% of the mass of the enteric outer layer; 所述肠溶外层的增重为9～200％。The weight gain of the enteric outer layer is 9-200%. 2.根据权利要求1所述的度洛西汀肠溶微丸，其特征在于：所述的HPMCP可溶解于pH值5.0以上的介质中。2. The duloxetine enteric-coated microcapsules according to claim 1, characterized in that: the HPMCP is soluble in a medium with a pH value above 5.0. 3.根据权利要求2所述的度洛西汀肠溶微丸，其特征在于：所述溶解于pH值5.0以上介质的HPMCP，其型号为HP-50。3. The duloxetine enteric-coated microcapsules according to claim 2, characterized in that: the HPMCP dissolved in a medium with a pH value above 5.0 is of type HP-50. 4.一种度洛西汀肠溶微丸，其特征在于含有含药丸芯、肠溶内层和肠溶外层；4. A duloxetine enteric-coated microcapsule, characterized in that it comprises a drug-containing core, an inner enteric layer, and an outer enteric layer; 所述的肠溶外层含有羟丙甲纤维素邻苯二甲酸酯(HPMCP)，其中HPMCP占肠溶外层的质量比为55.6～90.9％；The enteric outer layer contains hydroxypropyl methylcellulose phthalate (HPMCP), wherein HPMCP accounts for 55.6% to 90.9% of the mass of the enteric outer layer; 所述的HPMCP可溶解于pH值5.5以上的介质中；The HPMCP is soluble in media with a pH value above 5.5; 所述肠溶外层的增重为9％以上。The weight gain of the enteric outer layer is more than 9%. 5.根据权利要求4所述的度洛西汀肠溶微丸，其特征在于：所述溶解于pH值5.5以上介质的HPMCP，其型号为HP-55或HP-55S。5. The duloxetine enteric-coated microcapsules according to claim 4, characterized in that: the HPMCP dissolved in a medium with a pH value above 5.5 is of model HP-55 or HP-55S. 6.根据权利要求1-5任一项所述的度洛西汀肠溶微丸，其特征在于：6. The duloxetine enteric-coated microspheres according to any one of claims 1-5, characterized in that: 所述的肠溶内层含有肠溶材料，或者还含有一种以上的助剂；所述肠溶材料占肠溶内层质量的45.5～100％；The enteric inner layer contains enteric material, or may also contain one or more adjuvants; the enteric material accounts for 45.5% to 100% of the mass of the enteric inner layer; 所述肠溶材料为醋酸羟丙甲纤维素琥珀酸酯(HPMCAS)、甲基丙烯酸-丙烯酸乙酯共聚物及其水分散体、甲基丙烯酸共聚物A型或聚醋酸乙烯邻苯二甲酸酯中的至少一种；The enteric material is at least one of hydroxypropyl methylcellulose acetate succinate (HPMCAS), methacrylate-ethyl acrylate copolymer and its aqueous dispersion, methacrylate copolymer type A, or polyvinyl acetate phthalate. 所述肠溶内层的增重为15～65％。The weight gain of the enteric inner lining is 15-65%. 7.根据权利要求1-5任一项所述的度洛西汀肠溶微丸，其特征在于：所述的含药丸芯和肠溶内层之间设有隔离层。7. The duloxetine enteric-coated microcapsules according to any one of claims 1-5, characterized in that: an isolation layer is provided between the drug-containing core and the enteric inner layer. 8.根据权利要求1-5任一项所述的度洛西汀肠溶微丸，其特征在于：所述的度洛西汀肠溶微丸，在肠溶外层之外设有保护层。8. The duloxetine enteric-coated microspheres according to any one of claims 1-5, characterized in that: the duloxetine enteric-coated microspheres have a protective layer outside the enteric outer layer. 9.一种复方制剂，其特征在于：含有权利要求1-8任一项所述的度洛西汀肠溶微丸。9. A compound preparation, characterized in that it contains duloxetine enteric-coated microspheres as described in any one of claims 1-8. 10.根据权利要求9所述的复方制剂，其特征在于：所述的度洛西汀肠溶微丸的肠溶外层增重为：12～200％。10. The compound preparation according to claim 9, characterized in that: the weight gain of the enteric outer layer of the duloxetine enteric microspheres is 12-200%. 11.根据权利要求10所述的复方制剂，其特征在于：含有度洛西汀肠溶微丸和γ-氨基丁酸类似物。11. The compound preparation according to claim 10, characterized in that it contains duloxetine enteric-coated microspheres and a γ-aminobutyric acid analogue. 12.根据权利要求11所述的复方制剂，其特征在于：所述的γ-氨基丁酸类似物为速释形式。12. The compound preparation according to claim 11, wherein the γ-aminobutyric acid analogue is in an immediate-release form. 13.根据权利要求11或12所述的复方制剂，其特征在于：所述的γ-氨基丁酸类似物为普瑞巴林、加巴喷丁、美洛加巴林或苯磺酸克利加巴林。13. The compound preparation according to claim 11 or 12, characterized in that: the γ-aminobutyric acid analogue is pregabalin, gabapentin, melogabalin or cligabalin besylate. 14.根据权利要求13所述的复方制剂，其特征在于：所述普瑞巴林与度洛西汀的质量比为(3.75～5.00):1。14. The compound preparation according to claim 13, characterized in that: the mass ratio of pregabalin to duloxetine is (3.75-5.00):1. 15.根据权利要求14所述的复方制剂，其特征在于：所述的复方制剂含有普瑞巴林150mg、度洛西汀30～40mg，或者含有普瑞巴林75mg、度洛西汀15～20mg。15. The compound preparation according to claim 14, characterized in that: the compound preparation contains 150 mg of pregabalin and 30-40 mg of duloxetine, or contains 75 mg of pregabalin and 15-20 mg of duloxetine.
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