WO2012139485A1 - 一种复方抗结核药口服固体制剂及其制备方法 - Google Patents

一种复方抗结核药口服固体制剂及其制备方法 Download PDF

Info

Publication number
WO2012139485A1
WO2012139485A1 PCT/CN2012/073689 CN2012073689W WO2012139485A1 WO 2012139485 A1 WO2012139485 A1 WO 2012139485A1 CN 2012073689 W CN2012073689 W CN 2012073689W WO 2012139485 A1 WO2012139485 A1 WO 2012139485A1
Authority
WO
WIPO (PCT)
Prior art keywords
rifampicin
weight
water
coated
isoniazid
Prior art date
Application number
PCT/CN2012/073689
Other languages
English (en)
French (fr)
Other versions
WO2012139485A8 (zh
Inventor
顾茂健
郑启兰
许超
李宁
陈贵贤
郑兰
汪敏
姜林涛
Original Assignee
浙江海正药业股份有限公司
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 浙江海正药业股份有限公司 filed Critical 浙江海正药业股份有限公司
Priority to RU2013150254/15A priority Critical patent/RU2605388C2/ru
Priority to US14/111,323 priority patent/US9555003B2/en
Priority to BR112013026356A priority patent/BR112013026356A2/pt
Priority to LTEP12771448.3T priority patent/LT2698150T/lt
Priority to EP12771448.3A priority patent/EP2698150B1/en
Publication of WO2012139485A1 publication Critical patent/WO2012139485A1/zh
Publication of WO2012139485A8 publication Critical patent/WO2012139485A8/zh

Links

Classifications

    • 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
    • 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
    • A61K31/13—Amines
    • A61K31/133—Amines having hydroxy groups, e.g. sphingosine
    • 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
    • A61K31/4409—Non condensed pyridines; Hydrogenated derivatives thereof only substituted in position 4, e.g. isoniazid, iproniazid
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4965—Non-condensed pyrazines
    • 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
    • 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
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • 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
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • 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
    • 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
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A61P31/06—Antibacterial agents for tuberculosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2121/00—Preparations for use in therapy

Definitions

  • the invention relates to an oral solid preparation for a compound anti-tuberculosis drug and a preparation method thereof, in particular to a quadruple compound anti-tuberculosis comprising rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as active ingredients Oral solid preparation of the drug.
  • a quadruple compound anti-tuberculosis comprising rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as active ingredients Oral solid preparation of the drug.
  • Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis, which can affect all tissues and organs of the body, such as lungs, kidneys, intestines, bones, etc., but tuberculosis is the most common. Tuberculosis has always been a major problem for people in developing countries. In recent years, the incidence of mycobacteria in individuals infected with HIV has also increased, and the disease has gradually become a difficult problem faced by developed countries. According to official statistics released by the World Health Organization (WHO), more than 20 million active tuberculosis patients have been diagnosed worldwide, and 8.7 million new patients are found each year. The incidence of tuberculosis in Asia accounts for the worldwide incidence.
  • WHO World Health Organization
  • the quadruple drug which includes pyrazinamide (Z) and ethambutol hydrochloride in addition to the most effective rifampicin (R) and isoniazid (H) for the treatment of tuberculosis.
  • the quadruple compound can be a combination tablet, capsule, etc., and has been officially recognized and supported by WHO for the treatment of tuberculosis. Hold.
  • the quadruple drug constitutes a compound preparation, which improves patient compliance and can reduce the occurrence of drug resistance to some extent.
  • Rifampicin also known as rifampin, is a semi-synthetic rifamycin derivative, brick red crystal, melting point 183 ° C, insoluble in water (solubility 1.3 mg / ml water) pH4.3, 2.5mg/ml water pH7.3, 100mg/ml water DMSO), unstable in acid, and easy to react with isoniazid, it can also be oxidized by air, light and other factors.
  • Rifampicin is a high-efficiency broad-spectrum antibacterial drug with strong inhibition or killing of tuberculosis. Its anti-tuberculosis effect is second only to isoniazid, stronger than streptomycin, and the minimum inhibitory concentration is about 0.02 ⁇ 0.05 ⁇ 8 / ml. It not only has an effect on the tuberculosis of the breeding and stationary stages, but also is effective against other strains resistant to tuberculosis. It can kill macrophage, fibrosis, tubercle bacilli in cheese-like lesions, and has strong inhibitory effects on Gram-positive cocci, such as Staphylococcus aureus, Streptococcus, and pneumococci.
  • Gram-negative cocci such as meningococcus, Neisseria gonorrhoeae It also has a strong inhibitory effect and has a strong inhibitory effect on M. leprae.
  • High concentration of rifampicin has an inhibitory effect on variola virus and Chlamydia trachomatis.
  • Rifampicin is easy to produce drug resistance, and is often used in combination with other first-line drugs for patients with severe initial or retreatment, which can enhance the efficacy and delay the development of drug resistance. There is no cross-resistance between rifampicin and other anti-tuberculosis drugs.
  • Rifampin can selectively inhibit bacterial-dependent DNA RNA polymerase, which blocks mRNA synthesis, but has no effect on animal cell RNA polymerase.
  • Isoniazid also known as Remi seal, chemical name 4-pyridine formylhydrazine. Soluble in water, slightly soluble in ethanol, very slightly soluble in ether. The hydrazide structure is unstable, and under acid-base conditions, it can be hydrolyzed to form isonicotinic acid and hydrazine. Free hydrazine increases toxicity, and light, heavy metals, temperature, pH, etc. can accelerate hydrolysis.
  • Isoniazid has a good antibacterial effect on Mycobacterium tuberculosis, has good curative effect, small dosage, relatively low toxicity, and is easily accepted by patients.
  • the oral absorption rate of isoniazid was 90%; the serum drug concentration reached the peak 1 to 2 hours after administration; Vd was 0.61 ⁇ 0.11 L / kg, and the protein binding rate was very low.
  • Mainly used for the progression of various types of tuberculosis, dissolution and dissemination period, absorption and improvement period can still be used for tuberculous meningitis and other extrapulmonary tuberculosis. This product is often used in combination with other anti-tuberculosis drugs to enhance efficacy and overcome drug-resistant bacteria.
  • Pyrazinamide (Z) is slightly soluble in water, slightly soluble in ethanol, very slightly soluble in ether, and accelerates rifampicin and isoniazid. Its molecular structure is: Pyrazinamide has a good antibacterial effect on human Mycobacterium tuberculosis. At pH 5-5.5, the bactericidal effect is the strongest, especially for tuberculosis bacteria in phagocytic cells growing slowly in an acidic environment. The antibacterial concentration of this product in the body is 12.5 g/ml, up to 5 ( ⁇ g/ml can kill Mycobacterium tuberculosis.
  • the drug inhibits the concentration of Mycobacterium tuberculosis in cells 10 times lower than in the outside, in a neutral, alkaline environment There is almost no bacteriostatic action.
  • the mechanism of action may be related to pyrazinic acid. Pyrazinamide penetrates into phagocytic cells and enters the Mycobacterium tuberculosis. The amidase in the bacteria removes the amide group and converts it into pyrazine acid. Antibacterial effect. Because pyrazinamide is similar in chemical structure to nicotinamide, it interferes with dehydrogenase by substituting nicotinamide, prevents dehydrogenation, prevents the use of oxygen by tuberculosis, and affects the normal metabolism of bacteria and causes death.
  • E Ethylamine butanol
  • Ethambutol hydrochloride is suitable for the treatment of tuberculosis in combination with other anti-tuberculosis drugs, and the use of ethambutol hydrochloride alone is susceptible to drug resistance. It has strong activity against bacteria in the growth and reproduction period, and has little effect on bacteria in stationary phase. It has high antibacterial activity against various types of mycobacteria. Mycobacterium tuberculosis against this product and other drugs There is no cross-resistance between them. It is used in combination with rifampicin or isoniazid to treat various types of active tuberculosis. It can also be used for the treatment of atypical M. tuberculosis infection.
  • 3-formyl rifamycin and isoniazid have lower antibacterial activity than rifampicin.
  • pyrazinamide has a catalytic effect on the reaction of rifampicin with isoniazid, and the easy moisture absorption of ethambutol hydrochloride provides conditions for the degradation reaction of rifampicin and isoniazid. It is also a major factor that causes the formulation to be unstable and the bioavailability of rifampicin in the compound is lower than that of rifampicin in the unilateral.
  • rifampicin is a low-soluble hypertonic dissociative drug, its solubility is pH-dependent, and the solubility in different pH environments of the gastrointestinal tract is very different.
  • pH 1.4 It can reach about 125 mg/ml, and it can dissolve 80-90% in 10 minutes.
  • the solubility is less than 6 mg/ml. If only a simple enteric coating is used to prevent rifampicin from being released in the stomach and replaced in the intestine, the poor solubility of rifampicin in the intestine will directly lead to a decrease in the bioavailability of rifampicin.
  • the rifampicin solid dispersion in the solid preparation of the present invention can not only improve rifampicin Solubility and dissolution rate, but also ensure that rifampicin is released or not released in a small amount in the acidic environment of the stomach, reducing the reaction of rifampicin and isoniazid in the body, and the rifampicin and isoniazid in the preparation are also mutually Non-contact ensures the stability of the preparation during storage.
  • the stability of rifampicin in vitro and in RHZE compound helps to improve the bioavailability of rifampicin in the compound, ensuring therapeutic effect and reducing drug resistance. Summary of the invention
  • the compound oral solid core solid preparation of the present invention is a coated package chip comprising rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as active ingredients, and the inner core thereof comprises Isoniazid or rifampicin is coated with a water-insoluble non-pH-dependent coating film, and the core solid preparation is coated with a water-soluble pH-independent moisture-proof and light-proof coating film, and after administration, rifampicin and At least one active ingredient in isoniazid is released or not released in the stomach.
  • the compound oral solid core solid preparation of the present invention is a coated three-layer tablet comprising rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as active ingredients, the upper layer and The lower layer independently contains any one of isoniazid and rifampicin, and the intermediate layer contains at least one of pyrazinamide and ethambutol hydrochloride, and the three layers are coated with water-insoluble non-pH dependent type. After the film is taken, at least one active ingredient in rifampicin and isoniazid is released or not released in the stomach.
  • the compound oral solid core solid preparation of the present invention is a coated package chip comprising rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as active ingredients, and the inner core thereof comprises Isoniazid or rifampicin is coated with a water-soluble pH-independent barrier film, and rifampicin is a rifampicin enteric solid dispersion dispersed in an enteric solid carrier, said core-solid preparation
  • the layer is coated with a water-soluble, pH-independent, moisture-proof and light-proof coating film.
  • the compound oral solid core solid preparation of the present invention is a coated three-layer tablet comprising rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as active ingredients, the upper layer and The lower layer separately contains any one of isoniazid and rifampicin.
  • rifampicin-containing layer rifampicin is a rifampicin enteric solid dispersion dispersed in an enteric solid carrier, and the intermediate layer contains pyridin At least one of a azine amide and an ethambutol hydrochloride, the three layers are coated with a water-soluble pH-independent moisture-proof and light-proof coating film.
  • the water-insoluble pH-independent coating film in the first and second embodiments comprises a water-insoluble non-pH-dependent polymer film-forming material and a plasticizer, optionally further comprising One or more of a porogen and an anti-adhesive agent.
  • the water-insoluble non-pH dependent coating film of the second embodiment further comprises a light shielding agent.
  • the inner core of the first embodiment further comprises a water-absorbent rapidly disintegrating polymer and/or a small molecule penetration enhancer.
  • the rifampicin-containing layer of the second embodiment further comprises a water-absorbent rapidly disintegrating polymer, and the intermediate layer further contains a retarder.
  • the design of the compound oral solid preparation in the present invention is to prevent the two active ingredients of rifampicin and isoniazid from being directly contacted in the preparation, and to control the rifampicin and isoniazid therein after taking the medicine.
  • a small amount of at least one active ingredient is released or not released in the stomach; preferably, the release amount is not more than 15%, more preferably not more than 10%, still more preferably not more than 5%, of the indicated percentage, thereby improving the compound preparation Stability, and improve the bioavailability of rifampicin in the compound.
  • perfuming agent means a substance having a certain osmotic pressure to facilitate penetration of water molecules.
  • permeating agent which is commonly used in the field of pharmaceutical preparations of the present invention.
  • the "non-pH-dependent coating film” means a film containing a substance which is not pH-dependent.
  • non-pH-dependent substance means a substance which is dissolved in water and is not affected by pH.
  • the present invention is not particularly limited as long as it is a non-pH-dependent coating film which is commonly used in the field of pharmaceutical preparations of the present invention.
  • enteric-soluble carrier means a substance which is substantially insoluble in the acidic environment of the stomach but which is soluble in the pH environment of the intestine.
  • the present invention is not particularly limited as long as it is an enteric carrier which is commonly used in the field of pharmaceutical preparations of the present invention.
  • adheresive means a substance having a viscosity by which the separated powders are joined together by their adhesive properties.
  • lubricant means between two relatively moving objects having a substance that reduces friction and wear due to contact.
  • lubricant which is commonly used in the field of pharmaceutical preparations of the present invention.
  • the present invention relates to a compound oral coated solid preparation comprising rifampicin, isoniazid, pyrazinamide and ethambutol hydrochloride as active ingredients, and the active ingredient composition is 200-300 mg: 75 mg-300 mg: 250- 500 mg: 250-275 mg, preferably 150 mg: 75 mg: 400 mg: 275 mg combination.
  • a technical feature of the present invention is that one or more of the active ingredients of the compound oral solid preparation of the present invention are coated with a water-insoluble non-pH-dependent coating film having water permeability.
  • a water-insoluble non-pH-dependent coating film having water permeability To release controlled release of isoniazid or rifampicin, and one of rifampicin or isoniazid and other active ingredients are released quickly after administration, and the design features also ensure that rifampicin and isoniazid are not directly contact.
  • the compound oral solid preparation of this design feature may be a coated packet chip or a coated three-layer tablet.
  • the compound oral solid preparation of the present invention is a coated package chip, and the inner layer is an isoniazid layer, which may be coated with one or more independent water-insoluble non-pH-dependent coating films.
  • the inner core of the coating is coated with an outer layer containing rifampicin, pyrazinamide and ethambutol hydrochloride to form a coated chip, and the coated chip is coated with water-soluble non-pH dependent Moisture-proof and light-proof clothing film.
  • the inner core of the water-insoluble pH-independent film may further comprise a polymer that absorbs water and rapidly disintegrates, and optionally contains one or more A carrier selected from the group consisting of small molecule penetration enhancers, binders, and lubricants.
  • the water-absorbent rapidly disintegrating polymer is one or more selected from the group consisting of croscarmellose sodium (CCMC-Na), low-substituted hydroxypropylcellulose (L- HPC), sodium carboxymethylcellulose (CMC-Na), sodium carboxymethyl starch (CMS-Na), crospovidone (PVPP) and microcrystalline cellulose (MCC); small molecule penetration enhancer One or more substances selected from the group consisting of sodium chloride and potassium chloride.
  • CCMC-Na croscarmellose sodium
  • L- HPC low-substituted hydroxypropylcellulose
  • CMC-Na sodium carboxymethylcellulose
  • CMS-Na sodium carboxymethyl starch
  • PVPP crospovidone
  • MCC microcrystalline cellulose
  • small molecule penetration enhancer One or more substances selected from the group consisting of sodium chloride and potassium chloride.
  • the inner layer of the isoniazid layer coated water-insoluble non-pH-dependent coating film is 6-30% of the weight of the inner layer of isoniazid core, which has water permeability and contains water-insoluble non-pH.
  • a dependent polymer film-forming material, a plasticizer, and optionally a porogen and/or an anti-sticking agent is included in the coated package chip.
  • the water-insoluble pH-independent film comprises a film-forming material of from 70% by weight to 90% by weight, preferably from 70% by weight to 80% by weight, based on the total weight of the film, preferably from one or more of the following groups: Aquacoat ECD, Ethyl cellulose (EC), cellulose acetate (CA), polyvinyl chloride, polycarbonate, vinyl alcohol-vinyl acetate; plasticizer is 10% by weight to 30% by weight, preferably 13% by weight based on the total weight of the film.
  • Aquacoat ECD Ethyl cellulose
  • CA cellulose acetate
  • plasticizer is 10% by weight to 30% by weight, preferably 13% by weight based on the total weight of the film.
  • %-25% by weight preferably from one or more of the following groups: triethyl citrate (TEC), tributyl citrate (TBC), acetyl triethyl citrate (ATEC), bismuth Dimethyl methacrylate (DMS), dibutyl sebacate (DBS), dibutyl phthalate (DBP); porogen is 0% by weight to 15% by weight, preferably 4% by weight, based on the total weight of the film.
  • TEC triethyl citrate
  • TBC tributyl citrate
  • ATEC acetyl triethyl citrate
  • DMS dimethyl methacrylate
  • DBS dibutyl sebacate
  • DBP dibutyl phthalate
  • porogen is 0% by weight to 15% by weight, preferably 4% by weight, based on the total weight of the film.
  • - 13% by weight preferably from one or more of the following groups: polyethylene glycols, hydroxypropyl methylcellulose, Kolli COa t® IR, polyvinyl alcohol, urea; anti-adherent coating 0% by weight to 25% by weight, preferably 0% by weight to 15% by weight, based on the total weight of the film, selected from one or more of the following groups: talc, light micronized silica gel.
  • the preparation method of the coating package chip is:
  • the packaged chip contains a water-soluble non-pH-dependent moisture-proof and light-proof coating film.
  • the compound oral solid preparation of the present invention is a coated three-layer tablet composed of an upper layer, an intermediate layer and a lower layer, and the upper layer and the lower layer are respectively a rifampicin layer and isoniazid/pyrazine amide.
  • the layer and the middle layer are a layer of ethambutol hydrochloride, wherein the rifampicin layer contains a polymer which rapidly absorbs and swells by water absorption and other pharmaceutically acceptable carriers, and the ethylamine butanol layer contains a block of rapid disintegration of ethambutol hydrochloride.
  • the three-layer off-coated water-insoluble non-pH-dependent coating film has water permeability, and the coating film weight is 5-12% by weight of the uncoated core of the three-layer sheet, and comprises a water-insoluble non-pH-dependent polymer.
  • the film forming material, the plasticizer, optionally further comprising at least one selected from the group consisting of a porogen, a darkener, and an anti-adhesive, the water-insoluble non-pH-dependent film-forming material is selected from the group consisting of one or more of the following Substances: Aquacoat ECD, ethyl cellulose (EC), cellulose acetate (CA), polyvinyl chloride, polycarbonate, Vinyl alcohol-vinyl acetate, which accounts for 50% by weight to 80% by weight based on the total weight of the film;
  • the plasticizer is selected from one or more of the following groups: triethyl citrate (TEC), citric acid three Butyl ester (TBC), acetyl triethyl citrate (ATEC), dimethyl sebacate (DMS), dibutyl sebacate (DBS), dibutyl phthalate (DBP) 20% by weight to 45% by weight of the total weight of the film;
  • the porogen is selected from
  • the coated three-layer tablet of rifampicin contains a water-absorbing rapidly disintegrating swelling polymer which is one or more selected from the group consisting of croscarmellose sodium (CCMC-Na), Low-substituted hydroxypropyl cellulose (L-HPC), sodium carboxymethyl cellulose (CMC-Na), sodium carboxymethyl starch (CMS-Na), crospovidone (PVPP) and microcrystalline cellulose ( MCC).
  • CCMC-Na croscarmellose sodium
  • L-HPC Low-substituted hydroxypropyl cellulose
  • CMC-Na sodium carboxymethyl cellulose
  • CMS-Na sodium carboxymethyl starch
  • PVPP crospovidone
  • MCC microcrystalline cellulose
  • the coated three-layered ethylamine butanol layer contains a retarder which is one or more selected from the group consisting of water-insoluble framework materials such as ethyl cellulose, polyethylene, acrylic resin.
  • a retarder which is one or more selected from the group consisting of water-insoluble framework materials such as ethyl cellulose, polyethylene, acrylic resin.
  • Class erosive framework materials such as beeswax, hydrogenated vegetable oil, stearic acid, polyethylene glycol, carnauba wax, glyceryl stearate, propylene glycol stearate and octadecyl alcohol, water soluble framework materials such as hydroxypropyl Methyl cellulose, polyoxyethylene (PEO).
  • the preparation method of the coated three-layer tablet is:
  • rifampicin is a poorly soluble drug, and the solubility and dissolution rate of rifampicin are improved by using an enteric solid dispersion technique to improve the hair.
  • the design feature is that the compound oral solid preparation is a coated packet chip or a coated three-layer tablet.
  • the compound oral solid preparation is a coated package chip, the inner core of which contains isoniazid or rifampicin and coated with a water-soluble pH-independent barrier film, and rifampicin is dispersed
  • the rifampicin enteric solid dispersion in an enteric solid carrier is coated with a water-soluble pH-independent moisture-proof and light-proof coating film.
  • the weight ratio of rifampicin to enteric-type carrier in the rifampicin solid dispersion of the present invention is in the range of 2: 1-1:3, wherein the enteric solid dispersion carrier is selected from one or more selected Carriers from the following groups: polyvinyl alcohol acetate phthalate (PVAP), methacrylic acid/methyl methacrylate copolymers such as Eudragit L30D-55, Eudragit LI 00. Eudragit SI 00.
  • PVAP polyvinyl alcohol acetate phthalate
  • methacrylic acid/methyl methacrylate copolymers such as Eudragit L30D-55, Eudragit LI 00. Eudragit SI 00.
  • Cellulose and its derivatives such as cellulose acetate phthalate (cellulose acetate phthalate, CAP), cellulose acetate 1,2,4-benzenetricarboxylate (cellulose acetate, CAT), hydroxypropyl phthalate Methylcellulose (hypromellose phthalate, HPMCP), hydroxypropyl methylcellulose 1,2,4-benzenetricarboxylate (HPMCT); cellulose acetate succinate (CAS) and succinic acid acetate Hydroxypropyl methylcellulose (HPMCAS), hydroxypropylmethylcellulose acetate (HPMCAP), preferably hydroxypropylmethylcellulose succinate (HPMCAS) o
  • the film forming material of the water soluble non-pH dependent barrier film is selected from the group consisting of: hypromellose (HPMC), Kollicoat® IR and Opadry II.
  • the method for preparing a rifampicin solid dispersion according to the present invention may be a usual method for preparing a solid dispersion, such as a hot melt method, a spray drying method, a fluidized bed one-step granulation or a solvent drying method.
  • the preparation method of the coating package chip is:
  • rifampicin is first made into an enteric solid dispersion, and the rifampicin solid dispersion is mixed with pyrazinamide, ethambutol hydrochloride with filler, disintegrant, and The dry granules prepared by the preparation are mixed, added with a flow aid or a lubricant, sieved, and used.
  • the compound oral solid preparation is a coated three-layer tablet, and the upper layer and the lower layer respectively independently comprise any one of isoniazid and rifampicin, in the rifampicin-containing layer, Rifampicin is a rifampicin enteric solid dispersion dispersed in an enteric solid carrier, the intermediate layer comprising at least one of pyrazinamide and ethambutol hydrochloride, the three layers being coated with a water-soluble non-pH Dependent moisture-proof and light-proof coating film.
  • the weight ratio range of the rifampicin and the enteric carrier, the enteric solid dispersion carrier and the rifampicin solid dispersion preparation method are as described above.
  • the preparation method of the coated three-layer tablet is:
  • rifampicin layer rifampicin is first made into an enteric solid dispersion, and the rifampicin solid dispersion and other pharmaceutically acceptable carriers are mixed and granulated or used for directly pressing;
  • the water-soluble pH-independent coating film used as the moisture-proof and light-proof coating film described in the above embodiment contains a substance selected from the group consisting of Kollicoat® IR, hydroxypropylmethylcellulose (HPMC), and titanium dioxide.
  • the compound oral cored solid preparation of the present invention may further comprise another pharmaceutically acceptable carrier selected from the group consisting of a filler, a binder, a lubricant or a glidant and/or a disintegrant.
  • another pharmaceutically acceptable carrier selected from the group consisting of a filler, a binder, a lubricant or a glidant and/or a disintegrant.
  • FIG 1 Schematic diagram of the coating package chip; A: inner layer core; B: inner layer coating film; C: outer layer; D: film;
  • FIG. 2 Schematic diagram of the coated three-layer sheet; A: upper layer; B: intermediate layer; C: lower layer; D: clothing film; Figure 3 0811011 batch of rifampicin bulk drug 0-day determination of related substances HPLC; Figure 4: rifampicin solid dispersion prepared by spray drying method (sample of Example 8) HPLC chromatogram of 0-day related substance determination;
  • Figure 5 rifampicin solid dispersion prepared by the solvent natural evaporation method (sample of Example 11) 0 days HPLC chromatogram of substance determination;
  • Fig. 6 The rifampicin solid dispersion prepared by the hot melt method (sample of Example 7) HPLC spectrum of the substance measurement for 0 days;
  • Figure 7 Imported product 6-month accelerated test 40 ° C, 75% RH) HPLC chromatogram of the determination of related substances.
  • Figure 8 Self-made package chip 6-month accelerated test (40 °C, 75% RH) HPLC chromatogram of the substance.
  • Figure 9 Self-made package chip 12-month stability (25 ° C, 60% RH) HPLC chromatogram of the determination of the substance.
  • Figure 10 is a time-blood concentration curve after oral administration of self-administered rifampicin (Example 10 sample) and commercially available rifampicin.
  • Figure 11 Time-blood concentration curve of rifampicin and commercially available rifampicin and commercially available rifampicin after oral administration of rifampicin. detailed description
  • Example 1 The invention is further illustrated by the following examples, which are not intended to limit the invention.
  • Example 1 The invention is further illustrated by the following examples, which are not intended to limit the invention.
  • the coating of 20% Opadry ll coating liquid was prepared.
  • the temperature of the coating material was controlled at 40-45 °C, and the coating weight gain was about 3%.
  • Example 3 The outer layer pellet-coated chip of Example 1 was coated with a 20% strength Opadryll coating solution, and the coating material temperature was controlled at 40-45 ° C, and the coating weight gain was about 3%.
  • Example 3 The coating material temperature was controlled at 40-45 ° C, and the coating weight gain was about 3%.
  • Example 4 Take the outer layer of the outer layer of Example 1 and mix it with isoniazid: rifampicin: pyrazinamide: ethambutol hydrochloride 75 mg: 150 mg: 400 mg: 275 mg in a concentration of 20% Opadry ll coating liquid coating, the coating material temperature is controlled at 40-45 ° C, the coating weight gain is about 3%.
  • rifampicin pyrazinamide: ethambutol hydrochloride
  • 75 mg: 150 mg: 400 mg: 275 mg in a concentration of 20% Opadry ll coating liquid coating the coating material temperature is controlled at 40-45 ° C, the coating weight gain is about 3%.
  • the ratio of 400 mg was taken as a rifampicin layer, an ethylamine butanol hydrochloride layer, an isoniazid/pyrazineamide laminated three-layer tablet.
  • ethambutol hydrochloride 55.22 g of ethambutol hydrochloride, 5.99 g of microcrystalline cellulose, and 3.01 g of hydroxypropylcellulose K100M were mixed and ground through a 0.250 mm sieve, and a soft material having a pore diameter of 0.710 mm was prepared with a 70% aqueous solution of ethanol (v/v).
  • the granules were sieved and dried at 80 ° C until the moisture content of the granules was below 2.0%.
  • the dry granules were added with 0.5% by weight of stearic acid through a sieve having a pore size of 0.850 mm, and the mixture was uniformly mixed and to be tableted.
  • 0.108 g of isoniazid, 80.10 g of pyrazinamide and 8.10 g of microcrystalline cellulose were mixed and ground through a 0.250 mm sieve, and sieved with a 2% hydroxypropylmethylcellulose aqueous solution through a pore size of 0.710 mm at 80 ° C. Dry down, until the moisture content of the granules is below 3.0%, add 0.5% by weight of dry granules of stearic acid through a 0.850 mm sieve, mix well and wait for tableting.
  • the ratio of 400 mg was taken as a rifampicin layer, an ethylamine butanol hydrochloride layer, an isoniazid/pyrazineamide laminated three-layer tablet.
  • the coating weight gain of about 8 %, curing at 60 ° C for 2h.
  • 0.102g of isoniazid and 2.80g of microcrystalline cellulose were uniformly mixed, ground through a 0.250mm sieve, made of 2% hydroxypropylmethylcellulose, and sieved at a pore size of 0.710mm at 50°C. Dry, to the particle moisture content of less than 3.0%, add 1% by weight of dry magnesium stearate, mixed through a pore size of 0.85mm sieve, mix, tablet, die 6.5 shallow concave round punch, pressure control at 50- 65N.
  • the temperature of the coated tablet is controlled at 28 °C - 32 °C, and the weight gain of the tablet is about
  • the middle coated piece is the core piece, and 5) the middle particle is the outer laminated package chip.
  • the coating of 20% Opadry ll coating liquid was prepared.
  • the temperature of the coating material was controlled at 40-45 °C, and the coating weight gain was about 3%.
  • the butanol dry granules were mixed, and 0.5% by weight of the micronized silica gel of the mixed granules was passed through a sieve having a pore size of 0.600 mm, to be tableted.
  • the coated tablet in 2) of Example 7 was a core, and the particles in the present Example 2) were outer layer pellet-coated chips.
  • the coating of 20% Opadry ll coating liquid was prepared.
  • the temperature of the coating material was controlled at 40-45 °C, and the coating weight gain was about 3%.
  • the coated tablet in 2) of Example 7 was a core, and the particles in the present Example 2) were outer layer pellet-coated chips.
  • the coating of 20% Opadry ll coating liquid was prepared.
  • the temperature of the coating material was controlled at 40-45 °C, and the coating weight gain was about 3%.
  • rifampicin solid dispersion 60.30 g of rifampicin solid dispersion, 5.60 g of microcrystalline cellulose, 7.32 g of croscarmellose sodium, mixed milled through a pore size of 0.250 mm, and 2% hydroxypropyl methylcellulose.
  • the aqueous solution was granulated through a sieve having a pore size of 0.710 mm, and dried at 50 ° C until the moisture content of the granules was 3.0% or less, and 0.5% by weight of dry granules of stearic acid was passed through a sieve having a pore diameter of 0.850 mm, and uniformly mixed until being tableted.
  • ethylamine butanol 55.22 g of ethylamine butanol and 6.03 g of microcrystalline cellulose were mixed and ground through a 0.250 mm sieve, and sieved with a 5% hydroxypropylmethylcellulose aqueous solution through a pore size of 0.710 mm, and dried at 80 ° C until The moisture content of the granules is below 2.0%, and 0.5% by weight of dry granules of stearic acid is added through a sieve having a pore size of 0.850 mm, and the mixture is uniformly mixed, and is to be tableted.
  • the coating of 20% Opadryll coating liquid was prepared.
  • the temperature of the coating material was controlled at 40-45 °C, and the coating weight gain was about 3%.
  • Example 12 148.84 g of the rifampicin solid dispersion of Example 8 was mixed with 20.75 g of microcrystalline cellulose, 8.94 g of sodium carboxymethylcellulose, and 0.90 g of differential silica gel, and sieved, and the die was a 12.0 mm dimple circle. Rushing, pressure control at 50-90N, coating with 20% concentration of Opadry ll solution, material temperature is 40 °C-45 °C, coating weight gain 3%. The in vivo experimental data for the formulations of this example are shown in Tables 10-11.
  • Rifampin (Shenyang Antibiotic Factory); Isoniazid (Zhejiang Xinsai Pharmaceutical Co., Ltd.); Pyrazinamide (Jiangsu Sihuan Biotechnology Co., Ltd.); Ethambutol Hydrochloride (Shanghai Wuzhou Pharmaceutical Co., Ltd.); Imported TB4 package chip (Panacea Biotec Ltd); Domestic rifampicin capsule (Shenyang Hongqi Pharmaceutical Co., Ltd.); Domestic isoniazid tablets (Shenyang Hongqi Pharmaceutical Co., Ltd.); Microcrystalline cellulose (Asahi Kasei Chemicals Corporation); Low substituted hydroxy Propyl cellulose (Shin-Etsu); hydroxypropyl methylcellulose E5 and KlOOM (Colorcon); stearic acid (Hunan Huari Pharmaceutical Co., Ltd.); differential silica gel (Evonik); hydroxypropylmethyl succinate acetate Cellulose (Shin-Etsu); croscarmel
  • Mini multi-functional testing machine (Chongqing Jinggong Pharmaceutical Machinery Co., Ltd.); Single punching machine (Shanghai Tianfan Pharmaceutical Machine Manufacturing Factory); Spray Drying Machine (BUCHI); Moisture Analyzer (Beijing Sartorius Co., Ltd.); Intelligent Dissolution Test Instrument (Tianda Tianfa Company); constant temperature and humidity box 720 (BINDER); BT224S electronic balance (Beijing Sartorius Co., Ltd.); OHHARA laboratory type coating pot; Agilent 1200 high performance liquid chromatography (Agilent Technologies Limited) Company); FE20 pH meter (METTLER TOLEDO company: Phenomenex Luna C18 100A (250x4.6mm, 5 ⁇ , American Philomon); Agilent Eclipse XDB-C18 (150x4.6mm, 5 ⁇ , Agilent, USA).
  • the rupture time of the inner layer film can basically reach the time required for control, that is, within 30-60 minutes. After the rupture of the film, the drug can be completely released in a short time.
  • Table 2 Accumulated dissolution release table of isoniazid in aqueous medium in the isoniazid chip (Example 2)
  • the intermediate film of the formulation can be broken in 30-60 minutes, and the release of isoniazid in no more than 2% within 30 minutes, which is far below the standard of no more than 10% in the quality control optimization scheme. And it is almost completely released within 90 minutes.
  • Table 3 TB4 package chip Example 2 cumulative dissolution measurement table (dissolution medium: PBS 6.8 buffer 900 ml)
  • Dissolution conditions 1 acid and alkali (900ml respectively) different cups, separately, paddle method, lOOrpm, 37.0 °C; dissolution conditions 2 acid and alkali with the cup is first added 750ml acidic medium (0.1mol / l hydrochloric acid dissolution 45min When sampling and rehydration, add 250ml 0.2mol / l sodium p-acid solution, and add 4.5ml 2mol / l sodium hydroxide to adjust the pH of the solution to 6.8 ⁇ 0.05, as alkaline medium, paddle method, lOOrpm, 37.0 ° C
  • rifampicin group 12 beagle dogs were randomly divided into two groups. They were fed at 8 am in the morning and administered 0.5 h later.
  • Group A was given a self-made rifampicin tablet (150 mg, equivalent). At 10 mg/kg, rifampicin was first prepared by spray drying to form an enteric solid dispersion and then coated with other auxiliary materials (ie, sample of Example 11).
  • Group B was administered to Lifu produced by Shenyang Hongqi Pharmaceutical Co., Ltd. 1 capsule (150 mg, lot 0907011).
  • the combination of rifampicin and isoniazid was administered two weeks after the end of the experiment.
  • Group B and group B were fed for 0.5 hours, and group A was given 1 tablet of rifampicin (150 mg, equivalent to 10 mg). /kg, the sample is the same as the single-dose sample) and one isoniazid produced by Shenyang Hongqi Pharmaceutical Co., Ltd. (75 mg/granule, canned in 0.3g/tablet with batch number 0907011), B
  • the group is rifampicin capsules (rifampicin 150 mg, batch number 0907011) and isoniazid 1 (same group A) produced by Shenyang Hongqi Pharmaceutical Co., Ltd.
  • Relative bioavailability 1 (%) self-made unilateral rifampicin tablets average AUC 0-12 / commercial single rifampicin capsule average AUC 0-12 * 100%;
  • Relative bioavailability 2 (%) homemade compound rifampicin average AUC 0-12 / commercially available average compound rifampicin AUC 0-12*100%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Nutrition Science (AREA)
  • Physiology (AREA)
  • Pulmonology (AREA)
  • Communicable Diseases (AREA)
  • Oncology (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)

Description

一种复方抗结核药口服固体制剂及其制备方法 技术领域
本发明涉及一种复方抗结核药的口服固体制剂及其制备方法， 特别是 涉及一种包含利福平、 异烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分的 四联复方抗结核药的口服固体制剂。 背景技术
结核病是由结核杆菌引起的慢性传染病， 可累及全身各组织器官， 如 肺、 肾、 肠、 骨骼等， 但以肺结核最为常见。 结核病一直是困扰发展中国 家人们身体健康的一个主要问题， 近些年来由于感染 HIV的个体感染分支 杆菌的情况也在增加， 该病也逐渐成为发达国家面对的一个棘手问题。 据 世界卫生组织 (WHO)公布的正式统计数字， 全球已确诊的活动性结核病人 超过了 2000万人， 而每年新发现的患者高达 870万人， 其中亚洲肺结核的 发病率占据了全世界发病率的 70%, 印度与中国分居亚洲结核病发病率的 前两位。 临床上常常使用抗生素来进行治疗结核病， 但与治疗典型的病菌 感染不同， 结核病人要想得到彻底的治愈需更长的时间， 一般需要大约 6 到 12个月的治疗， 然而从临床治疗情况看， 由于服药时间长， 易产生耐药 性， 在某种程度上， 目前耐药性现象在全球正在逐渐加剧， 这主要是由于 治疗措施采取不当， 尤其是单一使用一种抗生素或病人未按医嘱进行正常 服药如漏服、服药剂量不够等原因所引起。据 WHO最新完成的《耐多药结 核病和广泛耐药结核病： 2010年全球监测与反应报告》估计， 2008年全球 范围内有 44万人患有耐多药结核病， 其中有三分之一已死亡。 WHO和国 际抗肺结核结核和肺疾联盟均已宣布对于治疗肺结核病进行紧急状态， 鉴 于耐药性现象的不断出现，使用复方 (FDC法)进行治疗肺结核得到了广泛应 用。 FDC法中有一种常用复方是四联用药， 即除了对治疗结核病最有效的 利福平 (R)和异烟肼 (H)外， 还包括吡嗪酰胺 (Z)和盐酸乙胺丁醇 (E), 该四联 复方可以是复方片剂、胶囊等， 已得到 WHO对治疗肺结核的正式认可和支 持。 该四联药组成一个复方制剂， 提高了病人的依从性， 从某种程度上可 减少耐药性现象的出现。
利福平 (R)又名甲哌利福霉素 (rifampin), 是半合成的利福霉素类衍生 物，砖红色结晶，熔点 183 °C，难溶于水 (溶解度 1.3mg/ml水 pH4.3， 2.5mg/ml 水 pH7.3， 100mg/ml水 DMSO), 酸中不稳定， 并易与异烟肼发生反应， 其 受空气、 光照等因素影响也均可氧化。
Figure imgf000004_0001
利福平为高效广谱抗菌药物， 有强大的抑制或杀灭结核杆菌作用， 抗 结核作用仅次于异烟肼， 强于链霉素， 最低抑菌浓度约为 0.02〜0.05μ8 / ml, 不但对繁殖期和静止期的结核杆菌有作用， 而且对其他抗结核药耐药 的菌株也有效。 能杀灭巨噬细胞、 纤维空洞、 干酪样病灶中的结核杆菌， 对革兰阳性球菌如金葡菌、 链球菌、 肺炎球菌有强大抑制作用， 对革兰阴 性球菌如脑膜炎球菌、 淋球菌也有较强抑制作用， 对麻风杆菌有强大抑制 作用。 高浓度利福平对天花病毒、 沙眼衣原体有抑制作用。 利福平单用易 产生耐药性， 常与其它一线药合用于重症的初治或复治患者， 可增强疗效 及延缓耐药性的产生。 利福平与其它抗结核药间无交叉耐药性。 利福平能 选择性抑制细菌依赖性 DNA的 RNA聚合酶， 阻碍 mRNA合成， 但对动物 细胞 RNA聚合酶则无影响。
异烟肼 (H)又名雷米封， 化学名为 4-吡啶甲酰肼。 水中易溶， 乙醇中微 溶， 乙醚中极微溶解。 酰肼结构不稳定， 在酸碱条件下， 可水解生成异烟 酸和肼， 游离肼使毒性增大， 光、 重金属、 温度、 pH等均可加速水解进行。
其分子结构式为：
Figure imgf000004_0002
异烟肼对结核杆菌有良好的抗菌作用， 疗效较好， 用量较小， 毒性相 对较低， 易为病人所接受。异烟肼的口服吸收率为 90% ; 服后 1〜2小时血 清药物浓度可达峰； Vd为 0.61±0.11L / kg， 蛋白结合率甚低。 主要用于各 型肺结核的进展期、 溶解播散期、 吸收好转期， 尚可用于结核性脑膜炎和 其他肺外结核等。 本品常需和其他抗结核病药联合应用， 以增强疗效和克 服耐药菌。
吡嗪酰胺 (Z)水中略溶， 乙醇中微溶， 乙醚中极微溶， 有加速利福平与 异烟 。 其分子结构式为：
Figure imgf000005_0001
吡嗪酰胺对人型结核杆菌有较好的抗菌作用， 在 pH 5-5.5时， 杀菌作 用最强， 尤其对处于酸性环境中缓慢生长的吞噬细胞内的结核菌是目前最 佳杀菌药物。本品在体内抑菌浓度 12.5 g/ml， 达 5(^g/ml可杀灭结核杆菌。 该药物在细胞内抑制结核杆菌的浓度比在细胞外低 10倍， 在中性、 碱性环 境中几乎无抑菌作用。 作用机制可能与吡嗪酸有关， 吡嗪酰胺渗透入吞噬 细胞后并进入结核杆菌菌体内， 菌体内的酰胺酶使其脱去酰胺基， 转化为 吡嗪酸而发挥抗菌作用。 另因吡嗪酰胺在化学结构上与烟酰胺相似， 通过 取代烟酰胺而干扰脱氢酶， 阻止脱氢作用， 妨碍结核杆菌对氧的利用， 而 影响细菌的正常代谢， 造成死亡。
盐酸乙胺丁醇 (E)水中易溶， 易吸潮， 为利福平与异烟肼的反应提供环 境， 其分子结构式为：
HCI ^-0H
H H τ
i Η Ή
H H CI 。 盐酸乙胺丁醇适用于与其他抗结核病药联合治疗肺结核， 单纯使用盐 酸乙胺丁醇易产生耐药性。 对生长繁殖期细菌具较强活性， 对静止期细菌 几无作用。 对各型分枝杆菌具高度抗菌活性。 结核杆菌对本品与其他药物 之间无交叉耐药现象。 与利福平或异烟肼等联用治疗各型活动性结核病。 亦可用于非典型结核分枝杆菌感染的治疗。
RHZE 组合在临床上虽然有一定临床意义， 但也存在着一些很大的问 题， 首先是利福平与异烟肼如果直接接触很容易发生反应， 尤其是在胃的 酸性环境中， 这使复方中利福平的生物利用度比单方利福平的生物利用度 低，从而使患者达不到治疗效果或产生耐药性。有文献 (参见 Sosa等人, 2005, Ars Pharm, 46:353-364)报道，在胃酸 (ρΗ1〜3)条件下利福平与异烟肼直接接 触很容易发生反应生成异烟腙， Singh等人 (参见 Singh等人， 2000, Pharm. Pharmacol. Commun. 6: 405-410.)的实验也证实了这一事实。 该研究表明， 在胃酸性环境中， 缺乏异烟肼时利福平分解为 3-甲酰基利福霉素， 当有异 烟肼存在时， 生成的 3-甲酰基利福霉素能快速通过二级反应与异烟肼生成 异烟腙。 由于异烟腙在酸性环境中不稳定， 以可逆方式通过缓慢的一级反 应再生成 3-甲酰基利福霉素和异烟肼。 在这种复杂的反应中利福平进一步 快速降解， 而异烟肼得到恢复。 3-甲酰基利福霉素和异烟腙虽有抗菌活性， 但比利福平要低。 同时 RHZE组合中， 吡嗪酰胺对利福平与异烟肼的反应 具有催化作用， 而盐酸乙胺丁醇的易吸潮又为利福平与异烟肼的降解反应 将提供了条件， 这些也是导致制剂不稳定、 复方中利福平生物利用度比单 方中利福平低的一些主要因素。 其次是利福平的溶解度问题， 利福平是低 溶高渗解离型药物， 其溶解度具有 pH依赖性， 在胃肠道不同 pH环境下的 溶解度有很大区别， 实验表明在 pH 1.4时可达约 125 mg/ml， 10分钟内能 溶解 80-90%, 而在 pH大于 3时， 溶解度不到 6mg/ml。 如果仅是采用简单 的肠溶包衣方式使利福平避免在胃中释放改为在肠道中释放， 由于利福平 在肠中的难溶性也会直接导致利福平生物利用度的降低。
因此， 怎样来提高四联 (RHZE)复方中利福平的生物利用度是许多药物 研发机构和生产商所需要解决的问题。 对此已有一些相关的研究报道， 如 在 WO02/11728中公开了将利福平与 pH依赖型载体溶解在溶媒中制备固体 分散体， 以此来提高了利福平的溶解度， 但本发明人从实验中发现， 由于 pH依赖型载体用量较少， 难于控制利福平在酸性环境中的大量释放， 该专 利在提高 RHZE复方中的利福平生物利用度方面不能达到本专利申请的固 体制剂的效果。 本发明固体制剂中的利福平固体分散体不仅能提高利福平 的溶解度和溶解速率， 而且还确保了利福平在胃的酸性环境中少量释放或 不释放， 减少利福平与异烟肼在体内的反应， 同时制剂中利福平与异烟肼 也互不接触确保了制剂存放过程中的稳定性， RHZE复方中利福平体内外的 稳定性有助于提高复方中利福平的生物利用度， 确保治疗效果， 减少耐药 性的产生。 发明内容
在第一项实施方案中， 本发明的复方口服包芯固体制剂为包衣包芯片， 其包含利福平、 异烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分， 其内层 芯包含异烟肼或利福平并包覆有水不溶性非 pH依赖型衣膜，并且所述包芯 固体制剂外层包覆有水溶性非 pH依赖型防潮避光衣膜， 服药后， 利福平和 异烟肼中的至少一种活性成分在胃中少量释放或不释放。
在第二项实施方案中， 本发明的复方口服包芯固体制剂为包衣三层片， 其包含利福平、 异烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分， 其上层 和下层分别独立地含有异烟肼和利福平中的任意一种， 中间层包含吡嗪酰 胺和盐酸乙胺丁醇中的至少一种，所述三层外包覆有水不溶性非 pH依赖型 衣膜， 服药后， 利福平和异烟肼中的至少一种活性成分在胃中少量释放或 不释放。
在第三项实施方案中， 本发明的复方口服包芯固体制剂为包衣包芯片， 其包含利福平、 异烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分， 其内层 芯包含异烟肼或利福平并包覆有水溶性非 pH依赖型隔离衣膜，并且利福平 为分散于肠溶固体载体中的利福平肠溶固体分散体， 所述包芯固体制剂外 层包覆有水溶性非 pH依赖型防潮避光衣膜。
在第四项实施方案中， 本发明的复方口服包芯固体制剂为包衣三层片， 其包含利福平、 异烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分， 其上层 和下层分别独立地含异烟肼和利福平中的任意一种， 在含利福平层中， 利 福平为分散于肠溶固体载体的利福平肠溶固体分散体， 中间层包含吡嗪酰 胺和盐酸乙胺丁醇中的至少一种，所述三层外包覆有水溶性非 pH依赖型防 潮避光衣膜。 在另一个实施方案中， 第一项和第二项实施方案中的所述水不溶性非 pH依赖型衣膜包含水不溶性非 pH依赖型高分子成膜材料和增塑剂， 任选 进一步含有选自致孔剂和抗粘剂的一种或多种。
在又一个实施方案中，第二项实施方案中的所述水不溶性非 pH依赖型 衣膜还包含避光剂。
在又一个实施方案中， 第一项实施方案中的所述内层芯中还包含吸水 快速崩解膨胀的聚合物和 /或小分子助渗剂。
在又一个实施方案中， 第二项实施方案中的含利福平层中还含有吸水 快速崩解膨胀的聚合物、 所述中间层还含有阻滞剂。 发明详述
不希望被任何理论所束缚， 本发明中复方口服固体制剂设计思路是通 过使制剂中利福平和异烟肼两种活性成分不直接接触， 服药后， 控制其中 的利福平和异烟肼中的至少一种活性成分在胃中的少量释放或者不释放； 优选释放量不超过标示百分含量的 15%, 更优选不超过 10%, 进一步更优 选不超过 5%， 从而既提高该复方制剂的稳定性， 又提高复方中利福平的生 物利用度。
本发明中， "助渗剂"是指具有一定渗透压而利于水分子渗入的物质。 在本发明中没有特殊限制， 只要是适用于本发明的药物制剂领域常用的助 渗剂均可。
本发明中， "非 pH依赖型衣膜"是指包含非 pH依赖型的物质的衣膜。 在本发明中， 术语 "非 pH依赖型物质"是指在水中溶解不受 pH值影响的 物质。 在本发明中没有特殊限制， 只要是适用于本发明的药物制剂领域常 用的非 pH依赖型衣膜均可。
本发明中， "肠溶型载体"是指在胃的酸性环境中基本不溶解， 但在 肠的 pH环境中能溶解的物质。在本发明中没有特殊限制， 只要是适用于本 发明的药物制剂领域常用的肠溶型载体均可。
本发明中， "粘合剂"是指具有粘性的物质， 借助其粘性能将分离的 粉末连接在一起。 在本发明中没有特殊限制， 只要是适用于本发明的药物 制剂领域常用的粘合剂均可。 本发明中， "润滑剂"是指介于两个相对运动的物体之间， 具有减少 因接触而产生的摩擦与磨损的物质。 在本发明中没有特殊限制， 只要是适 用于本发明的药物制剂领域常用的润滑剂均可。
本发明涉及一种复方口服包衣固体制剂， 其包含利福平、 异烟肼、 吡 嗪酰胺和盐酸乙胺丁醇作为活性成分， 其活性成分组成为 200-300mg : 75mg-300mg: 250-500mg: 250-275mg, 优选 150mg: 75 mg: 400 mg: 275 mg组合。
一方面， 本发明的一个技术特点是本发明所述的复方口服固体制剂的 活性成分中的一种或多种包覆有水不溶性非 pH依赖型衣膜，该衣膜具有水 渗透性， 用来控释异烟肼或利福平的延迟释放， 而利福平或异烟肼中的一 种和其它活性成分在服药后快速释放， 并且该设计特点还保证利福平和异 烟肼不直接接触。 该设计特点的复方口服包衣固体制剂可以是包衣包芯片 或包衣三层片。
在一个优选实施方案中， 本发明所述的复方口服固体制剂是包衣包芯 片， 其内层是异烟肼层， 可以是以一个或多个独立的包覆有水不溶性非 pH 依赖型衣膜的颗粒、 丸或小片的形式存在， 其包衣内层芯外包覆含有利福 平、 吡嗪酰胺和盐酸乙胺丁醇的外层形成包芯片， 所述包芯片外包覆水溶 性非 pH依赖型防潮避光衣膜。
在该包衣包芯片中， 除所述活性成分外， 所述水不溶性非 pH依赖型衣 膜的内层芯中还可包含吸水快速崩解膨胀的聚合物， 以及任选含有一种或 多种选自小分子助渗剂、 粘合剂和润滑剂的载体。 其中所述的吸水快速崩 解膨胀的聚合物为一种或多种选自以下组中的物质： 交联羧甲基纤维素钠 (CCMC-Na), 低取代羟丙基纤维素 (L-HPC)、 羧甲基纤维素钠 (CMC-Na)、 羧甲基淀粉钠 (CMS-Na)、 交联聚维酮 (PVPP)和微晶纤维素 (MCC); 小分子 助渗剂为一种或多种选自以下组中的物质： 氯化钠和氯化钾。
在该包衣包芯片中，内层异烟肼层包覆的水不溶性非 pH依赖型衣膜为 内层异烟肼片芯重量的 6-30%, 其具有水渗透性， 包含水不溶性非 pH依赖 型高分子成膜材料、 增塑剂， 并任选含有致孔剂和 /或抗粘剂。 其中水不溶 性非 pH依赖型衣膜含有成膜材料为衣膜总重的 70重量％-90重量％， 优选 70重量％-80重量％，其优选自一种或多种以下组中的物质： Aquacoat ECD, 乙基纤维素 (EC)、 醋酸纤维素 (CA)、 聚氯乙烯、 聚碳酸酯、 乙烯醇-乙酸乙 烯酯；增塑剂为衣膜总重的 10重量％-30重量％，优选 13重量％-25重量％， 其优选自一种或多种以下组中的物质： 柠檬酸三乙酯 (TEC)、 柠檬酸三丁酯 (TBC)、 乙酰柠檬酸三乙酯 (ATEC)、 癸二酸二甲酯 (DMS)、 癸二酸二丁酯 (DBS),邻苯二甲酸二丁酯 (DBP);致孔剂为衣膜总重的 0重量％-15重量％， 优选 4重量％-13重量％， 其优选自一种或多种以下组中的物质： 聚乙二醇 类、 羟丙基甲基纤维素、 KolliCOat®IR、 聚乙烯醇、 尿素； 抗粘剂为衣膜总 重的 0重量％-25重量％， 优选 0重量％-15重量％， 其选自一种或多种以下 组中的物质： 滑石粉、 轻质微粉硅胶。
该包衣包芯片的制备方法为：
1) 内层包衣芯的制备：将异烟肼与吸水快速崩解膨胀的聚合物和 /或小 分子助渗剂混和、 粉碎， 制粒或制微丸、 干燥， 再包水不溶性非 pH依赖型 衣膜； 如果需要制成包衣片内芯， 还需将颗粒再加助流剂或润滑剂混匀过 筛后压片， 再包水不溶性非 pH依赖型衣膜。
2) 外层颗粒制备： 将利福平、 吡嗪酰胺、 盐酸乙胺丁醇与填充剂、 崩 解剂混合， 用粘合剂制粒， 干燥， 加助流剂或润滑剂混匀， 过筛， 待用。
3) 压包芯片： 将 1)中包衣片芯做内芯， 2)中颗粒做外层， 压包芯片或 将 1)中包衣颗粒或包衣微丸与 2)中颗粒混合压片。
4) 包衣： 将 3)中包芯片包水溶性非 pH依赖型防潮避光衣膜。
在另一个优选实施方案中， 本发明所述的复方口服固体制剂是包衣三 层片， 由上层、 中间层和下层组成， 上层和下层分别是利福平层和异烟肼 / 吡嗪酰胺层、 中间层是盐酸乙胺丁醇层， 其中利福平层中含有吸水快速崩 解膨胀的聚合物和其它药用载体、 盐酸乙胺丁醇层含有阻滞盐酸乙胺丁醇 快速崩解或快速释放的阻滞剂和其它药用载体、 异烟肼 /吡嗪酰胺层含有其 它药用载体， 所述三层片外包覆水不溶性非 pH依赖型衣膜。
该三层片外包覆的水不溶性非 pH依赖型衣膜具有水渗透性，衣膜重量 为三层片未包衣片芯重量的 5-12%,其包含水不溶性非 pH依赖型高分子成 膜材料、 增塑剂， 任选地进一步含有选自致孔剂、 避光剂、 抗粘剂中的至 少一种， 水不溶性非 pH依赖型成膜材料选自一种或多种以下组中的物质： Aquacoat ECD, 乙基纤维素 (EC)、 醋酸纤维素 (CA)、 聚氯乙烯、 聚碳酸酯、 乙烯醇-乙酸乙烯酯， 其占衣膜总重量的 50重量％-80重量％； 增塑剂选自 一种或多种以下组中的物质： 柠檬酸三乙酯 (TEC)、 柠檬酸三丁酯 (TBC)、 乙酰柠檬酸三乙酯 (ATEC)、 癸二酸二甲酯 (DMS)、 癸二酸二丁酯 (DBS)、邻 苯二甲酸二丁酯 (DBP), 其占衣膜总重量的 20重量％-45重量％； 致孔剂选 自一种或多种以下组中的物质： 聚乙二醇类、 羟丙基甲基纤维素、 Kollicoat®IR、 聚乙烯醇、 尿素， 占衣膜总重量的 0重量％-15重量％； 抗粘 剂选自一种或多种以下组中的物质： 滑石粉、 轻质微分硅胶， 其占衣膜总 重量的 0重量％-20重量％； 避光剂为二氧化钛， 其占衣膜总重量的 0重量 %-20重量％。
该包衣三层片的利福平层中含有吸水快速崩解膨胀聚合物， 其是一种 或多种选自以下组中的物质： 交联羧甲基纤维素钠 (CCMC-Na)、 低取代羟 丙基纤维素 (L-HPC)、羧甲基纤维素钠 (CMC-Na)、羧甲基淀粉钠 (CMS-Na) 、 交联聚维酮 (PVPP)和微晶纤维素 (MCC)。
该包衣三层片的盐酸乙胺丁醇层中含有阻滞剂， 其是一种或多种选自 以下组中的物质： 水不溶性骨架材料如乙基纤维素、 聚乙烯类、 丙烯酸树 脂类， 溶蚀性骨架材料如蜂蜡、 氢化植物油、 硬脂酸、 聚乙二醇、 巴西棕 榈蜡、 甘油硬脂酸酯、 丙二醇硬脂酸酯和十八垸醇， 水溶性骨架材料如羟 丙基甲基纤维素， 聚氧乙烯 (PEO)。
该包衣三层片的制备方法为：
1) 利福平层的制备：将利福平和吸水快速崩解膨胀的聚合物混合粉碎、 过筛、 用粘合剂制粒， 干燥， 加助流剂或润滑剂混匀， 过筛， 待压片；
2) 盐酸乙胺丁醇层的制备： 将盐酸乙胺丁醇、 阻滞剂和填充剂混合粉 碎、 过筛、 用粘合剂制粒， 干燥， 加助流剂或润滑剂混匀， 过筛， 待压片；
3) 异烟肼 /吡嗪酰胺层的制备：将异烟肼、吡嗪酰胺与填充剂混合粉碎、 过筛、 用粘合剂制粒， 干燥， 加助流剂或润滑剂混匀， 过筛， 待压片；
4) 压三层片： 将 1)、 2)、 3)中的颗粒分别做为上、 中和下层进行压片；
5) 包衣： 将 4)中三层片包覆所述的水不溶性非 pH依赖型衣膜。
另一方面， 本发明的另一个设计特点在于考虑到利福平是难溶性药物， 通过采用肠溶固体分散体技术提高利福平的溶解度和溶解速率来提高本发 明复方药物制剂的稳定性和制剂中利福平的生物利用度。 该设计特点为复 方口服固体制剂是包衣包芯片或包衣三层片。
在一个优选实施方案中， 所述复方口服固体制剂是包衣包芯片， 其内 层芯包含异烟肼或利福平并包覆有水溶性非 pH依赖型隔离衣膜，并且利福 平为分散于肠溶固体载体中的利福平肠溶固体分散体， 所述包芯固体制剂 外层包覆有水溶性非 pH依赖型防潮避光衣膜。
本发明所述利福平固体分散体中利福平与肠溶型载体的重量比范围为 2： 1-1： 3， 其中所述的肠溶固体分散体载体选自一种或多种选自以下组中 的载体： 聚乙烯醇乙酸苯二甲酸酯 (PVAP)、 甲基丙烯酸 /甲基丙烯酸甲酯共 聚物如 Eudragit L30D-55、 Eudragit LI 00. Eudragit SI 00. 纤维素及其衍生 物如邻苯二甲酸乙酸纤维素 (乙酸纤维素酞酸酯， CAP)、 1,2,4-苯三甲酸乙 酸纤维素 (乙酸纤维素苯三酸酯， CAT)、 邻苯二甲酸羟丙基甲基纤维素 (羟 丙甲纤维素酞酸酯， HPMCP)、 1,2,4-苯三甲酸羟丙基甲基纤维素 (HPMCT); 琥珀酸乙酸纤维素 (CAS)和琥珀酸乙酸羟丙基甲基纤维素 (HPMCAS)、 醋酸 羟丙基甲基纤维素酞酸酯 (HPMCAP), 优选琥珀酸乙酸羟丙基甲基纤维素 (HPMCAS)o
所述水溶性非 pH依赖型隔离衣膜的成膜材料选自一种或多种以下组 中的物质： 羟丙甲纤维素 (HPMC)、 Kollicoat®IR和 OpadryII。
本发明所述的利福平固体分散体制备方法可以是制备固体分散体的常 用方法， 例如热熔法、 喷雾干燥法、 流化床一步法制粒或溶剂挥干法。
所述包衣包芯片的制备方法为：
1) 内层包衣芯的制备： 将异烟肼与填充剂混和、 粉碎， 用粘合剂制粒 或制微丸、 干燥， 再包覆所述水溶性非 pH依赖型隔离衣膜； 如果需要制成 包衣片内芯， 还需将颗粒再加助流剂或润滑剂混匀过筛后压片， 再包覆所 述水溶性非 pH依赖型衣膜作为隔离衣膜。
2) 外层颗粒的制备： 先将利福平制成肠溶型固体分散体， 再将利福平 固体分散体与吡嗪酰胺、 盐酸乙胺丁醇与填充剂、 崩解剂、 粘合剂制备的 干颗粒混合， 加助流剂或润滑剂混匀， 过筛， 待用。
3) 压包芯片： 将 1)中的包衣片芯做内芯， 2)中的颗粒做外层， 压包芯 片或将 1)中的包衣颗粒或包衣微丸与 2)中的颗粒混合压片。 4) 包衣：将 3)中的包芯片包覆所述水溶性非 pH依赖型防潮避光衣膜。 在另一个优选实施方案中， 所述复方口服固体制剂为包衣三层片， 其 上层和下层分别独立地含异烟肼和利福平中的任意一种， 在含利福平层中， 利福平为分散于肠溶固体载体的利福平肠溶固体分散体， 中间层包含吡嗪 酰胺和盐酸乙胺丁醇中的至少一种，所述三层外包覆有水溶性非 pH依赖型 防潮避光衣膜。 其中利福平与肠溶型载体的重量比范围、 肠溶固体分散体 载体和利福平固体分散体制备方法如上所述。
所述包衣三层片的制备方法为：
1) 利福平层的制备： 先将利福平制成肠溶型固体分散体， 再将利福平 固体分散体和其它药用载体混合制粒或用来直接待压片；
2) 盐酸乙胺丁醇层的制备:将盐酸乙胺丁醇和其它药用载体混合粉碎、 过筛、 用粘合剂制粒， 干燥， 加助流剂或润滑剂混匀， 过筛， 待压片；
3) 异烟肼吡嗪酰胺层的制备： 将异烟肼、 吡嗪酰胺与其它药用载体混 合粉碎、 过筛、 用粘合剂制粒， 干燥， 加助流剂或润滑剂混匀， 过筛， 待 压片；
4) 压三层片： 将 1)、 2)和 3)中的颗粒分别做上、 中和下层压片；
5) 包衣： 将 4)中三层片包覆所述水溶性非 pH依赖型衣膜。
以上实施方案中所述的用作防潮避光衣膜的水溶性非 pH依赖型衣膜 含有一种选自以下组中的物质： Kollicoat®IR、 羟丙基甲基纤维素 (HPMC)、 二氧化钛和滑石粉的组合物、 含有羟丙基甲基纤维素 (HPMC)、 二氧化钛和 滑石粉组合成分的 Opadryll。
本发明所述的复方口服包芯固体制剂还可包含选自以下组中的其它药 用载体： 填充剂、 粘合剂、 润滑剂或助流剂和 /或崩解剂。 附图说明
图 1 包衣包芯片示意图； A: 内层芯； B: 内层衣膜； C: 外层； D: 衣膜；
图 2 包衣三层片示意图； A: 上层； B: 中间层； C: 下层； D: 衣膜; 图 3 0811011批利福平原料药 0天有关物质测定 HPLC图谱； 图 4 喷雾干燥方法制备的利福平固体分散体 (实施例 8样品) 0天有关 物质测定的 HPLC图谱；
图 5 溶剂自然挥发方法制备的利福平固体分散体 (实施例 11样品） 0天 有关物质测定的 HPLC图谱；
图 6 热熔法方法制备的利福平固体分散体 (实施例 7样品） 0天有关物 质测定的 HPLC图谱；
图 7 进口产品 6个月加速试验40°C， 75%RH)有关物质测定的 HPLC 图谱。
图 8 自制包芯片 6个月加速试验 (40 °C， 75%RH)有关物质测定的 HPLC 图谱。
图 9 自制包芯片 12个月稳定性 (25°C， 60%RH)有关物质测定的 HPLC 图谱。
图 10比格犬口服给药自制利福平 (实施例 10 样品)与市售利福平单方 后的时间-血药浓度曲线。
图 11比格犬口服给药自制利福平 +市售异烟肼与市售利福平 +市售异 烟肼后利福平的时间-血药浓度曲线。 具体实施方式
以下通过实施例进一步说明本发明， 但并不意图对本发明进行限制。 实施例 1
包衣包芯片的制备
1) 未包衣片芯的制备
取异烟肼 75.00g、 氯化钠 2.00g、 微晶纤维素 18.70g、 交联羧甲基纤维 素钠 10.30g混合均匀， 研磨过孔径 0.250mm筛， 用 2%羟丙基甲基纤维素 制软材， 过孔径 0.710mm筛制粒， 于 50°C下干燥， 至颗粒水分含量在 3.0% 以下， 加干颗粒 1%重量的硬脂酸镁， 混合过孔径 0.85mm筛， 混匀， 压片， 冲模为 4*9mm异型冲模，压力控制在 50-65N,包衣前片芯崩解时间控制在 1分钟内最佳。
2) 内层片芯包衣 按 Aquacoat ECD固含量重量：柠檬酸三乙酯 (TEC): Kollicoat®IR=8.05 : 2.01： 0.50 比例配制固含量浓度为 15%的包衣液， 包衣片床温度控制在 39°C-42°C， 片增重 8%-10%， 包衣后在 60°C固化 2小时， 作包芯片内层片 芯待用。 该包衣内层片芯中异烟肼的释放情况见表 1。
3) 外层颗粒制备压片
取利福平 150.00 g、 吡嗪酰胺 400.00g、 盐酸乙胺丁醇 275.00g、微晶纤 维素 160.00g、 低取代羟丙基纤维素 54.00g混匀打粉， 过孔径 0.250mm筛 用 5%羟丙基甲基纤维素制粒， 于 50°C下干燥， 颗粒水分控制在小于 3%， 加干颗粒 0.5%重量的微粉硅胶过孔径 0.600mm筛， 压包芯片。
4) 外层包衣的制备
配制浓度为 20%的 Opadry ll包衣液包衣， 包衣物料温度控制在 40-45 °C， 包衣增重约 3%。
实施例 2
包衣包芯片的制备
1) 未包衣片芯的制备
取异烟肼 75.00g、微晶纤维素 18.70g、交联羧甲基纤维素钠 8.20g混合 均匀， 研磨过孔径 0.250mm筛， 用 2%羟丙基甲基纤维素制软材， 过孔径 0.710mm筛制粒， 于 50 °C下干燥， 至颗粒水分含量在 3.0%以下， 加干颗粒 1%重量的硬脂酸镁， 混合过孔径 0.85mm筛， 混匀， 压片， 冲模为 6.5浅凹 的圆冲， 压力控制在 50-65N, 包衣前片崩解时间优选控制在 1分钟内。
2) 内层片芯包衣
按 Aquacoat ECD固含量重量：柠檬酸三乙酯 (TEC): Kollicoat®IR=8.05 : 2.01： 0.50 比例配制固含量浓度为 15%的包衣液， 包衣片床温度控制在 39°C-42°C， 片增重 8%-10%， 包衣后在 60°C固化 2小时， 作包芯片内层片 芯待用。 该包衣内层片芯中异烟肼的释放情况见表 2。
3) 包芯片压片包衣
取实施例 1的外层颗粒压包芯片， 用浓度为 20%的 Opadryll包衣液包 衣， 包衣物料温度控制在 40-45 °C， 包衣增重约 3%。 实施例 3
包衣包芯片的制备
1) 未包衣丸芯的制备
取异烟肼 75.00g、微晶纤维素 18.70g、交联羧甲基纤维素钠 8.20g混合 均匀，研磨过孔径 0.250mm筛，用 2%羟丙基甲基纤维素制软材先将异烟肼 打粉过孔径 0.250mm筛， 用孔径 600μηι筛网挤出， 700rpm滚圆， 制备微 丸， 于 50°C下干燥。
2) 丸芯包衣
按 Aquacoat ECD固含量重量：柠檬酸三乙酯 (TEC): Kollicoat®IR=8.05 : 2.01： 0.50 比例配制固含量浓度为 15%的包衣液， 包衣片床温度控制在 39°C-42°C， 微丸包衣增重 22-25%, 包衣后在 60°C固化 2小时， 作包芯片 内层芯待用。
3) 包芯片压片包衣
取外层取实施例 1 的外层颗粒， 按异烟肼： 利福平： 吡嗪酰胺： 盐酸 乙胺丁醇为 75 mg: 150mg: 400 mg: 275 mg的比例混合压片， 用浓度为 20%的 Opadry ll包衣液包衣， 包衣物料温度控制在 40-45°C， 包衣增重约 3%。 实施例 4
包衣三层片的制备
1) 利福平层颗粒的制备
将利福平 30.03g、 微晶纤维素 5.60g、 交联羧甲基纤维素钠 7.40g混合 研磨过孔径 0.250mm筛， 用 2%羟丙基甲基纤维素水溶液过孔径 0.710mm 筛制粒， 于 50°C下干燥， 至颗粒水分含量在 3.0%以下， 加干颗粒 0.5%重 量的微分硅胶过孔径 0.850mm筛， 混合均匀， 待压片。
2) 盐酸乙胺丁醇层颗粒的制备
将盐酸乙胺丁醇 55.02g、 微晶纤维素 5.02g混合研磨过孔径 0.250mm 筛， 用 5%的乙基纤维素乙醇水溶液 (乙醇： 蒸馏水 =90 : 10， v/v)过孔径 0.710mm筛制粒， 于 80 °C下干燥， 至颗粒水分含量在 2.0%以下， 加干颗粒 0.5%重量的硬脂酸过孔径 0.850mm筛， 混合均匀， 待压片。 3) 异烟肼 /吡嗪酰胺层颗粒的制备
将异烟肼 15.00g、吡嗪酰胺 80.00g、微晶纤维素 8.02g混合研磨过孔径 0.250mm筛， 用 2%羟丙基甲基纤维素水溶液过孔径 0.710mm筛制粒， 于 80°C下干燥， 至颗粒水分含量在 3.0%以下， 加干颗粒 0.5%重量的硬脂酸过 孔径 0.850mm筛， 混合均匀， 待压片。
4) 压片
按利福平： 盐酸乙胺丁醇： 异烟肼： 吡嗪酰胺 =150mg: 275mg: 75mg:
400mg的比例取利福平层、盐酸乙胺丁醇层、异烟肼 /吡嗪酰胺层压三层片。
5) 包衣
按 Aquacoat ECD固含量重量： DBS: TEC: 二氧化钛 =60: 20： 10： 10 重量比配制 15%的包衣液， 包衣增重约 8 %， 60°C固化 2h。
实施例 5
包衣三层片的制备
1) 利福平层颗粒的制备
将利福平 30.13g、 微晶纤维素 5.66g、 交联羧甲基纤维素钠 7.50g混合 研磨过孔径 0.250mm筛， 用 2%羟丙基甲基纤维素水溶液过孔径 0.710mm 筛制粒， 于 50°C下干燥， 至颗粒水分含量在 3.0%以下， 加干颗粒 0.5%重 量的微分硅胶过孔径 0.850mm筛， 混合均匀， 待压片。
2) 盐酸乙胺丁醇层颗粒的制备
将盐酸乙胺丁醇 55.22 g、微晶纤维素 5.99g、羟丙基纤维素 K100M3.01g 混合研磨过孔径 0.250mm 筛， 用 70%的乙醇水溶液 (v/v)制软材过孔径 0.710mm筛制粒， 于 80 °C下干燥， 至颗粒水分含量在 2.0%以下， 加干颗粒 0.5%重量的硬脂酸过孔径 0.850mm筛， 混合均匀， 待压片。
3) 异烟肼 /吡嗪酰胺层颗粒的制备
将异烟肼 15.08g、吡嗪酰胺 80.10g、微晶纤维素 8.10g混合研磨过孔径 0.250mm筛， 用 2%羟丙基甲基纤维素水溶液过孔径 0.710mm筛制粒， 于 80°C下干燥， 至颗粒水分含量在 3.0%以下， 加干颗粒 0.5%重量的硬脂酸过 孔径 0.850mm筛， 混合均匀， 待压片。
4) 压片 按利福平： 盐酸乙胺丁醇： 异烟肼： 吡嗪酰胺 =150mg: 275mg: 75mg:
400mg的比例取利福平层、盐酸乙胺丁醇层、异烟肼 /吡嗪酰胺层压三层片。
5) 包衣
按 Aquacoat ECD固含量重量： DBS: TEC: 二氧化钛 =60: 20： 10：
10重量比配制 15%的包衣液， 包衣增重约 8 %， 60°C固化 2h。
实施例 6
取实施例 5中的三层片， 按 Aquacoat ECD固含量重量： TEC: HPMC: 二氧化钛 =70.8: 12.5： 8.3： 8.3重量比配制 15%的包衣液， 包衣增重约 8 %， 60°C固化 2h。
实施例 7
包衣包芯片的制备
1) 未包衣片芯的制备
取异烟肼 15.02g、 微晶纤维素 2.80g混合均匀， 研磨过孔径 0.250mm 筛， 用 2%羟丙基甲基纤维素制软材， 过孔径 0.710mm筛制粒， 于 50°C下 干燥， 至颗粒水分含量在 3.0%以下， 加干颗粒 1%重量的硬脂酸镁， 混合 过孔径 0.85mm筛，混匀，压片，冲模为 6.5浅凹的圆冲，压力控制在 50-65N。
2) 内层片芯包隔离衣
用 10% HPMC溶液包衣， 包衣片床温度控制在 28°C-32°C， 片增重约
5%。
3) 外层中利福平固体分散体的制备
取利福平 15.05g和琥珀酸乙酸羟丙基甲基纤维素 15.10g混匀， 用热熔 法制备利福平固体分散体， 粉碎， 过孔径 0.250mm筛。
4) 外层吡嗪酰胺 /盐酸乙胺丁醇颗粒的制备
取吡嗪酰胺 400.70g、 盐酸乙胺丁醇 275.05g、 微晶纤维素 161.04g、 低 取代羟丙基纤维素 54.50g混匀打粉， 过孔径 0.250mm筛用 5%羟丙基甲基 纤维素制粒， 干燥， 颗粒水分控制在小于 3%。 按利福平： 盐酸乙胺丁醇： 吡嗪酰胺 =150mg: 275mg: 400mg 的比例 取利福平固体分散体粉末与 4)中吡嗪酰胺 /盐酸乙胺丁醇干颗粒混合， 加混 合颗粒 0.5%重量的微粉硅胶过孔径 0.600mm筛， 待压片。
6) 压包芯片
取 2)中包衣片为片芯， 5)中颗粒为外层压包芯片。
7) 外层包衣
配制浓度为 20%的 Opadry ll包衣液包衣， 包衣物料温度控制在 40-45 °C， 包衣增重约 3%。
实施例 8
包衣包芯片的制备
1) 外层中利福平固体分散体的制备
取利福平 150.00 g和琥珀酸乙酸羟丙基甲基纤维素 150.00g混匀，分别 溶于 1500.0g的二氯甲垸和 1500.0g的丙酮中再将二者混合搅拌均匀， 采用 喷雾干燥法制备利福平固体分散体， 进风温度控制在 50-55°C。
2) 外层颗粒混合
按利福平： 盐酸乙胺丁醇： 吡嗪酰胺 =150mg: 275mg: 400mg 的比例 取喷雾干燥法制备的利福平固体分散体粉末与实施例 7的 4)中吡嗪酰胺 /盐 酸乙胺丁醇干颗粒混合， 加混合颗粒 0.5%重量的微粉硅胶过孔径 0.600mm 筛， 待压片。
3) 压包芯片
取实施例 7的 2)中的包衣片为片芯， 本实施例 2)中的颗粒为外层颗粒 压包芯片 。
4) 外层包衣
配制浓度为 20%的 Opadry ll包衣液包衣， 包衣物料温度控制在 40-45 °C， 包衣增重约 3%。
实施例 9
包衣包芯片的制备
1) 利福平溶液的配制 取利福平 150.00g和琥珀酸乙酸羟丙基甲基纤维素 150.00g混匀， 分别 溶于 1500.00g g的二氯甲垸和 1500.00g的丙酮中再将二者混合搅拌均匀， 待用。
2) 外层颗粒的制备
取吡嗪酰胺 400.00g、盐酸乙胺丁醇 275.00g微晶纤维素 160.00g、低取 代羟丙基纤维素 54.00g混匀， 研磨， 过孔径 0.250mm筛后倒入流化床中， 用 1)中利福平溶液进行一步法制粒， 物料温度控制在 35-40 °C， 颗粒水分控 制在小于 3%， 加处方量微粉硅胶过孔径 0.600mm筛， 待用。
3) 压包芯片
取实施例 7的 2)中的包衣片为片芯， 本实施例 2)中的颗粒为外层颗粒 压包芯片。
4) 外层包衣
配制浓度为 20%的 Opadry ll包衣液包衣， 包衣物料温度控制在 40-45 °C， 包衣增重约 3%。 实施例 10
包衣三层片的制备
1) 利福平层颗粒的制备
取实施例 8中的利福平固体分散体 60.30g、 微晶纤维素 5.60g、 交联羧 甲基纤维素钠 7.32g混合研磨过孔径 0.250mm筛，用 2%羟丙基甲基纤维素 水溶液过孔径 0.710mm筛制粒， 于 50°C下干燥， 至颗粒水分含量在 3.0% 以下，加干颗粒 0.5%重量的硬脂酸过孔径 0.850mm筛，混合均匀，待压片。
2) 盐酸乙胺丁醇层颗粒的制备
将盐酸乙胺丁醇 55.22 g、 微晶纤维素 6.03g混合研磨过孔径 0.250mm 筛， 用 5%羟丙基甲基纤维素水溶液过孔径 0.710mm筛制粒， 于 80°C下干 燥， 至颗粒水分含量在 2.0%以下， 加干颗粒 0.5%重量的硬脂酸过孔径 0.850mm筛， 混合均匀， 待压片。
3) 压片 按利福平： 盐酸乙胺丁醇： 异烟肼： 吡嗪酰胺 =150mg: 275mg: 75mg: 400mg的比例取 1)利福平层、 2)盐酸乙胺丁醇层、 实施例 5中的 3)异烟肼 吡嗪酰胺层颗粒压三层片。
4) 包衣
配制浓度为 20%的 Opadryll包衣液包衣， 包衣物料温度控制在 40-45 °C， 包衣增重约 3%。 实施例 11
取实施例 8中的利福平固体分散体 148.84g与微晶纤维素 20.75g、羧甲 基纤维素钠 8.94g、 微分硅胶 0.90g混合过筛， 压片， 冲模为 12.0mm浅凹 的圆冲， 压力控制在 50-90N, 用浓度为 20%的 Opadry ll溶液包衣， 物料温 度为 40°C-45°C， 包衣增重 3%。 该实施例制剂的体内实验数据见表 10-11。 实施例 12
采用溶剂自然挥干法制备不同比例的利福平固体分散体： 取 HPMCAS 9.0、 6.0、 3.0、 1.5g、 l.Og分别溶解在 90.0、 60.0. 30.0. 15.0g、 lO.Og丙酮 中配成溶液， 另取 5份 3.0g的利福平分别溶解在 30.0g的二氯甲垸中配制 成溶液， 再将利福平溶液分别倒入 HPMCAS溶液中混匀 lh后， 分别均匀 的倒入表面皿中， 放入通风橱中挥干， 得到利福平固体分散体， 粉碎， 待 用。 该实施例制剂中利福平的释放程度测定结果见表 5。 材料
利福平 (沈阳抗生素厂)； 异烟肼 (浙江新赛药业有限公司)； 吡嗪酰胺 (江 苏四环生物股份有限公司)； 盐酸乙胺丁醇 (上海五洲药业股份有限公司)； 进口 TB4包芯片 (Panacea Biotec Ltd); 国产利福平胶囊 (沈阳红旗制药有限 公司）； 国产异烟肼片 (沈阳红旗制药有限公司）； 微晶纤维素 (Asahi Kasei Chemicals Corporation); 低取代羟丙基纤维素 (Shin-Etsu); 羟丙基甲基纤维 素 E5 和 KlOOM(Colorcon); 硬脂酸 (湖南华日制药有限公司）； 微分硅胶 (Evonik); 琥珀酸乙酸羟丙基甲基纤维素 (Shin-Etsu); 交联羧甲基纤维素钠 (Nichirin Chemical Industries Ltd.); Aquacoat ECD(FMC Biopolymer)； 貯樣 酸三乙酯 (上海申宝香精香料有限公司)； Kollicoat®IR(BASF); 硬脂酸镁 (安 徽山河药用辅料有限公司)； 维生素 C 河北维尔康制药有限公司)； 十二垸 基硫酸钠 (安徽山河药用辅料有限公司); PEG600(K国药集团化学试剂有限公 司）； Opadryll (Colorcon); 二氯甲垸 (国药集团化学试剂有限公司）； 丙酮 (国 药集团化学试剂有限公司)； 氯化钠 (上海青析化工科技有限公司)； 乙腈 (色 谱纯， 美国 MERCK公司)； 无水憐酸氢二钠 (分析纯， 上海凌峰化学试剂公 司)； 憐酸 (分析纯， 国药集团化学试剂公司)； 氢氧化钠 (分析纯， 上海凌峰 化学试剂公司)； 乙酸 (分析纯， 上海凌峰化学试剂公司)。 设备与仪器
迷你多功能实验机 (重庆精工制药机械有限公司)； 单冲压片机 (上海天 凡药机制造厂)；喷雾干燥机 (BUCHI);水分测定仪 (北京赛多利斯有限公司); 智能溶出试验仪 (天大天发公司）； 恒温恒湿箱 720型 (BINDER); BT224S电 子天平 (北京赛多利斯有限公司）； OHHARA实验室型包衣锅； Agilent 1200 高效液相色谱仪 (安捷伦科技有限公司）; FE20型 pH计 (METTLER TOLEDO 公司： Phenomenex Luna C18 100A(250x4.6mm， 5μηι, 美国菲罗门公司）； Agilent Eclipse XDB-C18(150x4.6mm， 5μηι, 美国安捷伦）。 试验例
(一） 体外试验
表 1 异烟肼包芯片 (实施例 1)中异烟肼在水介质中累积溶出释放表
Figure imgf000022_0001
说明： 由于根据实验经验， 药片衣膜在未破裂时异烟肼释放较少， 少 于 10%, 所以片编号为 20、 26的样品未取样检测。
如表 1所示，内层衣膜破裂时间基本能达到控制的时间即 30-60分钟内 的要求， 衣膜破裂后， 药物在短时间内就可释放完全。 表 2 异烟肼包芯片 (实施例 2)中异烟肼在水介质中累积溶出释放表
Figure imgf000023_0001
如表 2所示， 该制剂中间层衣膜均在 30-60分钟能破裂， 30分钟内异 烟肼释放不超过 2%， 远低于质量控制的优化方案中的不超过 10%的标准， 并在 90分钟内基本完全释放。 表 3 TB4包芯片 (实施例 2)累积溶出度测定表 (溶出介质： PBS 6.8缓冲 液 900ml)
Figure imgf000023_0002
钟内释放小于 15%, 90分钟内释放大于 80% 表 4 TB4包衣三层片 (实施例 5)累积溶出度测定表 (溶出介质： PBS 6.8 缓冲液 900ml)
成分 30 min 45 min 60 min 90 min
Q 0 /0 (H) 2.51 5.07 54.80 98.17
Q 0 /0 (R) 80.10 97.55 97.51 96.88 Q 0 /0 (Z) 2.85 6.13 60.08 100.10
0 /0 (E) 51.32 84.46 98.31 100.99
Figure imgf000024_0001
表 5不同比例利福平： HPMCAS(w:w)固体分散体中利福平累积溶出标 示百分含量汇总表 (实施例 12)
Figure imgf000024_0002
说明： 1) 溶出条件①酸碱 (分别 900ml)不同杯， 分别单独进行， 桨法， lOOrpm, 37.0°C ;溶出条件②酸碱同杯即首先加入 750ml酸性介质 (0.1mol/l 盐酸 溶出 45min时取样并补液， 同时加入 250ml 0.2mol/l的憐酸钠溶液， 并加入 4.5ml 2mol/l的氢氧化钠将溶液调节 pH为 6.8±0.05，作为碱性介质， 桨法， lOOrpm, 37.0°C
如表 5所示，实验结果表明根据本发明，将利福平制备成固体分散体 (利 福平： HPMCAS为 3 : 1-1 3)对利福平都具有很好的增溶效果， 但由于利 福平: HPMCAS为 3 : 1时利福平在胃的酸性环境中的释放超过了控制范围， 所以不选择该比例进行制备。 从表中可看出， 选择利福平： HPMCAS的重 量比为 1 : 1时最合适， 不仅能增溶、 控制利福平在酸中的释放， 而且所用 量也相对较少。 表 6 不同制备方法制备利福平固体分散体 （实施例 7 8 9 12， 利福 HPMCAS=1 1)中利福平释放度的测定结果表
制备方法 实施例 pH1.2累积溶出 Q »% pH6.8累积溶出 Q 30min 60min 30min 60min 利福平原料药 无 62.07 62.66 27.77 46.45 热熔法 7 3.45 未取样 82.07 88.63 喷雾干燥法 8 7.98 未取样 100.59 89.64 一步法制粒 9 1.96 7.97 98.19 97.76 自然挥干法 12 0.93 0.61 80.58 90.13 表 6数据显示制备方法对利福平的增溶效果影响不大。 表 7 不同制备方法制备的利福平固体分散体 (利福平： HPMCAS=1 : 1) 在 0天的有关物质测定结果表
Figure imgf000025_0001
说明： 1)色谱图见图 1-4， 图中峰 2为利福平峰。
2) 仪器及色谱条件： Waters e2695- 2998高效液相色谱仪， Phenmenex luna C18(250x4.6mm, 5μηι)色谱柱；流速为 1.0 ml/min，检测波长为 238nm 流动相为八相= 1^ 6.8/乙腈 (96/4)， 8相= 1^ 6.8/乙腈 (50/50)， A相: B相 =25 75 ο
如表 7所示， 三种固体分散体制备方法对利福平的稳定性顺序是溶剂 自然挥发法 >喷雾干燥法 >热熔法， 结合生产的工业化特点， 优选喷雾干 燥法。 表 8 自制包芯片 (实施例 2)及市售进口产品 6个月加速试验 (40 °C 75%RH) 的有关物质测定表
Figure imgf000025_0002
96.33 104.82 4.68 97.25 108.06 6.48
95.17 106.68 5.81 96.13 107.76 8.20
93.09 103.04 5.05 87.18 108.16 12.39 说明： 1)进口四联包芯片为印度 Panacea Biotec Ltd生产 (批号： 9988512) 色谱图见图 5-6， 图中峰 1为吡嗪酰胺， 峰 2为利福平。
2) 仪器及色谱条件： Agilent 1200高效液相色谱仪， Phenmenex luna C18(250x4.6mm, 5μηι)色谱柱； 检测波长 238nm， 流速 1.0 ml/min， 流动 相： A相= pbs 6.8/乙腈 (96/4)， B相= pbs 6· 8/乙腈 (40/60)， 梯度如下表： 时间 (min) A相 (％) B相 (％)
0 100 0
10 100 0
15 65 35
50 65 35
56 100 0
60 100 0
表 8 中稳定性考察结果表明本发明产品比进口市售产品更稳定， 本发 有助于改善抗结核四联复方的稳定性。
9 自制样品 (实施例 2)12个月稳定性 (25°C， 60%RH)的有关物质测定表
Figure imgf000026_0001
说明： 1) 图谱见图 7， 图中峰 1为吡嗪酰胺， 峰 2为利福平。
2) 仪器及色谱条件： Waters e2695- 2998高效液相色谱仪，
Phenmenex luna C18(250x4.6mm, 5μηι)色谱柱； 流速 1.0 ml/min， 检测波长 238匪； 流动相为 A相= pbs 6.8/乙腈 (96/4)， B相= pbs 6.8/乙腈 (50/50)， 梯 度如下表：
时间 (min) A相 (％) B相 (％)
0 95 5 7 95 5
14 80 20
40 80 20
41 95 5
50 95 5
如表 9所示， 长期 12个月稳定性试验考察结果表明在常温放置下， 考 察期内的本发明制剂中因利福平、 异烟肼的杂质虽然增多， 但相对较稳定。
(二） 动物比格犬体内试验
单方利福平组给药方法 比格犬 12只， 随机分成 、 B两组， 早上 8点统 一进食， 0.5h后给药， A组给药自制的利福平片 1片 (150 mg,相当于 10mg/kg， 利福平先用喷雾干燥法制成肠溶型固体分散体再与其它辅料压片包衣样品 (即实施例 11样品)， B组给药沈阳红旗制药有限公司生产的利福平胶囊 1粒 (150 mg, 批号 0907011)。
利福平 +异烟肼联合给药方法 上述实验结束间隔两周后， 对 、 B两 组统一进食 0.5h后给药，A组给药自制的利福平 1片 (150 mg，相当于 10mg/kg， 样品与单方给药样品相同)和沈阳红旗制药有限公司生产的异烟肼 1粒 (75 mg/粒， 由批号为 0907011的 0.3g/片片剂研磨后罐装而成)， B组为沈阳红旗 制药有限公司生产的利福平胶囊 (利福平 150 mg, 批号 0907011)和异烟肼 1 粒 (同 A组)。
表 10 比格犬口服给药自制 (实施例 11样品)及市售利福平复方后异烟肼 的药代参数 (用非房室模型分析）
Figure imgf000028_0001
表 11 比格犬口服给药利福平的生物利用度
相对生物利用度 1(%) 152.01
相对生物利用度 2(%) 123.68
说明： 相对生物利用度 1(%)=自制单方利福平片平均 AUC 0-12/市售单 方利福平胶囊平均 AUC 0-12*100%；
相对生物利用度 2(%)=自制复方利福平平均 AUC 0-12/市售平均复方利 福平 AUC 0-12*100%。
从表 10中的 AUC 0-24h和 AUC 0-∞11数据与表 11中的数据可看出， 根据 本发明将利福平制成固体分散体后其生物利用度明显提高。

Claims

权 利 要 求 书
1. 一种复方口服包芯固体制剂， 其为包衣包芯片， 其包含利福平、 异 烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分， 其内层芯包含异烟肼或利 福平并包覆有水不溶性非 pH依赖型衣膜，并且所述包芯固体制剂外层包覆 有水溶性非 pH依赖型防潮避光衣膜， 服药后， 利福平和异烟肼中的至少一 种活性成分在胃中少量释放或不释放。
2. 一种复方口服包芯固体制剂， 其为包衣三层片， 其包含利福平、 异 烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分， 其上层和下层分别独立地 含有异烟肼和利福平中的任意一种， 中间层包含吡嗪酰胺和盐酸乙胺丁醇 中的至少一种， 所述三层外包覆有水不溶性非 pH依赖型衣膜， 服药后， 利 福平和异烟肼中的至少一种活性成分在胃中少量释放或不释放。
3. 一种复方口服包芯固体制剂， 其为包衣包芯片， 其包含利福平、 异 烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分， 其内层芯包含异烟肼或利 福平并包覆有水溶性非 pH依赖型隔离衣膜，并且利福平为分散于肠溶固体 载体中的利福平肠溶固体分散体， 所述包芯固体制剂外层包覆有水溶性非 pH依赖型防潮避光衣膜。
4. 一种复方口服包芯固体制剂， 其为包衣三层片， 其包含利福平、 异 烟肼、 吡嗪酰胺和盐酸乙胺丁醇作为活性成分， 其上层和下层分别独立地 含异烟肼和利福平中的任意一种， 在含利福平层中， 利福平为分散于肠溶 固体载体的利福平肠溶固体分散体， 中间层包含吡嗪酰胺和盐酸乙胺丁醇 中的至少一种， 所述三层外包覆有水溶性非 pH依赖型防潮避光衣膜。
5. 根据权利要求 1或 2所述的复方口服包芯固体制剂， 其中所述水不 溶性非 pH依赖型衣膜包含水不溶性非 pH依赖型高分子成膜材料和增塑 剂， 任选地进一步含有选自致孔剂和抗粘剂中的至少一种。
6. 根据权利要求 2所述的复方口服包芯固体制剂， 其中所述水不溶性 非 pH依赖型衣膜还包含避光剂。
7. 根据权利要求 5 所述的复方口服包芯固体制剂， 其水不溶性非 pH 依赖型衣膜含有 70重量％-90重量％的成膜材料、 10重量％-30重量％的增 塑剂、 0重量％-15重量％的致孔剂、 0重量％-25重量％的抗粘剂， 优选含 有 70重量％-80重量％的成膜材料、 13重量％-25重量％的增塑剂和 /或 4重 量％-13重量％的致孔剂和 /或 0重量％-15重量％的抗粘剂，所述的重量基于 衣膜总重。
8. 根据权利要求 1所述的复方口服包芯固体制剂， 其中所述水不溶性 非 pH依赖型衣膜增重为所述内层异烟肼芯重量的 6-30%。
9. 根据权利要求 1所述的复方口服包芯固体制剂， 其中所述内层芯中 还包含吸水快速崩解膨胀的聚合物和 /或小分子助渗剂。
10. 根据权利要求 1所述的复方口服包芯固体制剂， 其中利福平、盐酸 乙胺丁醇和吡嗪酰胺 45分钟内均释放大于标示百分含量的 80%,优选大于 85%； 内层芯所包覆的水不溶性非 pH依赖型衣膜 30-90分钟内破裂， 异烟 肼 30分内释放不超过标示百分含量的 15% , 而 90分钟内释放大于标示百 分含量的 80%, 优选大于标示百分含量的 85%。
11. 根据权利要求 2所述的复方口服包芯固体制剂， 其中服药后， 所述 利福平层所包覆的水不溶性非 pH依赖型衣膜 5-10分钟内首先破裂， 所述 中间层完全崩解时间大于 15分钟， 利福平 45分钟内释放大于标示百分含 量的 80% ,优选大于 85%;异烟肼 30分钟内释放不超过标示百分含量 15%, 90分钟内释放大于标示百分含量的 80% , 优选大于标示百分含量的 85%。
12. 根据权利要求 2所述的复方口服包芯固体制剂，其中所述水不溶性 非 pH依赖型衣膜含有 50重量％-80重量％的成膜材料、 20重量％-45重量 %的增塑剂、0重量％-20重量％的避光剂和 /或 0重量％-15重量％的致孔剂、 和 /或 0重量％-20重量％的抗粘剂， 所述的重量基于衣膜总重。
13. 根据权利要求 2所述的复方口服包芯固体制剂， 其中所述水不溶 性非 pH依赖型衣膜增重为所述包衣三层片片芯总重量的 5-12%。
14. 根据权利要求 2所述的复方口服包芯固体制剂， 其中含利福平层 中还含有吸水快速崩解膨胀的聚合物、 所述中间层还含有阻滞剂。
15. 根据权利要求 15所述的复方口服包芯固体制剂， 其中所述吸水快 速崩解膨胀聚合物为一种或多种选自以下组中的物质： 交联羧甲基纤维素 钠 (CCMC-Na)、 低取代羟丙基纤维素 (L-HPC)、 羧甲基纤维素钠 (CMC-Na)、 羧甲基淀粉钠 (CMS-Na)、 交联聚维酮 (PVPP)和微晶纤维素 (MCC)。
16. 根据权利要求 14所述的复方口服包芯固体制剂， 其中所述阻滞剂 为一种或多种选自以下组中的物质： 水不溶性骨架材料、 溶蚀性骨架材料、 和水溶性骨架材料。
17. 根据权利要求 3或 4所述的复方口服包芯固体制剂， 服药后， 利福 平在胃的酸性环境中 30分钟内释放不超过标示百分含量的 15%,优选不大 于 10%; 在肠道的 pH环境中 45分钟内释放标示百分含量大于 80%, 优选 大于 85%。
18. 根据权利要求 3或 4所述的复方口服包芯固体制剂，其中所述肠溶 固体分散体载体选自一种或多种以下组中的载体： 聚乙烯醇乙酸苯二甲酸 酯 (PVAP)、 甲基丙烯酸 /甲基丙烯酸甲酯共聚物、 纤维素及其衍生物， 优选 琥珀酸乙酸羟丙基甲基纤维素 (HPMCAS)。
19. 根据权利要求 3或 4所述的复方口服包衣固体制剂，在所述利福平 肠溶固体分散体中， 利福平： 所述肠溶固体载体的重量比范围为 2: 1-1： 3。
20. 根据权利要求 3所述的复方口服包芯固体制剂，其中所述水溶性非 pH依赖型隔离衣膜的成膜材料选自一种或多种以下组中的物质： 羟丙甲纤 维素 (HPMC)、 Kollicoat®IR和 OpadrylL
21. 根据权利要求 1、 3或 4中任一项所述的复方口服包芯固体制剂， 其中所述水溶性非 pH 依赖型防潮避光衣膜选自以下组中的一种： Kollicoat®IR、 羟丙基甲基纤维素 (HPMC)、 二氧化钛和滑石粉的组合物、 含有羟丙基甲基纤维素 (HPMC)、 二氧化钛、 滑石粉组合成分的 OpadryII。
22. 根据权利要求 1至 4中任一项所述的复方口服包芯固体制剂，服药 后， 其中的利福平和异烟肼中至少有一种活性成分在服药后 30分钟内释放 不超过标示百分含量 15%。
23. 根据权利要求 1至 4中任一项所述的复方口服包芯固体制剂，其中所 述复方口服包芯固体制剂还包含选自以下组中的其它药用载体： 填充剂、 粘合剂、 润滑剂或助流剂和 /或崩解剂。
PCT/CN2012/073689 2011-04-12 2012-04-10 一种复方抗结核药口服固体制剂及其制备方法 WO2012139485A1 (zh)

Priority Applications (5)

Application Number Priority Date Filing Date Title
RU2013150254/15A RU2605388C2 (ru) 2011-04-12 2012-04-10 Пероральный твердый препарат комбинированного противотуберкулезного лекарственного средства и способ его получения
US14/111,323 US9555003B2 (en) 2011-04-12 2012-04-10 Oral solid formulation of compound anti-tubercular drug and preparation method thereof
BR112013026356A BR112013026356A2 (pt) 2011-04-12 2012-04-10 formulação sólida oral do fármaco antituberculoso composto e método de preparo do mesmo
LTEP12771448.3T LT2698150T (lt) 2011-04-12 2012-04-10 Per burną vartojamas kietas prieštuberkuliozinio junginio vaistinis preparatas ir jo paruošimo būdas
EP12771448.3A EP2698150B1 (en) 2011-04-12 2012-04-10 Oral solid preparation of compound antituberculosis drug and preparation method thereof

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN201110091596.7 2011-04-12
CN2011100915967A CN102727496A (zh) 2011-04-12 2011-04-12 一种复方抗结核药口服固体制剂及其制备方法

Publications (2)

Publication Number Publication Date
WO2012139485A1 true WO2012139485A1 (zh) 2012-10-18
WO2012139485A8 WO2012139485A8 (zh) 2013-10-10

Family

ID=46984266

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2012/073689 WO2012139485A1 (zh) 2011-04-12 2012-04-10 一种复方抗结核药口服固体制剂及其制备方法

Country Status (7)

Country Link
US (1) US9555003B2 (zh)
EP (1) EP2698150B1 (zh)
CN (1) CN102727496A (zh)
BR (1) BR112013026356A2 (zh)
LT (1) LT2698150T (zh)
RU (1) RU2605388C2 (zh)
WO (1) WO2012139485A1 (zh)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104274456A (zh) * 2013-07-02 2015-01-14 安徽贝克生物制药有限公司 一种抗结核药物的四联复方制剂及其制备方法
TW201717919A (zh) * 2015-07-02 2017-06-01 國際藥品股份公司 雷諾多重壓縮錠劑
CN110898022A (zh) * 2019-12-31 2020-03-24 湖南嘉恒制药有限公司 一种异烟肼组合物及其制备方法
CN114354804A (zh) * 2021-12-31 2022-04-15 深圳市第三人民医院(深圳市肝病研究所) 试剂盒和样本中抗结核药物及其代谢物的检测方法

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1388758A (zh) * 2000-08-09 2003-01-01 灵药生物技术有限公司 抗结核病药物的新颖的药学组合物及其制备方法
CN1408354A (zh) * 2002-09-10 2003-04-09 上海信谊药业有限公司 一种含有利福平异烟肼的复方制剂及其制备方法
CN1602872A (zh) * 2003-09-29 2005-04-06 浙江可立思安制药有限公司 一种抗结核药物组合物
CN101524355A (zh) * 2008-03-04 2009-09-09 沈阳红旗制药有限公司 抗结核药物的复方制剂及其制备方法

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4681765A (en) * 1984-09-13 1987-07-21 American Home Products Corporation Rapid releasing triamterene containing gelatin capsule dosage forms for once daily antihypertensive use
IT1289883B1 (it) * 1996-10-09 1998-10-19 Lupin Lab Ltd Composizione farmaceutica antitubercolare e procedimento per la sua produzione
FR2772615B1 (fr) * 1997-12-23 2002-06-14 Lipha Comprime multicouche pour la liberation instantanee puis prolongee de substances actives
BR0116994A (pt) * 2001-04-27 2004-03-02 Lupin Ltd Um processo aperfeiçoado para a preparação de uma composição que abrange uma combinação de dose fixa (fdc) de quatro drogas antituberculose
RU2247561C1 (ru) * 2003-12-29 2005-03-10 Открытое акционерное общество "Химико-фармацевтический комбинат "АКРИХИН" (ОАО "АКРИХИН") Комбинированная фармацевтическая композиция с противотуберкулёзным действием

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1388758A (zh) * 2000-08-09 2003-01-01 灵药生物技术有限公司 抗结核病药物的新颖的药学组合物及其制备方法
CN1408354A (zh) * 2002-09-10 2003-04-09 上海信谊药业有限公司 一种含有利福平异烟肼的复方制剂及其制备方法
CN1602872A (zh) * 2003-09-29 2005-04-06 浙江可立思安制药有限公司 一种抗结核药物组合物
CN101524355A (zh) * 2008-03-04 2009-09-09 沈阳红旗制药有限公司 抗结核药物的复方制剂及其制备方法

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See also references of EP2698150A4 *

Also Published As

Publication number Publication date
CN102727496A (zh) 2012-10-17
RU2605388C2 (ru) 2016-12-20
LT2698150T (lt) 2018-01-25
RU2013150254A (ru) 2015-05-20
EP2698150B1 (en) 2017-09-20
US20140127294A1 (en) 2014-05-08
EP2698150A1 (en) 2014-02-19
WO2012139485A8 (zh) 2013-10-10
US9555003B2 (en) 2017-01-31
EP2698150A4 (en) 2014-09-24
BR112013026356A2 (pt) 2016-12-27

Similar Documents

Publication Publication Date Title
US11090269B1 (en) Controlled release dosage forms for high dose, water soluble and hygroscopic drug substances
AU2002314515B2 (en) Oral controlled release pharmaceutical composition for one-a-day therapy for the treatment and prophylaxis of cardiac and circulatory diseases
CA2604617C (en) Composition containing anti-dementia drug
CN102348458B (zh) 含有6-氟-3-羟基-2-吡嗪甲酰胺的片剂和粒状粉剂
US7063862B2 (en) Pharmaceutical composition and method for treating
US20080031948A1 (en) Sustained-release bupropion and bupropion/mecamylamine tablets
AU2002314515A1 (en) Oral controlled release pharmaceutical composition for one-a-day therapy for the treatment and prophylaxis of cardiac and circulatory diseases
WO2007118063A1 (en) Fast release paracetamol tablets
WO2006053089A2 (en) Methods and formulations for making pharmaceutical compositions containing bupropion
US20120141586A1 (en) Thrombin receptor antagonist and clopidogrel fixed dose tablet
WO2012139485A1 (zh) 一种复方抗结核药口服固体制剂及其制备方法
AU2004258732A1 (en) Sustained release formulation for venlafaxine hydrochloride
TWI745598B (zh) 非布司他控釋組合物及其製備方法
JP2009528301A (ja) アンドログラフィス抽出物製剤
WO2005077357A1 (en) Pharmaceutical composition containing platinum complex as active substance and method of manufacturing thereof
JP2002068964A (ja) 経口用徐放錠
WO2014063596A1 (zh) 一种治疗糖尿病的口服制剂
WO2008091870A2 (en) Pharmaceutical compositions comprising atorvastatin and nicotinic acid
EP3024443A1 (en) Anti-tuberculosis stable pharmaceutical composition in a form of a coated tablet comprising granules of isoniazid and granules of rifapentine and its process of preparation
WO2012131722A1 (en) Controlled release composition of betahistine
WO2024022382A1 (zh) 渗透泵控释制剂、渗透泵控释组合物、制备方法和应用
RU2423977C1 (ru) Противотуберкулезное лекарственное средство на основе 4-тиоуреидоиминометилпиридиния перхлората, способ его получения и способ лечения
WO2024084496A1 (en) Pharmaceutical compositions comprising acalabrutinib maleate

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 12771448

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

REEP Request for entry into the european phase

Ref document number: 2012771448

Country of ref document: EP

WWE Wipo information: entry into national phase

Ref document number: 2012771448

Country of ref document: EP

ENP Entry into the national phase

Ref document number: 2013150254

Country of ref document: RU

Kind code of ref document: A

WWE Wipo information: entry into national phase

Ref document number: 14111323

Country of ref document: US

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112013026356

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 112013026356

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20131011

ENPC Correction to former announcement of entry into national phase, pct application did not enter into the national phase

Ref document number: 112013026356

Country of ref document: BR

Kind code of ref document: A2

Free format text: ANULADA A PUBLICACAO CODIGO 1.3 NA RPI NO 2399 DE 27/12/2016 POR TER SIDO INDEVIDA.

REG Reference to national code

Ref country code: BR

Ref legal event code: B01E

Ref document number: 112013026356

Country of ref document: BR

Kind code of ref document: A2

Free format text: APRESENTE NOVAS FOLHAS DOS DESENHOS COM O TEXTO TRADUZIDO PARA O PORTUGUES, ADAPTADO A NORMA VIGENTE, CONFORME DETERMINA O ART. 7O DA RESOLUCAO INPI PR NO 77/2013 DE 18/03/2013.

ENPW Started to enter national phase and was withdrawn or failed for other reasons

Ref document number: 112013026356

Country of ref document: BR

Kind code of ref document: A2

Free format text: PEDIDO RETIRADO EM RELACAO AO BRASIL POR NAO ATENDER AS DETERMINACOES REFERENTES A ENTRADA DO PEDIDO NA FASE NACIONAL E POR NAO CUMPRIMENTO DA EXIGENCIA FORMULADA NA RPI NO 2585 DE 21/07/2020.