WO2019024310A1 - Pramipexole hydrochloride sustained release preparation and preparation method therefor. - Google Patents

Pramipexole hydrochloride sustained release preparation and preparation method therefor. Download PDF

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WO2019024310A1
WO2019024310A1 PCT/CN2017/110351 CN2017110351W WO2019024310A1 WO 2019024310 A1 WO2019024310 A1 WO 2019024310A1 CN 2017110351 W CN2017110351 W CN 2017110351W WO 2019024310 A1 WO2019024310 A1 WO 2019024310A1
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sustained
release
pellet
coating
pellets
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PCT/CN2017/110351
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French (fr)
Chinese (zh)
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林浩文
颜携国
陶安进
袁建成
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深圳翰宇药业股份有限公司
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5084Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425Thiazoles
    • A61K31/428Thiazoles condensed with carbocyclic rings
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38Cellulose; Derivatives thereof
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/0002Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5026Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5005Wall or coating material
    • A61K9/5021Organic macromolecular compounds
    • A61K9/5036Polysaccharides, e.g. gums, alginate; Cyclodextrin
    • A61K9/5042Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules 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
    • A61K9/5073Microcapsules 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
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00Drugs for disorders of the nervous system
    • A61P25/14Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
    • A61P25/16Anti-Parkinson drugs

Definitions

  • the invention belongs to the field of pharmaceutical preparations, and particularly relates to a pramipexole hydrochloride sustained-release preparation and a preparation method thereof, in particular to a pramipexole hydrochloride sustained-release capsule and a preparation method thereof.
  • Parkinson's disease (Parkinson Sdisease) is a common slow-developing neurodegenerative disease that occurs in middle-aged and elderly people. It is characterized by resting tremor, myotonia and dyskinesia. As the population ages, its prevalence increases year by year, and it has become a common neurological disease after cerebrovascular disease. For a long time, levodopa-based drug replacement therapy is the first choice for the treatment of Parkinson's disease, but the existing treatment measures can not effectively prevent or even slow the progress of the disease.
  • Parkinson's disease Treatment of early Parkinson's disease
  • levodopa has been the main effective drug for the treatment of Parkinson's disease, but the long-term use will cause fluctuations in the response including "end-of-agent phenomenon” and “switching phenomenon” and sports complications such as dyskinesia Dystonia.
  • end-of-agent phenomenon and "switching phenomenon”
  • sports complications such as dyskinesia Dystonia.
  • the emergence of a new generation of non-ergoline dopamine receptor agonist pramipexole has brought hope to patients with Parkinson's disease.
  • Pramexole can be used alone in the treatment of Parkinson's disease, reducing the incidence of dyskinesia caused by levodopa treatment, combined with levodopa, can reduce the dose and adverse reactions of levodopa. Early use of pramipexole in the early use of levodopa can delay the onset of these symptoms and improve the quality of life of patients.
  • Pramipexole hydrochloride was developed by Boehringer Ingelheim and has the structure shown in Formula 1. Pramipex hydrochloride was approved by the US FDA on July 1, 1997, and then approved by EMA on October 14, 1997. It was approved by the Japanese PMDA on December 2, 2003.
  • Pramipexole hydrochloride is a non-ergoline dopamine agonist with high in vitro relative specificity and complete intrinsic activity with the dopamine receptor D2 subfamily, and higher affinity to D2 or D4 for the dopamine D3 family. It is used to improve the symptoms and signs of spontaneous Parkinson's (PD) and moderate to severe restless leg syndrome (RLS).
  • PD spontaneous Parkinson's
  • RLS moderate to severe restless leg syndrome
  • Pramipexole hydrochloride belongs to the third category in the Biopharmaceutical Classification System (BCS), a highly soluble, low-permeability drug under physiological conditions.
  • the sustained-release preparation refers to a preparation which slowly releases the drug at a constant rate in a prescribed release medium as required, and which has a lower frequency of administration and can increase the compliance or efficacy of the patient in comparison with the conventional preparation.
  • the release rate of the active ingredient can be effectively controlled to achieve the effect of prolonging the action time of the drug.
  • the currently available pramipexole hydrochloride sustained-release dosage form is a tablet, and an extended release tablet comprising pramipexole and a salt thereof disclosed in Chinese Patent No. CN101005831B, which comprises an active ingredient, a pregelatinized starch in an anionic polymer and a Three water-swellable polymers for sustained release.
  • the anionic polymer described therein is selected from the group consisting of acrylic polymers, grade A acrylic copolymers, alginates, carrageenan, gum arabic, xanthan gum, chitosan, sodium carboxymethylcellulose, and added cellulose calcium. .
  • the preparation prepared by the above method has a burst effect under acidic conditions, and the burst effect causes a large amount of drug to be released in a short time, so that the blood level in the body is suddenly increased, and the optimal effect of the drug cannot be achieved. Increase the incidence of adverse reactions.
  • the object of the present invention is to provide a defect in the prior art.
  • the sustained release preparation of pramipexole hydrochloride of the invention can also be slowly and slowly released under acidic conditions, thereby effectively avoiding the burst effect of pramipexole hydrochloride under acidic conditions and reducing the incidence of adverse reactions.
  • the present invention adopts the following technical solutions:
  • a sustained release preparation of pramipexole hydrochloride comprising first sustained release pellets and third sustained release pellets, the first sustained release pellets comprising pramipexole hydrochloride first drug-containing pellets, a first coating and a second coating, the third sustained-release pellet comprises pramipexole hydrochloride third drug-containing pellets and a third coating, pramipexole hydrochloride and third sustained-release pellets in the first sustained-release pellet
  • the content of pramipexole hydrochloride is 4:1.
  • the content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets is 4:1, that is, the first
  • the sustained-release pellets are high drug-containing sustained-release pellets
  • the third sustained-release pellets are low-drug sustained-release pellets.
  • the first sustained release pellets contain two layers of coating
  • the third sustained release pellets contain a coating.
  • the first sustained release pellets have a slower release rate, and the third sustained release release rate is relatively fast.
  • the release rate of the released pellets is different, that is, the release rate of the low drug-containing sustained-release pellets is relatively fast, and the release rate of the high drug-containing sustained-release pellets is slow.
  • the pramipexole hydrochloride sustained-release preparation of the present invention two kinds of sustained-release pellets with different drug content and different release rates are mixed to obtain a preparation with sustained release effect, and the drug released from the early release is mainly composed of a low drug-containing sustained release microparticle.
  • Pills are provided, and in the later stage (after 2h), the release of the drug is mainly provided by the high drug-containing sustained-release pellets, and can also be slowly and slowly released under acidic conditions, which can effectively avoid the burst effect of pramipexole hydrochloride under acidic conditions.
  • the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is made of pramipexole hydrochloride, a first medicinal pellet core, a binder and a solvent
  • the first The coating is made of a first sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent
  • the second coating is made of a second sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent
  • the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet is made of pramipexole hydrochloride, a third medicinal pellet core, a binder and a solvent
  • the third coating It is made of a third sustained release film material, a plasticizer, an anti-adhesive agent and a solvent.
  • the first sustained-release pellet of the pramipexole hydrochloride sustained-release preparation of the present invention is prepared from the first medicinal pellet core in the presence of a binder and a solvent.
  • the first medicinal pellet core may be a sucrose-type medicinal pellet core, preferably 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type medicinal pellet core.
  • the first medicinal pellet core is a 0.3-0.425 mm sucrose-type medicinal pellet core.
  • the binder in the first drug-containing pellet is povidone K30. More preferably, povidone k30 has a concentration of 8%.
  • the solvent in the first drug-containing pellet is ethanol. More preferably, it is 95% ethanol.
  • the first drug-containing pellet of pramipexole hydrochloride is sequentially coated twice with the first coating and the second coating.
  • the first coating is an inner layer coating of the first sustained release pellets
  • the second coating is an outer coating of the first sustained release pellets.
  • the first coating is made of a first sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent
  • the second coating is composed of a second sustained release coating material, a plasticizer, an anti-adhesive agent, and Made of solvent.
  • the first sustained release coating material is quaternary ammonium methacrylate copolymer type B (RS) and/or quaternary ammonium methacrylate copolymer type A (RL);
  • the second sustained release coating material It is ethyl cellulose (7 cps), methacrylic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion ( 30D), at least one of cellulose acetate and methacrylic acid copolymer type B (S-100).
  • the first slow release coating material quaternary ammonium methacrylate copolymer type B (RS) and quaternary ammonium methacrylate copolymer type A (RL), are insoluble in water and below pH 7.0, different pH values. There is no effect on the dissolution profile, but pores are formed in the coating film through which the drug releases the drug.
  • the second sustained-release coating material is a water-insoluble material, and the formed film can avoid acid degradation, prevent sudden release under gastric acid conditions, and ensure release of pramipexole hydrochloride in the small intestine in the pramipexole hydrochloride sustained-release preparation. .
  • the first sustained release coating material is a mixture of a quaternary ammonium methacrylate copolymer type B (RS) and a quaternary ammonium methacrylate copolymer type A (RL) mass ratio of 9:1.
  • the second sustained release coating material is ethyl cellulose (7 cps) and methyl A mixture of acrylic acid copolymer type B mass ratio of 3:7.
  • the first sustained release coating material is an aqueous dispersion of methacrylic acid-ethyl acrylate copolymer (30D-55) and an aqueous dispersion of ethyl acrylate-methyl methacrylate copolymer (30D) a mixture having a mass ratio of 2:1, the second sustained release coating material being a mixture of cellulose acetate and methacrylic acid copolymer type B (S-100) in a mass ratio of 2:3.
  • the plasticizer in the first coating and the second coating is preferably triethyl citrate.
  • the coating process of the present invention also includes an anti-adhesive agent.
  • the drug-containing pellets and the coating film material are rubbed in the coating pan to generate static electricity, and the anti-adhesive agent may be added in the coating process to remove static electricity in time to avoid the adhesion of the drug-containing pellets.
  • the anti-adhesive agent in the first coating and the second coating of the present invention is talc.
  • the solvent in the first coating and the second coating of the present invention is preferably ethanol. More preferably, it is 95% ethanol.
  • the third medicinal pellet core may be a sucrose-type medicinal pellet core, preferably 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type medicinal pellet core.
  • the third medicinal micropellet core of the third sustained-release pellet of the pramipexole hydrochloride sustained-release preparation of the present invention may be the same as or different from the first medicinal micropellet core of the first sustained-release pellet.
  • the third medicinal pellet core is a 0.5-0.7 mm sucrose-type medicinal pellet core.
  • the binder in the third drug-containing pellet is povidone K30.
  • the solvent in the third drug-containing pellet is ethanol. More preferably, it is 95% ethanol.
  • the third drug-containing pellet of pramipexole hydrochloride in the pramipexole hydrochloride sustained-release preparation of the present invention is subjected to a third coating.
  • the third coating is made of a third sustained release coating material, a plasticizer, an anti-adhesive, and a solvent.
  • the third sustained release coating material is ethyl cellulose (7 cps), methyl propyl Alkenoic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate, methacrylic acid At least one of copolymer type B (S-100).
  • the third sustained release coating material is methacrylic acid copolymer type B (S-100).
  • Plasticizers and anti-adherents are also included in the third coating.
  • the plasticizer is preferably triethyl citrate; the anti-adhesive agent is talc.
  • the solvent in the third coating of the present invention is preferably ethanol. More preferably, it is 95% ethanol.
  • the content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet in the pramipexole hydrochloride sustained-release preparation of the present invention, and the first medicinal pellet core The ratio of the binder to the solvent is 1:41.7: (1 to 2): (11.8 to 23.6).
  • the content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is the same as that of the first medicinal pellet core, binder, solvent The dosage ratio is 1:41.7:1.3:15.3.
  • the ratio of the first drug-containing pellets of the pramipexole hydrochloride to the first sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the first coating of the first sustained-release pellet is 1 : (0.11 to 0.15): (0.01 to 0.03): (0.025 to 0.035): (1.58 to 2.16).
  • the ratio of the first drug-containing pellets of the pramipexole hydrochloride to the first sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the first coating is 1:0.11: 0.011: 0.031: 1.58.
  • the ratio of the first drug-containing pellets of the pramipexole hydrochloride to the second sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the second coating is 1:0.06: (0.005 to 0.007): (0.01 to 0.02): (0.075 to 0.088). In some embodiments, the ratio of the first drug-containing pellets of the pramipexole hydrochloride to the second sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the second coating is 1:0.06: 0.006:0.015:0.863.
  • the ratio of the amount of pramipexole hydrochloride to the third medicinal pellet core, the binder and the solvent in the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet is 1:166.7: 3 to 4): (34.5 to 46.0).
  • the third of pramipexole hydrochloride The dosage ratio of pramipexole hydrochloride to the third medicinal pellet core, binder and solvent in the drug-containing pellets was 1:166.7:3.33:38.3.
  • the ratio of the third drug-containing pellets of the pramipexole hydrochloride to the third sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the third coating is 1:0.025: (0.002 to 0.003): (0.005 to 0.0065): 0.475. In some embodiments, the ratio of the third drug-containing pellets of the pramipexole hydrochloride to the third sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the third coating is 1:0.025:0.0025 : 0.00625: 0.475.
  • the particle diameter of the first sustained-release pellet and the third sustained-release pellet is preferably 24-40 mesh.
  • the sustained release preparation of the present invention may be a capsule, and the first sustained release pellet and the third sustained release pellet are mixed according to a certain ratio, and the pramipexole hydrochloride sustained-release capsule can be obtained by filling the pharmaceutical capsule. It is worth noting that the mixing ratio of the first sustained-release pellets and the third sustained-release pellets in the pramipexole hydrochloride sustained-release capsule is not limited as long as the pramipexole hydrochloride and the third in the first sustained-release pellet are ensured.
  • the content ratio of pramipexole hydrochloride in the sustained-release pellets is 4:1.
  • the medicinal capsule is a medicinal gelatin capsule, such as 0# capsule, 1# capsule, 2# capsule, 3# capsule, 4# capsule, 5# capsule, and the like.
  • the invention also provides a preparation method of the sustained release preparation of pramipexole hydrochloride, comprising the following steps:
  • step 2) and step 3) is in no particular order.
  • the pelletizing process has certain requirements on the particle size of the material.
  • the pramipexole hydrochloride raw material is subjected to micronization treatment to increase the specific surface area of the raw material, so that the drug in the micropellet administration process can be uniformly distributed on the pellets, and at the same time obtain a circle. Better pellets.
  • the particle size of the micronized pramipexole hydrochloride is controlled to be less than 20 ⁇ m at D(90),
  • the first drug-containing pellet and the third drug-containing pellet obtained in the above step (1) of the preparation method need to be dried and sieved in time to avoid adhesion of the pellet.
  • the dry sieving is dried at 30-40 ° C, and the pellets between 30-60 mesh are collected by sieving.
  • the temperature of the pellets in the fluidized bed should be controlled between 20 and 30 °C.
  • a lower spray rate should be used to prevent solvent/water from penetrating into the interior of the pellet.
  • the spray rate can be increased.
  • Residual solvent or water will have the effect of increasing the speed and thus affect the permeability of the film. Therefore, after the completion of the pellet coating, the pellets need to be dried afterwards.
  • the drying process is dried at 40 ° C for 24 h.
  • step 2) and step 3) is sieved to a dry sieve and passed through a 24-40 mesh sieve to collect pellets between 24 and 40 mesh.
  • the present invention provides a pramipexole hydrochloride sustained-release preparation and a preparation method thereof.
  • the sustained release preparation of pramipexole hydrochloride of the present invention comprises a first sustained release pellet and a third sustained release pellet, the first sustained release pellet comprising pramipexole hydrochloride first drug-containing pellet, first coating And a second coating, the third sustained-release pellet comprises pramipexole hydrochloride third drug-containing pellets and a third coating, pramipexole hydrochloride and the third sustained release microparticle in the first sustained-release pellet
  • the content of pramipexole hydrochloride in the pellet was 4:1.
  • the content ratio of the lacquer is 4:1, while the first sustained-release pellet contains two coats, and the third sustained-release pellet contains a coat, and the release rates of the two sustained-release pellets are different.
  • the pramipexole hydrochloride sustained-release preparation of the invention two kinds of sustained-release pellets with different drug content and different release rates are mixed to obtain a preparation with sustained release effect, which can be slowly and slowly released under acidic conditions, thereby effectively avoiding hydrochloric acid.
  • the preparation method of the sustained-release preparation of pramipexole hydrochloride of the invention is simple in operation and suitable for industrialization.
  • Figure 1 shows the release profile of Example 3 in a pH 1.2 medium
  • Figure 2 shows the release profile of Example 5 in each dissolution medium.
  • the invention discloses a pramipexole hydrochloride sustained-release preparation and a preparation method thereof. Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention.
  • the method and product of the present invention have been described by the preferred embodiments, and it is obvious that those skilled in the art can change or appropriately modify and combine the methods described herein to implement and apply the present invention without departing from the spirit, scope and scope of the invention. Invention technology.
  • the reagents involved in the examples of the present invention are all commercially available products, both of which are Can be purchased through commercial channels.
  • pramipexole hydrochloride micronized treatment particle size control D (90) is less than 20 ⁇ m;
  • the high drug-containing pellets prepared in Example 1 were subjected to a sustained release coating film, and the film material was quaternary ammonium methacrylate copolymer type B (RS), quaternary ammonium methacrylate copolymer type A (RL), and B.
  • Base cellulose (7 cps) and methacrylic acid copolymer type B (S-100) gave high drug-containing sustained release pellets.
  • the prescription is shown in Table 1.
  • fluidized bed coating the pellets are placed in a fluidized bed for coating, the temperature of the pellets in the fluidized bed is controlled between 20-30 °C.
  • talc 0.5% talc was added as an anti-adhesive agent, and the pellet was dried at 40 ° C for 24 hours or more. The dried pellets are passed through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are the sustained release pellets A.
  • Ethyl cellulose (7 cps) and methacrylic acid copolymer type B (S-100) are dissolved in 95% ethanol and stirred until completely dissolved;
  • Fluidized bed coating The high-medicine sustained-release pellets containing the first layer of the coating film are placed in the second layer of the fluidized bed package, and the operation process is consistent with the first layer of the coating film.
  • the pellets were dried at 40 ° C for more than 24 hours.
  • the dried pellets are passed through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are sustained-release pellets B (high drug-containing sustained-release pellets).
  • the high drug-containing pellets prepared in Example 1 were subjected to a sustained release coating film to obtain a high drug-containing sustained-release pellet.
  • the coating film material is methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate, methacrylic acid copolymer Type B (S-100).
  • the prescription is shown in Table 2.
  • the high drug-containing pellets prepared in Example 1 were placed in a fluidized bed for coating.
  • fluidized bed coating the pellets are placed in a fluidized bed for coating, the temperature of the pellets in the fluidized bed is controlled between 20-30 °C.
  • talc 0.5% talc was added as an anti-adhesive agent, and the pellet was dried at 40 ° C for 24 hours or more. The dried pellets are passed through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are the sustained release pellets A.
  • Fluidized bed coating The high-medicine sustained-release pellets containing the first layer of the coating film are placed in the second layer of the fluidized bed package, and the operation process is consistent with the first layer of the coating film.
  • the pellets were dried at 40 ° C for more than 24 hours.
  • the dried pellets pass through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are the sustained-release pellets B (high drug-containing buffer) Released Pills).
  • the cellulose acetate obtained in the sustained release pellet B is a water-insoluble coating material, an aqueous dispersion of methacrylic acid-ethyl acrylate copolymer (30D-55), ethyl acrylate-
  • the methyl methacrylate copolymer aqueous dispersion (30D) is insoluble at pH 7.0 or lower, and different pH values have no effect on the dissolution profile, and the drug release is diffused through the pores of the coating film.
  • the release profile of the medium at pH 1.2 is shown in Figure 1.
  • the low drug-containing pellets sustained release coating film prepared in Example 1 was used to obtain a low drug-containing sustained-release pellet, and the coating film material was a methacrylic acid copolymer type B (S-100).
  • the prescription is shown in Table 3.
  • Example 2 The low-medication pellets prepared in Example 1 were placed in a fluidized bed for coating treatment, and then the pellets were dried at 40 ° C for 24 hours or more for curing treatment. The temperature of the pellets in the fluidized bed is controlled between 20-30 °C.
  • Example 4 The sustained release pellets prepared in the above Example 2, Example 3, and Example 4 were tested for the content of pramipexole hydrochloride, and the amount of the sustained release capsule was calculated based on the content. Listed in Table 4 below It is the content of pramipexole hydrochloride of the sustained release pellets of three specific examples:
  • Example Pramipexole hydrochloride content (%) Example 2 1.98% Example 3 1.90% Example 4 0.55%
  • the high drug-containing sustained-release pellets and the low drug-containing sustained-release pellets are mixed in a certain proportion, wherein the high drug-containing sustained-release pellets comprise 4 parts of pramipexole hydrochloride, and the low drug-containing sustained-release pellets comprise 1 part of pramipexole hydrochloride In order to calculate the amount of the two sustained release pellets.
  • 121 mg of the sustained-release pellets prepared in Example 2 and 109 mg of the sustained-release pellets prepared in Example 4 were placed in gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 3 mg, wherein the high drug-containing microparticles prepared in Example 2 were obtained.
  • the ratio of pramipexole hydrochloride in pramipexole hydrochloride to the low drug-containing pellets prepared in Example 4 was 4:1.
  • Example 3 63 mg of the sustained-release pellets prepared in Example 3 and 54.5 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a 1.5 mg-molecular Lactobacillus hydrochloride sustained-release capsule, wherein the high-medication microparticle prepared in Example 3 was obtained.
  • the ratio of pramipexole hydrochloride in pramipexole hydrochloride to the low drug-containing pellets prepared in Example 4 was 4:1.
  • Example 3 189 mg of the sustained-release pellets prepared in Example 3 and 163.5 mg of the sustained-release pellets prepared in Example 4 were placed in gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 4.5 mg, wherein the high-medication prepared in Example 3 was obtained.
  • the ratio of pramipexole hydrochloride in the pellets in the pellets to the low-medication pellets prepared in Example 4 was 4:1.
  • the amounts of the two kinds of pellets in the above Examples 5 to 10 are not a fixed value, and the amount thereof is converted based on the pramipexole hydrochloride content in the two kinds of sustained-release pellets, and the above is one of the embodiments.
  • the ratio of pramipexole hydrochloride to pramipexole hydrochloride in the high drug-containing pellets in each of the above examples was 4:1.

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Abstract

A pramipexole hydrochloride sustained release preparation and a preparation method therefor. The sustained release preparation comprises first sustained-release pellets and third sustained-release pellets. The first sustained-release pellets comprise pramipexole hydrochloride first medicated pellets, a first coating, and a second coating. The third sustained-release pellets comprise pramipexole hydrochloride third medicated pellets and a third coating. The content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets is 4:1. The burst effect of pramipexole hydrochloride under acidic conditions can be avoided.

Description

一种盐酸普拉克索缓释制剂及其制备方法Pramipexole hydrochloride sustained-release preparation and preparation method thereof
本申请要求于2017年7月31日提交中国专利局、申请号为201710642262.1、发明名称为“一种盐酸普拉克索缓释制剂及其制备方法”的中国专利申请的优先权,其全部内容通过引用结合在本申请中。This application claims the priority of the Chinese Patent Application filed on July 31, 2017, the Chinese Patent Office, the application number is 201710642262.1, the invention is entitled "a pramipexole hydrochloride sustained-release preparation and its preparation method", the entire contents of which are The citations are incorporated herein by reference.
技术领域Technical field
本发明属于药物制剂领域,具体涉及一种盐酸普拉克索缓释制剂及其制备方法,尤其是一种盐酸普拉克索缓释胶囊及其制备方法。The invention belongs to the field of pharmaceutical preparations, and particularly relates to a pramipexole hydrochloride sustained-release preparation and a preparation method thereof, in particular to a pramipexole hydrochloride sustained-release capsule and a preparation method thereof.
背景技术Background technique
帕金森病(Parkinson Sdisease)是一种常见的发生于中老年人的缓慢进展的神经系统变性疾病,临床以静止性震颤、肌强直和运动障碍为主要特征。随着人口老年化的进程,其患病率逐年增高,已成为仅次于脑血管病的神经系统常见病。长期以来,以左旋多巴为主的药物替代治疗是帕金森病治疗的首选方案,但是现有的治疗措施均不能有效阻止乃至减慢疾病的进展。治疗早期帕金森病近30年来,左旋多巴一直是治疗帕金森病的主要有效药物但长期使用会出现对反应的波动包括“剂末现象”及“开关现象”以及运动并发症,如运动障碍、肌张力障碍。新一代非麦角类多巴胺受体激动剂普拉克索的出现为帕金森病患者带来了希望。Parkinson's disease (Parkinson Sdisease) is a common slow-developing neurodegenerative disease that occurs in middle-aged and elderly people. It is characterized by resting tremor, myotonia and dyskinesia. As the population ages, its prevalence increases year by year, and it has become a common neurological disease after cerebrovascular disease. For a long time, levodopa-based drug replacement therapy is the first choice for the treatment of Parkinson's disease, but the existing treatment measures can not effectively prevent or even slow the progress of the disease. Treatment of early Parkinson's disease For nearly 30 years, levodopa has been the main effective drug for the treatment of Parkinson's disease, but the long-term use will cause fluctuations in the response including "end-of-agent phenomenon" and "switching phenomenon" and sports complications such as dyskinesia Dystonia. The emergence of a new generation of non-ergoline dopamine receptor agonist pramipexole has brought hope to patients with Parkinson's disease.
普拉克索可单独应用于帕金森病的治疗,减少左旋多巴治疗所致运动障碍的发生率,与左旋多巴联用,可减少左旋多巴的剂量和不良反应。早期使用普拉克索较早期使用左旋多巴能够延缓这些症状的出现,并能够改善患者的生存质量。Pramexole can be used alone in the treatment of Parkinson's disease, reducing the incidence of dyskinesia caused by levodopa treatment, combined with levodopa, can reduce the dose and adverse reactions of levodopa. Early use of pramipexole in the early use of levodopa can delay the onset of these symptoms and improve the quality of life of patients.
盐酸普拉克索由勃林格殷格翰(Boehringer Ingelheim)研发,结构如式1所示。盐酸普拉克索于1997年7月1日获得美国FDA批准,之后于1997年10月14日获得EMA批准,2003年12月2日获得日 本PMDA批准,其商品名为
Figure PCTCN2017110351-appb-000001
Pramipexole hydrochloride was developed by Boehringer Ingelheim and has the structure shown in Formula 1. Pramipex hydrochloride was approved by the US FDA on July 1, 1997, and then approved by EMA on October 14, 1997. It was approved by the Japanese PMDA on December 2, 2003.
Figure PCTCN2017110351-appb-000001
Figure PCTCN2017110351-appb-000002
Figure PCTCN2017110351-appb-000002
盐酸普拉克索是一种非麦角类多巴胺激动剂,与多巴胺受体D2亚族具有较高的体外相对专一性和完全的内在活性,对多巴胺D3家族受体亲和力高于D2或D4。
Figure PCTCN2017110351-appb-000003
用于改善自发性帕金森(PD)和中重度的不宁腿终合症(RLS)的症状和体征。
Pramipexole hydrochloride is a non-ergoline dopamine agonist with high in vitro relative specificity and complete intrinsic activity with the dopamine receptor D2 subfamily, and higher affinity to D2 or D4 for the dopamine D3 family.
Figure PCTCN2017110351-appb-000003
It is used to improve the symptoms and signs of spontaneous Parkinson's (PD) and moderate to severe restless leg syndrome (RLS).
盐酸普拉克索在生物药剂分类系统(BCS)中属于第三类,即在生理条件下的高溶解性、低渗透性药物。缓释制剂指在规定的释放介质中,按要求缓慢地非恒速释放药物,与普通制剂相比较,给药频率更低,能增加患者用药顺应性或者疗效的制剂。将盐酸普拉克索做成缓释微丸后,能有效控制活性成分的释放速率从而达到延长药物作用时间的效果。Pramipexole hydrochloride belongs to the third category in the Biopharmaceutical Classification System (BCS), a highly soluble, low-permeability drug under physiological conditions. The sustained-release preparation refers to a preparation which slowly releases the drug at a constant rate in a prescribed release medium as required, and which has a lower frequency of administration and can increase the compliance or efficacy of the patient in comparison with the conventional preparation. When pramipexole hydrochloride is made into sustained-release pellets, the release rate of the active ingredient can be effectively controlled to achieve the effect of prolonging the action time of the drug.
目前已上市的盐酸普拉克索缓释剂型为片剂,中国专利CN101005831B公开的一种包含普拉克索及其盐的延长释放片剂,其包含活性成分、预胶化淀粉于阴离子聚合物和第三种水溶胀性聚合物,从而达到缓释的效果。其中所述的阴离子聚合物选自丙烯酸聚合物、甲级丙烯酸共聚物、海藻酸盐、角叉菜胶、阿拉伯胶、黄原胶、壳聚糖、羧甲纤维素钠和所加纤维素钙。但采用上述方法制备的制剂在酸性条件下存在突释效应,突释效应造成在短时间内释放出大量的药物,使体内的血药水平陡然升高,无法达到药物的最佳作用效果,同时增加不良反应的发生几率。The currently available pramipexole hydrochloride sustained-release dosage form is a tablet, and an extended release tablet comprising pramipexole and a salt thereof disclosed in Chinese Patent No. CN101005831B, which comprises an active ingredient, a pregelatinized starch in an anionic polymer and a Three water-swellable polymers for sustained release. The anionic polymer described therein is selected from the group consisting of acrylic polymers, grade A acrylic copolymers, alginates, carrageenan, gum arabic, xanthan gum, chitosan, sodium carboxymethylcellulose, and added cellulose calcium. . However, the preparation prepared by the above method has a burst effect under acidic conditions, and the burst effect causes a large amount of drug to be released in a short time, so that the blood level in the body is suddenly increased, and the optimal effect of the drug cannot be achieved. Increase the incidence of adverse reactions.
发明内容Summary of the invention
有鉴于此,本发明的目的在于针对现有技术存在的缺陷,提供一 种盐酸普拉克索的缓释制剂及其制备方法。本发明所述盐酸普拉克索的缓释制剂在酸性条件下也可持续缓慢释放,有效避免盐酸普拉克索在酸性条件下的突释效应,减少不良反应的发生率。In view of this, the object of the present invention is to provide a defect in the prior art. A sustained release preparation of pramipexole hydrochloride and a preparation method thereof. The sustained release preparation of pramipexole hydrochloride of the invention can also be slowly and slowly released under acidic conditions, thereby effectively avoiding the burst effect of pramipexole hydrochloride under acidic conditions and reducing the incidence of adverse reactions.
为实现本发明的目的,本发明采用如下技术方案:In order to achieve the object of the present invention, the present invention adopts the following technical solutions:
一种盐酸普拉克索的缓释制剂,包含第一缓释微丸和第三缓释微丸,所述第一缓释微丸包含盐酸普拉克索第一含药微丸、第一包衣和第二包衣,所述第三缓释微丸包含盐酸普拉克索第三含药微丸和第三包衣,所述第一缓释微丸中的盐酸普拉克索与第三缓释微丸中的盐酸普拉克索的含量比为4:1。A sustained release preparation of pramipexole hydrochloride, comprising first sustained release pellets and third sustained release pellets, the first sustained release pellets comprising pramipexole hydrochloride first drug-containing pellets, a first coating and a second coating, the third sustained-release pellet comprises pramipexole hydrochloride third drug-containing pellets and a third coating, pramipexole hydrochloride and third sustained-release pellets in the first sustained-release pellet The content of pramipexole hydrochloride is 4:1.
本发明所述盐酸普拉克索缓释制剂中所述第一缓释微丸中的盐酸普拉克索与第三缓释微丸中的盐酸普拉克索的含量比为4:1,即第一缓释微丸为高含药缓释微丸,第三缓释微丸为低含药缓释微丸。而第一缓释微丸含有两层包衣,第三缓释微丸含有一层包衣,第一缓释微丸药物释放速度较慢,第三缓释释放速度相对较快,两种缓释微丸释放速度不同,即低含药缓释微丸释放速度相对较快,而高含药缓释微丸释放速度较慢。本发明所述盐酸普拉克索缓释制剂中两种不同含药量、不同释放速度的缓释微丸混合得到一个具有缓释效果制剂,药物释放的前期释放药物主要由低含药缓释微丸提供,而在后期(2h以后)药物的释放主要由高含药缓释微丸提供,在酸性条件下也可持续缓慢释放,可有效避免盐酸普拉克索在酸性条件下的突释效应。In the pramipexole hydrochloride sustained-release preparation of the present invention, the content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets is 4:1, that is, the first The sustained-release pellets are high drug-containing sustained-release pellets, and the third sustained-release pellets are low-drug sustained-release pellets. The first sustained release pellets contain two layers of coating, and the third sustained release pellets contain a coating. The first sustained release pellets have a slower release rate, and the third sustained release release rate is relatively fast. The release rate of the released pellets is different, that is, the release rate of the low drug-containing sustained-release pellets is relatively fast, and the release rate of the high drug-containing sustained-release pellets is slow. In the pramipexole hydrochloride sustained-release preparation of the present invention, two kinds of sustained-release pellets with different drug content and different release rates are mixed to obtain a preparation with sustained release effect, and the drug released from the early release is mainly composed of a low drug-containing sustained release microparticle. Pills are provided, and in the later stage (after 2h), the release of the drug is mainly provided by the high drug-containing sustained-release pellets, and can also be slowly and slowly released under acidic conditions, which can effectively avoid the burst effect of pramipexole hydrochloride under acidic conditions.
其中,所述第一缓释微丸中所述盐酸普拉克索的第一含药微丸由盐酸普拉克索、第一药用微丸丸芯、粘合剂和溶剂制成,所述第一包衣由第一缓释衣膜材料、增塑剂、抗黏剂和溶剂制成,所述第二包衣由第二缓释衣膜材料、增塑剂、抗黏剂和溶剂制成;所述第三缓释微丸中所述盐酸普拉克索的第三含药微丸由盐酸普拉克索、第三药用微丸丸芯、粘合剂和溶剂制成,所述第三包衣由第三缓释衣膜材料、增塑剂、抗黏剂和溶剂制成。Wherein the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is made of pramipexole hydrochloride, a first medicinal pellet core, a binder and a solvent, the first The coating is made of a first sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent, and the second coating is made of a second sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent; The third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet is made of pramipexole hydrochloride, a third medicinal pellet core, a binder and a solvent, and the third coating It is made of a third sustained release film material, a plasticizer, an anti-adhesive agent and a solvent.
本发明所述盐酸普拉克索缓释制剂的第一缓释微丸中盐酸普拉 克索与第一药用微丸丸芯在粘合剂和溶剂存在下制成盐酸普拉克索的第一含药微丸。所述第一药用微丸丸芯可以为蔗糖型药用微丸丸芯,优选为0.3-0.425mm蔗糖型药用微丸丸芯或0.5-0.7mm蔗糖型药用微丸丸芯。在一些实施方案中,所述第一药用微丸丸芯为0.3-0.425mm蔗糖型药用微丸丸芯。The first sustained-release pellet of the pramipexole hydrochloride sustained-release preparation of the present invention The first drug-containing pellet of pramipexole hydrochloride is prepared from the first medicinal pellet core in the presence of a binder and a solvent. The first medicinal pellet core may be a sucrose-type medicinal pellet core, preferably 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type medicinal pellet core. In some embodiments, the first medicinal pellet core is a 0.3-0.425 mm sucrose-type medicinal pellet core.
优选的,所述第一含药微丸中的粘合剂为聚维酮K30。更优选为浓度为8%的聚维酮k30。Preferably, the binder in the first drug-containing pellet is povidone K30. More preferably, povidone k30 has a concentration of 8%.
优选的,所述第一含药微丸中的溶剂为乙醇。更优选为95%乙醇。Preferably, the solvent in the first drug-containing pellet is ethanol. More preferably, it is 95% ethanol.
本发明所述盐酸普拉克索缓释制剂中盐酸普拉克索的第一含药微丸依次进行第一包衣和第二包衣两次包衣。所述第一包衣为第一缓释微丸的内层包衣,第二包衣为第一缓释微丸的外层包衣。所述第一包衣由第一缓释衣膜材料、增塑剂、抗黏剂和溶剂制成,所述第二包衣由第二缓释衣膜材料、增塑剂、抗黏剂和溶剂制成。In the pramipexole hydrochloride sustained-release preparation of the present invention, the first drug-containing pellet of pramipexole hydrochloride is sequentially coated twice with the first coating and the second coating. The first coating is an inner layer coating of the first sustained release pellets, and the second coating is an outer coating of the first sustained release pellets. The first coating is made of a first sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent, and the second coating is composed of a second sustained release coating material, a plasticizer, an anti-adhesive agent, and Made of solvent.
优选的,所述第一缓释衣膜材料为季铵基甲基丙烯酸酯共聚物B型(RS)和/或季铵基甲基丙烯酸酯共聚物A型(RL);所述第二缓释衣膜材料为乙基纤维素(7cps)、甲基丙烯酸共聚物A型、甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)、丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)、醋酸纤维素、甲基丙烯酸共聚物B型(S-100)中至少一种。Preferably, the first sustained release coating material is quaternary ammonium methacrylate copolymer type B (RS) and/or quaternary ammonium methacrylate copolymer type A (RL); the second sustained release coating material It is ethyl cellulose (7 cps), methacrylic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion ( 30D), at least one of cellulose acetate and methacrylic acid copolymer type B (S-100).
第一缓释衣膜材料季铵基甲基丙烯酸酯共聚物B型(RS)和季铵基甲基丙烯酸酯共聚物A型(RL)两种材料,在水中以及pH7.0以下均不溶解,不同pH值对溶出曲线无影响,但在包衣膜中形成孔道,药物通过这些孔道将药物进行释放。而第二缓释衣膜材料均为水不溶型材料,形成的衣膜可以避免酸降解,防止在胃酸条件下突释,保证盐酸普拉克索缓释制剂中盐酸普拉克索在小肠部位进行释放。The first slow release coating material, quaternary ammonium methacrylate copolymer type B (RS) and quaternary ammonium methacrylate copolymer type A (RL), are insoluble in water and below pH 7.0, different pH values. There is no effect on the dissolution profile, but pores are formed in the coating film through which the drug releases the drug. The second sustained-release coating material is a water-insoluble material, and the formed film can avoid acid degradation, prevent sudden release under gastric acid conditions, and ensure release of pramipexole hydrochloride in the small intestine in the pramipexole hydrochloride sustained-release preparation. .
在一些实施方案中,所述第一缓释衣膜材料为季铵基甲基丙烯酸酯共聚物B型(RS)与季铵基甲基丙烯酸酯共聚物A型(RL)质量比为9:1的混合物,所述第二缓释衣膜材料为乙基纤维素(7cps)与甲基 丙烯酸共聚物B型质量比为3:7的混合物。In some embodiments, the first sustained release coating material is a mixture of a quaternary ammonium methacrylate copolymer type B (RS) and a quaternary ammonium methacrylate copolymer type A (RL) mass ratio of 9:1. The second sustained release coating material is ethyl cellulose (7 cps) and methyl A mixture of acrylic acid copolymer type B mass ratio of 3:7.
在一些实施方案中,所述第一缓释衣膜材料为甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)与丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)质量比为2:1的混合物,所述第二缓释衣膜材料为或醋酸纤维素与甲基丙烯酸共聚物B型(S-100)质量比为2:3的混合物。In some embodiments, the first sustained release coating material is an aqueous dispersion of methacrylic acid-ethyl acrylate copolymer (30D-55) and an aqueous dispersion of ethyl acrylate-methyl methacrylate copolymer (30D) a mixture having a mass ratio of 2:1, the second sustained release coating material being a mixture of cellulose acetate and methacrylic acid copolymer type B (S-100) in a mass ratio of 2:3.
所述第一包衣和第二包衣中的增塑剂优选为柠檬酸三乙酯。The plasticizer in the first coating and the second coating is preferably triethyl citrate.
本发明所述包衣过程中还包括抗黏剂。在包衣过程中,含药微丸、包衣膜材料于包衣锅摩擦会产生静电,包衣过程中加入抗黏剂可以及时除静电,以避免含药微丸发生黏连的情况。优选的,本发明所述第一包衣和第二包衣中的抗黏剂为滑石粉。The coating process of the present invention also includes an anti-adhesive agent. In the coating process, the drug-containing pellets and the coating film material are rubbed in the coating pan to generate static electricity, and the anti-adhesive agent may be added in the coating process to remove static electricity in time to avoid the adhesion of the drug-containing pellets. Preferably, the anti-adhesive agent in the first coating and the second coating of the present invention is talc.
本发明所述第一包衣和第二包衣中溶剂优选为乙醇。更优选为95%乙醇。The solvent in the first coating and the second coating of the present invention is preferably ethanol. More preferably, it is 95% ethanol.
本发明所述盐酸普拉克索缓释制剂的第三缓释微丸中盐酸普拉克索与第三药用微丸丸芯在粘合剂和溶剂存在下制成盐酸普拉克索的第三含药微丸。The third drug-containing pramipexole hydrochloride in the presence of a binder and a solvent in the third sustained-release pellet of the pramipexole hydrochloride sustained-release preparation of the present invention, the pramipexole hydrochloride and the third medicinal pellet core Pellet.
所述第三药用微丸丸芯可以为蔗糖型药用微丸丸芯,优选为0.3-0.425mm蔗糖型药用微丸丸芯或0.5-0.7mm蔗糖型药用微丸丸芯。The third medicinal pellet core may be a sucrose-type medicinal pellet core, preferably 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type medicinal pellet core.
本发明所述盐酸普拉克索缓释制剂的第三缓释微丸中第三药用微丸丸芯与第一缓释微丸中第一药用微丸丸芯可以相同也可以不同。在一些实施方案中,所述第三药用微丸丸芯为0.5-0.7mm蔗糖型药用微丸丸芯。The third medicinal micropellet core of the third sustained-release pellet of the pramipexole hydrochloride sustained-release preparation of the present invention may be the same as or different from the first medicinal micropellet core of the first sustained-release pellet. In some embodiments, the third medicinal pellet core is a 0.5-0.7 mm sucrose-type medicinal pellet core.
优选的,所述第三含药微丸中的粘合剂为聚维酮K30。Preferably, the binder in the third drug-containing pellet is povidone K30.
优选的,所述第三含药微丸中的溶剂为乙醇。更优选为95%乙醇。Preferably, the solvent in the third drug-containing pellet is ethanol. More preferably, it is 95% ethanol.
本发明所述盐酸普拉克索缓释制剂中盐酸普拉克索的第三含药微丸进行第三包衣。所述第三包衣由第三缓释衣膜材料、增塑剂、抗黏剂和溶剂制成。The third drug-containing pellet of pramipexole hydrochloride in the pramipexole hydrochloride sustained-release preparation of the present invention is subjected to a third coating. The third coating is made of a third sustained release coating material, a plasticizer, an anti-adhesive, and a solvent.
优选的,所述第三缓释衣膜材料为乙基纤维素(7cps)、甲基丙 烯酸共聚物A型、甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)、丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)、醋酸纤维素、甲基丙烯酸共聚物B型(S-100)中至少一种。Preferably, the third sustained release coating material is ethyl cellulose (7 cps), methyl propyl Alkenoic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate, methacrylic acid At least one of copolymer type B (S-100).
在一些实施方案中,所述第三缓释衣膜材料为甲基丙烯酸共聚物B型(S-100)。In some embodiments, the third sustained release coating material is methacrylic acid copolymer type B (S-100).
所述第三包衣中也包括增塑剂和抗黏剂。所述增塑剂优选为柠檬酸三乙酯;所述抗黏剂为滑石粉。Plasticizers and anti-adherents are also included in the third coating. The plasticizer is preferably triethyl citrate; the anti-adhesive agent is talc.
本发明所述第三包衣中溶剂优选为乙醇。更优选为95%乙醇。The solvent in the third coating of the present invention is preferably ethanol. More preferably, it is 95% ethanol.
本发明所述盐酸普拉克索缓释制剂中所述第一缓释微丸中所述盐酸普拉克索的第一含药微丸中盐酸普拉克索的含量与第一药用微丸丸芯、粘合剂、溶剂的用量比为1:41.7:(1~2):(11.8~23.6)。在一些实施方案中,所述第一缓释微丸中所述盐酸普拉克索的第一含药微丸中盐酸普拉克索的含量与第一药用微丸丸芯、粘合剂、溶剂的用量比为1:41.7:1.3:15.3。The content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet in the pramipexole hydrochloride sustained-release preparation of the present invention, and the first medicinal pellet core, The ratio of the binder to the solvent is 1:41.7: (1 to 2): (11.8 to 23.6). In some embodiments, the content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is the same as that of the first medicinal pellet core, binder, solvent The dosage ratio is 1:41.7:1.3:15.3.
所述第一缓释微丸中第一包衣中所述盐酸普拉克索的第一含药微丸与第一缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比为1:(0.11~0.15):(0.01~0.03):(0.025~0.035):(1.58~2.16)。在一些实施方案中,第一包衣中所述盐酸普拉克索的第一含药微丸与第一缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比为1:0.11:0.011:0.031:1.58。The ratio of the first drug-containing pellets of the pramipexole hydrochloride to the first sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the first coating of the first sustained-release pellet is 1 : (0.11 to 0.15): (0.01 to 0.03): (0.025 to 0.035): (1.58 to 2.16). In some embodiments, the ratio of the first drug-containing pellets of the pramipexole hydrochloride to the first sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the first coating is 1:0.11: 0.011: 0.031: 1.58.
第二包衣中所述盐酸普拉克索的第一含药微丸与第二缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比为1:0.06:(0.005~0.007):(0.01~0.02):(0.075~0.088)。在一些实施方案中,第二包衣中所述盐酸普拉克索的第一含药微丸与第二缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比为1:0.06:0.006:0.015:0.863。The ratio of the first drug-containing pellets of the pramipexole hydrochloride to the second sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the second coating is 1:0.06: (0.005 to 0.007): (0.01 to 0.02): (0.075 to 0.088). In some embodiments, the ratio of the first drug-containing pellets of the pramipexole hydrochloride to the second sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the second coating is 1:0.06: 0.006:0.015:0.863.
所述第三缓释微丸中所述盐酸普拉克索的第三含药微丸中盐酸普拉克索与第三药用微丸丸芯、粘合剂和溶剂的用量比为1:166.7:(3~4):(34.5~46.0)。在一些实施方案中,所述盐酸普拉克索的第三 含药微丸中盐酸普拉克索与第三药用微丸丸芯、粘合剂和溶剂的用量比为1:166.7:3.33:38.3。The ratio of the amount of pramipexole hydrochloride to the third medicinal pellet core, the binder and the solvent in the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet is 1:166.7: 3 to 4): (34.5 to 46.0). In some embodiments, the third of pramipexole hydrochloride The dosage ratio of pramipexole hydrochloride to the third medicinal pellet core, binder and solvent in the drug-containing pellets was 1:166.7:3.33:38.3.
第三包衣中所述盐酸普拉克索的第三含药微丸与第三缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比为1:0.025:(0.002~0.003):(0.005~0.0065):0.475。在一些实施方案中,第三包衣中所述盐酸普拉克索的第三含药微丸与第三缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比1:0.025:0.0025:0.00625:0.475。The ratio of the third drug-containing pellets of the pramipexole hydrochloride to the third sustained-release film material, the plasticizer, the anti-adhesive agent and the solvent in the third coating is 1:0.025: (0.002 to 0.003): (0.005 to 0.0065): 0.475. In some embodiments, the ratio of the third drug-containing pellets of the pramipexole hydrochloride to the third sustained-release film material, the plasticizer, the anti-adhesive agent, and the solvent in the third coating is 1:0.025:0.0025 : 0.00625: 0.475.
本发明所述缓释制剂中所述第一缓释微丸与第三缓释微丸的粒径优选为24-40目。In the sustained-release preparation of the present invention, the particle diameter of the first sustained-release pellet and the third sustained-release pellet is preferably 24-40 mesh.
本发明所述缓释制剂可以为胶囊剂,第一缓释微丸与第三缓释微丸按照一定比例混合,填入药用胶囊中即可获得盐酸普拉克索缓释胶囊。值得注意的是所述盐酸普拉克索缓释胶囊中第一缓释微丸与第三缓释微丸的混合比例没有限定,只要保证第一缓释微丸中的盐酸普拉克索与第三缓释微丸中的盐酸普拉克索的含量比为4:1即可。The sustained release preparation of the present invention may be a capsule, and the first sustained release pellet and the third sustained release pellet are mixed according to a certain ratio, and the pramipexole hydrochloride sustained-release capsule can be obtained by filling the pharmaceutical capsule. It is worth noting that the mixing ratio of the first sustained-release pellets and the third sustained-release pellets in the pramipexole hydrochloride sustained-release capsule is not limited as long as the pramipexole hydrochloride and the third in the first sustained-release pellet are ensured. The content ratio of pramipexole hydrochloride in the sustained-release pellets is 4:1.
优选的,所述药用胶囊为药用明胶胶囊,如0#号胶囊、1#号胶囊、2#号胶囊、3#号胶囊、4#号胶囊、5#号胶囊等。Preferably, the medicinal capsule is a medicinal gelatin capsule, such as 0# capsule, 1# capsule, 2# capsule, 3# capsule, 4# capsule, 5# capsule, and the like.
本发明还提供了所述盐酸普拉克索的缓释制剂的制备方法,包括以下步骤:The invention also provides a preparation method of the sustained release preparation of pramipexole hydrochloride, comprising the following steps:
1)将盐酸普拉克索与第一药用微丸丸芯、粘合剂和溶剂混合制备第一含药微丸,干燥后过筛;将盐酸普拉克索与第三药用微丸丸芯、粘合剂和溶剂混合制备第三含药微丸,干燥后过筛;1) mixing pramipexole hydrochloride with the first medicinal micropellet core, binder and solvent to prepare the first drug-containing pellet, drying and sieving; pramipexole hydrochloride and the third medicinal pellet core, sticky Mixing the mixture and the solvent to prepare the third drug-containing pellet, drying and sieving;
2)将第一缓释衣膜材料与增塑剂、抗黏剂和溶剂混合制成第一包衣液,对第一含药微丸进行包衣形成第一包衣,干燥后过筛得缓释微丸A;将第二缓释衣膜材料与增塑剂、抗黏剂和溶剂混合制成第二包衣液,对缓释微丸A进行包衣形成第二包衣,干燥后过筛得第一缓释微丸;2) mixing the first sustained release coating material with a plasticizer, an anti-adhesive agent and a solvent to prepare a first coating liquid, coating the first drug-containing pellets to form a first coating, drying and sieving Sustained-release pellet A; mixing the second sustained-release film material with a plasticizer, an anti-adhesive agent and a solvent to prepare a second coating liquid, and coating the sustained-release pellet A to form a second coating, after drying Screening the first sustained release pellets;
3)将第三缓释衣膜材料与增塑剂、抗黏剂和溶剂混合制成第三包衣液,对第二含药微丸进行包衣形成第三包衣,干燥后过筛得第三 缓释微丸;3) mixing the third sustained-release film material with a plasticizer, an anti-adhesive agent and a solvent to prepare a third coating liquid, and coating the second drug-containing pellet to form a third coating, which is dried and sieved. Third Sustained release pellets;
4)将第一缓释微丸与第三缓释微丸混合,控制所述第一缓释微丸中的盐酸普拉克索与第三缓释微丸中的盐酸普拉克索的含量比为4:1;4) mixing the first sustained-release pellets with the third sustained-release pellets, and controlling the content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets 4:1;
其中,对步骤2)和步骤3)的顺序不分先后。Wherein, the order of step 2) and step 3) is in no particular order.
微丸上药过程对物料的粒度有一定的要求。优选的,本发明所述制备方法中,所述盐酸普拉克索原料经过微粉化处理,以增大原料的比表面积,使得微丸上药过程药物能够均匀地分布在微丸上面,同时获得圆整度更好的微丸。在一些实施方案中,所述微粉化盐酸普拉克索的粒径控制在D(90)小于20μm,The pelletizing process has certain requirements on the particle size of the material. Preferably, in the preparation method of the present invention, the pramipexole hydrochloride raw material is subjected to micronization treatment to increase the specific surface area of the raw material, so that the drug in the micropellet administration process can be uniformly distributed on the pellets, and at the same time obtain a circle. Better pellets. In some embodiments, the particle size of the micronized pramipexole hydrochloride is controlled to be less than 20 μm at D(90),
上述制备方法步骤1)制得第一含药微丸和第三含药微丸需要及时干燥过筛,以免造成微丸的黏连。优选的,所述干燥过筛为30-40℃干燥,过筛收集30-60目之间的微丸。The first drug-containing pellet and the third drug-containing pellet obtained in the above step (1) of the preparation method need to be dried and sieved in time to avoid adhesion of the pellet. Preferably, the dry sieving is dried at 30-40 ° C, and the pellets between 30-60 mesh are collected by sieving.
上述制备方法步骤2)和步骤3)中所述包衣过程中,流化床中微丸的温度应控制在20-30℃之间。在喷雾开始阶段,应采用较低的喷速度以防止溶剂/水渗透进入到微丸内部,待微丸包上一层衣膜之后,可以将喷速提高。In the coating process in the above preparation steps 2) and 3), the temperature of the pellets in the fluidized bed should be controlled between 20 and 30 °C. At the beginning of the spray, a lower spray rate should be used to prevent solvent/water from penetrating into the interior of the pellet. After the pellet is coated with a film, the spray rate can be increased.
残余的溶剂或水会产生增速的效果从而影响衣膜的渗透性,因此在完成微丸包衣之后,需要对微丸进行后需干燥处理。优选的,所述干燥过程均采用40℃干燥24h。Residual solvent or water will have the effect of increasing the speed and thus affect the permeability of the film. Therefore, after the completion of the pellet coating, the pellets need to be dried afterwards. Preferably, the drying process is dried at 40 ° C for 24 h.
优选的,步骤2)和步骤3)所述包衣过筛为干燥后过24-40目筛,收集24-40目之间的微丸。Preferably, the coating of step 2) and step 3) is sieved to a dry sieve and passed through a 24-40 mesh sieve to collect pellets between 24 and 40 mesh.
由上述技术方案可知,本发明提供了一种盐酸普拉克索缓释制剂及其制备方法。本发明所述盐酸普拉克索的缓释制剂包含第一缓释微丸和第三缓释微丸,所述第一缓释微丸包含盐酸普拉克索第一含药微丸、第一包衣和第二包衣,所述第三缓释微丸包含盐酸普拉克索第三含药微丸和第三包衣,所述第一缓释微丸中的盐酸普拉克索与第三缓释微丸中的盐酸普拉克索的含量比为4:1。两种缓释微丸中的盐酸普 拉克索的含量比为4:1,而第一缓释微丸含有两层包衣,第三缓释微丸含有一层包衣,两种缓释微丸释放速度不同。本发明所述盐酸普拉克索缓释制剂中两种不同含药量、不同释放速度的缓释微丸混合得到一个具有缓释效果制剂,在酸性条件下也可持续缓慢释放,可有效避免盐酸普拉克索在酸性条件下的突释效应。本发明所述盐酸普拉克索的缓释制剂制备方法操作简单,适合于产业化。According to the above technical solution, the present invention provides a pramipexole hydrochloride sustained-release preparation and a preparation method thereof. The sustained release preparation of pramipexole hydrochloride of the present invention comprises a first sustained release pellet and a third sustained release pellet, the first sustained release pellet comprising pramipexole hydrochloride first drug-containing pellet, first coating And a second coating, the third sustained-release pellet comprises pramipexole hydrochloride third drug-containing pellets and a third coating, pramipexole hydrochloride and the third sustained release microparticle in the first sustained-release pellet The content of pramipexole hydrochloride in the pellet was 4:1. Hydrochloride in two sustained-release pellets The content ratio of the lacquer is 4:1, while the first sustained-release pellet contains two coats, and the third sustained-release pellet contains a coat, and the release rates of the two sustained-release pellets are different. In the pramipexole hydrochloride sustained-release preparation of the invention, two kinds of sustained-release pellets with different drug content and different release rates are mixed to obtain a preparation with sustained release effect, which can be slowly and slowly released under acidic conditions, thereby effectively avoiding hydrochloric acid. The burst effect of pramipexole under acidic conditions. The preparation method of the sustained-release preparation of pramipexole hydrochloride of the invention is simple in operation and suitable for industrialization.
附图说明DRAWINGS
为了更清楚地说明本发明实施例或现有技术中的技术方案,下面将对实施例或现有技术描述中所需要使用的附图作简单地介绍。In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the embodiments or the prior art description will be briefly described below.
图1示实施例3在pH1.2介质的释放曲线;Figure 1 shows the release profile of Example 3 in a pH 1.2 medium;
图2示实施例5在各个溶出介质中的释放曲线。Figure 2 shows the release profile of Example 5 in each dissolution medium.
具体实施方式Detailed ways
本发明公开了一种盐酸普拉克索缓释制剂及其制备方法。本领域技术人员可以借鉴本文内容,适当改进工艺参数实现。特别需要指出的是,所有类似的替换和改动对本领域技术人员来说是显而易见的,它们都被视为包括在本发明。本发明的方法及产品已经通过较佳实施例进行了描述,相关人员明显能在不脱离本发明内容、精神和范围内对本文所述的方法进行改动或适当变更与组合,来实现和应用本发明技术。The invention discloses a pramipexole hydrochloride sustained-release preparation and a preparation method thereof. Those skilled in the art can learn from the contents of this document and appropriately improve the process parameters. It is to be understood that all such alternatives and modifications are obvious to those skilled in the art and are considered to be included in the present invention. The method and product of the present invention have been described by the preferred embodiments, and it is obvious that those skilled in the art can change or appropriately modify and combine the methods described herein to implement and apply the present invention without departing from the spirit, scope and scope of the invention. Invention technology.
为了进一步理解本发明,下面将结合本发明实施例,对本发明实施例中的技术方案进行清楚、完整地描述,显然,所描述的实施例仅仅是本发明一部分实施例,而不是全部的实施例。基于本发明中的实施例,本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例,都属于本发明保护的范围。For a better understanding of the present invention, the embodiments of the present invention will be clearly and completely described in the embodiments of the present invention. It is obvious that the described embodiments are only a part of the embodiments of the present invention, but not all embodiments. . All other embodiments obtained by a person of ordinary skill in the art based on the embodiments of the present invention without creative efforts are within the scope of the present invention.
如无特殊说明,本发明实施例中所涉及的试剂均为市售产品,均 可以通过商业渠道购买获得。Unless otherwise stated, the reagents involved in the examples of the present invention are all commercially available products, both of which are Can be purchased through commercial channels.
实施例1:含药微丸的制备Example 1: Preparation of drug-containing pellets
1、高含药微丸的处方:1. Prescription of high-containing pellets:
Figure PCTCN2017110351-appb-000004
Figure PCTCN2017110351-appb-000004
2、低含药微丸的处方:2. Prescription of low-containing pellets:
Figure PCTCN2017110351-appb-000005
Figure PCTCN2017110351-appb-000005
3、制备工艺3. Preparation process
3.1原料前处理:将盐酸普拉克索进行微粉化处理,粒径控制D(90)小于20μm;3.1 pretreatment of raw materials: pramipexole hydrochloride micronized treatment, particle size control D (90) is less than 20μm;
3.2微丸上药:将药用微丸丸芯加入到离心造粒机中进行微丸上药,粘合剂为8%的聚维酮K30;完成微丸上药之后将微丸置于30-40℃条件下进行干燥。3.2 Pills: The medicinal pellets are added to the centrifugal granulator for the pellets, and the binder is 8% povidone K30; after the pellets are finished, the pellets are placed at 30- Drying was carried out at 40 °C.
3.3过筛处理:将含药品微丸过筛,保留30-60目之间的微丸。3.3 Screening treatment: The drug-containing pellets are sieved to retain the pellets between 30-60 mesh.
实施例2:Example 2:
取实施例1所制备的高含药微丸进行包缓释衣膜,衣膜材料为季铵基甲基丙烯酸酯共聚物B型(RS)、季铵基甲基丙烯酸酯共聚物A型(RL)、乙基纤维素(7cps)、甲基丙烯酸共聚物B型(S-100)得到高含药缓释微丸。处方如表1所示。The high drug-containing pellets prepared in Example 1 were subjected to a sustained release coating film, and the film material was quaternary ammonium methacrylate copolymer type B (RS), quaternary ammonium methacrylate copolymer type A (RL), and B. Base cellulose (7 cps) and methacrylic acid copolymer type B (S-100) gave high drug-containing sustained release pellets. The prescription is shown in Table 1.
表1 高含药缓释微丸释衣膜处方Table 1 High drug-containing sustained-release pellets release film prescription
Figure PCTCN2017110351-appb-000006
Figure PCTCN2017110351-appb-000006
Figure PCTCN2017110351-appb-000007
Figure PCTCN2017110351-appb-000007
制备工艺Preparation Process
1、包第一层衣膜1, the first layer of clothing film
1.1、包衣液的配制1.1, the preparation of coating liquid
(1)将季铵基甲基丙烯酸酯共聚物B型(RS)和季铵基甲基丙烯酸酯共聚物A型(RL)溶于95%乙醇中,搅拌至完全溶解;(1) dissolving quaternary ammonium methacrylate copolymer type B (RS) and quaternary ammonium methacrylate copolymer type A (RL) in 95% ethanol, stirring until completely dissolved;
(2)完全溶解后,加入滑石粉、柠檬酸三乙酯搅拌均匀,在包衣过程中持续搅拌。(2) After completely dissolving, talc powder and triethyl citrate are added and stirred uniformly, and stirring is continued during the coating process.
1.2、流化床包衣:将微丸置于流化床进行包衣,流化床中微丸的温度控制在20-30℃之间。1.2, fluidized bed coating: the pellets are placed in a fluidized bed for coating, the temperature of the pellets in the fluidized bed is controlled between 20-30 °C.
1.3、干燥固化:1.3, dry curing:
包衣结束之后,加入0.5%滑石粉作为抗粘剂,将微丸置于40℃条件下干燥24小时以上。干燥微丸过24-40目筛,则24到40目之间的微丸即为缓释微丸A。After the end of the coating, 0.5% talc was added as an anti-adhesive agent, and the pellet was dried at 40 ° C for 24 hours or more. The dried pellets are passed through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are the sustained release pellets A.
2、包第二层衣膜2, the second layer of clothing film
2.1、包衣液的配制2.1, the preparation of coating liquid
(1)将乙基纤维素(7cps)和甲基丙烯酸共聚物B型(S-100)溶于95%乙醇中,搅拌至完全溶解; (1) Ethyl cellulose (7 cps) and methacrylic acid copolymer type B (S-100) are dissolved in 95% ethanol and stirred until completely dissolved;
(2)完全溶解后,加入滑石粉、柠檬酸三乙酯搅拌均匀,在包衣过程中持续搅拌。(2) After completely dissolving, talc powder and triethyl citrate are added and stirred uniformly, and stirring is continued during the coating process.
2.2、流化床包衣:将包完第一层衣膜的高含药缓释微丸置于流化床包第二层缓释衣膜,操作过程与包第一层衣膜一致。2.2. Fluidized bed coating: The high-medicine sustained-release pellets containing the first layer of the coating film are placed in the second layer of the fluidized bed package, and the operation process is consistent with the first layer of the coating film.
2.3、干燥固化:2.3, dry curing:
包衣之后,将微丸置于40℃条件下干燥24小时以上。干燥微丸过24-40目筛,则24到40目之间的微丸即为缓释微丸B(高含药缓释微丸)。After coating, the pellets were dried at 40 ° C for more than 24 hours. The dried pellets are passed through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are sustained-release pellets B (high drug-containing sustained-release pellets).
实施例3:Example 3:
取实施例1所制备的高含药微丸进行包缓释衣膜,得到高含药缓释微丸。包衣膜材料为甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)、丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)、醋酸纤维素、甲基丙烯酸共聚物B型(S-100)。处方如表2所示。The high drug-containing pellets prepared in Example 1 were subjected to a sustained release coating film to obtain a high drug-containing sustained-release pellet. The coating film material is methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate, methacrylic acid copolymer Type B (S-100). The prescription is shown in Table 2.
表2 高含药缓释微丸释衣膜处方Table 2 High drug-containing sustained-release pellets release film prescription
Figure PCTCN2017110351-appb-000008
Figure PCTCN2017110351-appb-000008
Figure PCTCN2017110351-appb-000009
Figure PCTCN2017110351-appb-000009
将实施例1制备的高含药微丸置于流化床进行包衣。The high drug-containing pellets prepared in Example 1 were placed in a fluidized bed for coating.
制备工艺:Preparation Process:
1、包第一层衣膜1, the first layer of clothing film
1.1、包衣液的配制1.1, the preparation of coating liquid
(1)将甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)和季丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)溶于纯化水中,搅拌至完全溶解;(1) dissolving a methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55) and a quaternary ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D) in purified water, stirring until completely dissolved;
(2)待完全溶解后,加入滑石粉、柠檬酸三乙酯搅拌均匀,在包衣过程中持续搅拌。(2) After completely dissolved, talc powder and triethyl citrate are added and stirred uniformly, and stirring is continued during the coating process.
1.2、流化床包衣:将微丸置于流化床进行包衣,流化床中微丸的温度控制在20-30℃之间。1.2, fluidized bed coating: the pellets are placed in a fluidized bed for coating, the temperature of the pellets in the fluidized bed is controlled between 20-30 °C.
1.3、干燥固化:1.3, dry curing:
包衣结束之后,加入0.5%滑石粉作为抗粘剂,将微丸置于40℃条件下干燥24小时以上。干燥微丸过24-40目筛,则24到40目之间的微丸即为缓释微丸A。After the end of the coating, 0.5% talc was added as an anti-adhesive agent, and the pellet was dried at 40 ° C for 24 hours or more. The dried pellets are passed through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are the sustained release pellets A.
2、包第二层衣膜2, the second layer of clothing film
(1)将醋酸纤维素、甲基丙烯酸共聚物B型(S-100)溶于95%乙醇中,搅拌至完全溶解;(1) Dissolving cellulose acetate and methacrylic acid copolymer type B (S-100) in 95% ethanol, stirring until completely dissolved;
(2)完全溶解后,加入滑石粉、柠檬酸三乙酯搅拌均匀,在包衣过程中持续搅拌。(2) After completely dissolving, talc powder and triethyl citrate are added and stirred uniformly, and stirring is continued during the coating process.
2.2、流化床包衣:将包完第一层衣膜的高含药缓释微丸置于流化床包第二层缓释衣膜,操作过程与包第一层衣膜一致。2.2. Fluidized bed coating: The high-medicine sustained-release pellets containing the first layer of the coating film are placed in the second layer of the fluidized bed package, and the operation process is consistent with the first layer of the coating film.
2.3、干燥固化:2.3, dry curing:
包衣之后,将微丸置于40℃条件下干燥24小时以上。干燥微丸过24-40目筛,则24到40目之间的微丸即为缓释微丸B(高含药缓 释微丸)。After coating, the pellets were dried at 40 ° C for more than 24 hours. The dried pellets pass through a 24-40 mesh sieve, and the pellets between 24 and 40 mesh are the sustained-release pellets B (high drug-containing buffer) Released Pills).
制得的缓释微丸B(高含药缓释微丸)中醋酸纤维素为水不溶性包衣材料,甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)、丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)在pH7.0以下不溶,不同pH值对溶出曲线无影响,药物释放是透过包衣膜空隙扩散。其中在pH1.2介质的释放曲线如图1所示。The cellulose acetate obtained in the sustained release pellet B (high drug-containing sustained-release pellet) is a water-insoluble coating material, an aqueous dispersion of methacrylic acid-ethyl acrylate copolymer (30D-55), ethyl acrylate- The methyl methacrylate copolymer aqueous dispersion (30D) is insoluble at pH 7.0 or lower, and different pH values have no effect on the dissolution profile, and the drug release is diffused through the pores of the coating film. The release profile of the medium at pH 1.2 is shown in Figure 1.
实施例4Example 4
取实施例1所制备的低含药微丸包缓释衣膜,得到低含药缓释微丸,包衣膜材料为甲基丙烯酸共聚物B型(S-100)。处方如表3所示。The low drug-containing pellets sustained release coating film prepared in Example 1 was used to obtain a low drug-containing sustained-release pellet, and the coating film material was a methacrylic acid copolymer type B (S-100). The prescription is shown in Table 3.
表3 低含药缓释微丸释衣膜处方Table 3 Low drug-containing sustained-release pellets release film prescription
Figure PCTCN2017110351-appb-000010
Figure PCTCN2017110351-appb-000010
制备工艺:Preparation Process:
1、包衣液的配制1. Preparation of coating liquid
(1)将甲基丙烯酸共聚物B型(S-100)溶于95%乙醇中,搅拌至完全溶解;(1) Dissolving methacrylic acid copolymer type B (S-100) in 95% ethanol and stirring until completely dissolved;
(2)待完全溶解后,加入滑石粉、柠檬酸三乙酯搅拌均匀,在包衣过程中持续搅拌。(2) After completely dissolved, talc powder and triethyl citrate are added and stirred uniformly, and stirring is continued during the coating process.
2、将实施例1制备的低含药微丸置于流化床中进行包衣处理,之后将微丸置于40℃条件下干燥24小时以上进行固化处理。流化床中微丸的温度控制在20-30℃之间。2. The low-medication pellets prepared in Example 1 were placed in a fluidized bed for coating treatment, and then the pellets were dried at 40 ° C for 24 hours or more for curing treatment. The temperature of the pellets in the fluidized bed is controlled between 20-30 °C.
将上述实施例2、实施例3、实施例4所制备的缓释微丸检测盐酸普拉克索的含量,根据含量计算缓释胶囊的填装量。下表4列出的 是3个具体实施例的缓释微丸的盐酸普拉克索的含量:The sustained release pellets prepared in the above Example 2, Example 3, and Example 4 were tested for the content of pramipexole hydrochloride, and the amount of the sustained release capsule was calculated based on the content. Listed in Table 4 below It is the content of pramipexole hydrochloride of the sustained release pellets of three specific examples:
表4 各实施例缓释微丸的盐酸普拉克索Table 4 Example of sustained release pellets of pramipexole hydrochloride
实施例Example 盐酸普拉克索含量(%)Pramipexole hydrochloride content (%)
实施例2Example 2 1.98%1.98%
实施例3Example 3 1.90%1.90%
实施例4Example 4 0.55%0.55%
取高含药缓释微丸和低含药缓释微丸以一定比例混合,其中高含药缓释微丸包含4份盐酸普拉克索,低含药缓释微丸包含1份盐酸普拉克索,以此计算两种缓释微丸的用量。The high drug-containing sustained-release pellets and the low drug-containing sustained-release pellets are mixed in a certain proportion, wherein the high drug-containing sustained-release pellets comprise 4 parts of pramipexole hydrochloride, and the low drug-containing sustained-release pellets comprise 1 part of pramipexole hydrochloride In order to calculate the amount of the two sustained release pellets.
实施例5Example 5
取实施例2制备的缓释微丸121mg以及实施例4制备的缓释微丸109mg装进明胶胶囊,得到规格为3mg的盐酸普拉克索缓释胶囊,其中实施例2制备的高含药微丸中的盐酸普拉克索与实施例4制备的低含药微丸中的盐酸普拉克索含量比例为4:1。121 mg of the sustained-release pellets prepared in Example 2 and 109 mg of the sustained-release pellets prepared in Example 4 were placed in gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 3 mg, wherein the high drug-containing microparticles prepared in Example 2 were obtained. The ratio of pramipexole hydrochloride in pramipexole hydrochloride to the low drug-containing pellets prepared in Example 4 was 4:1.
分别将制得的3mg的盐酸普拉克索缓释胶囊置于pH1.2、pH4.5、pH6.8和水中进行释放实验,比较在各个溶出介质对制得盐酸普拉克索缓释胶囊的缓释效果的影响,结果如图2所示。The prepared 3 mg pramipexole hydrochloride sustained-release capsules were placed in pH 1.2, pH 4.5, pH 6.8 and water for release experiments, and the preparation of pramipexole hydrochloride sustained-release capsules in each dissolution medium was compared. The effect of the release effect, the results shown in Figure 2.
比较制得的盐酸普拉克索缓释胶囊在各个溶出介质中的释放曲线,结果显示,制得的盐酸普拉克索缓释胶囊在各个溶出介质均能缓慢释放,不存在突释现象。The release curves of the obtained pramipexole hydrochloride sustained-release capsules in each dissolution medium were compared, and the results showed that the prepared pramipexole hydrochloride sustained-release capsules were slowly released in each dissolution medium, and there was no sudden release phenomenon.
实施例6Example 6
取实施例3制备的缓释微丸126mg以及实施例4制备的缓释微丸109mg装明胶胶囊,得到规格为3mg的盐酸普拉克索缓释胶囊,其中实施例3制备的高含药微丸中的盐酸普拉克索与实施例4制备的低含药微丸中的盐酸普拉克索含量比例为4:1。 126 mg of the sustained-release pellets prepared in Example 3 and 109 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 3 mg, wherein the high-medication micropellets prepared in Example 3 were obtained. The ratio of pramipexole hydrochloride in pramipexole hydrochloride to the low drug-containing pellets prepared in Example 4 was 4:1.
实施例7Example 7
取实施例2制备的缓释微丸60.5mg以及实施例4制备的缓释微丸54.5mg装明胶胶囊,得到规格为1.5mg的盐酸普拉克索缓释胶囊,其中实施例2制备的高含药微丸中的盐酸普拉克索与实施例4制备的低含药微丸中的盐酸普拉克索含量比例为4:1。60.5 mg of the sustained-release pellets prepared in Example 2 and 54.5 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 1.5 mg, wherein the high content of the preparation of Example 2 was obtained. The ratio of pramipexole hydrochloride in the pellets of the drug pellets to the low-medication pellets prepared in Example 4 was 4:1.
实施例8Example 8
取实施例3制备的缓释微丸63mg以及实施例4制备的缓释微丸54.5mg装明胶胶囊,得到规格为1.5mg的盐酸拉克索缓释胶囊,其中实施例3制备的高含药微丸中的盐酸普拉克索与实施例4制备的低含药微丸中的盐酸普拉克索含量比例为4:1。63 mg of the sustained-release pellets prepared in Example 3 and 54.5 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a 1.5 mg-molecular Lactobacillus hydrochloride sustained-release capsule, wherein the high-medication microparticle prepared in Example 3 was obtained. The ratio of pramipexole hydrochloride in pramipexole hydrochloride to the low drug-containing pellets prepared in Example 4 was 4:1.
实施例9Example 9
取实施例2制备的缓释微丸181.5mg以及实施例4制备的缓释微丸163.5mg装明胶胶囊,得到规格为4.5mg的盐酸普拉克索缓释胶囊,其中实施例2制备的高含药微丸中的盐酸普拉克索与实施例4制备的低含药微丸中的盐酸普拉克索含量比例为4:1。181.5 mg of the sustained-release pellets prepared in Example 2 and 163.5 mg of the sustained-release pellets prepared in Example 4 were filled with gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 4.5 mg, wherein the high content of the preparation of Example 2 was obtained. The ratio of pramipexole hydrochloride in the pellets of the drug pellets to the low-medication pellets prepared in Example 4 was 4:1.
实施例10Example 10
取实施例3制备的缓释微丸189mg以及实施例4制备的缓释微丸163.5mg装明胶胶囊,得到规格为4.5mg的盐酸普拉克索缓释胶囊,其中实施例3制备的高含药微丸中的盐酸普拉克索与实施例4制备的低含药微丸中的盐酸普拉克索含量比例为4:1。189 mg of the sustained-release pellets prepared in Example 3 and 163.5 mg of the sustained-release pellets prepared in Example 4 were placed in gelatin capsules to obtain a pramipexole hydrochloride sustained-release capsule having a specification of 4.5 mg, wherein the high-medication prepared in Example 3 was obtained. The ratio of pramipexole hydrochloride in the pellets in the pellets to the low-medication pellets prepared in Example 4 was 4:1.
上述实施例5至实施例10中两种微丸的用量并非一个固定值,其用量是基于两种缓释微丸中的盐酸普拉克索含量进行折算而来,上述是其中一个实施方案。其中上述各实施例中高含药微丸中的盐酸普拉克索与低含药微丸中的盐酸普拉克索的比例均为4:1。 The amounts of the two kinds of pellets in the above Examples 5 to 10 are not a fixed value, and the amount thereof is converted based on the pramipexole hydrochloride content in the two kinds of sustained-release pellets, and the above is one of the embodiments. The ratio of pramipexole hydrochloride to pramipexole hydrochloride in the high drug-containing pellets in each of the above examples was 4:1.
比较实施例6至实施例10制得的盐酸普拉克索缓释胶囊在各个溶出介质中的释放曲线,结果显示,实施例6至实施例10制得的盐酸普拉克索缓释胶囊在各个溶出介质也均能缓慢释放,不存在突释现象。 Comparing the release curves of pramipexole hydrochloride sustained-release capsules prepared in Examples 6 to 10 in each dissolution medium, the results showed that the pramipexole hydrochloride sustained-release capsules prepared in Examples 6 to 10 were each dissolved. The medium can also be released slowly without sudden release.

Claims (10)

  1. 一种盐酸普拉克索的缓释制剂,其特征在于,包含第一缓释微丸和第三缓释微丸,所述第一缓释微丸包含盐酸普拉克索第一含药微丸、第一包衣和第二包衣,所述第三缓释微丸包含盐酸普拉克索第三含药微丸和第三包衣,所述第一缓释微丸中的盐酸普拉克索与第三缓释微丸中的盐酸普拉克索的含量比为4:1。A sustained release preparation of pramipexole hydrochloride, comprising: first sustained release pellets and third sustained release pellets, wherein the first sustained release pellet comprises pramipexole hydrochloride first drug-containing pellets, a coating and a second coating, the third sustained-release pellet comprises pramipexole hydrochloride third drug-containing pellets and a third coating, pramipexine hydrochloride and the third in the first sustained-release pellet The content ratio of pramipexole hydrochloride in the sustained release pellets was 4:1.
  2. 根据权利1所述的缓释制剂,其特征在于,所述第一缓释微丸中所述盐酸普拉克索的第一含药微丸由盐酸普拉克索、第一药用微丸丸芯、粘合剂和溶剂制成,所述第一包衣由第一缓释衣膜材料、增塑剂、抗黏剂和溶剂制成,所述第二包衣由第二缓释衣膜材料、增塑剂、抗黏剂和溶剂制成;所述第三缓释微丸中所述盐酸普拉克索的第三含药微丸由盐酸普拉克索、第三药用微丸丸芯、粘合剂和溶剂制成,所述第三包衣由第三缓释衣膜材料、增塑剂、抗黏剂和溶剂制成。The sustained-release preparation according to claim 1, wherein the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is composed of pramipexole hydrochloride, a first medicinal pellet core, Made of a binder and a solvent, the first coating is made of a first sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent, and the second coating is composed of a second sustained release coating material, a plasticizer, an anti-adhesive agent and a solvent; the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet comprises pramipexole hydrochloride, a third medicinal pellet core, and a binder The agent is prepared from a third sustained release film material, a plasticizer, an anti-adhesive agent, and a solvent.
  3. 根据权利2所述的缓释制剂,其特征在于,所述第一含药微丸中的第一药用微丸丸芯为0.3-0.425mm蔗糖型药用微丸丸芯或0.5-0.7mm蔗糖型药用微丸丸芯;所述第一缓释衣膜材料为季铵基甲基丙烯酸酯共聚物B型(RS)和/或季铵基甲基丙烯酸酯共聚物A型(RL);所述第二缓释衣膜材料为乙基纤维素(7cps)、甲基丙烯酸共聚物A型、甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)、丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)、醋酸纤维素、甲基丙烯酸共聚物B型(S-100)中至少一种。The sustained release preparation according to claim 2, wherein the first medicinal pellet core in the first drug-containing pellet is 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type a medicinal micropellet pellet; the first sustained release coating material is a quaternary ammonium methacrylate copolymer type B (RS) and/or a quaternary ammonium methacrylate copolymer type A (RL); the second sustained release The coating material is ethyl cellulose (7 cps), methacrylic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer water At least one of the dispersion (30D), cellulose acetate, and methacrylic acid copolymer type B (S-100).
  4. 根据权利3所述的缓释制剂,其特征在于,所述第一含药微丸中的第一药用微丸丸芯为0.3-0.425mm蔗糖型药用微丸丸芯,所述粘合剂为聚维酮K30;所述第一缓释衣膜材料为季铵基甲基丙烯酸酯共聚物B型(RS)与季铵基甲基丙烯酸酯共聚物A型(RL)质量比为9:1的混合物或甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)与丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)质量比为2:1的混合物;所述第二缓释衣膜材料为乙基纤维素(7cps)与甲基丙烯酸共 聚物B型质量比为3:7的混合物或醋酸纤维素与甲基丙烯酸共聚物B型(S-100)质量比为2:3的混合物;所述增塑剂为柠檬酸三乙酯;所述抗黏剂为滑石粉;所述溶剂为95%乙醇。The sustained release preparation according to claim 3, wherein the first medicinal pellet core in the first drug-containing pellet is 0.3-0.425 mm sucrose-type medicinal pellet core, and the binder is Povidone K30; the first sustained release coating material is a mixture of quaternary ammonium methacrylate copolymer type B (RS) and quaternary ammonium methacrylate copolymer type A (RL) mass ratio of 9:1 or a mixture of an aqueous acrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55) and an ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D) having a mass ratio of 2:1; the second sustained release coating The membrane material is ethyl cellulose (7 cps) and methacrylic acid a mixture having a mass ratio of B:3:7 or a mixture of cellulose acetate and methacrylic acid copolymer type B (S-100) in a mass ratio of 2:3; the plasticizer is triethyl citrate; The anti-adhesive agent is talc; the solvent is 95% ethanol.
  5. 根据权利2所述的缓释制剂,其特征在于,所述第三含药微丸中的第三药用微丸丸芯为0.3-0.425mm蔗糖型药用微丸丸芯或0.5-0.7mm蔗糖型药用微丸丸芯;所述第三缓释衣膜材料为乙基纤维素(7cps)、甲基丙烯酸共聚物A型、甲基丙烯酸-丙烯酸乙酯共聚物水分散体(30D-55)、丙烯酸乙酯-甲基丙烯酸甲酯共聚物水分散体(30D)、醋酸纤维素、甲基丙烯酸共聚物B型(S-100)中至少一种。The sustained release preparation according to claim 2, wherein the third medicinal pellet core in the third drug-containing pellet is 0.3-0.425 mm sucrose-type medicinal pellet core or 0.5-0.7 mm sucrose-type a medicinal micropellet core; the third sustained release film material is ethyl cellulose (7 cps), methacrylic acid copolymer type A, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), At least one of ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate, and methacrylic acid copolymer type B (S-100).
  6. 根据权利5所述的缓释制剂,其特征在于,所述第三含药微丸中的第三药用微丸丸芯为0.5-0.7mm蔗糖型药用微丸丸芯,所述粘合剂为聚维酮K30;所述第三缓释衣膜材料为甲基丙烯酸共聚物B型(S-100);所述增塑剂为柠檬酸三乙酯;所述抗黏剂为滑石粉;所述溶剂为95%乙醇。The sustained release preparation according to claim 5, wherein the third medicinal pellet core in the third drug-containing pellet is 0.5-0.7 mm sucrose-type medicinal pellet core, and the binder is Povidone K30; the third sustained release coating material is methacrylic acid copolymer type B (S-100); the plasticizer is triethyl citrate; the anti-adhesive agent is talc; The solvent is 95% ethanol.
  7. 根据权利2所述的缓释制剂,其特征在于,所述第一缓释微丸中所述盐酸普拉克索的第一含药微丸中盐酸普拉克索的含量与第一药用微丸丸芯、粘合剂、溶剂的用量比为1:41.7:(1~2):(11.8~23.6);第一包衣中所述盐酸普拉克索的第一含药微丸与第一缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比为1:(0.11~0.15):(0.01~0.03):(0.025~0.035):(1.58~2.16);第二包衣中所述盐酸普拉克索的第一含药微丸与第二缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比为1:0.06:(0.005~0.007):(0.01~0.02):(0.075~0.088);The sustained-release preparation according to claim 2, wherein the content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet is the first medicinal micro-pill The ratio of the core, the binder and the solvent is 1:41.7: (1 to 2): (11.8 to 23.6); the first drug-containing pellet of the pramipexole hydrochloride in the first coating and the first sustained release The ratio of the film material, plasticizer, anti-adhesive agent and solvent is 1: (0.11 - 0.15): (0.01 - 0.03): (0.025 - 0.035): (1.58 - 2.16); The ratio of the first drug-containing pellets of pramipexole hydrochloride to the second sustained-release film material, plasticizer, anti-adhesive agent and solvent is 1:0.06: (0.005-0.007): (0.01-0.02): 0.075 to 0.088);
    所述第三缓释微丸中所述盐酸普拉克索的第三含药微丸中盐酸普拉克索与第三药用微丸丸芯、粘合剂和溶剂的用量比为1:166.7:(3~4):(34.5~46.0);第三包衣中所述盐酸普拉克索的第三含药微丸与第三缓释衣膜材料、增塑剂、抗黏剂和溶剂的用量比为1:0.025:(0.002~0.003):(0.005~0.0065):0.475。The ratio of the amount of pramipexole hydrochloride to the third medicinal pellet core, the binder and the solvent in the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet is 1:166.7: 3 to 4): (34.5 to 46.0); the ratio of the third drug-containing pellets of pramipexole hydrochloride to the third sustained-release film material, plasticizer, anti-adhesive agent and solvent in the third coating It is 1:0.025: (0.002 to 0.003): (0.005 to 0.0065): 0.475.
  8. 根据权利1所述的缓释制剂,其特征在于,所述制剂为胶囊 剂,还包括药用明胶胶囊。The sustained release preparation according to claim 1, wherein the preparation is a capsule The agent also includes a medicinal gelatin capsule.
  9. 权利要求1所述盐酸普拉克索的缓释制剂的制备方法,其特征在于,包括以下步骤:A method for preparing a sustained release preparation of pramipexole hydrochloride according to claim 1, comprising the steps of:
    1)将盐酸普拉克索与第一药用微丸丸芯、粘合剂和溶剂混合制备第一含药微丸,干燥后过筛;将盐酸普拉克索与第三药用微丸丸芯、粘合剂和溶剂混合制备第三含药微丸,干燥后过筛;1) mixing pramipexole hydrochloride with the first medicinal micropellet core, binder and solvent to prepare the first drug-containing pellet, drying and sieving; pramipexole hydrochloride and the third medicinal pellet core, sticky Mixing the mixture and the solvent to prepare the third drug-containing pellet, drying and sieving;
    2)将第一缓释衣膜材料与增塑剂、抗黏剂和溶剂混合制成第一包衣液,对第一含药微丸进行包衣形成第一包衣,干燥后过筛得缓释微丸A;将第二缓释衣膜材料与增塑剂、抗黏剂和溶剂混合制成第二包衣液,对缓释微丸A进行包衣形成第二包衣,干燥后过筛得第一缓释微丸;2) mixing the first sustained release coating material with a plasticizer, an anti-adhesive agent and a solvent to prepare a first coating liquid, coating the first drug-containing pellets to form a first coating, drying and sieving Sustained-release pellet A; mixing the second sustained-release film material with a plasticizer, an anti-adhesive agent and a solvent to prepare a second coating liquid, and coating the sustained-release pellet A to form a second coating, after drying Screening the first sustained release pellets;
    3)将第三缓释衣膜材料与增塑剂、抗黏剂和溶剂混合制成第三包衣液,对第二含药微丸进行包衣形成第三包衣,干燥后过筛得第三缓释微丸;3) mixing the third sustained-release film material with a plasticizer, an anti-adhesive agent and a solvent to prepare a third coating liquid, and coating the second drug-containing pellet to form a third coating, which is dried and sieved. Third sustained release pellets;
    4)将第一缓释微丸与第三缓释微丸混合,控制所述第一缓释微丸中的盐酸普拉克索与第三缓释微丸中的盐酸普拉克索的含量比为4:1;4) mixing the first sustained-release pellets with the third sustained-release pellets, and controlling the content ratio of pramipexole hydrochloride in the first sustained-release pellets to pramipexole hydrochloride in the third sustained-release pellets 4:1;
    其中,对步骤2)和步骤3)的顺序不分先后。Wherein, the order of step 2) and step 3) is in no particular order.
  10. 根据权利要求9所述的制备方法,其特征在于,步骤1)所述盐酸普拉克索的粒剂D(90)小于20μm;步骤1)所述干燥后过筛为30-40℃干燥,过筛收集30-60目之间的微丸;步骤2)和步骤3)所述包衣温度控制在20-30℃;步骤2)和步骤3)所述干燥后过筛为于40℃条件下干燥24小时以上,干燥后过24-40目筛,收集24-40目之间的微丸。 The preparation method according to claim 9, wherein the step 1) the granule D (90) of pramipexole hydrochloride is less than 20 μm; the step 1) is dried and sieved to dry at 30-40 ° C, The sieve collects the pellets between 30-60 mesh; the coating temperature of step 2) and step 3) is controlled at 20-30 ° C; the drying of the step 2) and the step 3) is carried out at 40 ° C Dry for more than 24 hours, dry and pass through a 24-40 mesh sieve to collect pellets between 24-40 mesh.
PCT/CN2017/110351 2017-07-31 2017-11-10 Pramipexole hydrochloride sustained release preparation and preparation method therefor. WO2019024310A1 (en)

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