CN109316466B - Pramipexole dihydrochloride sustained-release preparation and preparation method thereof - Google Patents
Pramipexole dihydrochloride sustained-release preparation and preparation method thereof Download PDFInfo
- Publication number
- CN109316466B CN109316466B CN201710642262.1A CN201710642262A CN109316466B CN 109316466 B CN109316466 B CN 109316466B CN 201710642262 A CN201710642262 A CN 201710642262A CN 109316466 B CN109316466 B CN 109316466B
- Authority
- CN
- China
- Prior art keywords
- release
- sustained
- pellet
- coating
- drug
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Active
Links
Images
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/41—Heterocyclic 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
- A61K31/425—Thiazoles
- A61K31/428—Thiazoles condensed with carbocyclic rings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
- A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
- A61K47/38—Cellulose; Derivatives thereof
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5026—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5005—Wall or coating material
- A61K9/5021—Organic macromolecular compounds
- A61K9/5036—Polysaccharides, e.g. gums, alginate; Cyclodextrin
- A61K9/5042—Cellulose; Cellulose derivatives, e.g. phthalate or acetate succinate esters of hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Epidemiology (AREA)
- Engineering & Computer Science (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Inorganic Chemistry (AREA)
- Biomedical Technology (AREA)
- Neurology (AREA)
- Neurosurgery (AREA)
- Psychology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Organic Chemistry (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the field of medicinal preparations, and discloses a pramipexole dihydrochloride sustained-release preparation and a preparation method thereof. The pramipexole dihydrochloride sustained-release preparation comprises a first sustained-release pellet and a third sustained-release pellet, wherein the first sustained-release pellet comprises a first pramipexole dihydrochloride drug-containing pellet, a first coating and a second coating, the third sustained-release pellet comprises a third pramipexole dihydrochloride drug-containing pellet and a third coating, and the content ratio of the pramipexole dihydrochloride in the first sustained-release pellet to the pramipexole dihydrochloride in the third sustained-release pellet is 4: 1. The pramipexole dihydrochloride sustained-release preparation provided by the invention is prepared by mixing two sustained-release pellets with different drug contents and different release speeds, can be sustained and slowly released under an acidic condition, and can effectively avoid the burst release effect of pramipexole dihydrochloride under the acidic condition. The preparation method of the pramipexole dihydrochloride sustained-release preparation is simple to operate and suitable for industrialization.
Description
Technical Field
The invention belongs to the field of medicinal preparations, particularly relates to a pramipexole dihydrochloride sustained-release preparation and a preparation method thereof, and particularly relates to a pramipexole dihydrochloride sustained-release capsule and a preparation method thereof.
Background
Parkinson's disease (Parkinson Sdis) is a common, slowly progressing degenerative disease of the nervous system occurring in the elderly, clinically characterized by resting tremor, myotonia and dyskinesia. With the aging process of the population, the prevalence rate of the disease is increased year by year, and the disease becomes a common disease of the nervous system next to cerebrovascular disease. Drug replacement therapy based on levodopa has long been the first choice for the treatment of parkinson's disease, but none of the existing therapeutic measures is effective in preventing or even slowing down the progression of the disease. For the last 30 years of treatment of early-stage Parkinson's disease, levodopa has been the main effective drug for treating Parkinson's disease, but the long-term use of levodopa causes fluctuations in response, including 'end-of-dose' and 'switching' phenomena, and motor complications, such as dyskinesia and dystonia. The emergence of the new generation of pramipexole, a non-ergot dopamine receptor agonist, holds promise for parkinson's disease patients.
The pramipexole can be independently applied to the treatment of the Parkinson's disease, reduces the incidence rate of dyskinesia caused by the treatment of the levodopa, and can reduce the dose and adverse reaction of the levodopa by combining the pramipexole with the levodopa. Early pramipexole use delays the onset of these symptoms and improves the quality of life of the patient compared to earlier levodopa use.
Pramipexole dihydrochloride was developed by Boehringer invagrehn (Boehringer Ingelheim) and has a structure shown in formula 1. Pramipexole dihydrochloride received U.S. FDA approval at 1/7/1997, followed by EMA approval at 14/10/1997 and japanese PMDA approval at 2/12/2003, under the trade name of pramipexole dihydrochloride
Pramipexole dihydrochloride is a non-ergot dopamine agonist, has high in vitro relative specificity and complete in-vivo activity with the dopamine receptor D2 subfamily, and has higher affinity to the dopamine D3 family receptor than D2 or D4.
Is used for improving symptoms and signs of idiopathic Parkinson (PD) and severe Restless Leg Syndrome (RLS).
Pramipexole dihydrochloride belongs to the third class in the Biopharmaceutical Classification System (BCS), a highly soluble, low permeability drug under physiological conditions. The sustained release preparation is a preparation which slowly releases the drug at a non-constant speed in a specified release medium according to requirements, has lower administration frequency compared with the common preparation, and can increase the medication compliance or curative effect of patients. After the pramipexole dihydrochloride is prepared into the sustained-release pellets, the release rate of the active ingredients can be effectively controlled, so that the effect of prolonging the action time of the medicine is achieved.
The pramipexole dihydrochloride sustained-release preparation currently on the market is a tablet, and a prolonged-release tablet containing pramipexole and a salt thereof disclosed in chinese patent CN101005831B comprises an active ingredient, pregelatinized starch in an anionic polymer and a third water-swellable polymer, thereby achieving a sustained-release effect. Wherein said anionic polymer is selected from the group consisting of acrylic acid polymers, methacrylic acid copolymers, alginates, carrageenans, gum arabic, xanthan gum, chitosan, sodium carboxymethylcellulose, and added calcium cellulose. However, the preparation prepared by the method has burst effect under acidic condition, and the burst effect causes a large amount of medicine to be released in a short time, so that the blood level in the body is suddenly increased, the optimal action effect of the medicine cannot be achieved, and the occurrence probability of adverse reaction is increased.
Disclosure of Invention
In view of the above, the present invention aims to provide a pramipexole dihydrochloride sustained release preparation and a preparation method thereof, aiming at the defects existing in the prior art. The pramipexole dihydrochloride sustained-release preparation disclosed by the invention can be continuously and slowly released under an acidic condition, so that the burst release effect of pramipexole dihydrochloride under the acidic condition is effectively avoided, and the incidence rate of adverse reactions is reduced.
In order to realize the purpose of the invention, the invention adopts the following technical scheme:
a sustained-release preparation of pramipexole dihydrochloride comprises a first sustained-release pellet and a third sustained-release pellet, wherein the first sustained-release pellet comprises a first pramipexole dihydrochloride-containing pellet, a first coating and a second coating, the third sustained-release pellet comprises a third pramipexole dihydrochloride-containing pellet and a third coating, and the content ratio of the pramipexole dihydrochloride in the first sustained-release pellet to the pramipexole dihydrochloride in the third sustained-release pellet is 4: 1.
In the pramipexole dihydrochloride sustained-release preparation, the content ratio of pramipexole dihydrochloride in the first sustained-release pellets to pramipexole dihydrochloride in the third sustained-release pellets is 4:1, namely the first sustained-release pellets are high-drug-content sustained-release pellets, and the third sustained-release pellets are low-drug-content sustained-release pellets. The first sustained-release pellet comprises two layers of coatings, the third sustained-release pellet comprises one layer of coating, the drug release speed of the first sustained-release pellet is slower, the third sustained-release speed is relatively higher, the two sustained-release pellets have different release speeds, namely the low drug-containing sustained-release pellet has relatively higher release speed, and the high drug-containing sustained-release pellet has relatively lower release speed. The pramipexole dihydrochloride sustained-release preparation provided by the invention is prepared by mixing two sustained-release pellets with different drug contents and different release speeds, the preparation with sustained-release effect is obtained, the early-stage drug release of the drug release is mainly provided by the low-drug-containing sustained-release pellets, and the later-stage drug release (after 2 h) is mainly provided by the high-drug-containing sustained-release pellets, and the sustained-release drug release can be sustained and sustained under an acidic condition, so that the burst release effect of pramipexole dihydrochloride under the acidic condition can be effectively avoided.
The first sustained-release pellets of the pramipexole dihydrochloride are prepared from pramipexole dihydrochloride, a first medicinal pellet core, an adhesive and a solvent, the first coating is prepared from a first sustained-release coating film material, a plasticizer, an anti-sticking agent and a solvent, and the second coating is prepared from a second sustained-release coating film material, a plasticizer, an anti-sticking agent and a solvent; the third sustained-release pellet is prepared from pramipexole dihydrochloride, a third medicinal pellet core, an adhesive and a solvent, and the third coating is prepared from a third sustained-release coating film material, a plasticizer, an anti-sticking agent and a solvent.
In the first sustained-release pellet of the pramipexole dihydrochloride sustained-release preparation, pramipexole dihydrochloride and a pellet core of a first medicinal pellet are prepared into a first medicinal pellet of pramipexole dihydrochloride in the presence of an adhesive and a solvent. The first medicinal pellet core can be a sucrose type medicinal pellet core, and is preferably a sucrose type medicinal pellet core of 0.3-0.425mm or a sucrose type medicinal pellet core of 0.5-0.7 mm. In some embodiments, the first pharmaceutical pellet core is a sucrose-type pharmaceutical pellet core of 0.3-0.425 mm.
Preferably, the binder in the first drug-containing pellet is povidone K30. More preferably povidone k30 at a concentration of 8%.
Preferably, the solvent in the first drug-containing pellet is ethanol. More preferably 95% ethanol.
The pramipexole dihydrochloride sustained-release preparation disclosed by the invention is characterized in that a first drug-containing pellet of pramipexole dihydrochloride is sequentially coated with a first coating and a second coating twice. The first coating is an inner layer coating of the first sustained-release pellet, and the second coating is an outer layer coating of the first sustained-release pellet. The first coating is made of a first slow-release coating film material, a plasticizer, an anti-sticking agent and a solvent, and the second coating is made of a second slow-release coating film material, a plasticizer, an anti-sticking agent and a solvent.
Preferably, the first slow-release coating material is quaternary ammonium methacrylate copolymer B type (RS) and/or quaternary ammonium methacrylate copolymer A type (RL); the second slow-release coating film material is at least one of ethyl cellulose (7cps), methacrylic acid copolymer A type, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate and methacrylic acid copolymer B type (S-100).
The first slow release coating film material is composed of a quaternary ammonium group methacrylate copolymer B (RS) and a quaternary ammonium group methacrylate copolymer A (RL), which are insoluble in water and below pH7.0, and different pH values have no influence on the dissolution curve, but pores are formed in the coating film, and the drug is released through the pores. The second sustained-release coating film is made of water-insoluble materials, so that the formed coating film can avoid acid degradation, prevent sudden release under gastric acid conditions and ensure that the pramipexole dihydrochloride in the pramipexole dihydrochloride sustained-release preparation is released at the small intestine.
In some embodiments, the first slow release coating material is a mixture of quaternary ammonium methacrylate copolymer type B (RS) and quaternary ammonium methacrylate copolymer type a (RL) in a mass ratio of 9:1, and the second slow release coating material is a mixture of ethyl cellulose (7cps) and methacrylic acid copolymer type B in a mass ratio of 3: 7.
In some embodiments, the first slow release coating film material is a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55) and ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D) in a mass ratio of 2:1, and the second slow release coating film material is 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 and second coatings is preferably triethyl citrate.
The coating process of the invention also comprises an anti-adhesion agent. During the coating process, the friction of the drug-containing pellets and the coating film material in the coating pan can generate static electricity, and the antistatic agent can be added during the coating process to remove the static electricity in time so as to avoid the sticking of the drug-containing pellets. Preferably, the anti-adhesion agent in the first coating and the second coating is talc.
The solvent in the first coating and the second coating of the present invention is preferably ethanol. More preferably 95% ethanol.
In the third sustained-release pellet of the pramipexole dihydrochloride sustained-release preparation, pramipexole dihydrochloride and a third medicinal pellet core are prepared into a third medicinal pellet of the pramipexole dihydrochloride in the presence of an adhesive and a solvent.
The third medicinal pellet core can be a sucrose type medicinal pellet core, and is preferably a sucrose type medicinal pellet core of 0.3-0.425mm or a sucrose type medicinal pellet core of 0.5-0.7 mm.
The third medicinal pellet core in the third sustained-release pellet of the pramipexole dihydrochloride sustained-release preparation can be the same as or different from the first medicinal pellet core in the first sustained-release pellet. In some embodiments, the third pharmaceutical pellet core is a sucrose-type pharmaceutical pellet core of 0.5-0.7 mm.
Preferably, the binder in the third drug-containing pellet is povidone K30.
Preferably, the solvent in the third drug-containing pellet is ethanol. More preferably 95% ethanol.
The third drug-containing pellet of pramipexole dihydrochloride in the pramipexole dihydrochloride sustained-release preparation is coated for the third time. The third coating is made of a third slow-release coating film material, a plasticizer, an anti-sticking agent and a solvent.
Preferably, the third sustained-release coating material is at least one of ethyl cellulose (7cps), methacrylic acid copolymer A type, methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55), ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D), cellulose acetate and methacrylic acid copolymer B type (S-100).
In some embodiments, the third extended release coating material is methacrylic acid copolymer type B (S-100).
The third coating also includes a plasticizer and an anti-tack agent. The plasticizer is preferably triethyl citrate; the anti-adhesion agent is talcum powder.
The solvent in the third coating of the present invention is preferably ethanol. More preferably 95% ethanol.
The content of pramipexole hydrochloride in the first drug-containing pellet of pramipexole hydrochloride in the first sustained-release pellet in the pramipexole hydrochloride sustained-release preparation is 1: 41.7: (1-2): (11.8-23.6). In some embodiments, the ratio of the content of pramipexole hydrochloride in the first drug-containing pellet of pramipexole hydrochloride in the first sustained-release pellet to the dosage of the first medicinal pellet core, the binder and the solvent is 1: 41.7: 1.3: 15.3.
the dosage ratio of the first drug-containing pellet of the pramipexole dihydrochloride in the first coating in the first sustained-release pellets to the first sustained-release coating film material, the plasticizer, the anti-adhesive agent and the solvent is 1: (0.11-0.15): (0.01-0.03): (0.025-0.035): (1.58-2.16). In some embodiments, the dosage ratio of the first drug-containing pellet of pramipexole dihydrochloride to the first sustained-release coating film material, the plasticizer, the anti-sticking agent and the solvent in the first coating is 1: 0.11: 0.011: 0.031: 1.58.
in the second coating, the dosage ratio of the first drug-containing pellet of the pramipexole dihydrochloride to the second sustained-release coating material, the plasticizer, the anti-sticking agent and the solvent is 1: 0.06: (0.005-0.007): (0.01-0.02): (0.075-0.088). In some embodiments, the dosage ratio of the first drug-containing pellet of pramipexole dihydrochloride to the second sustained-release coating film material, the plasticizer, the anti-sticking agent and the solvent in the second coating is 1: 0.06: 0.006: 0.015: 0.863.
the dosage ratio of the pramipexole hydrochloride in the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet to the pellet core of the third drug-containing pellet, the adhesive and the solvent is 1: 166.7: (3-4): (34.5-46.0). In some embodiments, the pramipexole dihydrochloride-containing third drug-containing pellet has a pramipexole dihydrochloride-containing pellet core, a binder and a solvent in an amount ratio of 1: 166.7: 3.33: 38.3.
in the third coating, the dosage ratio of the third drug-containing pellet of pramipexole dihydrochloride to the third sustained-release coating material, the plasticizer, the anti-sticking agent and the solvent is 1: 0.025: (0.002-0.003): (0.005-0.0065): 0.475. in some embodiments, the dosage ratio of the third drug-containing pellet of pramipexole dihydrochloride to the third sustained-release coating film material, the plasticizer, the anti-sticking agent and the solvent in the third coating is 1: 0.025: 0.0025: 0.00625: 0.475.
the particle size of the first sustained-release pellet and the third sustained-release pellet in the sustained-release preparation of the invention is preferably 24-40 meshes.
The sustained-release preparation can be a capsule, and the first sustained-release pellet and the third sustained-release pellet are mixed according to a certain proportion and filled into a medicinal capsule to obtain the pramipexole dihydrochloride sustained-release capsule. It should be noted that the mixing ratio of the first sustained-release pellet and the third sustained-release pellet in the pramipexole dihydrochloride sustained-release capsule is not limited, as long as the content ratio of pramipexole dihydrochloride in the first sustained-release pellet to pramipexole dihydrochloride in the third sustained-release pellet is ensured to be 4: 1.
Preferably, the medicinal capsule is a medicinal gelatin capsule, such as 0# capsule, 1# capsule, 2# capsule, 3# capsule, 4# capsule, 5# capsule, etc.
The invention also provides a preparation method of the pramipexole dihydrochloride sustained-release preparation, which comprises the following steps:
1) mixing pramipexole dihydrochloride with the pellet core of the first medicinal pellet, an adhesive and a solvent to prepare a first medicament-containing pellet, drying and sieving; mixing pramipexole dihydrochloride with a third medicinal pellet core, an adhesive and a solvent to prepare a third medicament-containing pellet, drying and sieving;
2) mixing the first sustained-release coating film material with a plasticizer, an anti-sticking agent and a solvent to prepare a first coating solution, coating the first drug-containing pellet to form a first coating, drying and sieving to obtain a sustained-release pellet A; mixing the second sustained-release coating film material with a plasticizer, an anti-sticking agent and a solvent to prepare a second coating solution, coating the sustained-release pellet A to form a second coating, drying and sieving to obtain a first sustained-release pellet;
3) mixing the third sustained-release coating film material with a plasticizer, an anti-sticking agent and a solvent to prepare a third coating solution, coating the second drug-containing pellets to form a third coating, drying and sieving to obtain third sustained-release pellets;
4) mixing the first sustained-release pellet and the third sustained-release pellet, and controlling the content ratio of pramipexole hydrochloride in the first sustained-release pellet to pramipexole hydrochloride in the third sustained-release pellet to be 4: 1;
wherein, the sequence of the step 2) and the step 3) is not divided into sequence.
The process of feeding the micro-pills has certain requirements on the granularity of materials. Preferably, in the preparation method of the present invention, the pramipexole dihydrochloride raw material is subjected to micronization treatment to increase the specific surface area of the raw material, so that the drug can be uniformly distributed on the pellets in the pellet administration process, and the pellets with better roundness are obtained. In some embodiments, the particle size of the micronized pramipexole dihydrochloride is controlled to have a D (90) of less than 20 μm,
the first drug-containing pellet and the third drug-containing pellet prepared in the step 1) of the preparation method need to be dried and sieved in time so as to avoid the adhesion of the pellets. Preferably, the drying and sieving are performed at 30-40 ℃, and the micropellets of 30-60 meshes are collected by sieving.
In the coating process in the step 2) and the step 3) of the preparation method, the temperature of the pellets in the fluidized bed is controlled to be between 20 and 30 ℃. At the beginning of spraying, a lower spraying speed should be adopted to prevent the solvent/water from penetrating into the interior of the pellets, and after the pellets are coated with a coating film, the spraying speed can be increased.
Residual solvent or water can produce a speed-increasing effect and thus affect the permeability of the coating film, so that after the pellet coating is completed, the pellets need to be subjected to post-drying treatment. Preferably, the drying process adopts 40 ℃ for drying for 24 hours.
Preferably, the coating in the step 2) and the step 3) is sieved by a 24-40 mesh sieve after being dried, and the pellets between 24 and 40 meshes are collected.
According to the technical scheme, the invention provides a pramipexole dihydrochloride sustained-release preparation and a preparation method thereof. The pramipexole dihydrochloride sustained-release preparation comprises a first sustained-release pellet and a third sustained-release pellet, wherein the first sustained-release pellet comprises a first pramipexole dihydrochloride drug-containing pellet, a first coating and a second coating, the third sustained-release pellet comprises a third pramipexole dihydrochloride drug-containing pellet and a third coating, and the content ratio of the pramipexole dihydrochloride in the first sustained-release pellet to the pramipexole dihydrochloride in the third sustained-release pellet is 4: 1. The content ratio of pramipexole dihydrochloride in the two sustained-release pellets is 4:1, the first sustained-release pellet contains two layers of coatings, the third sustained-release pellet contains one layer of coating, and the two sustained-release pellets have different release speeds. The pramipexole dihydrochloride sustained-release preparation provided by the invention is prepared by mixing two sustained-release pellets with different drug contents and different release speeds, can be sustained and slowly released under an acidic condition, and can effectively avoid the burst release effect of pramipexole dihydrochloride under the acidic condition. The preparation method of the pramipexole dihydrochloride sustained-release preparation is simple to operate and suitable for industrialization.
Drawings
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 description of the embodiments or the prior art will be briefly described below.
FIG. 1 shows the release profile of example 3 in medium at pH 1.2;
figure 2 shows the release profile of example 5 in various dissolution media.
Detailed Description
The invention discloses a pramipexole dihydrochloride sustained-release preparation and a preparation method thereof. Those skilled in the art can modify the process parameters appropriately to achieve the desired results with reference to the disclosure herein. It is expressly intended that all such similar substitutes and modifications which would be obvious to one skilled in the art are deemed to be included in the invention. While the methods and products of the present invention have been described in terms of preferred embodiments, it will be apparent to those of ordinary skill in the art that variations and modifications of the methods described herein, as well as other suitable variations and combinations, may be made to implement and use the techniques of the present invention without departing from the spirit and scope of the invention.
In order to further understand the present invention, the technical solutions in the embodiments of the present invention will be clearly and completely described below with reference to the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Unless otherwise specified, the reagents involved in the examples of the present invention are all commercially available products, and all of them are commercially available.
Example 1: preparation of drug-containing micro-pill
1. Prescription of high drug-containing pellet:
2. prescription of low-drug-content pellets:
3. preparation process
3.1 pretreatment of raw materials: micronizing pramipexole dihydrochloride, and controlling the particle size D (90) to be less than 20 mu m;
3.2, pellet application: adding the medicinal pellet core into a centrifugal granulator to apply medicine to the pellets, wherein the adhesive is 8% of povidone K30; drying the pellets at 30-40 deg.C after the pellet is applied.
3.3 sieving treatment: sieving the drug-containing pellets, and keeping the pellets of 30-60 meshes.
Example 2:
and (2) coating the high-drug-content pellets prepared in the embodiment 1 with a slow release coating film, wherein the coating film is made of a quaternary ammonium methacrylate copolymer B type (RS), a quaternary ammonium methacrylate copolymer A type (RL), ethyl cellulose (7cps) and a methacrylic acid copolymer B type (S-100) to obtain the high-drug-content slow release pellets. The recipe is shown in table 1.
TABLE 1 high drug-containing sustained-release pellet coating film prescription
Preparation process
1. First layer coating film
1.1 preparation of coating solution
(1) Dissolving a quaternary ammonium group methacrylate copolymer B type (RS) and a quaternary ammonium group methacrylate copolymer A type (RL) in 95% ethanol, and stirring until the quaternary ammonium group methacrylate copolymer B type (RS) and the quaternary ammonium group methacrylate copolymer A type (RL) are completely dissolved;
(2) after the materials are completely dissolved, adding the talcum powder and the triethyl citrate, stirring uniformly, and continuously stirring in the coating process.
1.2, fluidized bed coating: coating the pellet in fluidized bed at 20-30 deg.C.
1.3, drying and curing:
after the coating is finished, 0.5% of talcum powder is added as an anti-sticking agent, and the micro-pill is dried for more than 24 hours at the temperature of 40 ℃. And (3) sieving the dried pellets by a 24-40 mesh sieve, wherein the pellets between 24 and 40 meshes are the sustained-release pellets A.
2. Coating the second layer of coating film
2.1 preparation of coating solution
(1) Dissolving ethyl cellulose (7cps) and methacrylic acid copolymer B type (S-100) in 95% ethanol, and stirring to dissolve completely;
(2) after the materials are completely dissolved, adding the talcum powder and the triethyl citrate, stirring uniformly, and continuously stirring in the coating process.
2.2, fluidized bed coating: the high drug-containing sustained-release pellets coated with the first layer of coating film are placed in a fluidized bed to be coated with the second layer of sustained-release coating film, and the operation process is consistent with the operation process of coating the first layer of coating film.
2.3, drying and curing:
after coating, the pellets were dried at 40 ℃ for more than 24 hours. And (3) sieving the dried pellets by a 24-40 mesh sieve, wherein the pellets between 24 and 40 meshes are the sustained-release pellets B (high-drug-content sustained-release pellets).
Example 3:
and (3) coating the high-drug-content pellets prepared in the example 1 with a slow-release coating to obtain the high-drug-content slow-release pellets. 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 B type (S-100). The recipe is shown in table 2.
TABLE 2 high drug-containing sustained-release pellet coating film prescription
The high drug-containing pellets prepared in example 1 were coated in a fluidized bed.
The preparation process comprises the following steps:
1. first layer coating film
1.1 preparation of coating solution
(1) Dissolving an aqueous methacrylic acid-ethyl acrylate copolymer dispersion (30D-55) and an aqueous quaternary ethyl acrylate-methyl methacrylate copolymer dispersion (30D) in purified water, and stirring until the aqueous methacrylic acid-ethyl acrylate copolymer dispersion and the aqueous quaternary ethyl acrylate-methyl methacrylate copolymer dispersion are completely dissolved;
(2) after the materials are completely dissolved, adding the talcum powder and the triethyl citrate, stirring uniformly, and continuously stirring in the coating process.
1.2, fluidized bed coating: coating the pellet in fluidized bed at 20-30 deg.C.
1.3, drying and curing:
after the coating is finished, 0.5% of talcum powder is added as an anti-sticking agent, and the micro-pill is dried for more than 24 hours at the temperature of 40 ℃. And (3) sieving the dried pellets by a 24-40 mesh sieve, wherein the pellets between 24 and 40 meshes are the sustained-release pellets A.
2. Coating the second layer of coating film
(1) Dissolving cellulose acetate and methacrylic acid copolymer B type (S-100) in 95% ethanol, and stirring until the cellulose acetate and the methacrylic acid copolymer B type are completely dissolved;
(2) after the materials are completely dissolved, adding the talcum powder and the triethyl citrate, stirring uniformly, and continuously stirring in the coating process.
2.2, fluidized bed coating: the high drug-containing sustained-release pellets coated with the first layer of coating film are placed in a fluidized bed to be coated with the second layer of sustained-release coating film, and the operation process is consistent with the operation process of coating the first layer of coating film.
2.3, drying and curing:
after coating, the pellets were dried at 40 ℃ for more than 24 hours. And (3) sieving the dried pellets by a 24-40 mesh sieve, wherein the pellets between 24 and 40 meshes are the sustained-release pellets B (high-drug-content sustained-release pellets).
The cellulose acetate in the prepared sustained-release pellet B (high drug-containing sustained-release pellet) is a water-insoluble coating material, the methacrylic acid-ethyl acrylate copolymer aqueous dispersion (30D-55) and the ethyl acrylate-methyl methacrylate copolymer aqueous dispersion (30D) are insoluble at the pH value of below 7.0, the different pH values have no influence on the dissolution curve, and the drug release is through the diffusion of the coating film gaps. The release profile of the medium at pH1.2 is shown in FIG. 1.
Example 4
And (3) coating the low-drug-containing pellets prepared in the example 1 with a slow-release coating film to obtain the low-drug-containing slow-release pellets, wherein the coating film material is methacrylic acid copolymer B (S-100). The recipe is shown in table 3.
TABLE 3 Low-drug-content sustained-release pellet coating film prescription
The preparation process comprises the following steps:
1. preparation of coating liquid
(1) Dissolving methacrylic acid copolymer B type (S-100) in 95% ethanol, and stirring until the methacrylic acid copolymer B type (S-100) is completely dissolved;
(2) after the materials are completely dissolved, adding the talcum powder and the triethyl citrate, stirring uniformly, and continuously stirring in the coating process.
2. The low drug-containing pellets prepared in example 1 were coated in a fluidized bed, and then the pellets were dried at 40 ℃ for 24 hours or more to be cured. The temperature of the pellets in the fluidized bed is controlled between 20-30 ℃.
The contents of pramipexole dihydrochloride in the sustained-release pellets prepared in the above examples 2, 3 and 4 were measured, and the filling amount of the sustained-release capsule was calculated based on the contents. Table 4 below shows the pramipexole dihydrochloride content of the sustained release pellets of 3 specific examples:
table 4 pramipexole dihydrochloride of the sustained release pellets of each example
| Examples | Pramipexole dihydrochloride content (%) |
| Example 2 | 1.98％ |
| Example 3 | 1.90％ |
| Example 4 | 0.55％ |
Mixing the high-drug-content sustained-release pellets and the low-drug-content sustained-release pellets according to a certain proportion, wherein the high-drug-content sustained-release pellets comprise 4 parts of pramipexole hydrochloride, and the low-drug-content sustained-release pellets comprise 1 part of pramipexole hydrochloride, so that the dosage of the two sustained-release pellets is calculated.
Example 5
The sustained-release pellets 121mg prepared in example 2 and 109mg prepared in example 4 were filled into gelatin capsules to obtain pramipexole dihydrochloride sustained-release capsules with the specification of 3mg, wherein the content ratio of pramipexole dihydrochloride in the high-drug-content pellets prepared in example 2 to pramipexole dihydrochloride in the low-drug-content pellets prepared in example 4 was 4: 1.
The prepared pramipexole dihydrochloride sustained-release capsules of 3mg were placed in water at ph1.2, ph4.5 and ph6.8 respectively for release experiments, and the effects of the respective dissolution media on the sustained-release effect of the prepared pramipexole dihydrochloride sustained-release capsules were compared, and the results are shown in fig. 2.
The results of comparison of the release curves of the prepared pramipexole dihydrochloride sustained-release capsules in various dissolution media show that the prepared pramipexole dihydrochloride sustained-release capsules can be slowly released in various dissolution media and have no burst release phenomenon.
Example 6
Taking 126mg of the sustained-release pellets prepared in example 3 and 109mg of the sustained-release pellets prepared in example 4 to fill in gelatin capsules, a pramipexole dihydrochloride sustained-release capsule with the specification of 3mg is obtained, wherein the content ratio of the pramipexole dihydrochloride in the high-drug-content pellets prepared in example 3 to the pramipexole dihydrochloride in the low-drug-content pellets prepared in example 4 is 4: 1.
Example 7
Taking 60.5mg of the sustained-release pellets prepared in example 2 and 54.5mg of the sustained-release pellets prepared in example 4 to fill in gelatin capsules, obtaining pramipexole dihydrochloride sustained-release capsules with the specification of 1.5mg, wherein the content ratio of pramipexole hydrochloride in the high-drug-content pellets prepared in example 2 to pramipexole hydrochloride in the low-drug-content pellets prepared in example 4 is 4: 1.
Example 8
The sustained-release pellets 63mg prepared in example 3 and 54.5mg prepared in example 4 were filled in gelatin capsules to obtain 1.5mg of a pramipexole dihydrochloride sustained-release capsule, wherein the content ratio of pramipexole hydrochloride in the high-drug-content pellets prepared in example 3 to pramipexole hydrochloride in the low-drug-content pellets prepared in example 4 was 4: 1.
Example 9
Taking 181.5mg of the sustained-release pellets prepared in example 2 and 163.5mg of the sustained-release pellets prepared in example 4 to fill in gelatin capsules, pramipexole dihydrochloride sustained-release capsules with the specification of 4.5mg are obtained, wherein the content ratio of pramipexole hydrochloride in the high-drug-content pellets prepared in example 2 to pramipexole hydrochloride in the low-drug-content pellets prepared in example 4 is 4: 1.
Example 10
189mg of the sustained-release pellets prepared in example 3 and 163.5mg of the sustained-release pellets prepared in example 4 were filled in a gelatin capsule to obtain a pramipexole dihydrochloride sustained-release capsule with the specification of 4.5mg, wherein the content ratio of pramipexole hydrochloride in the high-drug-content pellets prepared in example 3 to pramipexole hydrochloride in the low-drug-content pellets prepared in example 4 was 4: 1.
The amount of the two pellets in examples 5 to 10 above is not a fixed value, and is based on the pramipexole dihydrochloride content of the two sustained release pellets, which is one embodiment. In each of the above examples, the ratio of pramipexole hydrochloride in the high drug-containing pellets to pramipexole hydrochloride in the low drug-containing pellets was 4: 1.
The results of comparing the release profiles of the pramipexole dihydrochloride sustained-release capsules prepared in examples 6 to 10 in each dissolution medium show that the pramipexole dihydrochloride sustained-release capsules prepared in examples 6 to 10 can slowly release in each dissolution medium without burst release.
Claims (9)
1. The sustained-release preparation of pramipexole dihydrochloride is characterized by comprising a first sustained-release pellet and a third sustained-release pellet, wherein the first sustained-release pellet comprises a first drug-containing pramipexole dihydrochloride pellet, a first coating and a second coating, the third sustained-release pellet comprises a third drug-containing pramipexole dihydrochloride pellet and a third coating, and the content ratio of the pramipexole dihydrochloride in the first sustained-release pellet to the pramipexole dihydrochloride in the third sustained-release pellet is 4: 1;
the first drug-containing pellet of the pramipexole dihydrochloride in the first sustained-release pellets is prepared from pramipexole dihydrochloride, a pellet core of the first drug-containing pellet, an adhesive and a solvent, the first coating is prepared from a first sustained-release coating film material, a plasticizer, an anti-sticking agent and a solvent, and the second coating is prepared from a second sustained-release coating film material, a plasticizer, an anti-sticking agent and a solvent; the third drug-containing pellet of the pramipexole dihydrochloride in the third sustained-release pellets is prepared from pramipexole dihydrochloride, a pellet core of the third drug-containing pellet, an adhesive and a solvent, and the third coating is prepared from a third sustained-release coating film material, a plasticizer, an anti-sticking agent and a solvent; the first slow-release coating material is a mixture of a quaternary ammonium group methacrylate copolymer B type (RS) and a quaternary ammonium group methacrylate copolymer A type (RL) in a mass ratio of 9:1 or a mixture of methacrylic acid-ethyl acrylate copolymer aqueous dispersion 30D-55 and ethyl acrylate-methyl methacrylate copolymer aqueous dispersion 30D in a mass ratio of 2: 1; the second slow-release coating material is a mixture of ethyl cellulose 7cps and methacrylic acid copolymer B type with the mass ratio of 3:7 or a mixture of cellulose acetate and methacrylic acid copolymer B type with the mass ratio of S-100 of 2: 3; the third slow-release coating film material is methacrylic acid copolymer B type S-100; the first coating is an inner layer coating of the first sustained-release pellet, and the second coating is an outer layer coating of the first sustained-release pellet;
the ratio of the content of pramipexole hydrochloride in the first drug-containing pellet of the pramipexole hydrochloride in the first sustained-release pellet to the dosage of the pellet core, the adhesive and the solvent of the first medicinal pellet is 1: 41.7: (1-2): (11.8-23.6); the dosage ratio of the pramipexole hydrochloride in the third drug-containing pellet of the pramipexole hydrochloride in the third sustained-release pellet to the pellet core of the third drug-containing pellet, the adhesive and the solvent is 1: 166.7: (3-4): (34.5-46.0).
2. The sustained-release preparation of claim 1, wherein the first medicinal pellet core in the first drug-containing pellet is sucrose-type medicinal pellet core of 0.3-0.425mm or sucrose-type medicinal pellet core of 0.5-0.7 mm.
3. The sustained-release preparation according to claim 2, wherein the first medicinal pellet core in the first drug-containing pellet is sucrose-type medicinal pellet core of 0.3-0.425mm, and the binder is povidone K30; the plasticizer in the first coating and the second coating is triethyl citrate; the anti-adhesion agent in the first coating and the second coating is talcum powder; the solvent in the first and second coatings was 95% ethanol.
4. The sustained-release preparation of claim 1, wherein the third medicinal pellet core in the third drug-containing pellet is sucrose-type medicinal pellet core of 0.3-0.425mm or sucrose-type medicinal pellet core of 0.5-0.7 mm.
5. The sustained-release preparation according to claim 4, wherein the third medicinal pellet core in the third drug-containing pellet is sucrose-type medicinal pellet core of 0.5-0.7mm, and the binder is povidone K30; the third slow-release coating film material is methacrylic acid copolymer B type (S-100); the plasticizer in the third coating is triethyl citrate; the anti-adhesion agent in the third coating is talcum powder; the solvent in the third coating is 95% ethanol.
6. The sustained-release preparation according to claim 1, wherein the dosage ratio of the first drug-containing pellet of pramipexole dihydrochloride to the first sustained-release coating film material, the plasticizer, the anti-adhesive agent and the solvent in the first coating is 1: (0.11-0.15): (0.01-0.03): (0.025-0.035): (1.58-2.16); in the second coating, the dosage ratio of the first drug-containing pellet of the pramipexole dihydrochloride to the second sustained-release coating material, the plasticizer, the anti-sticking agent and the solvent is 1: 0.06: (0.005-0.007): (0.01-0.02): (0.075-0.088);
in the third coating, the dosage ratio of the third drug-containing pellet of pramipexole dihydrochloride to the third sustained-release coating material, the plasticizer, the anti-sticking agent and the solvent is 1: 0.025: (0.002-0.003): (0.005-0.0065): 0.475.
7. the sustained-release preparation according to claim 1, wherein the preparation is a capsule, further comprising a pharmaceutical gelatin capsule.
8. A method for preparing a sustained release formulation of pramipexole dihydrochloride according to claim 1, which comprises the following steps:
1) mixing pramipexole dihydrochloride with the pellet core of the first medicinal pellet, an adhesive and a solvent to prepare a first medicament-containing pellet, drying and sieving; mixing pramipexole dihydrochloride with a third medicinal pellet core, an adhesive and a solvent to prepare a third medicament-containing pellet, drying and sieving;
2) mixing the first sustained-release coating film material with a plasticizer, an anti-sticking agent and a solvent to prepare a first coating solution, coating the first drug-containing pellet to form a first coating, drying and sieving to obtain a sustained-release pellet A; mixing the second sustained-release coating film material with a plasticizer, an anti-sticking agent and a solvent to prepare a second coating solution, coating the sustained-release pellet A to form a second coating, drying and sieving to obtain a first sustained-release pellet;
3) mixing the third sustained-release coating film material with a plasticizer, an anti-sticking agent and a solvent to prepare a third coating solution, coating the third drug-containing pellets to form a third coating, drying and sieving to obtain third sustained-release pellets;
4) mixing the first sustained-release pellet and the third sustained-release pellet, and controlling the content ratio of pramipexole hydrochloride in the first sustained-release pellet to pramipexole hydrochloride in the third sustained-release pellet to be 4: 1;
wherein, the sequence of the step 2) and the step 3) is not divided into sequence.
9. The method of claim 8, wherein the particle size D90 of the pramipexole dihydrochloride obtained in step 1) is less than 20 μm; drying, sieving at 30-40 deg.C, sieving, and collecting 30-60 mesh pellets; controlling the coating temperature of the step 2) and the step 3) to be 20-30 ℃; drying and sieving in the step 2) and the step 3) for more than 24 hours at 40 ℃, sieving by a 24-40 mesh sieve after drying, and collecting pellets of 24-40 meshes.
Priority Applications (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710642262.1A CN109316466B (en) | 2017-07-31 | 2017-07-31 | Pramipexole dihydrochloride sustained-release preparation and preparation method thereof |
| PCT/CN2017/110351 WO2019024310A1 (en) | 2017-07-31 | 2017-11-10 | Pramipexole hydrochloride sustained release preparation and preparation method therefor. |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201710642262.1A CN109316466B (en) | 2017-07-31 | 2017-07-31 | Pramipexole dihydrochloride sustained-release preparation and preparation method thereof |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN109316466A CN109316466A (en) | 2019-02-12 |
| CN109316466B true CN109316466B (en) | 2022-04-05 |
Family
ID=65233350
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN201710642262.1A Active CN109316466B (en) | 2017-07-31 | 2017-07-31 | Pramipexole dihydrochloride sustained-release preparation and preparation method thereof |
Country Status (2)
| Country | Link |
|---|---|
| CN (1) | CN109316466B (en) |
| WO (1) | WO2019024310A1 (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114342951B (en) * | 2021-12-09 | 2024-01-16 | 湖南农业大学 | Composite nanoparticle for accelerating degradation of pesticide residues as well as preparation method and application thereof |
| CN114425046B (en) * | 2021-12-16 | 2023-10-20 | 南通联亚药业股份有限公司 | Diltiazem hydrochloride sustained-release capsule |
| CN116650444B (en) * | 2023-07-31 | 2023-10-31 | 国药集团川抗制药有限公司 | Tacrolimus slow-release drug and preparation method thereof |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784155A (en) * | 2015-05-15 | 2015-07-22 | 中国药科大学 | Pramipexole dihydrochloride combined pellet capsule and preparation method thereof |
| CN105663095A (en) * | 2015-12-24 | 2016-06-15 | 寿光富康制药有限公司 | Preparation method of (R)-lansoprazole sustained-release capsule |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20050226926A1 (en) * | 2002-07-25 | 2005-10-13 | Pfizer Inc | Sustained-release tablet composition of pramipexole |
| EP1901721A1 (en) * | 2005-06-23 | 2008-03-26 | Spherics, Inc. | Delayed release or extended-delayed release dosage forms of pramipexole |
| CN101375869B (en) * | 2008-10-10 | 2011-08-17 | 中国药科大学 | Slow/controlled release pellet composition containing ginkgo leaf extracts and preparation method thereof |
| CN102406626B (en) * | 2011-12-02 | 2013-08-28 | 深圳海王药业有限公司 | Pramipexole hydrochloride slow release tablet and preparation method thereof |
| CN104367565A (en) * | 2014-11-21 | 2015-02-25 | 哈尔滨圣吉药业股份有限公司 | Pramipexole dihydrochloride sustained release pellets |
| CN105616358B (en) * | 2016-02-17 | 2018-12-07 | 南京卓康医药科技有限公司 | A kind of sustained-release micro-pellet of trimetazidine composition and preparation method thereof |
-
2017
- 2017-07-31 CN CN201710642262.1A patent/CN109316466B/en active Active
- 2017-11-10 WO PCT/CN2017/110351 patent/WO2019024310A1/en active Application Filing
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN104784155A (en) * | 2015-05-15 | 2015-07-22 | 中国药科大学 | Pramipexole dihydrochloride combined pellet capsule and preparation method thereof |
| CN105663095A (en) * | 2015-12-24 | 2016-06-15 | 寿光富康制药有限公司 | Preparation method of (R)-lansoprazole sustained-release capsule |
Also Published As
| Publication number | Publication date |
|---|---|
| CN109316466A (en) | 2019-02-12 |
| WO2019024310A1 (en) | 2019-02-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| US6958161B2 (en) | Modified release coated drug preparation | |
| CN108066319B (en) | Tofacitinib citrate enteric sustained-release pellet and preparation method thereof | |
| CN1134108A (en) | Beads for controlled release and pharmaceutical preparation contg. same | |
| JP2004512296A (en) | Methylphenidate modified release formulation | |
| CN103181914B (en) | Memantine hydrochloride sustained-release capsule and preparation method thereof | |
| CN109316466B (en) | Pramipexole dihydrochloride sustained-release preparation and preparation method thereof | |
| WO2022012172A1 (en) | Oral sustained-release composition for insoluble drug, and preparation method thereof | |
| EP2884967A1 (en) | Pharmaceutical compositions of memantine | |
| WO2021217388A1 (en) | Memantine hydrochloride extended-release capsule and preparation method therefor | |
| AU2018320946A1 (en) | Amantadine compositions, preparations thereof, and methods of use | |
| Karvekar et al. | A brief review on sustained release matrix type drug delivery system | |
| CN102552218A (en) | Memantine hydrochloride capsule sustained-release preparation and preparation method for same | |
| CN114748443B (en) | Memantine hydrochloride sustained-release pellets and preparation method thereof | |
| CA2480783C (en) | An improved modified release preparation | |
| RU2411035C2 (en) | Modified release 6-methyl-2-ethyl-hydroxypyridine succinate dosage form | |
| CN102247326B (en) | Oral chronopharmacologic drug delivery mini-pill preparation of propranolol and its salts | |
| CN114425046B (en) | Diltiazem hydrochloride sustained-release capsule | |
| CN110638791A (en) | Topiramate sustained-release capsule and preparation method thereof | |
| CN114432257B (en) | Bluprofen sustained-release tablet and preparation method thereof | |
| CN104906077A (en) | Choline fenofibrate controlled release preparation with biphase drug release characteristic, and preparation method thereof | |
| WO2004058228A1 (en) | Enteric coated fluoxetine composition | |
| EP2736496B1 (en) | Pharmaceutical composition containing an antimuscarinic agent and method for the preparation thereof | |
| Sonawane et al. | Formulation aspects and effect of critical factors for designing extended release pellets: an updated review | |
| JPH06345649A (en) | Ipsapyrone pharmaceutical composition | |
| AU2003213876B2 (en) | An improved modified release preparation |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| GR01 | Patent grant | ||
| GR01 | Patent grant |