Drug – bio-affecting and body treating compositions – Preparations characterized by special physical form – Particulate form
Utility Patent
1999-03-05
2001-01-02
Page, Thurman K. (Department: 1615)
Drug, bio-affecting and body treating compositions
Preparations characterized by special physical form
Particulate form
C424S489000, C424S490000, C424S494000, C424S495000, C424S497000, C427S002140, C514S356000, C514S962000
Utility Patent
active
06168806
ABSTRACT:
I. FIELD OF THE INVENTION
The present invention relates to an orally administrable nifedipine pellet and a process for the preparation thereof. In particular, the present invention relates to a nifedipine-containing pellet which provides for a fast as well as a prolonged release pattern of nifedipine upon oral administration, and the process for the preparation thereof.
II. BACKGROUND OF THE INVENTION
Nifedipine, 1,4-dihydro-2,6-dimethyl-4-(2-nitrophenyl)pyridinedicarboxylic acid dimethyl ester, is a known active compound from the substance class of the dihydropyridines, which affects the circulation. Nifedipine has been widely used as a coronary vasodilator or calcium channel antagonist in treatment of coronary insufficiency and angina.
Nifedipine is very poorly soluble in water. Nifedipine will dissolve in water only to an extent of about 1:200,000 and is sparingly soluble in ethanol and in glycerol but more readily soluble in chloroform and acetone. Owing to its low solubility, nifedipine has in most cases been embedded in soluble, hydrophilic polymers such as polyethylene glycol (PEG), polyvinylpyrrolidone (PVP) or cellulose ethers. This gives rise to solid solutions if it dissolves in the molten form of, for example, PEG, or to coprecipitates, for example, in PVP, with suitable solvents and then precipitated in a very finely divided form by removal of the solvents.
Nifedipine is generally delivered in two patterns, i.e., a quick release form and a slow release form, based upon the types of medical treatments. For instance, for the acute treatment of angina, it is desirable to attain relatively high nifedipine concentrations in plasma quickly and a fast release preparation of nifedipine is thus preferred. On the other hand, for the treatment of hypertension, it is more desirable to maintain plasma nifedipine concentrations within a much lower concentration range and a slow release preparation of nifedipine is thus preferred.
The fast release form of nifedipine is currently served by a preparation consisting of an aqueous or aqueous alcoholic solution of nifedipine having a polyalkylene glycol and/or a polyoxyethylene ester component within a soft gelatin capsule. (See e.g., U.S. Pat. Nos. 4,978,533 and 5,200,192). The slow release form of nifedipine is currently available by dissolving microcrystalline particles of nifedipine in the presence of polyvinyl-pyrrolidone (PVP). (See e.g., U.S. Pat. No. 5,145,683). However, both of the above mentioned forms of nifedipine are difficult to prepare, which significantly affect the manufacturing costs for production.
In the invention to be presented below, a new form of nifedipine delivery system will be introduced. This new nifedipine delivery system is in the form of an orally administrable nifedipine pellet which can be encapsulated for easy uptake. This new nifedipine pellet can function as both of the fast and the slow release forms of nifedipine, depending upon the compositional and structural configuration of the pellet. Also, because this new nifedipine pellet can be manufactured by any conventional particle coating devices such as Glatt and Huttlin, it has the advantages of cost effectiveness.
III. SUMMARY OF THE INVENTION
The first embodiment of the present invention provides a fast release form of nifedipine pellet which comprises (1) a particulate core, and (2) a nifedipine coating layer which is coated onto said particulate core. This nifedipine pellet can be administered orally.
The particulate core comprises an excipient which can be water-soluble or water-insoluble and a pharmacologically acceptable carrier. The water-soluble excipient comprises at least one selected from the group consisting of mannose, galactose, glucose, fructose, sucrose, lactose, maltose, dextrin, glycogen, and inulin. The water-insoluble excipient is at least one selected from the group consisting of starch, micro-crystalline cellulose, and talc. The preferable pharmacologically acceptable carrier is sucrose.
The nifedipine coating layer comprises an effective amount of nifedipine which is dissolved in organic solvents. The preferable organic solvents include acetone, alcohol, and isopropanol. The preferable organic solvent for dissolving nifedipine contains a mixture of acetone and alcohol in the ratio (vol/vol) of 1:1.1 to 1:4. A 0 to 30% (by volume) of distilled water can be added to the acetone and alcohol mixture.
The nifedipine dissolved in organic solvent can be further mixed with an emulsified dispersing suspension which comprises an emulsifier, an adhesive, and a dispersant. The preferable emulsifier includes poloxamer 188, Tween 80, and sodium lauryl sulfate. The preferable adhesive includes polyvinylpyrrolidone, hydroxypropylcellulose, methylcellulose, and hydroxypropylmethylcellulose. The preferable dispersant includes lactose, sucrose, fructose, maltose, mannose, glucose, and polyethylene glycol (PEG) with molecular weight of 4,000, 6,000, 8,000 and 20,000. Among the various molecular weights of PEG, the most preferable one is PEG 20,000. In the case where the emulsified dispersing suspension is used in forming the nifedipine coating layer, the ratio (by weight) of said particulate core and said nifedipine coating layer is 1: 0.04-0.14% of nifedipine, 1-7% of emulsifier, 0.4-7% of adhesive, 0.9-11% of dispersant, 7-15% of organic solvent, and 4-10% of distilled water. The preferable composition of the nifedipine pellet comprises 20-70% by weight of the particulate core, 3 to 15% by weight of the nifedipine, 1-20% by weight of the emulsifier, 1-20% by weight of the adhesive, and 1-30% by weight of the dispersant.
The second embodiment of the present invention provides a prolonged release form of nifedipine pellet which comprises (1) a particulate core, (2) a nifedipine coating layer which covers the particulate core, and (3) a surface coating layer which covers the nifedipine coating layer.
The chemical compositions of the particulate core and the nifedipine coating layer are the same as those described in the first embodiment. The surface coating layer comprises at least one selected from the group consisting of polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, and ethylcellulose. This surface coating layer can further comprise at least one selected from the group consisting of triethylcitrate, triacetin, and diethyl phthalate.
The third embodiment of the present invention provides a method for preparing the nifedipine pellet as described in the first and the second embodiments. The method of making the nifedipine pellet described in the first embodiment comprises the steps of: (1) forming a particulate core, and (2) spraying a nifedipine coating layer onto said particulate core. The method of making the nifedipine pellet described in the second embodiment adds a step of spraying a surface coating layer onto the nifedipine coating layer.
The particulate core is made by the steps of: (1) dissolving polyvinylpyrrolidone in an organic solvent (such as isopropanol); (2) mixing said dissolved polyvinylpyrrolidone with distilled water to form an adhesive solution; (3) mixing a pharmacologically acceptable carrier and an excipient in a particle pelletizing device (by rotation); and (4) spraying said adhesive solution via spraying nozzles in the particle pelletizing device onto said pharmacologically acceptable carrier and said excipient. The newly formed particulate core can be further dried via filtered or heated air within the particle pelletizing device. The preferable particle pelletizing devices are the ones manufactured by Glatt or Huttlin.
The method of making the nifedipine coating layer comprises the steps of: (1) dissolving nifedipine in an organic solvent; and (2) spraying said dissolved nifedipine onto said particulate core. The preferred method is to mix the dissolved nifedipine in an emulsified dispersing suspension which is prepared by mixing the adhesive, the emulsifier, and the dispersant together to form a nifedipine coating solution, followed by spraying the nifedipine coating solution onto the
Chen Shan-chiung
Kuo Han-Chiang
Lee Fang-Yu
Chao Fei-Fei
Page Thurman K.
Seidleck Brian K.
Venable Baetjer Howard & Civiletti LLP
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