CN106474084B - Pramipexole dihydrochloride sustained-release preparation and preparation method thereof - Google Patents
Pramipexole dihydrochloride sustained-release preparation and preparation method thereof Download PDFInfo
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Abstract
The pramipexole dihydrochloride sustained-release preparation provided by the invention has the advantages that the obtained sustained-release preparation not only has the sustained-release performance equivalent to that of the original medicine, but also has good content uniformity by adding the non-cellulose neutral sustained-release material and the crosslinked polyvinylpyrrolidone into the pramipexole dihydrochloride sustained-release tablet.
Description
Technical Field
The invention relates to the field of medicinal preparations, in particular to a pramipexole dihydrochloride sustained-release preparation and a preparation method thereof.
Background
Pramipexole dihydrochloride, chemical name: (S) -2-amino-4, 5,6, 7-tetrahydro-6-propylamine-benzothiazole monohydrate, the structural formula is shown as the formula (I),
pramipexole dihydrochloride is a dopamine receptor agonist, relieves dyskinesia of Parkinson patients by exciting striatal dopamine receptors, and is used for treating signs and symptoms of adult idiopathic Parkinson's disease. Pramipexole dihydrochloride is used as a first-line medicament for patients with early PD, is superior to bromocriptine in improving the dysfunction of late PD, and is clinically accepted and accepted by neurologists and patients with PD. Pramipexole dihydrochloride is the unique 2011 medicament which is recommended by MDS and is effective in treating Parkinson's disease depression. Pramipexole dihydrochloride is also a first-line drug for the treatment of RLS, all of which are type a evidence in the european and american guidelines.
The pramipexole dihydrochloride sustained-release tablet is a new dosage form developed on the basis of the immediate-release tablet, and the two are different in the way of releasing the drug. Compared with the quick-release tablet, the sustained-release tablet can continuously release the medicine, thereby prolonging the half-life period of the blood plasma, being more accordant with the physiological state, reducing the daily administration times and the number of tablets, increasing the convenience of patients and nursing staff and improving the compliance of the patients. And clinical tests further prove that the pramipexole sustained-release preparation has safety and tolerance similar to those of a quick-release preparation in the treatment of early-stage PD and the adjuvant treatment of late-stage PD. So far, no report about the increase of adverse reactions by using pramipexole dihydrochloride sustained-release tablets exists.
Currently, many studies on pramipexole dihydrochloride sustained-release tablets are carried out, such as: 1) patent CN200580027634.5 describes a pramipexole extended release tablet composition in oral administration form comprising pramipexole dihydrochloride dispersed in a matrix comprising at least two water swellable polymers other than pregelatinized starch, and one of which is an anionic polymer, preferably an acrylic polymer, more preferably carbomer, in an amount of about 1% to 10% by weight of the total tablet weight; another water-swellable polymer of the non-pre-crosslinked starch type is a neutral polymer, preferably hydroxypropyl cellulose, more preferably hypromellose, in an amount of about 25% to 65% by weight of the total tablet weight. However, the sustained release tablet is a preparation with pH value-dependent release characteristics, which not only increases the complexity of the preparation, but also increases the difference of release and absorption in human body. 2) Patent CN201310475466.2 discloses a pramipexole extended release tablet composition in the form of an oral administration, differing from the original research in that the matrix comprises at least two neutral polymers, one being a non-cellulose neutral polymer, preferably a combination of polyvinylpyrrolidone and vinyl acetate; the other is cellulose neutral polymer, preferably hypromellose, the release characteristic of the prepared sustained release tablet is not influenced by the pH value, but the medicine dispersion uniformity of the preparation is poor, the standard deviation (RSD) of the release degree has unqualified risk, the quality difference of each batch of samples can be caused by the batch-to-batch difference of the granularity, the fluidity, the bulk density physical property and the like of raw and auxiliary materials, and the uniformity and the reproducibility of the product are poor. 3) Patent CN201210351475.6 describes a preparation method of pramipexole dihydrochloride sustained release tablets with high content uniformity, which solves the problem of poor mixing uniformity of low dosage, but because the sustained release mechanism of pramipexole dihydrochloride sustained release tablets only depends on a hydrophilic gel skeleton of hypromellose, and the content of pramipexole hydrochloride sustained release tablets is 30% -60%, sustained release performance consistent with that of the original research cannot be achieved.
Therefore, the pramipexole dihydrochloride sustained-release tablets provided have high content uniformity and good sustained-release performance, which is a technical problem to be solved at present.
Disclosure of Invention
In view of the above, the technical problem to be solved by the present invention is to provide a pramipexole dihydrochloride sustained release preparation and a preparation method thereof, and the pramipexole dihydrochloride sustained release tablet provided by the present invention has good sustained release performance and good content uniformity of the sustained release tablet.
The invention provides a pramipexole dihydrochloride sustained-release preparation which comprises the following components: pramipexole dihydrochloride, a first non-cellulose neutral slow-release material, a second non-cellulose neutral slow-release material and cross-linked polyvinylpyrrolidone;
wherein the first non-cellulose neutral slow-release material is one or more of vinyl acetate, polyvinylpyrrolidone, polyvinyl alcohol and polyalkylene oxide;
the second non-cellulose neutral slow-release material is one or more of glyceryl behenate, glyceryl monostearate, cetyl alcohol, stearyl alcohol and carnauba wax.
Preferably, the mass ratio of the first non-cellulose neutral sustained-release material to the sustained-release preparation is (25-70): 100, preferably (30-60): 100.
preferably, the mass ratio of the non-cellulose neutral sustained-release material to the sustained-release preparation is (5-40): 100, preferably (10-30): 100.
preferably, the mass ratio of the crosslinked polyvinylpyrrolidone to the sustained-release preparation is (3-30): 100, preferably (4-20): 100.
preferably, the mass ratio of the pramipexole dihydrochloride to the sustained-release preparation is (0.1-3): 100, preferably (0.15-2): 100.
preferably, the sustained release formulation further comprises an excipient.
Preferably, the excipient is one or more of microcrystalline cellulose, micro-powder silica gel and magnesium stearate.
The invention also provides a preparation method of the pramipexole dihydrochloride sustained-release preparation, which comprises the following steps:
1) mixing the pramipexole dihydrochloride solution and crosslinked polyvinylpyrrolidone for granulation to obtain particles containing pramipexole dihydrochloride;
2) and mixing the obtained pramipexole dihydrochloride-containing particles, the first non-cellulose slow-release material, the second non-cellulose slow-release material and the excipient to obtain the pramipexole dihydrochloride slow-release preparation.
Preferably, the excipient is one or more of aerosil, microcrystalline cellulose and magnesium stearate.
Preferably, the step 2) is specifically:
mixing the second non-cellulose neutral slow-release material with the micropowder silica gel in the excipient to obtain a mixture containing the second non-cellulose neutral slow-release material;
and (2) adding the mixture containing the second non-cellulose neutral sustained-release material, then adding the first non-cellulose neutral sustained-release material and the particles containing the pramipexole dihydrochloride obtained in the step 1), mixing, then adding the microcrystalline cellulose in the excipient, continuously mixing, and finally adding the magnesium stearate in the excipient, and mixing to obtain the pramipexole dihydrochloride sustained-release preparation.
Compared with the prior art, the pramipexole dihydrochloride sustained-release preparation provided by the invention has the advantages that the obtained sustained-release preparation has the sustained-release performance equivalent to that of the original medicine, and the content uniformity is good by adding the non-cellulose neutral sustained-release material and the cross-linked polyvinylpyrrolidone, and the experimental result shows that the sustained-release preparation prepared by the invention has good sustained-release performance in solutions with different pH values, the content uniformity A +1.8S is less than 15 and as low as 4.2, and the content uniformity is good.
Compared with the prior art, the preparation method of the pramipexole dihydrochloride sustained-release preparation provided by the invention has the advantages that the pramipexole dihydrochloride solution is mixed with the crosslinked polyvinylpyrrolidone, and then the sustained-release material is mixed with the excipient, so that the prepared pramipexole dihydrochloride sustained-release preparation has good content uniformity and good sustained-release performance.
Drawings
Fig. 1 is a release curve of pramipexole dihydrochloride sustained release tablets in example 1 of the present invention under different pH conditions;
fig. 2 is a release curve of pramipexole dihydrochloride sustained release tablets according to embodiment 2 of the present invention under different pH conditions;
fig. 3 is a release curve of pramipexole dihydrochloride sustained release tablets according to embodiment 3 of the present invention under different pH conditions;
fig. 4 is a release curve of pramipexole dihydrochloride sustained release tablets according to embodiment 4 of the present invention under different pH conditions.
Detailed Description
The invention provides a pramipexole dihydrochloride sustained-release preparation which comprises the following components: pramipexole dihydrochloride, a first non-cellulose neutral slow-release material, a second non-cellulose neutral slow-release material and cross-linked polyvinylpyrrolidone.
According to the invention, the mass ratio of the pramipexole dihydrochloride to the sustained-release preparation is preferably (0.1-3): 100, more preferably (0.15 to 2): 100, most preferably (0.3 to 1.5): 100.
the first non-cellulose neutral slow-release material is preferably one or more of vinyl acetate, polyvinylpyrrolidone (povidone), polyvinyl alcohol and polyalkylene oxide; preferably a mixture of povidone and vinyl acetate, more preferably a mixture of povidone and vinyl acetate in a weight ratio of 2: 8; the mass ratio of the first non-cellulose neutral slow-release material to the slow-release preparation is (25-70): 100, more preferably (30 to 60): 100, most preferably (40-55): 100.
the second non-cellulose neutral slow-release material is one or more of glyceryl behenate, glyceryl monostearate, cetyl alcohol, stearyl alcohol and carnauba wax, more preferably one or more of glyceryl behenate, glyceryl monostearate, cetyl alcohol and stearyl alcohol, and most preferably glyceryl behenate or glyceryl monostearate. The mass ratio of the second non-cellulose neutral slow-release material to the slow-release preparation is (5-40): 100, more preferably (10 to 30): 100, most preferably (20-25): 100.
the mass ratio of the crosslinked polyvinylpyrrolidone to the sustained-release preparation is preferably (3-30): 100, more preferably (4-20): 100, most preferably (5-10): 100, most preferably (6-8): 100.
according to the invention, the sustained-release preparation also comprises an excipient, the excipient has no special requirement, and any excipient which can be applied to the sustained-release preparation and is known by the technical personnel in the field can be used, preferably one or more of microcrystalline cellulose, aerosil and magnesium stearate, and more preferably microcrystalline cellulose, aerosil and magnesium stearate; the mass ratio of the microcrystalline cellulose to the sustained-release preparation is preferably (10-60): 100, more preferably (20 to 50): 100, respectively; the mass ratio of the superfine silica powder to the sustained-release preparation is preferably (0.1-1): 100, more preferably (0.5 to 0.8): 100, the mass ratio of the magnesium stearate to the sustained-release preparation is preferably (0.1-1): 100, more preferably (0.5 to 0.8): 100.
according to the pramipexole dihydrochloride sustained-release preparation provided by the invention, the non-cellulose neutral sustained-release material and the cross-linked polyvinylpyrrolidone are added, wherein the first non-cellulose neutral sustained-release material and the second non-cellulose neutral sustained-release material are added, so that the obtained sustained-release preparation has the sustained-release performance equivalent to that of the original medicine, and meanwhile, the sustained-release preparation is both neutral sustained-release materials, and the release of the sustained-release preparation is not limited by the pH value environment; by adding crosslinked polyvinylpyrrolidone, it was unexpectedly found that the content uniformity of the sustained-release preparation obtained by mixing becomes excellent.
The invention also provides a preparation method of the pramipexole dihydrochloride sustained-release preparation, which comprises the following steps:
1) mixing the pramipexole dihydrochloride solution and crosslinked polyvinylpyrrolidone for granulation to obtain particles containing pramipexole dihydrochloride;
2) and mixing the obtained pramipexole dihydrochloride-containing particles, the first cellulose sustained-release material, the second cellulose sustained-release material and the excipient to obtain the pramipexole dihydrochloride sustained-release preparation.
According to the invention, pramipexole dihydrochloride solution and crosslinked polyvinylpyrrolidone are mixed and granulated to obtain particles containing pramipexole dihydrochloride;
the pramipexole dihydrochloride solution is preferably an ethanol aqueous solution of pramipexole dihydrochloride, and the volume ratio of ethanol to water in the ethanol aqueous solution is (40-90): (10-60); the dosage of the ethanol aqueous solution is to dissolve the pramipexole dihydrochloride; the mass ratio of the pramipexole dihydrochloride to the crosslinked polyvinylpyrrolidone is (0.1-3): (3-30), more preferably (0.15-2): (4-20), most preferably (0.15-1.5): (5-10).
The invention has no special requirement on granulation, and the granulation is known by the technicians in the field, and in order to ensure that the content uniformity of the prepared sustained-release preparation is better, the invention preferably ensures that the mesh number of the granules containing the pramipexole dihydrochloride obtained by granulation is more than 20 meshes; the invention also comprises drying the granulated pramipexole dihydrochloride-containing particles to obtain dried pramipexole dihydrochloride-containing particles, and the drying mode is not particularly limited in the invention, and can be any drying mode known in the art.
According to the invention, the obtained pramipexole dihydrochloride-containing particles, the first cellulose sustained-release material, the second cellulose sustained-release material and the excipient are mixed to obtain the pramipexole dihydrochloride sustained-release preparation;
wherein, the first non-cellulose neutral slow-release material is preferably one or more of vinyl acetate, polyvinylpyrrolidone, polyvinyl alcohol and polyalkylene oxide, preferably a mixture of povidone and vinyl acetate, and more preferably a mixture of povidone and vinyl acetate in a weight ratio of 2: 8; the mass ratio of the first non-cellulose neutral slow-release material to the slow-release preparation is (25-70): 100, more preferably (30 to 60): 100, most preferably (40-55): 100. the second non-cellulose neutral slow-release material is one or more of glyceryl behenate, glyceryl monostearate, cetyl alcohol, stearyl alcohol and carnauba wax, more preferably one or more of glyceryl behenate, glyceryl monostearate, cetyl alcohol and stearyl alcohol, and most preferably glyceryl behenate or glyceryl monostearate. The mass ratio of the second non-cellulose neutral slow-release material to the slow-release preparation is (5-40): 100, more preferably (10 to 30): 100, most preferably (20-25): 100. the mass ratio of the crosslinked polyvinylpyrrolidone to the sustained-release preparation is preferably (3-30): 100, more preferably (4-20): 100, most preferably (5-10): 100, most preferably (6-8): 100. the sustained-release preparation also comprises an excipient, the excipient has no special requirement, and the excipient which can be applied to the sustained-release preparation and is known by the technical personnel in the field can be any, preferably one or more of microcrystalline cellulose, micropowder silica gel and magnesium stearate, and more preferably microcrystalline cellulose, micropowder silica gel and magnesium stearate; the mass ratio of the microcrystalline cellulose to the sustained-release preparation is preferably (10-60): 100, more preferably (20 to 50): 100, respectively; the mass ratio of the superfine silica powder to the sustained-release preparation is preferably (0.1-1): 100, more preferably (0.5 to 0.8): 100, the mass ratio of the magnesium stearate to the sustained-release preparation is preferably (0.1-1): 100, more preferably (0.5 to 0.8): 100.
in the present invention, the mixing method is not particularly required, and the mixing method can be used in the preparation process of the pharmaceutical preparation, which is well known in the art.
Specifically, in order to mix the raw materials more uniformly, the step 2) is preferably:
mixing the second non-cellulose neutral slow-release material with the micropowder silica gel in the excipient to obtain a mixture containing the second non-cellulose neutral slow-release material;
mixing the mixture containing the second non-cellulose neutral sustained-release material, the first non-cellulose neutral sustained-release material and the particles containing the pramipexole dihydrochloride obtained in the step 1), adding microcrystalline cellulose in the excipient, continuously mixing, and finally adding magnesium stearate in the excipient, and mixing to obtain the pramipexole dihydrochloride sustained-release preparation.
In the preparation method of the invention, the mixing mode is a conventional mixing mode used for preparing the pharmaceutical preparation by a person skilled in the art, and has no special requirement, and the mixing temperature is normal temperature.
The shape of the pramipexole dihydrochloride sustained-release preparation is not specially required, and the solid sustained-release preparation known in the field can be prepared into any shape, such as tablets and granules.
According to the preparation method of the pramipexole dihydrochloride sustained-release preparation, provided by the invention, the problem of uneven mixing of pramipexole dihydrochloride in subsequent mixing is solved by mixing the solution of pramipexole dihydrochloride with the crosslinked polyvinylpyrrolidone, and meanwhile, the mixing uniformity of the obtained sustained-release preparation is further improved by mixing the second non-cellulose neutral sustained-release material with the superfine silica gel powder in the excipient, and then mixing the second non-cellulose neutral sustained-release material with the first non-cellulose neutral sustained-release material, the microcrystalline cellulose and the pramipexole dihydrochloride-containing particles obtained in the step 1).
The following will clearly and completely describe the technical solutions of 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.
Example 1
1) Dissolving pramipexole dihydrochloride in 40 wt% ethanol water solution to obtain pramipexole dihydrochloride solution;
2) adding crosslinked polyvinylpyrrolidone (Kollidon CL-SF) into the pramipexole dihydrochloride solution for adsorbing the ethanol solution of pramipexole dihydrochloride, stirring while adding to obtain a soft material, granulating with a 20-mesh sieve, and drying to obtain particles containing pramipexole dihydrochloride;
3) mixing silica gel micropowder with glyceryl behenate
888ATO), and adding a mixture of povidone and vinyl acetate (Kolidon SR) and the pramipexole dihydrochloride-containing granules prepared in step 2)And mixing, adding microcrystalline cellulose, continuously mixing, adding magnesium stearate, mixing, and tabletting to obtain the pramipexole dihydrochloride sustained-release tablet.
The amount of each raw material used in the preparation method described in example 1 is added according to the content of each raw material in the pramipexole dihydrochloride sustained-release tablet described in example 1, the content of each raw material in the pramipexole dihydrochloride sustained-release tablet is shown in table 1, and table 1 shows the content of each raw material in the pramipexole dihydrochloride sustained-release tablet prepared in example 1 of the present invention.
Table 1 contents of respective raw materials in pramipexole dihydrochloride sustained-release tablets prepared in example 1 of the present invention
The pramipexole dihydrochloride sustained release tablets prepared in example 1 are measured according to a first dissolution method in 2010 edition of Chinese pharmacopoeia, wherein dissolution media are hydrochloric acid solution with pH value of 1.2, acetate buffer solution with pH value of 4.5, 500ml of phosphate buffer solution with pH value of 6.8, water with the rotation speed of 100rpm, the temperature of the dissolution media is 37 ℃ plus or minus 0.5 ℃, samples are respectively taken at 1 hour, 2 hours, 4 hours, 6 hours, 9 hours, 12 hours, 16 hours, 20 hours and 24 hours, and the release curves are shown in figure 1, and figure 1 is the release curves of the pramipexole dihydrochloride sustained release tablets in example 1 of the invention under different pH values; as can be seen from figure 1, the pramipexole dihydrochloride sustained-release tablets are sustained-release in 4 dissolution media for 24 hours, are independent of pH and have good sustained-release performance.
According to the content uniformity inspection regulation of the appendix XE of the second part of the version 2010 of Chinese pharmacopoeia, the uniformity of the pramipexole dihydrochloride sustained release tablets prepared in example 1 is detected, specifically, 10 pramipexole dihydrochloride sustained release tablets prepared in example 1 are taken for measurement, the relative content X of each tablet with the marked amount as 100 is respectively measured by high performance liquid chromatography, and the average value X and the standard deviation S as well as the absolute value A of the difference between the marked amount and the average value are obtained (A ═ 100-X |); if A +1.80S is less than or equal to 15.0, the content uniformity of the sample meets the specification; the result shows that the content uniformity A +1.80S of the sustained-release tablet prepared in example 1 is 4.2; the uniformity is higher.
Example 2
1) Dissolving pramipexole dihydrochloride in 80 wt% ethanol water solution to obtain pramipexole dihydrochloride solution;
2) adding Kollidon CL-SF into the pramipexole dihydrochloride solution to adsorb an ethanol solution of pramipexole dihydrochloride, stirring while adding to obtain a soft material, granulating by using a 20-mesh sieve, and drying to obtain particles containing pramipexole dihydrochloride;
3) uniformly mixing the superfine silica powder and glyceryl behenate, adding Kolidon SR and the particles containing the pramipexole dihydrochloride prepared in the step 2), mixing, adding microcrystalline cellulose, continuously mixing, adding magnesium stearate, mixing, and tabletting to obtain the pramipexole dihydrochloride sustained-release tablets.
The amount of each raw material used in the preparation method described in example 2 is added according to the content of each raw material in the pramipexole dihydrochloride sustained-release tablet described in example 2, the content of each raw material in the pramipexole dihydrochloride sustained-release tablet is shown in table 2, and table 2 shows the content of each raw material in the pramipexole dihydrochloride sustained-release tablet prepared in example 2 of the present invention.
Table 2 contents of respective raw materials in pramipexole dihydrochloride sustained-release tablets prepared in example 2 of the present invention
The pramipexole dihydrochloride sustained release tablets prepared in example 2 are measured according to a first dissolution method in 2010 edition of Chinese pharmacopoeia, wherein dissolution media are hydrochloric acid solution with pH value of 1.2, acetate buffer solution with pH value of 4.5, 500ml of phosphate buffer solution with pH value of 6.8, water with the rotation speed of 100rpm, the temperature of the dissolution media is 37 ℃ plus or minus 0.5 ℃, samples are respectively taken at 1 hour, 2 hours, 4 hours, 6 hours, 9 hours, 12 hours, 16 hours, 20 hours and 24 hours, and the release curves are shown in fig. 2, and fig. 2 is the release curves of the pramipexole dihydrochloride sustained release tablets in example 2 of the present invention under different pH value conditions; as can be seen from figure 2, the pramipexole dihydrochloride sustained-release tablets are sustained-release in 4 dissolution media for 24 hours, are independent of pH and have good sustained-release performance.
According to the content uniformity inspection regulation of the appendix XE of the second part of the version 2010 of Chinese pharmacopoeia, the uniformity of the pramipexole dihydrochloride sustained release tablets prepared in example 2 is detected, specifically, 10 pramipexole dihydrochloride sustained release tablets prepared in example 2 are taken for measurement, the relative content X of each tablet with the marked amount as 100 is respectively measured by adopting a high performance liquid chromatography, and the average value X and the standard deviation S as well as the absolute value A of the difference between the marked amount and the average value are obtained (A ═ 100-X |); if A +1.80S is less than or equal to 15.0, the content uniformity of the sample meets the specification; the result shows that the content uniformity A +1.80S of the sustained-release tablet prepared in the example 2 is 3.6; the uniformity is higher.
Example 3:
1) dissolving pramipexole dihydrochloride in 80 wt% ethanol water solution to obtain pramipexole dihydrochloride solution;
2) adding Kollidon CL-SF into the pramipexole dihydrochloride solution to adsorb an ethanol solution of pramipexole dihydrochloride, stirring while adding to obtain a soft material, granulating by using a 20-mesh sieve, and drying to obtain particles containing pramipexole dihydrochloride;
3) uniformly mixing the superfine silica powder and glyceryl behenate, adding Kolidon SR and the particles containing the pramipexole dihydrochloride prepared in the step 2), mixing, adding microcrystalline cellulose, continuously mixing, adding magnesium stearate, mixing, and tabletting to obtain the pramipexole dihydrochloride sustained-release tablets.
The amount of each raw material used in the preparation method described in example 3 is added according to the content of each raw material in the pramipexole dihydrochloride sustained-release tablet described in example 3, the content of each raw material in the pramipexole dihydrochloride sustained-release tablet is shown in table 3, and table 3 shows the content of each raw material in the pramipexole dihydrochloride sustained-release tablet prepared in example 3 according to the present invention.
Table 3 contents of respective raw materials in pramipexole dihydrochloride sustained-release tablets prepared in example 3 of the present invention
The pramipexole dihydrochloride sustained release tablets prepared in example 3 are measured according to the first dissolution method in the version 2010 of the chinese pharmacopoeia, wherein dissolution media respectively include hydrochloric acid solution with pH1.2, acetate buffer solution with pH4.5, 500ml of phosphate buffer solution with pH6.8, water, the rotation speed is 100rpm, the temperature of the dissolution media is 37 ℃ ± 0.5 ℃, samples are respectively taken at 1, 2, 4, 6, 9, 12, 16, 20 and 24 hours, the release curve is shown in fig. 3, and fig. 3 is the release curve of the pramipexole dihydrochloride sustained release tablets in example 2 of the present invention under different pH conditions; as can be seen from fig. 3, the pramipexole dihydrochloride sustained-release tablets show 24-hour sustained release in 4 dissolution media, are not pH-dependent, and have good sustained release performance.
According to the content uniformity inspection method specified in appendix XE of the second part of the version 2010 of Chinese pharmacopoeia, the uniformity of the pramipexole dihydrochloride sustained release tablets prepared in example 3 is detected, specifically, 10 pramipexole dihydrochloride sustained release tablets prepared in example 3 are taken for measurement, the relative content X of each tablet with the labeled amount as 100 is respectively measured by high performance liquid chromatography, and the average value X and the standard deviation S as well as the absolute value A of the difference between the labeled amount and the average value are obtained (A ═ 100-X |); if A +1.80S is less than or equal to 15.0, the content uniformity of the sample meets the specification; the result shows that the content uniformity A +1.80S of the sustained-release tablet prepared in example 3 is 3.2; the uniformity is higher.
Example 4
1) Dissolving pramipexole dihydrochloride in 90 wt% ethanol water solution to obtain pramipexole dihydrochloride solution;
2) adding Kollidon CL-SF into the pramipexole dihydrochloride solution to adsorb an ethanol solution of pramipexole dihydrochloride, stirring while adding to obtain a soft material, granulating by using a 20-mesh sieve, and drying to obtain particles containing pramipexole dihydrochloride;
3) uniformly mixing the superfine silica powder and glyceryl behenate, adding Kolidon SR and the particles containing the pramipexole dihydrochloride prepared in the step 2), mixing, adding microcrystalline cellulose, continuously mixing, adding magnesium stearate, mixing, and tabletting to obtain the pramipexole dihydrochloride sustained-release tablets.
The amount of each raw material used in the preparation method described in example 4 is added according to the content of each raw material in the pramipexole dihydrochloride sustained-release tablet described in example 4, the content of each raw material in the pramipexole dihydrochloride sustained-release tablet is shown in table 4, and table 4 shows the content of each raw material in the pramipexole dihydrochloride sustained-release tablet prepared in example 4 of the present invention.
Table 4 contents of respective raw materials in pramipexole dihydrochloride sustained-release tablets prepared in example 4 of the present invention
The pramipexole dihydrochloride sustained release tablets prepared in example 4 are measured according to the first dissolution method in the version 2010 of the chinese pharmacopoeia, wherein dissolution media respectively include a hydrochloric acid solution with a pH of 1.2, an acetate buffer solution with a pH of 4.5, 500ml of a phosphate buffer solution with a pH of 6.8, water, a rotation speed of 100rpm, a temperature of the dissolution medium of 37 ℃ ± 0.5 ℃, and samples are taken at 1, 2, 4, 6, 9, 12, 16, 20 and 24 hours, a release curve is shown in fig. 4, and fig. 4 is a release curve of the pramipexole dihydrochloride sustained release tablets described in example 4 of the present invention under different pH conditions; as can be seen from figure 4, the pramipexole dihydrochloride sustained-release tablets are sustained-release in 4 dissolution media for 24 hours, are not pH-dependent, and have good sustained-release performance.
According to the content uniformity inspection method specified in the appendix XE of the second part of the version 2010 of Chinese pharmacopoeia, the uniformity of the pramipexole dihydrochloride sustained release tablets prepared in example 4 is detected, specifically, 10 pramipexole dihydrochloride sustained release tablets prepared in example 4 are taken for measurement, the relative content X of each tablet with the labeled amount as 100 is measured by high performance liquid chromatography, and the average value X, the standard deviation S and the absolute value A of the difference between the labeled amount and the average value are obtained (A is 100-X); if A +1.80S is less than or equal to 15.0, the content uniformity of the sample meets the specification; the result shows that the content uniformity A +1.80S of the sustained-release tablet prepared in the example 4 is 2.8; the uniformity is higher.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. It should be noted that, for those skilled in the art, it is possible to make various improvements and modifications to the present invention without departing from the principle of the present invention, and those improvements and modifications also fall within the scope of the claims of the present invention.
Claims (10)
1. A sustained release formulation of pramipexole dihydrochloride comprising: pramipexole dihydrochloride, a first non-cellulose neutral slow-release material, a second non-cellulose neutral slow-release material and cross-linked polyvinylpyrrolidone; the sustained release preparation also comprises an excipient, wherein the excipient is one or more of microcrystalline cellulose, micropowder silica gel and magnesium stearate;
wherein the first non-cellulose neutral sustained-release material is a mixture of povidone and vinyl acetate;
the mass ratio of the first non-cellulose neutral slow-release material to the slow-release preparation is (25-70): 100, respectively;
the second non-cellulose neutral slow-release material is one or more of glyceryl behenate, glyceryl monostearate, cetyl alcohol and stearyl alcohol;
the mass ratio of the second non-cellulose neutral slow-release material to the slow-release preparation is (5-40): 100, respectively;
the mass ratio of the crosslinked polyvinylpyrrolidone to the sustained-release preparation is (3-30): 100, respectively;
the preparation method of the sustained-release preparation comprises the following steps: mixing the pramipexole dihydrochloride solution with the cross-linked polyvinylpyrrolidone for granulation to obtain particles containing pramipexole dihydrochloride, and then mixing the particles with the first non-cellulose neutral slow-release material, the second non-cellulose neutral slow-release material and the excipient to obtain the pramipexole dihydrochloride slow-release preparation.
2. The formulation according to claim 1, wherein the first non-cellulose based neutral slow release material is a mixture of povidone and vinyl acetate in a weight ratio of 2: 8.
3. The formulation according to claim 1, wherein said second non-cellulose neutral slow-release material is glyceryl behenate or glyceryl monostearate.
4. The preparation according to claim 1, wherein the mass ratio of the first non-cellulose neutral sustained-release material to the sustained-release preparation is (30-60): 100.
5. the preparation according to claim 1, wherein the mass ratio of the second non-cellulose neutral sustained-release material to the sustained-release preparation is (10-30): 100.
6. the preparation according to claim 1, wherein the mass ratio of the cross-linked polyvinylpyrrolidone to the sustained-release preparation is (4-20): 100.
7. the preparation according to claim 1, wherein the mass ratio of the pramipexole dihydrochloride to the sustained-release preparation is (0.1-3): 100.
8. the preparation according to claim 1, wherein the mass ratio of the pramipexole dihydrochloride to the sustained-release preparation is (0.15-2): 100.
9. a preparation method of a pramipexole dihydrochloride sustained-release preparation comprises the following steps:
1) mixing the pramipexole dihydrochloride solution and crosslinked polyvinylpyrrolidone for granulation to obtain particles containing pramipexole dihydrochloride;
2) mixing the obtained pramipexole dihydrochloride-containing particles, the first non-cellulose neutral slow-release material, the second non-cellulose neutral slow-release material and an excipient to obtain a pramipexole dihydrochloride slow-release preparation;
wherein the first non-cellulose neutral sustained-release material is a mixture of povidone and vinyl acetate;
the mass ratio of the first non-cellulose neutral slow-release material to the slow-release preparation is (25-70): 100, respectively;
the second non-cellulose neutral slow-release material is one or more of glyceryl behenate, glyceryl monostearate, cetyl alcohol and stearyl alcohol;
the mass ratio of the second non-cellulose neutral slow-release material to the slow-release preparation is (5-40): 100, respectively;
the mass ratio of the crosslinked polyvinylpyrrolidone to the sustained-release preparation is (3-30): 100, respectively;
the excipient is one or more of superfine silica gel powder, microcrystalline cellulose and magnesium stearate.
10. The preparation method according to claim 9, wherein the step 2) is specifically:
uniformly mixing the second non-cellulose neutral slow-release material with the micropowder silica gel in the excipient to obtain a mixture containing the second non-cellulose neutral slow-release material;
and (2) adding the mixture containing the second non-cellulose neutral sustained-release material, then adding the first non-cellulose neutral sustained-release material and the particles containing the pramipexole dihydrochloride obtained in the step 1), mixing, then adding the microcrystalline cellulose in the excipient, continuously mixing, and finally adding the magnesium stearate in the excipient, and mixing to obtain the pramipexole dihydrochloride sustained-release preparation.
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| CN104367562A (en) * | 2013-08-15 | 2015-02-25 | 上海星泰医药科技有限公司 | Pramipexole dihydrochloride slow-release tablets and preparation method thereof |
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| WO2008067991A2 (en) * | 2006-12-08 | 2008-06-12 | Antares Pharma Ipl Ag | Skin-friendly drug complexes for transdermal administration |
| WO2011086182A2 (en) * | 2010-01-18 | 2011-07-21 | Synthon Bv | Pramipexole extended release tablets |
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