CN109966256B - Pramipexole sustained-release pharmaceutical composition, preparation method and application thereof - Google Patents
Pramipexole sustained-release pharmaceutical composition, preparation method and application thereof Download PDFInfo
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- CN109966256B CN109966256B CN201811623992.8A CN201811623992A CN109966256B CN 109966256 B CN109966256 B CN 109966256B CN 201811623992 A CN201811623992 A CN 201811623992A CN 109966256 B CN109966256 B CN 109966256B
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
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- 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
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
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- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Pharmacology & Pharmacy (AREA)
- Epidemiology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Animal Behavior & Ethology (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Preparation (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention belongs to the fields of pharmacology and pharmaceutics, and relates to a pramipexole sustained-release pharmaceutical composition, a preparation method and application thereof. Specifically, the invention relates to a pramipexole sustained-release pharmaceutical composition, which comprises pramipexole or a pharmaceutically acceptable salt thereof and a sustained-release material, wherein the sustained-release material consists of a neutral water-swellable polymer and an anionic water-swellable polymer; wherein, the weight percentage of the pharmaceutical composition is as follows: 0.05% -1% of pramipexole or a pharmaceutically acceptable salt thereof, 80% -99% of neutral water-swellable polymer and 1% -10% of anionic water-swellable polymer. The preparation of the invention has better stability, less impurities and better safety.
Description
Technical Field
The invention belongs to the fields of pharmacology and pharmaceutics, and relates to a pramipexole sustained-release pharmaceutical composition, a preparation method and application thereof.
Background
Pramipexole is known as dopamine D 2 A receptor agonist. It is structurally different from ergot-derived drugs, such as bromocriptine or pergolide. It is a full dopamine agonist and has D-effect on dopamine 2 Family receptors are selective. The chemical name of pramipexole is: (S) -2-amino-4, 5,6, 7-tetrahydro-6- (propylamino) benzothiazole with the molecular formula of C 10 H 17 N 3 S, relative molecular weight 211.33. The chemical formula is shown as the following formula A.
The pramipexole salt commonly used is pramipexole dihydrochloride monohydrate (formula C) 10 H 17 N 3 S·2HCl·H 2 O; relative molecular weight 302.27). The chemical formula is shown as the following formula B. Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs at 296 ℃ to 301 ℃ with decomposition. Pramipexole is a chiral compound having one chiral center, and an aqueous solution thereof is sensitive to light.
In 1997, the pramipexole general tablet (IR) agent was first approved in the united states. Subsequently marketed in the european union, swiss, canada and south america, and in the eastern european countries and asia, respectively. It is used to treat signs and symptoms of parkinson's disease, either alone (without levodopa) or in combination with levodopa. For example, the therapeutic effects of levodopa gradually diminish or change and fluctuate in the later stages of the disease. The pramipexole general tablet needs to be taken three times a day, and in view of the problems that a Parkinson patient has mobility inconvenience and regular medicine taking is difficult to guarantee, the FDA in the United states of 2010 approves the pramipexole dihydrochloride sustained-release tablet Mirapex ER developed by Boehringer Ingelheim pharmaceutical company, and is used for treating disease signs and symptoms of the Parkinson patient at the early stage and the advanced stage 1 time per day.
Patent CN 101005831B of Boehringer Ingelheim pharmaceutical ltd shows that pramipexole sustained release preparation adopts powder direct compression process, and requires that active ingredients and part of excipients are ground together and then mixed with other excipients. The process is complicated, and the content uniformity of the active ingredients is difficult to ensure.
With the enhancement of the post-marketing supervision and evaluation management of medicines, some medicines are discovered to have adverse reaction events due to improper storage, storage or transportation management in recent years. Because of the safety problem of the clinical use of the medicine, particularly the adverse reaction phenomenon is related to the pharmacological activity of the medicine, and sometimes also has a great relationship with impurities in the medicine.
Therefore, improvement of the quality of the drug, that is, further reduction of the types and/or contents of impurities in the raw materials or preparations of the drug, will be of great significance in greatly improving the safety and stability of the drug after the drug is marketed. Moreover, the quality standards of the medicines on the market are generally high, and how to further reduce the types or contents of impurities is also very difficult.
The inventor of the present invention found that the stability of the existing pramipexole preparation is not satisfactory, and particularly, impurities are easily generated under a high temperature and/or high humidity environment, which threatens the safety of the medicine to a certain extent.
Therefore, development of a new pramipexole formulation with higher stability is required.
Disclosure of Invention
The inventor prepares the pramipexole sustained-release pharmaceutical composition through deep research and creative work. The present inventors have surprisingly found that pramipexole sustained release pharmaceutical compositions having excellent stability, even when stored for a long period of time under high temperature and/or high humidity conditions, with very low impurity levels, when the pramipexole sustained release pharmaceutical composition comprises 85-93% by weight of a neutral water swellable polymer having a viscosity; the fluidity is good in sample preparation, and tabletting is convenient; the content uniformity is better, the weight of the tablet is easy to control, the phenomena of sticking and the like are avoided, and the production efficiency is high.
One aspect of the present invention relates to a pramipexole sustained-release pharmaceutical composition comprising pramipexole or a pharmaceutically acceptable salt thereof and a sustained-release material,
wherein the slow release material consists of a neutral water swellable polymer and an anionic water swellable polymer;
wherein, the weight percentage of the pharmaceutical composition is as follows:
0.05 to 1 percent of pramipexole or medicinal salt thereof,
from 80% to 99% of a neutral water-swellable polymer, and
1% -10% of anionic water-swellable polymer.
In one or more embodiments of the present invention, the pramipexole sustained-release pharmaceutical composition comprises, in terms of weight percentage of the pharmaceutical composition:
80% -98% of neutral water-swelling polymer.
In one or more embodiments of the invention, the pramipexole sustained release pharmaceutical composition is characterized by any one or more of the following items (1) to (10) (e.g., any of items 2, 3, 4,5,6,7, 8, 9, or 10 below item 10):
(1) the pharmaceutically acceptable salt of pramipexole is pramipexole dihydrochloride or pramipexole dihydrochloride monohydrate;
(2) the neutral water-swellable polymer is selected from one or more of alkyl cellulose, hydroxyalkyl alkyl cellulose, hydroxyalkyl cellulose ester, methacrylate copolymer, polyvinyl alcohol, polyvinyl pyrrolidone, copolymer of polyvinyl pyrrolidone and vinyl acetate, a combination of polyvinyl alcohol and polyvinyl pyrrolidone, and polyalkylene oxide;
(3) the anionic water-swellable polymer is selected from one or more of polymers of acrylic acid (e.g. carbomer), cross-linked polymers of acrylic acid, copolymers of methacrylic acid, alginate, acacia, xanthan gum and sodium carboxymethylcellulose;
(4) the pramipexole or a pharmaceutically acceptable salt thereof is present in an amount of 0.1% to 0.8%, such as 0.1% to 0.6%, 0.15% to 0.35%, 0.18% to 0.3%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7% or 0.75% by weight;
(5) the neutral water-swellable polymer is 80-98%, 85-95%, 85-94.4643%, 85-94%, 89-95%, 89-94.4643%, 89-94%, 91-95%, 91-94.4643%, 91-94%, 90-93.7%, 91.25-93% or 91-93.7% by weight;
(6) the anionic water-swellable polymer is present in an amount of 2% to 7% by weight, such as 3% to 5%, 2%, 3%, 4%, 5%, 6% or 7%; preferably 2% -6% or 2% -5%;
(7) the pramipexole sustained-release pharmaceutical composition also comprises one or more other auxiliary materials;
(8) the pramipexole sustained-release pharmaceutical composition does not contain starch, mannitol and/or sorbitol; preferably, the pramipexole sustained release pharmaceutical composition does not contain any filler; such starches include, but are not limited to: pregelatinized starch, starch derivatives, corn starch, and the like;
(9) the pramipexole sustained-release medicine composition is a tablet, a granule or a capsule;
(10) the pramipexole sustained-release medicine composition also contains effective dose of one or more of levodopa, rasagiline and ropinirole hydrochloride.
In one embodiment of the present invention, the pramipexole sustained release pharmaceutical composition does not contain any filler.
In one embodiment of the invention, the pramipexole sustained release pharmaceutical composition is free of starch fillers, such as pregelatinized starch, starch derivatives and corn starch.
In one or more embodiments of the present invention, the pramipexole sustained release pharmaceutical composition further comprises a filler, wherein the neutral water-swellable polymer is present in an amount of 80-89 wt%; preferably, the filler is selected from any one or more of starch, dextrin, microcrystalline cellulose, lactose, mannitol, and calcium hydrogen phosphate; preferably, the content of the filler is 1 to 25 percent by weight.
In one or more embodiments of the invention, the pramipexole sustained release pharmaceutical composition wherein the neutral water swellable polymer is one or more hydroxypropyl methylcellulose (HPMC);
preferably, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with viscosity of 4000 to 100000mPa & s;
more preferably, the hydroxypropyl methylcellulose is hydroxypropyl methylcellulose with viscosity of 10000 to 100000mPa & s;
particularly preferably, the hydroxypropylmethylcellulose is a hydroxypropylmethylcellulose having a viscosity of 15000 to 100000 mPa-s, for example HPMC K4M, HPMC K100M or HPMC K15M;
further preferably, the hydroxypropylmethylcellulose is hydroxypropylmethylcellulose having a viscosity of 15000mPa · s to 20000mPa · s;
preferably, the neutral water-swellable polymer is a viscous hydroxypropylmethylcellulose.
The viscosity of the hydroxypropyl methylcellulose is the marked viscosity of the product and meets the viscosity standard of hydroxypropyl methylcellulose as a medicinal auxiliary material in 2015 edition of Chinese pharmacopoeia.
In one or more embodiments of the invention, the pramipexole sustained release pharmaceutical composition is a viscous hydroxypropylmethylcellulose, and the hydroxypropylmethylcellulose is present in an amount of 85% to 95%, 85% to 94.4643%, 85% to 94%, 89% to 95%, 89% to 94.4643%, 89% to 94%, 91% to 94.4643%, 90% to 93.7% by weight; 91% -93.7%; 91.25% -93% or 91% -94%.
Preferably, the pramipexole sustained release pharmaceutical composition is free of starch, mannitol and/or sorbitol;
preferably, the pramipexole sustained release pharmaceutical composition does not contain any filler.
In one or more embodiments of the invention, the pramipexole sustained release pharmaceutical composition wherein the anionic water swellable polymer is carbomer; preferably, the carbomer is selected from
934P、
974P、
971P and
71G; more preferably, the carbomer is
971P and/or
71G。
In one or more embodiments of the invention, the pramipexole sustained release pharmaceutical composition comprises HPMC and carbomer in a weight percentage selected from the group consisting of:
HPMC 70-98% and carbomer 1-10%;
HPMC 80-97% and carbomer 1-9%;
HPMC 85-97% and carbomer 2-8%;
HPMC 89-95% and carbomer 2-7%;
HPMC 91-95% and carbomer 2-5%.
HPMC 91-94% and carbomer 2-5%.
Without being limited by theory, the use amount of the HPMC higher than 70% is not common generally, because the use amount of the HPMC higher than 70% has higher requirements on the production process, especially higher requirements on the uniformity of the medicament in the sustained-release preparation, and because the content of the raw material medicament in the preparation is relatively lower, the difficulty of quality control is further increased, and if the mixing is not uniform, the phenomena of large tablet weight difference and unqualified content uniformity caused by poor fluidity and unsmooth tabletting can occur.
According to the invention, particularly, the HPMC content in the prescription is 91-94% of the composition, the weight difference of the tablet is within +/-3%, and the content uniformity of the tablet meets the requirements of the preparation. Particularly, the samples of the production scale have small batch-to-batch difference and meet the requirements under the item of general preparation rules and tablets in an appendix of pharmacopoeia of 2015 edition.
The dosage of HPMC is 85% -94.4643%, and the dosage of one or more of the following auxiliary materials can be increased:
glidants, such as silicon dioxide;
a lubricant, for example, selected from one or more of magnesium stearate, calcium stearate, stearic acid, and talc;
preferably, the pramipexole sustained release pharmaceutical composition contains glidant (e.g. silicon dioxide) in an amount of 0.5-10%, more preferably 0.5-9%, 1-10%, 0.5-3%, 1-5%, 2-5% or 2-3%.
The HPMC is used in 70-85% or 70-89%, and the dosage of one or more of the following auxiliary materials can be increased:
glidants, such as silicon dioxide;
a lubricant, for example, selected from one or more of magnesium stearate, calcium stearate, stearic acid, and talc;
fillers, for example, selected from one or more of starch, pregelatinized starch, microcrystalline cellulose (MCC), dextrin, lactose, mannitol and dibasic calcium phosphate.
Preferably, the pramipexole sustained release pharmaceutical composition contains glidant (e.g. silicon dioxide) in an amount of 0.5-10%, more preferably 0.5-9%, 1-10%, 0.5-3%, 1-5%, 2-5% or 2-3%.
In one or more embodiments of the invention, the pramipexole sustained-release pharmaceutical composition is characterized in that the auxiliary material is a glidant and/or a lubricant; preferably, the glidant is silicon dioxide; preferably, the lubricant is magnesium stearate.
Preferably, the pramipexole sustained release pharmaceutical composition contains 0.5% to 5%, more preferably 1% to 2% of a lubricant (e.g., magnesium stearate).
In one or more embodiments of the invention, the pramipexole sustained release pharmaceutical composition contains Rac-7-oxo-pramipexole in an amount of not greater than 0.01%, not greater than 0.1%, not greater than 0.2%, not greater than 0.3%, not greater than 0.4%, not greater than 0.5%, or is undetectable.
In one or more embodiments of the present invention, the pramipexole sustained-release pharmaceutical composition is characterized by the following (i) and/or (ii):
placing the pramipexole sustained-release medicinal composition for 10-30 days at the temperature of 40 ℃ and at 75% RH, wherein the content of Rac-7-oxo-pramipexole is not higher than 0.1%, not higher than 0.2%, not higher than 0.3% or not higher than 0.4%;
② the pramipexole sustained-release pharmaceutical composition is placed for 10-30 days at the temperature of 25 ℃ and the RH of 90 percent, wherein, the content of Rac-7-oxo-pramipexole is not higher than 3.6 percent, not higher than 4.5 percent, not higher than 5.0 percent, not higher than 6.0 percent or not higher than 8.0 percent.
The invention also relates to a pramipexole sustained-release pharmaceutical composition which comprises the following components in percentage by weight of the total weight of the pharmaceutical composition:
preferably, the following components are contained:
or,
or,
or,
or,
another aspect of the present invention relates to a method for preparing a pramipexole sustained release pharmaceutical composition according to any one of the preceding claims, comprising the steps of:
(1) uniformly mixing pramipexole or a pharmaceutically acceptable salt thereof, a partially neutral water-swellable polymer, an optional anionic water-swellable polymer, an optional glidant and an optional lubricant to obtain a first mixture; the weight of the first mixture is 4-15 percent of the total weight of the pramipexole slow-release medicine composition, and preferably 5-10 percent;
(2) adding the rest auxiliary materials, and uniformly mixing to obtain a second mixture;
(3) and (3) preparing the second mixture into a required dosage form, for example, tabletting the second mixture to prepare the pramipexole dihydrochloride sustained-release tablets.
Yet another aspect of the present invention relates to the use of a sustained release pharmaceutical composition of pramipexole according to any of the preceding claims for the preparation of a medicament for the treatment and/or prevention of parkinson's, duller's syndrome, depression, fibromyalgia or schizophrenia.
In the present invention, if not specifically stated, the percentage contents of each component or impurity in the pramipexole sustained release pharmaceutical composition (or pramipexole sustained release preparation) of the present invention are all the weight percentage contents, and are calculated according to the total weight of the pramipexole sustained release pharmaceutical composition.
Advantageous effects of the invention
The invention has at least one of the following technical effects:
(1) the preparation has good content uniformity;
(2) the stability is better; especially, the stability is better under special conditions; is suitable for long-term storage. The preparation of the invention is relatively stable under high temperature and high humidity conditions, and can solve the problem that patients take medicines irregularly or forget to take medicines (for example, medicines are exposed in the air for a long time); under some unqualified high-temperature and high-humidity storage or transportation conditions or non-standard operation, the medicine of the invention can still be relatively stable; such as: adverse reaction events caused by cold chain logistics occur when the vaccine is not required, so that the improvement of the stability of the medicine under high humidity and other conditions is also a solution.
(3) Less impurities and better safety;
(4) has good drug effect;
(5) has good release degree.
Drawings
FIG. 1: dissolution profile for in vitro release of formulations with different amounts of carbomer, pH6.8 medium.
FIG. 2: dissolution curve of in vitro release of HPMC preparation with different viscosity, pH6.8 medium.
FIG. 3A: dissolution profile for in vitro release, pH 1.2 medium.
FIG. 3B: dissolution profile for in vitro release, pH 4.5 medium.
FIG. 3C: dissolution profile of in vitro release, medium 0.9% NaCl aqueous solution.
FIG. 3D: dissolution profile for in vitro release, pH6.8 medium.
FIG. 4: dissolution profile for in vitro release, pH6.8 medium, samples 1, 10.
FIG. 5: dissolution profile for in vitro release, pH6.8 medium, samples 1, 10.
Detailed Description
Embodiments of the present invention will be described in detail below with reference to examples, but those skilled in the art will appreciate that the following examples are only illustrative of the present invention and should not be construed as limiting the scope of the present invention. The examples, in which specific conditions are not specified, were conducted under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used are not indicated by the manufacturer, and are all conventional products commercially available.
Preparation example 1: preparation of pramipexole sustained release formulation sample 1 (specification of 0.375 mg/tablet)The formulation composition of sample 1 is shown in table 1 below:
TABLE 1
The preparation was carried out according to the following procedure:
(1) uniformly mixing pramipexole dihydrochloride monohydrate, silicon dioxide and a portion of HPMC K15M, wherein the total weight is about 5% of the total formula weight;
(2) adding the rest of the auxiliary materials, and uniformly mixing;
(3) tabletting to obtain the pramipexole dihydrochloride sustained-release tablets.
Thus, pramipexole sustained release formulation sample 1 (specification of 0.375 mg/tablet) was prepared.
Preparation example 2: preparation of pramipexole sustained release preparation sample 2 (specification of 0.75 mg/tablet)
The formulation composition of sample 2 is shown in table 2 below:
TABLE 2
The preparation was carried out according to the following procedure:
(1) uniformly mixing pramipexole dihydrochloride monohydrate, silicon dioxide, magnesium stearate and a small amount of HPMC, wherein the total weight is about 5% of the total prescription amount;
(2) adding the rest of the auxiliary materials, and uniformly mixing;
(3) tabletting to obtain the pramipexole dihydrochloride sustained-release tablets.
Thus, pramipexole sustained release preparation sample 2 (specification of 0.75 mg/tablet) was prepared.
Preparation example 3: preparation of pramipexole sustained release preparation sample 3 (specification of 1.5 mg/tablet)
The formulation composition of sample 3 is shown in table 3 below:
TABLE 3
The preparation was carried out according to the following procedure:
(1) uniformly mixing pramipexole dihydrochloride monohydrate, silicon dioxide, magnesium stearate, a small amount of HPMC (hydroxy propyl methyl cellulose) and carbomer 71G, wherein the total weight is about 10% of the total prescription weight;
(2) adding the rest of the auxiliary materials, and uniformly mixing;
(3) tabletting to obtain the pramipexole dihydrochloride sustained-release tablets.
Thus, pramipexole sustained release preparation sample 3 (specification of 1.5 mg/tablet) was prepared.
Preparation examples 4 to 6: preparation of pramipexole sustained Release formulations samples 4-6
The formulation composition of samples 4-6 is shown in Table 4 below:
TABLE 4
| Sample No. 4 | Sample No. 5 | Sample No. 6 | |
| Sample composition | Percentage content | Percentage content | Percentage content |
| Pramipexole dihydrochloride monohydrate | 0.1875％ | 0.1875％ | 0.1875％ |
| HPMC K15M | 93.8125％ | 92.8125％ | 91.8125 |
| Carbomer | |||
| 71G | 3.0％ | 4.0％ | 5.0％ |
| Silicon dioxide | 2.0％ | 2.0％ | 2.0％ |
| Magnesium stearate | 1.0％ | 1.0％ | 1.0％ |
| Specifications (mg) | 0.375 | 0.375 | 0.375 |
| Tablet weight (mg) | 200 | 200 | 200 |
Preparation examples 7 to 9: preparation of pramipexole sustained Release formulations samples 7-9
The formulation composition of samples 7-9 is shown in Table 5 below:
TABLE 5
The preparation process was carried out according to preparation example 1.
Experimental example 1: stability test (1)
1. Experimental medicine
TABLE 6
| Composition (I) | Every 0.75mg of the tablet |
| Pramipexole dihydrochloride monohydrate | 0.75 |
| Hydroxypropyl methylcellulose K15M | 157.5 |
| Carbomer 941 | 3.5 |
| Corn starch | 183.7 |
| Silica gel micropowder | 2.8 |
| Magnesium stearate | 1.75 |
2. Experimental methods
The placing conditions are as follows: 75% RH, 40 ℃.
Reference is made to the literature on the analysis of related substances (impurities) (preparation of pramipexole dihydrochloride sustained-release pellet capsules and related substance detection, gowenlan, vol.27, No. 31, 2016; see gowenlan section "2.2 on substance examination".
2.2.1 chromatographic conditions column:
measured according to high performance liquid chromatography (appendix V D of the second part of the 2010 edition of the Chinese pharmacopoeia).
Performing gradient elution by using a C18(150 x 4.6, 5um) chromatographic column, wherein a mobile phase A is phosphate buffer solution (900mL of water, 9.1g of monopotassium phosphate, 4.6g of anhydrous octane sodium sulfonate, diluted phosphoric acid for adjusting the pH to 3.0 and adding water for diluting to 1000mL), and a mobile phase B is a mixed solvent of acetonitrile and water (9:1), and the flow rate is 0.5 mL/min; the detection wavelength of the main drug is 262nm, the detection wavelengths of the impurity d and the impurity f are 240nm, the detection wavelengths of the impurity a, the impurity IV and the impurity g are 262nm, and the detection wavelength of the impurity c is 326 nm; the temperature is room temperature; the sample volume was 100. mu.l.
2.2.2 preparation of test solution A proper amount of the product is taken, ground, precisely weighed and placed in a 250ml measuring flask, added with 10ml acetonitrile and 40ml methanol, shaken and ultrasonically treated; adding phosphate buffer (pH2-3)140ml enzyme solution 10ml, and shaking; diluting with phosphate buffer solution to scale and shaking up; filtering with 0.45 μm filter membrane, and collecting the filtrate.
2.2.3 preparation of Mixed control solutions impurities a, c, d, g, IV and f were weighed accurately. And dissolving a proper amount of a reference substance by using a phosphate buffer solution, and quantitatively diluting to prepare a mixed reference substance solution containing 0.06 mu g of impurities c, d and f in each 1ml of the mixed reference substance solution and 0.15 mu g of impurities a, g and IV in each 1ml of the mixed reference substance solution.
3. Results of the experiment
As shown in table 7 below.
TABLE 7
The results show that no impurities other than c were detected in comparison of the two sets of data under high temperature and high humidity conditions. The preparation of the invention has no newly increased impurity species, and the sample of the invention has obviously lower impurity content and increase speed than the reference sample along with the extension of the standing time, the quality of the product of the invention has unexpected improvement, the impurity c content of the sample 1 in 10 days and 30 days is respectively reduced by 56 percent and 69 percent compared with the reference sample 1, and the product quality is greatly improved.
The total impurities detected by the method are the sum of known impurities and unknown impurities, and the known impurities are impurities a (Rac-trans-7-Hydroxy-praamixole), c (Rac-7-Oxo-praamixole DiHCL), d (Rac N-Propyl-2 cyanotropic Acid-5-acetic Acid), f (2-aminobenzoxazole), g (2-Aminobenzothiazole), and IV (Rac-cis-7-Hydroxy-praamixole).
The results also show that impurities a, d, IV, g and f were not detected in sample 1 and control sample 1.
Therefore, when the HPMC with higher content is used, the product has good stability and can be stored for a long time even under extreme conditions of high temperature and high humidity. The stability of the formulation of the present invention is significantly better than that of control sample 1.
According to the invention, a large number of prescription researches show that the impurity content of the preparation is low and the quality is more stable by optimizing the composition of HPMC and carbomer and/or not using a filler. Preferably, the tablet weight is reduced to make it easier for the patient to take.
In addition, the samples of the same batch were placed at 25 ℃ and 60% RH for the detection of substances with stability for 1, 3 and 6 months. The result shows that no impurities (including impurities a, c, d, f, g and IV reported by Gowenlan) are detected in 1/3/6 months, which indicates that the product has good long-term stability.
Experimental example 2: stability test (2)
1. Experimental medicine
2. Experimental methods
90% Relative Humidity (RH), 25 deg.C
See experimental example 1 for analytical methods.
3. Results of the experiment
As shown in table 8 below.
TABLE 8
The results show that the content of impurity c: the samples of the present invention are 3.556%, 4.996%, which are significantly lower than the control, 3.906%, 5.803%, respectively. Neither sample 2 nor control sample 2 detected impurities d, g and f in the goven literature. Also, the total impurity level 6.317% for inventive sample 2 was about 50% of control 2 (11.823%) at 10 days.
The results show that the content of known impurities, unknown impurities and all impurities of the samples of the invention is obviously lower than that of the reference product at the extreme high humidity condition of 10 and 30 days. Therefore, when the HPMC content is higher, the product stability is good, and the method has unexpected technical effect. The invention can be stored for a long time even under extreme conditions of high temperature and high humidity.
Experimental example 3: in vitro release behavior study of formulations with different amounts of carbomer
1. Experimental sample
2. Experimental methods
The release behavior of the formulations was examined at 3%, 4% and 5% carbomer. Taking 6 tablets of the product, and adopting a device of a first method (basket method) according to a method for measuring dissolution rate and release rate (0931 in the four general guidelines of the 2015 edition of Chinese pharmacopoeia) and taking 500ml of phosphate buffer (pH6.8) as a release medium; the rotating speed is 100 revolutions per minute, and the operation is carried out according to law; taking 6ml of the solution at the time of 1, 2, 4, 6, 9, 12, 16, 20 and 24 hours respectively, filtering, taking the subsequent filtrate as a test solution, and immediately supplementing the release medium with the same volume and the same temperature in the dissolution cup. Wherein, the phosphate buffer solution (pH6.8) is prepared as follows: 6.8g of monopotassium phosphate is weighed, 800ml of water is added for dissolution, the pH value is adjusted to 6.8 by 2mol/L sodium hydroxide solution, and the solution is diluted to 1000ml by water.
3. Results of the experiment
The result shows that in a pH6.8 medium, the dosages of 3%, 4% and 5% carbomer in the formula have better sustained-release effect, the sustained-release preparation meets the release requirement of the sustained-release preparation, the release is similar to that of the original research and is more than 80%, and the in vitro curve is more similar.
Experimental example 4: in vitro release behavior study of HPMC formulations of different viscosities
1. Experimental sample
Samples 7 to 9 obtained in the previous preparation examples 7 to 9.
2. Experimental methods
Refer to the foregoing experimental example 3.
3. Results of the experiment
As shown in fig. 2.
The results show that HPMC K4M, K15M and K100M are respectively adopted to prepare the sustained-release tablets, the in-vitro release is slowed along with the increase of the viscosity of HPMC, but samples 7 to 9 can meet the requirements of sustained-release preparations, namely, the viscosity can reach the sustained-release effect between K4M and K100M, and the release data shows that the release effect of the viscosity similar to that of K15M is better.
Experimental example 5: in vitro release behavior study of different mediators
1. Experimental sample
2. Experimental methods
The release behavior of the formulation in different media was examined with 5% carbomer. The experimental procedure for the in vitro release behavior study was the same as in experimental example 3.
3. Results of the experiment
As shown in fig. 3A-3D.
The results show that the samples of the invention are in pH 1.2 medium, pH 4.5 medium, 0.9% NaCl aqueous solution and pH6.8 medium, respectively, f 2 72.5, 80.7, 76.8 and 94.9 respectively, which are all highly similar to the commercial products. The product can be fully released in different media, and the release is smooth and can be compared favorably with the products sold in the market.
Experimental example 6: in vitro release behavior study of formulations of different neutral Water-swellable polymers
1. Experimental sample
In addition, samples of the same specifications were prepared for comparison, the formulation composition was as shown in the following Table 9, and the preparation process was carried out with reference to the foregoing preparation example 1.
TABLE 9
2. Experimental methods
The experimental procedure for the in vitro release behavior study was the same as in experimental example 3.
3. Results of the experiment
As shown in fig. 4 and 5.
Figures 4 and 5 show that the release of sample 1 is significantly lower than sample 10 and the burst control effect is more pronounced 4 hours, especially around 1 hour, before the release of the sample. The release of sample 1 of the present invention was similar to 10 at the remaining time points and at 24 hours, the release of sample 1 was approximately 85% with complete release.
It can be seen from the comparative release curves that the effect of controlling the "burst" at the initial release stage of the drug is relatively better when one HPMC is used than when two HPMC formulations are used, so that the drug can exert its effect better in the human body.
In addition, researches show that the HPMC is simple in process operation, namely, impurities are prevented from being introduced, and the content uniformity is easy to control. The results for the uniformity of the samples show that the RSD of sample 1 is < 3%, showing that the content of sample 1 is uniform to meet the formulation requirements.
The release was relatively complete compared to the other formulation samples 1, it can be seen that the release was more complete when using an HPMC, especially at levels above 85%, especially at levels above 90%.
Experimental example 7: research on influence of HPMC (hydroxy propyl methyl cellulose) with different viscosities on preparation hardness
1. Experimental sample
Samples were prepared with HPMC2208 of different viscosities, according to the recipe and process of experimental sample 1.
2. Experimental methods
And (4) putting the sample into a hardness detector, and detecting according to a conventional method. The main pressure of the tabletting machine is the same.
3. Results of the experiment
As shown in table 10 below.
| Type viscosity | 4K | 10K | 15K | 20K | 100K |
| Hardness (kg) | 8 | 8 | 11 | 9 | 9 |
Under the condition of the same HPMC content, the compressibility and hardness of the tablet with the viscosity of 4K-100K are better when the hardness of the tablet with different viscosity grades is compared; when the compressibility and hardness of the tablet are particularly outstanding between 15K and 20K, and particularly when the viscosity is 15K, a wet process or a direct pressing process is adopted, and besides the outstanding hardness and compressibility effects, the preparation process of the preparation is easy to realize.
By using the preparation formula of the invention and respectively adopting a powder direct compression process and a wet granulation process, the prepared tablets can meet the related requirements of hardness and friability. When wet granulation is used, PEG milling may not be required.
Experimental example 8: stability test (3)
1. Experimental medicine
The sample prescription composition is shown in tables 11 and 12 below.
TABLE 11
TABLE 12
2. Experimental methods
90% Relative Humidity (RH), 25 deg.C
The analytical method is referred to in example 1.
3. Results of the experiment
As shown in table 13 below.
Watch 13
The results show that:
(1) the impurity c is one of the impurities with higher content in the pramipexole preparation, and the data in the table can show that: when only one HPMC is used and the content is more than 85 percent, the stability of the product is better. And with the increase of the content, the content of impurities tends to decrease, and particularly when the content is 85-95%, the product quality is obviously better. In particular, samples 1, 2 (data in Table 8), 9 had lower impurity levels than sample 13, and it was found that the stability was better than 95% for HPMC contents of 91% to 93.7%. The stability of the product is particularly outstanding when the content is 91-94%.
The content of the HPMC is known to be increased in the prior art, and the phenomenon of moisture absorption increase is likely to occur, and researches show that when the content range of the HPMC is 85% -94.4643%, particularly 90% -94% and 91% -93.7%, the samples 1 and 9 and the like have good formability, the content uniformity and Release Standard Deviation (RSD) meet the requirements, and the condition that the moisture absorption does not meet the requirements does not occur, so that the prejudice of the prior art on the dosage of the HPMC is overcome.
Therefore, when the HPMC content is 85% -94%, the stability of the product is better and better along with the increase of the HPMC content under the extreme condition of high temperature and high humidity; particularly, when the content is 90-93.7% and no filler is contained, the impurity content is lower, the product stability is outstanding, and the problem that the product is limited in long-term storage or transportation under various extreme conditions is well solved.
Researches show that when the HPMC content is more than 95%, the requirement on the production process is high, when the powder property is adjusted, the adjustable space of other auxiliary materials is small, for example, a retention aid and a lubricant are added, so that the mixed powder has poor fluidity, the compressibility control difficulty is high, the phenomena of large sheet weight difference, sticking and the like are easy to occur, and the defects of high production cost and long production time are caused. Therefore, the HPMC content used in the invention is more ideal at 85-95%, especially 90-93.7%.
(2) The comparison shows that the impurity content of the HPMC with the content of more than 85 percent is obviously lower than that of the sample 14 with two HPMC, especially compared with the sample 1 with the same content of HPMC, the impurity content of the prescription product of the invention is obviously lower than that of the prescription with the same content and consisting of more than one HPMC, and obviously, the quality and the stability of the product of the invention have unexpected technical effects. Especially when using an HPMC of 90% -94% and 91% -93.7%, the quality stability of the prescription is outstanding.
(3) Comparing the same HPMC levels in samples 12 and 15, it was found that the stability of the product was particularly outstanding when a high HPMC level was used without filler.
The impurity C (2.4%, 0.78%) and total impurities (6.6%, 2.4%) in samples 1, 9 were significantly lower than either of the other samples. Moreover, the rate of impurity growth is significantly lower over time, and the impurity results for sample 9 are shown in table 14 below.
TABLE 14
Obviously, when the HPMC content is within a certain range, particularly 90% -94%, particularly under the condition of not containing fillers (such as starch, mannitol, sorbitol and the like), particularly the HPMC content is within a range of 91% -93%, the stability of the product is particularly outstanding, and the method has remarkable progress. The hardness requirement of the tablet can be met, the prejudice of the prior art is overcome, the toughness is better, the degree of crushing is excellent, and the requirements of the flowability and the compressibility of the tablet can be completely met; more particularly, the impurity content is remarkably low, and the method has unexpected technical effects. Especially under various extreme storage conditions, the samples are extremely stable, and the impurities grow at a significantly lower rate over time than other formulations, and the quality is significantly stable.
Although specific embodiments of the invention have been described in detail, those skilled in the art will appreciate. Various modifications and substitutions of those details may be made in light of the overall teachings of the disclosure, and such changes are intended to be within the scope of the present invention. The full scope of the invention is given by the appended claims and any equivalents thereof.
Claims (3)
1. The pramipexole sustained-release pharmaceutical composition comprises the following components in percentage by weight of the total weight of the pharmaceutical composition:
2. the pramipexole sustained release pharmaceutical composition according to claim 1, which consists of the following components:
or
3. Use of a pramipexole sustained release pharmaceutical composition according to any one of claims 1-2 for the manufacture of a medicament for the treatment and/or prevention of parkinson's disease, dulex syndrome, depression, fibromyalgia or schizophrenia.
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| CN101884626A (en) * | 2004-08-13 | 2010-11-17 | 贝林格尔.英格海姆国际有限公司 | The prolongation release tablet, the Preparation Method And The Use that comprise pramipexole or its officinal salt |
| WO2011037976A2 (en) * | 2009-09-22 | 2011-03-31 | Dr. Reddy's Laboratories Limited | Pramipexole pharmaceutical formulations |
| WO2011086182A2 (en) * | 2010-01-18 | 2011-07-21 | Synthon Bv | Pramipexole extended release tablets |
| CN106983729A (en) * | 2016-01-21 | 2017-07-28 | 北京北大维信生物科技有限公司 | Pramipexole sustained release tablets and preparation method |
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| KR101307334B1 (en) * | 2010-07-02 | 2013-09-12 | 주식회사 바이오파마티스 | Sustained-release pharmaceutical composition comprising pramipexole or pharmaceutically acceptable salt thereof having improved stability |
| CN103520128B (en) * | 2013-10-12 | 2018-08-21 | 石家庄杏林锐步医药科技股份有限公司 | A kind of sustained-release tablet of Pramipexole, preparation method and its usage |
| CN105796519A (en) * | 2014-12-30 | 2016-07-27 | 浙江京新药业股份有限公司 | Pramipexole dihydrochloride sustained-release tablet and preparation method thereof |
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| CN101884626A (en) * | 2004-08-13 | 2010-11-17 | 贝林格尔.英格海姆国际有限公司 | The prolongation release tablet, the Preparation Method And The Use that comprise pramipexole or its officinal salt |
| WO2011037976A2 (en) * | 2009-09-22 | 2011-03-31 | Dr. Reddy's Laboratories Limited | Pramipexole pharmaceutical formulations |
| WO2011086182A2 (en) * | 2010-01-18 | 2011-07-21 | Synthon Bv | Pramipexole extended release tablets |
| CN106983729A (en) * | 2016-01-21 | 2017-07-28 | 北京北大维信生物科技有限公司 | Pramipexole sustained release tablets and preparation method |
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