CN106983728B - Pramipexole sustained release tablet and preparation method thereof - Google Patents

Pramipexole sustained release tablet and preparation method thereof Download PDF

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CN106983728B
CN106983728B CN201610039175.2A CN201610039175A CN106983728B CN 106983728 B CN106983728 B CN 106983728B CN 201610039175 A CN201610039175 A CN 201610039175A CN 106983728 B CN106983728 B CN 106983728B
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pramipexole
sustained release
water
release formulation
formulation according
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CN106983728A (en
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郭树仁
彭博
樊利青
潘健腾
薛兰
王茹萍
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Beijing Peking University WBL Biotech Co Ltd
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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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/428—Thiazoles condensed with carbocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • 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

Abstract

The invention relates to a pramipexole sustained-release tablet and a preparation method thereof. The pramipexole sustained-release tablet comprises the following components in percentage by weight:

Description

Pramipexole sustained release tablet and preparation method thereof
Technical Field
The invention belongs to the field of medicinal preparations, and particularly relates to a pramipexole sustained-release tablet, a preparation method and application thereof.
Background
Pramipexole is known as dopamine D2A 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 dopamine2Family 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 C10H17N3S, relative molecular weight 211.33. The chemical formula is as follows:
Figure BDA0000911133120000011
the pramipexole salt commonly used is pramipexole dihydrochloride monohydrate (formula C)10H17N3S·2HCl·H2O; relative molecular weight 302.27). Pramipexole dihydrochloride monohydrate is a white to off-white, tasteless, crystalline powder. Melting occurs at 296 ℃ to 301 ℃ with decomposition. Pramipexole is chiral with one chiral centerA compound is provided.
Pramipexole dihydrochloride monohydrate is a highly soluble compound. The water solubility is greater than 20mg/ml, and the solubility in a buffer medium of pH2 to pH7.4 is generally greater than 10 mg/ml. Pramipexole dihydrochloride monohydrate is non-hygroscopic and has high crystalline properties. Under milling, the crystal modification (monohydrate) does not change. Pramipexole is very stable in the solid state, while its solution 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. The product 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 the pramipexole sustained release preparation adopts a powder direct compression process, requires that the active ingredient and part of the auxiliary materials are ground together and then mixed with other auxiliary materials, and has a complex process and difficult guarantee of content uniformity.
In addition, the release of the commercial preparation is greatly influenced by the ionic strength, and the commercial preparation (batch number: 308044D specification: 0.375mg) has higher in-vitro release in media with pH1.2, pH4.5 and pH6.8, and only releases about 20 percent in water for 24 h; the ionic strength changes in the human gastrointestinal tract are complex, and therefore release of commercially available formulations in vivo is difficult to control.
The moisture content of a commercially available preparation (lot No. 308044D: 0.375mg) measured by the Kaschin's method was 6.20%, and the moisture content was too high, which may affect the stability.
Upon observing the appearance of the commercially available formulation (lot No. 308044D size: 0.375mg), it was evident that the tablet was rough in surface and was soft to the touch, indicating that the moldability was not good, as shown in FIGS. 1 a-c.
Several impurities exist in the commercial preparation, and for the low-content pharmaceutical preparation, the monitoring of the impurities is also important and has great significance for improving the stability of the product.
Disclosure of Invention
The commercially available or proprietary formulations suffer from the following disadvantages:
1. the formability is poor, the sheet surface is rough and powder falls easily;
2. the moisture content is higher;
3. the release is greatly influenced by the ionic strength.
The invention provides a pramipexole sustained-release preparation which is prepared from a water-swelling framework material and a water-insoluble framework material and can solve one or more of the problems.
1 according to one embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000031
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000032
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000041
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000042
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000043
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000044
Figure BDA0000911133120000051
according to one embodiment, the excipient may be one of a lubricant, a glidant.
According to another embodiment, the excipient may be both a lubricant and a glidant.
The technical proposal meets the requirements of the preparation and does not need coating.
To meet certain special purposes or requirements, further coating can be carried out on the basis of the technical scheme. For example, a controlled release preparation is prepared by adding a film coating or adding certain auxiliary materials.
In addition, the present invention provides a method for preparing the pramipexole sustained release tablet of the present invention.
The preparation method 1 comprises the following steps:
1) gradually premixing pramipexole and a certain amount of other excipients in equal amount to obtain a premix;
2) sieving the premix;
3) adding the rest auxiliary materials, and uniformly mixing;
4) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
Alternatively, pramipexole sustained release tablets are prepared by preparation method 2, comprising the steps of:
1) dissolving pramipexole in 50% -99% ethanol solution to be used as an adhesive;
2) mixing the water-swellable framework material and the water-insoluble framework material uniformly;
3) adding a binding agent, and performing wet granulation;
4) drying in a drying device, and finishing;
5) adding a lubricant and a glidant and mixing;
6) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
Alternatively, pramipexole sustained release tablets are prepared by preparation method 3, comprising the steps of:
1) heating and melting the lipid skeleton material, adding the pramipexole and stirring uniformly;
2) cooling, preparing granules by a granulator;
3) mixing the granules with other adjuvants;
4) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
The method has the advantages of scientific operation process and simple steps.
Brief Description of Drawings
FIGS. 1a-c show the appearance of a commercially available tablet.
Figure 2 is a release profile of the formulation of example 1.
Fig. 3 and 4 are release profiles of the formulation of example 2.
Figure 5 is a release profile of the formulation of example 3.
Figure 6 is a release profile of the formulation of example 4.
Figure 7 is a release profile of the formulation of example 5.
Fig. 8 is the appearance of the tablet of example 14.
Detailed Description
In order to solve the problems of the prior art, the invention provides a pramipexole sustained-release preparation which is prepared from a water-swelling framework material and a water-insoluble framework material. In general, sustained-release matrix materials can be classified into water-swellable matrix materials, insoluble matrix materials. Water-swellable matrix material means: the material can expand when meeting water skeleton to form gel shielding to control the medicine dissolution; water-insoluble framework material means: after the gastrointestinal fluid permeates into the gaps of the skeleton, the medicine is dissolved and slowly diffuses outwards through the intricate and complex superfine pore diameters in the skeleton;
the release mechanisms of different framework materials are different, the water-swelling framework material can form gel when meeting water, and the release speed of the drug depends on the diffusion speed of the drug through the gel layer; while the insoluble matrix material forms an insoluble network throughout the formulation, the release of the drug can be controlled by gradual erosion of the insoluble matrix material or by diffusion from the interstices formed by hydrophilic components of the formulation, the rate of release being controlled by the extent of the interstices. The pramipexole sustained release preparation containing the water-swelling matrix material and the water-insoluble matrix material combines the drug release mechanisms of the two materials, and overcomes the following defects of the commercially available or patented preparation:
1. the formability is poor, the sheet surface is rough and powder falls easily;
2. the moisture content is higher;
3. the release is greatly influenced by the ionic strength.
The water swellable backbone material is selected from the group consisting of neutral water swellable polymers and anionic water swellable polymers.
The neutral water-swellable polymer is selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, hydroxyalkylcellulose esters, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinyl alcohol and polyvinylpyrrolidone, polyalkylene oxides.
Of these, preferably, the neutral water swellable polymer is selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, polyvinylpyrrolidones, copolymers of polyvinylpyrrolidones with vinyl acetate.
The anionic water-swellable polymer is selected from the group consisting of acrylic acid polymers, cross-linked acrylic acid polymers, methacrylic acid copolymers, alginates, gum arabic, xanthan gum, sodium carboxymethylcellulose.
Of these, preferably the anionic water swellable polymer is selected from the group consisting of acrylic polymers, cross-linked acrylic polymers, methacrylic acid copolymers, sodium carboxymethyl cellulose.
In one embodiment, the water-swellable polymer is a neutral water-swellable polymer, which may be selected from the group consisting of alkylcelluloses, hydroxyalkylcelluloses, hydroxyalkylalkylcelluloses, hydroxyalkylcellulose esters, polysaccharides, methacrylate copolymers, polyvinyl alcohol, polyvinylpyrrolidone, copolymers of polyvinylpyrrolidone with vinyl acetate, combinations of polyvinyl alcohol and polyvinylpyrrolidone, polyalkylene oxides. One or more of the above polymers may optionally be used.
In another embodiment, the water-swellable polymer is an anionic water-swellable polymer, and may be selected from the group consisting of acrylic polymers, cross-linked acrylic polymers, methacrylic acid copolymers, alginates, gum arabic, xanthan gum, sodium carboxymethylcellulose. One or more of the above polymers may optionally be used.
In yet another embodiment, the water-swellable polymer can be any one or more neutral water-swellable polymers and/or any one or more anionic water-swellable polymer combination.
In one embodiment, the neutral water swellable polymer is an alkylcellulose, a hydroxyalkylcellulose, a hydroxyalkylalkylcellulose, a polyvinylpyrrolidone, a copolymer of polyvinylpyrrolidone and vinyl acetate. One or more of the above polymers may optionally be used.
The neutral water-swellable polymer is preferably an alkylcellulose, a hydroxyalkylcellulose, a hydroxyalkylalkylcellulose.
More preferably, the neutral water-swellable polymer is hydroxypropyl methylcellulose.
Hydroxypropylmethylcellulose (HPMC) of varying viscosity grades is commercially available.
Preferably a viscosity grade of 4000 to 100000 mPas; more preferably a viscosity grade of 10000 to 100000 mPas; more preferably, the viscosity grade is 15000 to 100000 mPas.
The present invention may use one or more viscosity grades of HPMC, preferably a mixture of viscosity grades 15000 to 100000 mPa-s.
The anionic polymer is preferably an acrylic polymer, a crosslinked acrylic polymer, a methacrylic acid copolymer, sodium carboxymethyl cellulose.
The anionic water-swellable polymer is preferably a crosslinked acrylic polymer.
More preferably, the anionic water-swellable polymer is carbomer.
The carbomer (Carbopol) may be different types of carbomer, or a mixture of two or more types of carbomer, respectively, and is commercially available.
The preferred model is
Figure BDA0000911133120000091
Figure BDA0000911133120000092
More preferred is the model
Figure BDA0000911133120000093
And
Figure BDA0000911133120000094
one or more types of Carbopol may be used in the present invention, with the preferred type being
Figure BDA0000911133120000095
And
Figure BDA0000911133120000096
a mixture of (a).
One or more of the above water-swellable skeletal materials may be selected for use in the present invention.
The water-insoluble framework material is selected from lipid materials and water-insoluble polymers, wherein the lipid materials are selected from glyceryl behenate, hydrogenated castor oil, stearic acid, stearyl alcohol, carnauba wax and paraffin;
the water insoluble polymer is selected from ethyl cellulose, vinyl acetate, and acrylic resin.
Among them, the lipid-based material may preferably be: glyceryl behenate, hydrogenated castor oil, stearic acid, carnauba wax;
the lipid-based material is more preferably: stearic acid, carnauba wax.
The invention can select one or more than one water-insoluble framework materials; preferably one or more lipid-based materials.
One or more lipid-based framework materials may be preferred in the present invention.
According to one embodiment, the sustained release formulation provided by the present invention has the following components in weight percent:
Figure BDA0000911133120000101
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000102
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000103
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000111
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000112
according to another embodiment, the present invention provides a sustained release formulation having the following components in weight percent:
Figure BDA0000911133120000113
the other excipients can be pharmaceutical excipients for improving compressibility, fluidity, appearance, taste, etc. of the preparation, such as glidant, binder, lubricant, anticaking agent, and flavoring agent.
The glidant is selected from silica gel micropowder, magnesium trisilicate, powdered cellulose, pulvis Talci, calcium phosphate, etc.
The lubricant can be selected from magnesium stearate, calcium stearate, sodium fumarate stearate, pulvis Talci, zinc stearate, poloxamer, etc.
The excipient can be one or more of lubricant, glidant, binder, anticaking agent and correctant.
The excipients may be both a lubricant and a glidant.
According to another more particularly preferred embodiment, the water-swellable matrix material consists of hydroxypropylmethylcellulose in an amount of 68% to 77% and carbomer; the dosage of hydroxypropyl methylcellulose is preferably 70-76%; the using amount of carbomer is 1-8%; the preferable dosage of carbomer is 2% -5%;
the water insoluble matrix material is selected from one or more of glyceryl behenate, carnauba wax, hydrogenated castor oil, and stearic acid; and other excipients, wherein the excipients are lubricant and glidant.
In addition, the present invention provides a method for preparing the pramipexole sustained release tablet.
The preparation method 1 comprises the following steps:
1) gradually premixing pramipexole and a certain amount of other excipients in equal amount to obtain a premix;
2) sieving the premix;
3) adding the rest auxiliary materials, and uniformly mixing;
4) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
Alternatively, pramipexole sustained release tablets are prepared by preparation method 2, comprising the steps of:
1) dissolving pramipexole in 50% -99% ethanol solution to be used as an adhesive;
2) mixing the water-swellable framework material and the water-insoluble framework material uniformly;
3) adding a binding agent, and performing wet granulation;
4) drying in a drying device, and finishing;
5) adding a lubricant and a glidant and mixing;
6) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
Alternatively, pramipexole sustained release tablets are prepared by preparation method 3, comprising the steps of:
1) heating and melting the lipid skeleton material, adding the pramipexole and stirring uniformly;
2) cooling, preparing granules by a granulator;
3) mixing the granules with other adjuvants;
4) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
The formulations of the invention are released in phosphate buffer medium at ph6.8 according to the method of appendix XD and appendix XC of the second part of the pharmacopeia, version 2010, as follows:
the release rate at 2 hr is 12-32%
The release rate at 9 hr is 42-62%
The release at 24 hours was greater than 70%.
Examples
Method for the preparation of dissolution media:
pH6.8 buffer: taking 250ml of 0.2mol/l potassium dihydrogen phosphate and 112ml of 0.2mol/l sodium hydroxide, adding water to dilute to 1000ml, and shaking up to obtain the potassium dihydrogen phosphate.
ph4.5 buffer: taking 2.99g of sodium acetate and 14ml of 2mol/l acetic acid solution, adding water to dissolve and dilute the solution to 1000ml, and shaking up the solution to obtain the sodium acetate.
ph1.2 buffer: and (3) taking 7.65ml of hydrochloric acid, adding water to dilute the hydrochloric acid to 1000ml, and shaking up the hydrochloric acid to obtain the compound.
Release profile determination method: the basket method is 100 r/min, the temperature is 37.5 ℃, and the sampling time points are 1, 2, 4, 6, 9, 12, 16, 20 and 24 hours.
Example 1
Prescription:
Figure BDA0000911133120000141
the process comprises the following steps:
1. gradually mixing pramipexole with the same amount of aerosil, magnesium stearate, carbomer and HPMC until the weight of the pramipexole is 10 percent of the total weight of the prescription;
2. sieving the mixture with a 60-mesh sieve for 3 times;
3. adding the rest adjuvants, and mixing;
4. and (6) tabletting.
The release results of the medium with different pH values are shown in the attached figure 2.
Can achieve the effect of slow release under different pH values, has good formability, smooth sheet surface and water content of less than 2.5 percent, and is obviously reduced by about 6 percent compared with the commercially available preparation.
Example 2
Prescription:
Figure BDA0000911133120000151
the process comprises the following steps:
1. gradually mixing pramipexole with the same amount of aerosil, magnesium stearate, carbomer and HPMC until the weight of the pramipexole is 10 percent of the total weight of the prescription;
3. sieving the premix with a 60-mesh sieve for 3 times;
4. adding the rest adjuvants, and mixing;
5. and (6) tabletting.
The release results of the medium at pH6.8 are shown in FIG. 3.
The release in the medium at pH6.8 slowed down with increasing amounts of carbomer.
The results of the release in water are shown in FIG. 4.
The results of the release in water show that the amount of carbomer in the formulation increases the less the release in water, but all significantly above the commercial formulation (lot # 308044D gauge: 0.375mg), i.e., the formulation of the present invention is less affected by ionic strength than the commercial formulation (lot # 308044D gauge: 0.375 mg).
Because the water-swellable sustained-release framework material carbomer is greatly influenced by the ionic strength, the pramipexole release amount is low when the ionic strength is small (in water); however, the composition controlled release of the prescription of the patent not only depends on the water swelling sustained-release framework material, but also depends on the insoluble framework material, shares the sustained-release effect of carbomer, and simultaneously reduces the influence of ionic strength.
Example 3
Prescription:
Figure BDA0000911133120000161
the process comprises the following steps:
1. gradually mixing pramipexole with the silica gel micropowder, magnesium stearate, carbomer and part of HPMC in equal amount until the weight is 10 percent of the total weight of the prescription;
2. sieving the mixture with 60 mesh sieve for 3 times;
3. adding the rest adjuvants, and mixing;
4. and (6) tabletting.
The release results are shown in figure 5.
The slow release effect can be achieved under different pH values, the release is quicker in a medium with pH value of 1.2 and is close to that in water and a medium with pH value of 6.8 and pH value of 4.5.
Example 4 (prescription screening)
The preparation process comprises the following steps:
1. progressively premixing pramipexole and a certain amount of other excipients in an equal amount to obtain a premix;
2. sieving the premix;
3. adding the rest adjuvants, and mixing;
4. and (3) selecting a proper tablet machine for tabletting to prepare the skeleton tablet.
Figure BDA0000911133120000181
The results show that formulations with different waxy materials release in vitro similarly, but the results of acceleration and stability tests show that over time, formulations of stearic acid and carnauba wax are significantly superior, with no detectable impurities.
The release results are shown in figure 6.
Example 5
Prescription:
Figure BDA0000911133120000191
the process 1 comprises the following steps:
1. heating stearic acid at 80 ℃ to melt, adding API, stirring uniformly, and cooling;
2. sieving with 40 mesh sieve, and granulating;
3. mixing with other adjuvants;
4. and (6) tabletting.
And (2) a process:
1. dissolving API into proper amount of 95% ethanol to serve as a binder;
2. mixing other adjuvants uniformly;
3. adding an ethanol solution of API to prepare soft granules, and granulating with a 20-mesh sieve;
4. drying at 50 deg.C, and sieving with 20 mesh sieve
5. And (6) tabletting.
And (3) a process:
1. gradually mixing pramipexole with the same amount of aerosil, magnesium stearate, carbomer and HPMC until the weight of the pramipexole is 10 percent of the total weight of the prescription;
2. sieving the pre-mixture with a 60-mesh sieve for 3 times,
3. adding the rest adjuvants, and mixing;
4. and (6) tabletting.
The release results are shown in FIG. 7.
The release speed of the sustained-release tablet prepared by wet granulation (process 2) and direct compression (process 3) in the medium with pH6.8 is close; the sustained release tablets prepared by melt granulation (process 1) are relatively slow in release rate.
The content uniformity (a +1.8S) of the sustained-release tablets prepared by wet granulation (process 2) and melt granulation (process 1) was 5.4 and 4.6, respectively, and the content uniformity (a +1.8S) of the sustained-release tablets prepared by direct compression (process 3) was 9.9.
The prescription overcomes the defects that the release of the preparation sold in the market is greatly influenced by strong ions and has poor formability, and the water content is obviously reduced compared with the water content sold in the market; the method can be realized by adopting direct tabletting, melt granulation and wet granulation processes, wherein the content uniformity of the melt granulation and the wet granulation processes is slightly good.
Example 6
Prescription:
Figure BDA0000911133120000211
the process comprises the following steps:
1. gradually mixing pramipexole with the silica gel micropowder, magnesium stearate, carbomer and part of HPMC in equal amount until the weight is 10 percent of the total weight of the prescription;
2. sieving the mixture with 50 mesh sieve for 3 times;
3. adding the rest adjuvants, and mixing;
4. and (6) tabletting.
Example 7
Comparison of a commercially available formulation (batch No.: 308044D size: 0.375mg) with the formulation 1:
Figure BDA0000911133120000221
pramipexole is unstable in wet and hot environments and is more unstable after being prepared into a solution; pramipexole tablets are also greatly affected by the moisture in the formulation. The patent prescription drying weight loss is disclosed to be 6.8%, and the prescription 1 and the prescription 11 drying weight loss are only 1.9% and 2.3%, and are obviously lower than the patent prescription in the condition of accelerating for 9 months.
Method for loss on drying: the determination was carried out according to the method of drying weight loss measurement, appendix III L of the second division of the version 2010 from the Chinese pharmacopoeia.
In addition, the Carr index and the hardness of the prescription 1 and the prescription 11 sustained-release tablets are both larger than those of the patent prescription, and the tablet surface is smooth and has no pitted surface; the patent prescription has rough surface and is easy to fall off.
The preparation of the invention improves the stability problem of patent prescription, and overcomes the defects of poor compressibility and pitted skin.
Example 8
Prescription:
Figure BDA0000911133120000231
the process comprises the following steps:
1. gradually mixing pramipexole with aerosil, magnesium stearate and part of ethyl cellulose in equal amount until the weight of the pramipexole is 10 percent of the total weight of the prescription;
2. sieving the mixture with 60 mesh sieve for 3 times;
3. adding the rest adjuvants, and mixing;
4. and (6) tabletting.
Release results
The process is feasible by adopting ethyl cellulose as an insoluble framework material, and the slow release effect can reach 24 hours in media with pH1.2, pH4.5 and pH6.8.
Example 9
Prescription:
Figure BDA0000911133120000241
example 10
Prescription:
Figure BDA0000911133120000242
example 11
Prescription:
composition of Prescription 15 (%) Function(s)
Pramipexole dihydrochloride 0.15 Raw material medicine
HPMC K15M 70 Sustained release matrix material
Carbomer 971P
4 Sustained release matrix material
Stearic acid 22.85 Sustained release matrix material
Magnesium stearate
1 Lubricant agent
Silica gel micropowder 2 Glidants
Example 12
Prescription:
composition of Prescription 16 (%) Function(s)
Pramipexole dihydrochloride 0.15 Raw material medicine
HPMC K15M 80 Sustained release matrix material
Carbomer 971P 3 Sustained release matrix material
Stearic acid 13.85 Sustained release matrix material
Magnesium stearate
1 Lubricant agent
Silica gel micropowder 2 Glidants
Example 13
Prescription:
Figure BDA0000911133120000261
example 14
Prescription (1.5mg specification, tablet weight 280 mg):
composition of Prescription 18 (%) Function(s)
Pramipexole dihydrochloride 0.536 Raw material medicine
HPMC K15M 75 Sustained release matrix material
Carbomer 971P 3 Sustained release matrix material
Stearic acid 18.464 Sustained release matrix material
Magnesium stearate
1 Lubricant agent
Silica gel micropowder 2 Glidants
The process comprises the following steps:
1. gradually mixing pramipexole with the same amount of aerosil, magnesium stearate and carbomer until the weight of the mixture is 5 percent of the total weight of the prescription;
2. the mixture is sieved by a 60-mesh sieve for 3 times,
3. adding the rest adjuvants, and mixing;
4. double-sided lettering special-shaped stamping sheets.
As a result, the shaped sheet was obtained with a clear cut, a smooth surface and a hardness of 93KN as shown in FIG. 8.
The formulations of the above examples had good moldability, smooth surfaces, and significantly lower moisture than the commercially available formulations.
Example 15
According to the impurity inspection method of Pramipexole dihydrochloride monohydrate in EUROPEAN PHARMACOPOEIA 8.0, the following impurities are not detected in the formula 1 after the standing for 6 months and 12 months.
Figure BDA0000911133120000271
In addition, other impurities were not detected.

Claims (21)

1. A pramipexole sustained release preparation comprises the following components in percentage by weight:
Figure FDA0002895497510000011
wherein:
the water-swellable framework material is selected from a neutral water-swellable polymer and an anionic water-swellable polymer, the neutral water-swellable polymer is hydroxypropyl methylcellulose, and the anionic water-swellable polymer is carbomer; and the water swellable backbone material is a combination of said neutral water swellable polymer and said anionic water swellable polymer;
the water-insoluble framework material is selected from lipid materials and water-insoluble polymers, the lipid materials are selected from one or more of glyceryl behenate, hydrogenated castor oil, stearic acid and carnauba wax, and the water-insoluble polymers are ethyl cellulose; and the water-insoluble matrix material may be any one or a combination of more than one lipid-based material and/or water-insoluble polymer.
2. Pramipexole sustained release formulation according to claim 1 having the following composition in weight percent:
Figure FDA0002895497510000012
3. pramipexole sustained release formulation according to claim 1 having the following composition in weight percent:
Figure FDA0002895497510000013
4. pramipexole sustained release formulation according to claim 1 having the following composition in weight percent:
Figure FDA0002895497510000014
Figure FDA0002895497510000021
5. pramipexole sustained release formulation according to claim 1 having the following composition in weight percent:
Figure FDA0002895497510000022
6. pramipexole sustained release formulation according to claim 1 having the following composition in weight percent:
Figure FDA0002895497510000023
7. the pramipexole sustained release formulation according to any one of claims 1 to 6, wherein the excipient is one or more of a lubricant and a glidant.
8. The pramipexole sustained release formulation according to any of claims 1-6, wherein the excipients are both a lubricant and a glidant.
9. Pramipexole sustained release formulation according to any of claims 1-8, wherein the hydroxypropylmethylcellulose has a viscosity grade of 4000 to 100000 mPa-s.
10. Pramipexole sustained release formulation according to any of claims 1-8, wherein the hydroxypropylmethylcellulose has a viscosity grade of 10000 to 100000 mPa-s.
11. Pramipexole sustained release formulation according to any of claims 1-8, wherein the hydroxypropylmethylcellulose has a viscosity grade of 15000 to 100000 mPa-s.
12. Pramipexole sustained release formulation according to any of claims 1-8, wherein the carbomer is of the type
Figure FDA0002895497510000024
934P、
Figure FDA0002895497510000025
974P、
Figure FDA0002895497510000026
971P、
Figure FDA0002895497510000027
71G。
13. Pramipexole sustained release formulation according to any of claims 1-8, wherein the carbomer is of the type
Figure FDA0002895497510000028
971P and
Figure FDA0002895497510000029
71G。
14. pramipexole sustained release formulations according to any of claims 1 to 13, wherein the water swellable matrix material consists of hydroxypropyl methylcellulose and carbomer, the amount of hydroxypropyl methylcellulose being 68% to 77%; the using amount of carbomer is 1-8%; the water insoluble matrix material is selected from one or more of glyceryl behenate, carnauba wax, hydrogenated castor oil, stearic acid, and ethyl cellulose; and other excipients, wherein the excipients are lubricant and glidant.
15. The pramipexole sustained release formulation according to claim 14, wherein the amount of hydroxypropylmethylcellulose ranges from 70% to 76%.
16. Pramipexole sustained release formulations according to claim 14, wherein the amount of carbomer is between 2% and 5%.
17. A pramipexole sustained release preparation comprises the following components in percentage by weight:
Figure FDA0002895497510000031
Figure FDA0002895497510000032
Figure FDA0002895497510000041
Figure FDA0002895497510000042
Figure FDA0002895497510000043
Figure FDA0002895497510000044
Figure FDA0002895497510000051
Figure FDA0002895497510000052
Figure FDA0002895497510000053
Figure FDA0002895497510000061
Figure DA00028954975166479
Figure DA00028954975166498
Figure FDA0002895497510000062
Figure FDA0002895497510000071
Figure DA00028954975166542
Figure FDA0002895497510000072
Figure FDA0002895497510000073
Figure FDA0002895497510000081
18. a process for preparing a sustained release formulation of pramipexole according to any of claims 1-17 comprising the steps of:
1) gradually premixing pramipexole and a certain amount of other excipients in equal amount to obtain a premix;
2) sieving the premix;
3) adding the rest auxiliary materials, and uniformly mixing;
4) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
19. A process for preparing a sustained release formulation of pramipexole according to any of claims 1-17 comprising the steps of:
1) dissolving pramipexole in 50% -99% ethanol solution to be used as an adhesive;
2) mixing the water-swellable framework material and the water-insoluble framework material uniformly;
3) adding a binding agent, and performing wet granulation;
4) drying in a drying device, and finishing;
5) adding a lubricant and a glidant and mixing;
6) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
20. A process for preparing a sustained release formulation of pramipexole according to any of claims 1-17 comprising the steps of:
1) heating and melting the lipid skeleton material, adding the pramipexole and stirring uniformly;
2) cooling, preparing granules by a granulator;
3) mixing the granules with other adjuvants;
4) and tabletting by using a proper tabletting machine to prepare the skeleton tablet.
21. Use of a sustained release formulation of pramipexole according to any of claims 1-17 in the manufacture of a medicament for the treatment of parkinson's disease.
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