CN104758937B - A kind of metoprolol sustained-release pellet preparations - Google Patents
A kind of metoprolol sustained-release pellet preparations Download PDFInfo
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- CN104758937B CN104758937B CN201410001217.4A CN201410001217A CN104758937B CN 104758937 B CN104758937 B CN 104758937B CN 201410001217 A CN201410001217 A CN 201410001217A CN 104758937 B CN104758937 B CN 104758937B
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Abstract
The invention discloses a kind of new film-coating composition, film clothing and the thus pharmaceutical preparations of film clothing coatings, more particularly, to a kind of metoprolol or the sustained-release pellet preparation of its salt and preparation method thereof.The film-coating composition includes: a) copolymer of ethyl acrylate and methyl methacrylate, b) copolymer of ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester, c) optionally, a kind of liquid, aqueous containing stabilizer and d).Film-coating adhesion of the present invention, mechanical strength are strong, and are not required to that antiplastering aid and/or plasticizer is added.
Description
Technical field
The invention belongs to field of pharmaceutical preparations, are related to a kind of new sustained release film coating, wherein the film coating is available
In the environment of substantially water.Moreover, it relates to which a kind of pharmaceutical preparation of thus film coating cladding, especially relates to
And a kind of sustained-release pellet preparation of metoprolol or its salt.
Background technique
The mechanism of pharmaceutically active substance release is controlled, can be generally divided into two kinds: one is drugs to mix with host material
Skeleton system (usually a kind of polymer or wax)；Another kind is by medicine ordinance to the core (piece wrapped up by thin polymer film
Or piller) drug-reservoir system, film is then a kind of control that rate of release is determined by such as its permeability, the dissolubility of substance etc.
The barrier of system.
From the viewpoint of flexibility, it is more advantageous that drug is formulated into the small discrete unit preparation with film clothing: 1.
It can be uniformly distributed in alimentary canal, avoid local concentration excessively high, reduce the stimulation to stomach and intestine；2. partial size is small, substantially not by gastric emptying
It is influenced with feed, gastrointestinal transit is constant, and individual difference is small；3. the defect of individual discrete unit preparation such as pellet will not influence drug release
The change of behavior, avoids dosage from being released, and guarantees clinical application safety；4. discrete unit preparation can be mixed with food, it is easy to take in,
This is particularly important for gerontal patient；5. different dosage forms can be developed, such as capsule, tablet；6. dosage can be made to be sized for
Fixed administering drug combinations；7. tablet can be made alienable, more flexible dosage etc. is provided for clinical application.
Metroprolol succinate (metoprolol succinate), is a kind of β1Selectivity (heart selectivity) adrenal gland
Plain receptor blocker, for treating hypertension, angina pectoris, the chronic mental and physical efforts stable with the symptom of Assessment of Left Ventricular Systolic Function exception
Failure etc., is listed with sustained release tablets.Entitled 1- isopropylamino -3- [p- (2- methoxyethyl) the benzene oxygen of metroprolol succinate chemistry
Base] -2- propyl alcohol succinate, chemical structural formula is as follows:
。
The method that US4927640 and US4957745 describes preparation metoprolol salt pellet and sustained release tablets.By metoprolol
After salt is mixed with methylene chloride and ethyl alcohol, in the heart coated in blank pill, ethyl cellulose and hypromellose are then used
It is sprayed in methylene chloride and aqueous isopropanol, sustained release film coat is made.Methylene chloride is " intrinsic toxicity " solvent, out
In the reason of the environmental protection, the film coating for using organic solvent need to be replaced with the filmogen based on water.
Water based film-forming polymer latex for pharmaceuticals industry just there is known in the eighties in last century, and subsequent constantly have
New product development listing.From previous product and research, it can be gathered that a kind of more interested dispersing agent Utech®NE30D
(Eudragit®NE30D), it includes the ethyl acrylate of 28.5% w/w and methyl methacrylate (2:1) copolymer pellet and
The nonionic surfactant nonylphenol polyoxyethylene ether 100(nonoxynol 100 of about 1.5% w/w as stabilizer).It should
The glass transition temperature (Tg) of latex polymer is low, and film-forming temperature is low, about 5 DEG C of minimum film formation temperature, is easy to form a film, and film is soft
Good toughness.However, Utech®When NE is as coating, suffers from the drawback that and strict control is 1. needed to be coated temperature, temperature of charge
No more than 28 DEG C, usually 20~25 DEG C of temperature of charge of control, when being coated temperature and increasing, viscosity is sharply increased, and keeps coating tired
Difficulty is coated poor reproducibility；2. there are more rigors to coating equipment in sugar production line and art for coating, industrialization difficulty is caused to increase；3. outstanding
It is special odd®NE film is easy softening, will lead to tablet, piller or more particles and generates adhesion.Therefore, Utech®NE is for being coated
When need to add a large amount of antiplastering aid, prevent coating and storage process in generate adhesion.Most common antiplastering aid is monostearate
Glyceride (GMS), talcum powder and silica.When antiplastering aid must be used, most commonly surfactant and talcum powder
Or the combination of stearate.But there may be some problems for these methods, combination, a large amount of additional dispersion such as Incompatible Substance
It is body additives, not reproducible etc. in the fabrication process.
Aqueous dispersion Utech®RS30D, Utech®RL30D is also based on the coating membrane of water, they include about 30%
The copolymer of the ethyl acrylate of w/w, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester, wherein especially
It is odd®The molar ratio of ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester is 1:2 in RS:
The molar ratio of ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester is in 0.1, Utech RL
1:2:0.1.Utech®RS and Utech®RL film flexibility is poor, and minimum film formation temperature is high, and the temperature that when coating needs is high.It is logical
Often, the flexibility for increasing coating membrane by addition plasticizer, as the dosage of plasticizer increases, the flexibility of coating membrane increases
Add.But due to Utech®RS and Utech®RL brittleness is big, and the dosage of plasticizer is more than that 20% or more can not reach and be used for
Flexibility needed for multiple unit pharmaceutical preparation coating membrane, and the dosage of plasticizer increases, and the viscosity of coating membrane increases, and makes art for coating
Difficulty, therefore sometimes for being added plasticizer and antiplastering aid simultaneously.
It is especially beautiful therefore, it is necessary to find one kind suitably film coating based on water to be used in sustained and controlled release medicament preparation
In Tuo Luoer or its pharmaceutical salts sustained release pellet pharmaceutical preparation.
Summary of the invention
The purpose of the present invention is to provide a kind of new film-coating system, which resists without additional be added
Stick or plasticizer, and there is high mechanical strength and reproducibility.Another aspect of the present invention additionally provides this kind of film clothes body
It is the pharmaceutical preparation of cladding, the especially sustained-release pellet preparation of metoprolol or its pharmaceutical salts.
Therefore, one aspect of the present invention provides a kind of film-coating composition suitable for coated pharmaceutical preparation, it is characterised in that:
The film-coating composition includes: a) copolymer of ethyl acrylate and methyl methacrylate, b) ethyl acrylate, methyl
The copolymer of methyl acrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester, c) optionally, it is containing stabilizer and d) a kind of
It is liquid, aqueous.
Another aspect of the present invention provides a kind of film clothing for covering drug core, it is characterised in that: the film clothing includes: a)
The copolymer of ethyl acrylate and methyl methacrylate, b) ethyl acrylate, methyl methacrylate and methacrylic acid
The copolymer of trimethyl ammonium chloride base ethyl ester and c) optionally, containing stabilizer, wherein film clothing from it is a kind of it is liquid, aqueous in sink
Product.
The film clothing thickness range appropriate is 1-100 μm, preferably 5-50 μm, more preferably 10-30 μm.
Another aspect of the present invention provides a kind of pharmaceutical preparation, it is characterised in that: the pharmaceutical preparation includes:
1. a kind of drug core including active pharmaceutical ingredient and optional one or more pharmaceutically acceptable excipient；
2. a kind of film clothing, comprising: a) copolymer of ethyl acrylate and methyl methacrylate, b) ethyl acrylate,
The copolymer of methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester and c) optionally, containing stabilizer,
Middle film clothing is from a kind of liquid, aqueous middle deposition.
Wherein:
Stabilizer in the film-coating composition or film clothing is nonylphenol polyoxyethylene ether 100.
Preferably, in the film-coating composition or film clothing, the copolymerization of the ethyl acrylate and methyl methacrylate
Object and stabilizer are by Utech®NE30D is provided, the ethyl acrylate, methyl methacrylate and methacrylic acid chlorination three
The copolymer of methylamino ethyl ester is by Utech®RS30D and/or Utech®RL30D is provided.Further, the film-coating combination
Utech in object or film clothing®NE30D and Utech®RL30D or Utech®The weight ratio of RS30D is 1:0.1 ~ 10, preferably
1:0.2 ~ 5, more preferably 1:0.3 ~ 2；Or Utech®NE30D and Utech®The weight ratio of RL30D/ RS30D mixture is 1:
0.1 ~ 10, preferably 1:0.2 ~ 5, more preferably 1:0.3 ~ 2, Utech®RL30D and Utech®RS30D is mixed with arbitrary proportion
It closes.
Preferably, a kind of film-coating composition (in terms of 100g) includes: a) Utech of 5-50g weight®NE30D water dispersion
Body；B) Utech of 5~50g weight®RL30D aqueous dispersion；C) a kind of liquid, aqueous, add to 100g, total polymer concentration
It is preferred that 15 ± 2%(w/w).
Preferably, a kind of film-coating composition (in terms of 100g) includes: a) Utech of 5~50g weight®NE30D moisture
Granular media；B) Utech of 5~50g weight®RS30D30D aqueous dispersion；C) a kind of liquid, aqueous, 100g is added to, polymer is total
Concentration preferably 15 ± 2%(w/w).
Preferably, a kind of film-coating composition (in terms of 100g) includes: a) Utech of 5~50g weight®NE30D30D water
Dispersion；B) Utech of 5~50g weight®RL30D/RS30D mixture, wherein Utech®RL30D and Utech®
RS30D is mixed with arbitrary proportion；C) a kind of liquid, aqueous, add to 100g, total polymer concentration preferably 15 ± 2%(w/w).
The coating solution of other weight can refer to above-mentioned film-coating composition equal proportion and amplify to obtain.
The liquid, aqueous mixing liquid including water or water and a kind of water-soluble organic solvent.It is described water-soluble
Organic solvent is C1-3Lower alcohol, preferably ethyl alcohol or isopropanol；From safety considerations, the ratio of organic solvent is preferably protected
It holds in bottom line, such as 0-20% volume.Consider that preferred liquid is water from environmental angle.
Preferably, the drug core in pharmaceutical preparation provided by the invention is multiple comprising active pharmaceutical ingredient and optionally containing
There is the pellet of one or more pharmaceutically acceptable excipient, wherein each pellet surface is coated with film packet defined above
Clothing.The pellet of such film coating can be fitted into bag or be put into capsule, such as in a kind of hard gelatin capsule, Huo Zheyu
The acceptable additive of the other medicines being optionally added together, is pressed into tablet with known method.Coating micro-pill tabletting this field
Well known conventional method obtains.
In process of production, other ingredients can also be added, e.g., filler appropriate can be added in tabletting, such as crystallite fibre
Element, talcum powder, sodium stearyl fumarate etc. are tieed up, can be used for that preparation is made to obtain acceptable tabletting characteristics, such as the hardness of tablet.
Suitable drug core diameter is 0.01-2mm, preferably 0.05-1.0mm, more preferably 0.1-0.7mm.
The pellet can be optionally comprising a kind of inactive blank core, and active constituent is deposited with for example spraying method
On it.As blank core suitable material be silica, glass, plastic resin such as polypropylene or polyethylene, sucrose,
Microcrystalline cellulose etc., preferably microcrystalline cellulose.The diameter of the blank core be 0.01-2mm, preferably 0.05-0.5mm,
More preferably 0.1-0.3mm.
Preferably, the present invention provides a kind of controlled release agent types, wherein the active pharmaceutical ingredient and the medicine released immediately
Piece is compared, and is discharged in a long period by controlled release, such as 8-24 hours, preferably 20 to 24 hours.
Preferably, the active pharmaceutical ingredient is metoprolol or its pharmaceutically acceptable salt, more preferably succinic acid beauty
Tuo Luoer.
Another aspect of the present invention provides a kind of metoprolol sustained-release pellet preparations, comprising:
A) a kind of medicine including metoprolol or its pharmaceutical salts and optional one or more pharmaceutically acceptable excipient
Object core；
B) a kind of film coating as defined above.
Preferably, the core including metoprolol or its pharmaceutical salts is multiple optionally acceptable containing one or more drugs
Excipient pellet, wherein each pellet surface be coated with film coating defined above.
Preferably, the pellet includes a kind of inactive blank core, and the blank core is preferably microcrystalline cellulose
Preferably, used excipient is hydroxypropyl methylcellulose in the core, and blank capsule core used is micro- in the core
Crystalline cellulose blank capsule core.
Applicable metoprolol pharmaceutical salts include tartrate, succinate, fumarate, benzoate or sorbic acid
Salt, preferably succinate.
Preferably, pellet is fitted into bag or capsule, or one or more pharmaceutically acceptable excipient is added and are pressed into
Piece.
Preferably, described includes that label, coatings optionally contain matcoveredn between label and coatings；It is described
The excipient of label includes filler, disintegrating agent, lubricant, and the excipient is preferably microcrystalline cellulose, and the disintegrating agent is excellent
It is selected as croscarmellose sodium, the lubricant is preferably magnesium stearate；Coating material used in the coatings is soluble in the stomach
Type Opadry such as Opadry Y-17000, adhesive therefor are the ethyl alcohol of water and 95%；The protective layer used excipient is selected from poly-
Ethylene glycol and hydroxypropyl methylcellulose.
Another aspect of the present invention provides a kind of method for preparing film-coating composition as described above, it is characterised in that: institute
The method of stating includes copolymer dispersion in the range of 0-40 DEG C by ethyl acrylate and methyl methacrylate, with acrylic acid
The copolymer dispersion of ethyl ester, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester mixes.
Preferably, the method for preparing film-coating composition as described above includes: by ethyl acrylate and methacrylic acid
The copolymer dispersion of methyl esters, with ethyl acrylate, methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester
Copolymer dispersion mixes at 20-30 DEG C, stirs, and sieving obtains film coating composition solution.
Preferably, the method for preparing film-coating composition as described above includes: by Utech®NE30D and Utech®
RL30D and/or Utech®RS30D is mixed；2. liquid feeding body to acrylic polymer concentration is 5-20%, stirring is obtained
Film coating composition solution.
Wherein, the liquid is water；2. middle acrylic polymer concentration is preferably 15 ± 2% to step.
Another aspect of the present invention provides a kind of method for film coated pharmaceutical core, wherein with as defined above one
Kind film coating composition coats core.Preferably film coating composition is coated with spray method, such as in a kind of fluidized bed
It is upper to be sprayed using top spray or Bottom spray technique.Other coating methods used are in the coating disk of standard with more
Porose disc, Accela-cote, immersion swords, glatt or dipping tube coating, referring to (Lachman is compiled, by Lea
" Theory and practice in Industrial Pharmacy " third edition that and Feabiger 1986 is published).
Another aspect of the present invention additionally provides a kind of preparation method of film coating as defined above, including from as defined above
Film coating composition in remove liquid.The removing liquid processes used are evaporations, such as are done by spraying in a kind of fluidized bed
It is dry.When coating tablet in standard application disk, it is dried with hot-air.
Another aspect of the present invention provides a kind of method for preparing pharmaceutical preparation as described above, it is characterised in that: the side
Method includes using film clothing coated drugs core as defined above, preferably with the multiple pellets of film clothing coating.
Film coating flexibility of the invention is good, and minimum film formation temperature is moderate, and permeability is moderate, and resists without additional be added
Stick or plasticizer, the sustained release pharmaceutical formulation release being coated are close to constant release conditions, and it is small that release time is 20
When.
Specific embodiment
Embodiment below, which is only that, is described in more detail the present invention, rather than limits the present invention.
Embodiment 1: the preparation of film-coating
Remarks: each Utech aqueous dispersion grammes per square metre described in table refers to be the weight of aqueous acrylic resin dispersion in 100g water
Amount.
At 0-40 DEG C, the various Utech aqueous dispersions in above scheme are first uniformly mixed, are then being slowly stirred
Under, the purified water dilution of equivalent is added, is stirred for 0.5-2h after mixing, is sieved, as required film coating solution.
A certain amount of prepared film coating solution is uniformly spread over and is covered on the glass plate of polytetrafluoro film, is horizontally arranged
Dry in 40 DEG C of baking ovens object to be polymerized forms a film and takes film after drying completely for 24 hours, saves in drier.Measure film difference portion
Position thickness, is averaged (n=10), RSD < 10% after selective membrane, and the film for observing no indentation under the microscope is spare, no indentation
Film is stored in drier.
Embodiment 2: film-coating performance test (breaking strain, minimum film formation temperature)
The film that each scheme of embodiment 1 is prepared carry out breaking strain, minimum film formation temperature, water vapour permeability
Performance measurement, experimental method is as follows, and experimental result is shown in Table 2.
1, breaking strain
Under the premise of not destroying film coating, coating subunit is pressed into enough hardness and low friability tablet,
And film-coating is kept not rupture, one of key is ensuring that film-coating has sufficiently flexible property.Film is measured using tensiometer
Breaking strain: to prepared film, the width and thickness of precise measurement film is clamped along film y direction with fixture and is tried
Sample, oriented film to sample fracture, reads load and elongation, and calculate breaking strain round about.
In general, breaking strain, which should at least reach 100% or more, just has enough flexibilities, coated granule or coating are micro-
Ball just can be suitably used for preparing multiple unit pharmaceutical preparation.Additive, which is added, can improve film performance, and antiplastering aid, which is such as added, can reduce coating
Fluid viscosity reduces coating difficulty；Pigment, which is added, can reach shading and aesthetic function.However additive usually becomes film-coating
Firmly, it is easily broken off, elongation at break reduces.
2, film minimum film formation temperature (MET/ DEG C)
Temperature when minimum film formation temperature, that is, film initially forms is the characteristic parameter of dispersion liquid.Minimum film formation temperature is
The minimum temperature that flawless film is formed.The polymeric latex particle contained in aqueous dispersion, with the evaporation of moisture, when each
Grain is close to each other, but does not generate mutual infiltration.Only when particle collides, and polymer spherolite have it is sufficiently resilient
When, particle is since the left and right of surface tension merges, to form uniform film.Minimum film formation temperature, which determines, to be coated
The temperature of journey.Usual product temperature should be at least above 10 DEG C of minimum film formation temperature or more.
3, the water vapour permeability of film-coating
Water vapo(u)r transmission is measured using infrared sensor water vapour permeability analyzer.The film pre-processed is pressed from both sides
Tightly between test chamber, there is the nitrogen for stablizing relative humidity to flow in the side of film, drying nitrogen is in the other side of film
Flowing；Due to the presence of moist gradient, vapor can pass through film diffusion to low humidity side from high wet side；In low humidity side, transmission
The drying nitrogen that vapor is flowed is carried to infrared sensor, and electric signal in proportion can be generated when into sensor, is passed through
To the analytical calculation of sensor electric signal, to obtain the water vapor permeability rates of sample.
The breaking strain of each scheme film-coating of 2 embodiment of table 1, minimum film formation temperature, water vapour permeability result
。
Test result shows, Utech®RL or Utech®When RS individually forms a film, breaking strain < 100% are not suitable for
Sustained release pellet is coated in multi-unit sustained-release piece.Utech®RL and/or Utech®RS and Utech®After NE is shared, fracture is answered
Change dramatically increases, and works as Utech®NE30D and Utech®RL and/or Utech®When the weight ratio of RS >=0.1, the fracture of gained film
Strain is all larger than 200%, works as Utech®NE30D and Utech®RL and/or Utech®When the weight ratio of RS >=0.2, gained film
Breaking strain is all larger than 250%, works as Utech®NE30D and Utech®RL and/or Utech®When the weight ratio of RS >=0.5, gained
The breaking strain of film is all larger than 300%.
Utech®RL or Utech®The minimum film formation temperature of RS is higher, and >=40 DEG C, and the brittleness of film is big, even if
Adding a large amount of antiplastering aid, also effect is unobvious, and film blocking also easily occurs for storage process.Utech®RL and/or Utech®
RS and Utech®After NE is shared, significantly reduce Utech®RL or Utech®The minimum film formation temperature of RS, increases film
Flexibility.Work as Utech®NE30D and Utech®RL and/or Utech®The weight ratio of RS within the scope of 1:0.1-10, it is minimum at
Film temperature is about 7-33 DEG C, and minimum film formation temperature is moderate, is suitble to coating, wherein work as Utech®NE30D and Utech®RL and/or
Utech®For the weight ratio of RS in 1:0.2-5, minimum film formation temperature is about 9-25 DEG C, more preferably；Work as Utech®NE30D and outstanding
It is special odd®RL and/or Utech®For the weight ratio of RS in 1:0.3-2, minimum film formation temperature is about 12-18 DEG C, most preferably.
Utech®RL and/or Utech®RS and Utech®NE is shared, and works as Utech®NE30D and Utech®RL and/or
Utech®The weight ratio of RS is within the scope of 1:0.1-10, and the water vapour permeability of gained film-coating is between 280-420, permeability
It is relatively mild, wherein to work as Utech®NE30D and Utech®RL and/or Utech®The weight ratio of RS is in 1:0.2-5, gained
The water vapour permeability of film-coating is between 280-420, more preferably；Work as Utech®NE30D and Utech®RL and/or Utech®RS's
For weight ratio in 1:0.3-2, the water vapour permeability of gained film-coating is between about 290-385, most preferably.In addition, Utech®RL,
And/or Utech®RS and Utech®NE is shared, and can also reduce or avoid Utech®RL and/or Utech®RS film seeps
The shortcomings that permeability and drug release rate are influenced by ion and PH.
Embodiment 3: the preparation of metoprolol sustained-release pellet
(blank core is crystallite to the film coating of progress metroprolol succinate particle on the fluidized-bed coating machine of laboratory
Cellulose capsule core, partial size are 0.2-0.3mm).
By the scheme 3-4,9-10,14- in metroprolol succinate particle (particle size range 0.3-0.6mm) embodiment
15 film coating solution are coated, acrylic resin concentration 15%, wherein 3,9,14,15 coating weight gain 25% of scheme, and scheme 4 is coated
Weight gain 30%, 10 coating weight gain 22% of scheme.Coating Solution is sprayed to succinic acid beauty in the fluidized bed plant of laboratory scale
On Tuo Luoer particle, coating conditions are as follows:
Metoprolol particle 300g
Be coated liquid measure 500g(scheme 3,9,14,15)；
600g(scheme 4)；
440g(scheme 10)
Spray velocity 5g/min
Ventilation quantity 40m3/h
42 DEG C of inlet air temperature
32 DEG C of leaving air temp
After spraying, by particle 40 DEG C of drying about 30min in a fluidized bed.
As a result: art for coating is smooth, has no adhesion.
Embodiment 4: the release of metroprolol succinate sustained-release pellet
According to drug release determination method (two annex of Chinese Pharmacopoeia version in 2010, Ⅹ the first method of D), using dissolution determination
Method (two annex of Chinese Pharmacopoeia version in 2010, Ⅹ the second method of C) device, (takes 0.2mol/L phosphorus with phosphate buffer (pH6.8)
Acid dihydride potassium solution 250mL adds 0.2mol/L sodium hydroxide solution 118mL, is diluted with water to 1000mL, shake up to get)
500mL is dissolution medium, and revolving speed is 50 turns per minute, is operated according to methods.1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16
When hour and 20 hours, solution 5mL is taken respectively, is filtered, and supplements mutually synthermal, same volume dissolution medium immediately, respectively
Take subsequent filtrate as test solution.Metroprolol succinate reference substance separately is taken, it is accurately weighed, add phosphate buffer
(pH6.8) it dissolves and quantifies the solution for diluting and being made in every 1mL containing about 0.05mg, as reference substance solution.According to content determination item
Under method measurement, the every the amount of dissolution in different time is calculated separately with peak area by external standard method.Following table is is surveyed release
Data.
The release (PH6.8) of 3 metoprolol sustained-release pellet of table
。
Conclusion: by upper table result it is found that with scheme 3-4 in embodiment 1,9-10, the amber of 14-15 film-coating solution coating
Sour metoprolol pellet is close to constant release conditions, and release time is 20 hours.
Embodiment 5: the preparation of metoprolol sustained-release piece
The microcrystalline cellulose of the particle equivalent being coated with scheme 14 prepared according to embodiment 3 mixes in hopper mixing machine
About 10min, rear 0.5% magnesium stearate that is added discharge after continueing to mix 2min as lubricant.Total mix particle is in rotary tablet compression
Machine tabletting.Slice weight 300mg, 47.5mg containing metroprolol succinate, hardness about 8KN.
As a result: loose pieces not occurring during total mix granulation, the problems such as slice weight does not conform to.Tableting processes are smooth.
Embodiment 6: the release of Metoprolol succinate sustained-release tablets
According to drug release determination method (two annex of Chinese Pharmacopoeia version in 2010, Ⅹ the first method of D), using dissolution determination
Method (two annex of Chinese Pharmacopoeia version in 2010, Ⅹ the second method of C) device, (takes 0.2mol/L phosphorus with phosphate buffer (pH6.8)
Acid dihydride potassium solution 250mL adds 0.2mol/L sodium hydroxide solution 118mL, is diluted with water to 1000mL, shake up to get)
500mL is dissolution medium, and revolving speed is 50 turns per minute, is operated according to methods.1 hour, 2 hours, 4 hours, 8 hours, 12 hours, 16
When hour and 20 hours, solution 5mL is taken respectively, is filtered, and supplements mutually synthermal, same volume dissolution medium immediately, respectively
Take subsequent filtrate as test solution.Metroprolol succinate reference substance separately is taken, it is accurately weighed, add phosphate buffer
(pH6.8) it dissolves and quantifies the solution for diluting and being made in every 1mL containing about 0.05mg, as reference substance solution.According to content determination item
Under method measurement, the every the amount of dissolution in different time is calculated separately with peak area by external standard method.Following table is gained release
Degree evidence.
The release of 4 Metoprolol succinate sustained-release tablets of table
。
Conclusion: it can be seen that the dissolution of sustained-release tablets result from 4 test result of table and use the micro- of the coating of scheme 14 in table 3
The release result of ball is almost the same, shows that the pellet that will be coated with film-coating of the present invention is tabletted, is still able to maintain good
Release characteristics.
Claims (7)
1. a kind of pharmaceutical preparation, it is characterised in that: the pharmaceutical preparation includes:
1. a kind of drug core including active pharmaceutical ingredient and optional one or more pharmaceutically acceptable excipient；It is described
Active pharmaceutical ingredient is metroprolol succinate；Used excipient is hydroxypropyl methylcellulose, institute in the core in the core
It is microcrystalline cellulose blank pellet with blank capsule core；
2. a kind of film coating, comprising: a) copolymer of ethyl acrylate and methyl methacrylate, b) ethyl acrylate,
The copolymer of methyl methacrylate and methacrylic acid trimethyl ammonium chloride base ethyl ester and c) stabilizer, the stabilizer are nonyl
Base phenol polyethenoxy ether 100, wherein film coating is from a kind of liquid, aqueous middle deposition, and the liquid is water, wherein acrylic acid
The copolymer of ethyl ester and methyl methacrylate, with ethyl acrylate, methyl methacrylate and methacrylic acid chlorination front three
The weight ratio of the copolymer of aminoethyl is 1:0.3 ~ 2.
2. pharmaceutical preparation as described in claim 1, it is characterised in that: the pharmaceutical preparation is a kind of sustained release pellet.
3. pharmaceutical preparation as claimed in claim 2, it is characterised in that: one or more drugs are added in sustained release pellet and are subjected to
Excipient it is tabletted.
4. pharmaceutical preparation as claimed in claim 3, it is characterised in that: described includes label, coatings, optionally, in piece
Contain matcoveredn between core and coatings；The excipient of the label includes microcrystalline cellulose, croscarmellose sodium and
Magnesium stearate；Coating material used in the coatings is stomach dissolution type Opadry, and adhesive therefor is the ethyl alcohol of water and 95%；It is described
Protective layer used excipient is selected from polyethylene glycol and hydroxypropyl methylcellulose.
5. the pharmaceutical preparation as described in claim 1-4 is any, it is characterised in that: the ethyl acrylate and methyl methacrylate
The copolymer and stabilizer of ester are provided by Utech NE, the ethyl acrylate, methyl methacrylate and methacrylic acid
The copolymer of trimethyl ammonium chloride base ethyl ester is provided by Utech RS and/or Utech RL.
6. a kind of method for preparing the described in any item pharmaceutical preparations of claim 1-4, it is characterised in that: the method includes with
Film clothing coated drugs core.
7. a kind of method for preparing pharmaceutical preparation as claimed in claim 6, it is characterised in that: the method includes being coated with film clothing
Multiple pellets.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN201410001217.4A CN104758937B (en) | 2014-01-02 | 2014-01-02 | A kind of metoprolol sustained-release pellet preparations |
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| CN107149597A (en) * | 2017-03-27 | 2017-09-12 | 广西厚德大健康产业股份有限公司 | A kind of preparation method of metroprolol succinate sustained-release compaction of pellet |
| US11406599B2 (en) * | 2019-04-30 | 2022-08-09 | Evonik Operations Gmbh | Pellet and multi-unit pellet system (MUPS) |
| CN110420196A (en) * | 2019-09-04 | 2019-11-08 | 西安科力康医药科技有限公司 | A kind of preparation method of metoprolol tartrate sustained release preparation |
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| CN1659196A (en) * | 2002-04-12 | 2005-08-24 | 阿斯特拉曾尼卡有限公司 | New film coating |
| CN101085853A (en) * | 2001-12-19 | 2007-12-12 | 阿斯特拉曾尼卡有限公司 | New film coating |
| CN101143140A (en) * | 2006-09-15 | 2008-03-19 | 上海医药(集团)有限公司 | Isosorbide mononitrate timely quick-release and slow-release preparation |
| CN101190180A (en) * | 2006-11-20 | 2008-06-04 | 北京利龄恒泰药业有限公司 | Metoprolol sustained release medicinal compositions and preparation method thereof |
| CN102973515A (en) * | 2012-11-28 | 2013-03-20 | 康普药业股份有限公司 | Sustained release preparation for treating hypertention and angina, and preparation method thereof |
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| CN101085853A (en) * | 2001-12-19 | 2007-12-12 | 阿斯特拉曾尼卡有限公司 | New film coating |
| CN1659196A (en) * | 2002-04-12 | 2005-08-24 | 阿斯特拉曾尼卡有限公司 | New film coating |
| CN101143140A (en) * | 2006-09-15 | 2008-03-19 | 上海医药(集团)有限公司 | Isosorbide mononitrate timely quick-release and slow-release preparation |
| CN101190180A (en) * | 2006-11-20 | 2008-06-04 | 北京利龄恒泰药业有限公司 | Metoprolol sustained release medicinal compositions and preparation method thereof |
| CN102973515A (en) * | 2012-11-28 | 2013-03-20 | 康普药业股份有限公司 | Sustained release preparation for treating hypertention and angina, and preparation method thereof |
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