CN104013971B - A kind of bromocriptine composition sustained-release preparation and preparation method thereof - Google Patents
A kind of bromocriptine composition sustained-release preparation and preparation method thereof Download PDFInfo
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- CN104013971B CN104013971B CN201410283043.5A CN201410283043A CN104013971B CN 104013971 B CN104013971 B CN 104013971B CN 201410283043 A CN201410283043 A CN 201410283043A CN 104013971 B CN104013971 B CN 104013971B
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Abstract
The invention belongs to technical field of medicine, a kind of bromocriptine composition sustained-release preparation and preparation method thereof is disclosed.The bromocriptine composition sustained-release preparation that the present invention is provided includes bromocriptine, the slow-release material of 15~60 parts by weight of 10~70 parts by weight.Blood concentration is steady after the had good sustained release effect of the bromocriptine composition sustained-release preparation, administration, the long period can maintain effective blood drug concentration, administration number of times can significantly be reduced, the Compliance of patient is improved, and its preparation method is simple, is more beneficial for the popularization of bromocriptine and uses.
Description
Technical field
The invention belongs to technical field of medicine, more particularly to a kind of bromocriptine composition sustained-release preparation and its preparation side
Method.
Background technology
Bromocriptine, alias is called bromocriptine parlodel, bromine square ring peptide mesylate, bromocriptine, bromocriptine parlodel, suppression Ru Ting, guarantor
Newborn tune, bromocryptine, the hidden front yard of bromine, the hidden front yard of methanesulfonic acid bromine, bromocriptine first.Chemical name is 2- bromocriptines-mono- methanesulfonic acid
Salt, molecular formula is C32H40BrN5O5CH4O3S, and molecular weight is 750.70.In June, 1978, U.S. FDA have approved Novartis
(Novartis) bromocriptine methanesulfonate is used for the related dysfunction of hyperprolactinemia, acromegalia, Parkinson's disease.
Bromocriptine is a kind of dopamine-receptor stimulant, is mainly used in treatment hyperprolactinemia, acromegalia, handkerchief gold
Gloomy disease and diabetes etc..The mechanism of action of Treatment of Hyperprolactinemia with Bromocriptine: Analysis is point for suppressing tethelin prolactin(PRL
Secrete, the normal level without influenceing other pituitrins；The mechanism of action for the treatment of acromegalia is that reduction acromegalia is suffered from
The level of prolactin(PRL and growth hormone in person；Treat the mechanism of action of Parkinson's for directly excited corpus straitum dopamine by
Body, so as to play therapeutic action；And the mechanism of action for treating diabetes is not yet clear and definite.
At present, the formulation of the bromocriptine of listing mainly has a tablet and capsule, the specification of formulation be respectively 0.8mg tablets,
2.5mg tablets and 5mg capsules.For 0.8mg tablet, when for treating type ii diabetes, adult patient need to from morning 2h
Interior to be taken altogether with food, one time a day；For treating the related dysfunction of hyperprolactinemia, acromegalia, Parkinson's disease
When, it need to be taken in meal, it is daily 2-3 times.And specification is 2.5mg tablets and 5mg capsules for treating endocrine indication month
During through uncomfortable and female infertility, it is also desirable to which medication 2-3 times daily, administration time is up to 6-8 weeks or even longer.So, it is existing
The tablet or capsule of bromocriptine, administration number of times are excessively frequent, and insoluble drug release is difficult to control, and also results in the larger ripple of blood concentration
Dynamic, validity and compliance are poor, and side effect is obvious.Studies have found that bromocriptine, which is used for a long time, in high dose may occur fiber
Change.Therefore, in the urgent need to inventing a kind of bromocriptine slow release formulation, to reduce administration number of times, steady blood concentration, the secondary work of reduction
With being more beneficial for the popularization of bromocriptine and use.
The content of the invention
The goal of the invention of the present invention is to provide a kind of bromocriptine composition sustained-release preparation and preparation method thereof.The bromocriptine
The sustained release preparation had good sustained release effect of combination, can maintain effective blood drug concentration the long period, can significantly reduce administration number of times, improve
The Compliance of patient, is more beneficial for the popularization of bromocriptine and uses.
In order to realize the goal of the invention of the present invention, the present invention is adopted the following technical scheme that：
The invention provides a kind of bromocriptine composition sustained-release preparation, include the component of following parts by weight：
10~70 parts of bromocriptine
15~60 parts of slow-release material.
Preferably, the sustained release preparation that the present invention is provided, includes the component of following parts by weight：
12~70 parts of bromocriptine
15~41 parts of slow-release material.
It is further preferable that the sustained release preparation that the present invention is provided, includes the component of following parts by weight：
32 parts of bromocriptine
41 parts of slow-release material；
Or
70 parts of bromocriptine
15 parts of slow-release material；
Or
50 parts of bromocriptine
15 parts of slow-release material.
Preferably, the component in the sustained release preparation that the present invention is provided also includes adhesive, diluent, lubricant or wetting agent
One or both of thing mixed above.
Preferably, in the sustained release preparation that the present invention is provided, slow-release material is sodium alginate, calcium alginate, hydroxylmethyl cellulose
It is element, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, carboxymethyl cellulose, carboxyethyl cellulose, chitosan, poly-
One or both of oxygen ethene, carbomer, polyvinylpyrrolidone, cyclodextrin, prefabricated starch or chitin thing mixed above.
It is further preferable that in the sustained release preparation that the present invention is provided, slow-release material is hydroxypropyl methylcellulose, sodium alginate, card
One or both of ripple nurse, polyvinylpyrrolidone or chitosan thing mixed above.These slow-release materials, which meet water, can form solidifying
Glue-line, medicine is gradually discharged by gel layer, reaches preferable slow releasing function, is able to maintain that comparatively ideal drug release rate, drug release
Gel skeleton is dissolved in body fluid afterwards, noresidue composition, with preferable biocompatibility.
It is further preferred that in the sustained release preparation that provides of the present invention, slow-release material be hydroxypropyl methylcellulose, sodium alginate,
One or both of polyvinylpyrrolidone or carbomer thing mixed above.
In some embodiments of the invention, in the sustained release preparation that provides of the present invention, slow-release material be hydroxypropyl methylcellulose,
One or both of sodium alginate or carbomer thing mixed above.Hydroxypropyl methylcellulose is hydrophilic gel material, bio-compatible
Property is good；Sodium alginate and carbomer are plant extracts, and viscosity and rheological properties are good, have no toxic side effect, can be as long-acting
Slow-release auxiliary material.
In the other embodiment of the present invention, in the sustained release preparation that the present invention is provided, slow-release material is that hydroxypropyl first is fine
During dimension element, specially HPMC Methocel K4M.
Preferably, in the sustained release preparation that provides of the present invention, adhesive be hydroxypropyl methylcellulose, starch slurry, ethyl cellulose,
One or both of gelatin, sodium carboxymethylcellulose, polyethylene glycol, PVP, water or ethanol thing mixed above.
It is further preferable that in the sustained release preparation that the present invention is provided, adhesive is gelatin, sodium carboxymethylcellulose, starch slurry
Or one kind in PVP or both thing mixed above.
In some embodiments of the invention, in the sustained release preparation that the present invention is provided, adhesive is starch slurry and/or poly- dimension
Ketone.Starch slurry has good adhesive effect, can be adjusted by various concentrations, can equably soak raw material, be less prone to
Local overly moist phenomenon, be that adhesive is pelletized with the aqueous solution of starch slurry, outward appearance, the hardness for the piece being pressed into is good, particularly medicine
Dissolution rate is good, its single consumption it is general for 1%~4%；PVP (abbreviation PVP) uses K30 types, and mean molecule quantity is 6.0
× 104, the suitable concentration aqueous solution can be used for adhesive, single consumption is generally 0.5%~2%；PVP also dissolves in second
Alcohol, can be wet adhesive with its alcoholic solution, not only improve wetting medicine and be easy to granulation, and because improving the wetability of medicine
Be conducive to drug-eluting.Wet adhesive is used as present invention preferably employs starch slurry and/or PVP, hence it is evident that reduce adhesive
Consumption, with less amount adhesive with regard to the effect of wet adhesive can be reached.
Preferably, in the sustained release preparation that the present invention is provided, diluent is starch, sucrose, lactose, pregelatinized starch, sweet dew
One or both of alcohol, microcrystalline cellulose, calcium monohydrogen phosphate, calcium sulfate or dextrin thing mixed above.
It is further preferable that in the sustained release preparation that the present invention is provided, diluent is in mannitol, calcium sulfate, starch or lactose
One or both thing mixed above.
In some embodiments of the invention, in the sustained release preparation that the present invention is provided, diluent is starch and/or lactose.
Preferably, in the sustained release preparation that the present invention is provided, lubricant is magnesium stearate, talcum powder, silica, hydrogenation plant
One or both of thing oil, polyethylene glycol, calcium stearate, Stepanol MG or lauryl sodium sulfate are mixed above
Thing.
It is further preferable that in the sustained release preparation that provides of the present invention, lubricant is polyethylene glycol, Stepanol MG, hard
One or both of fatty acid magnesium or silica thing mixed above.
In some embodiments of the invention, in the sustained release preparation that the present invention is provided, lubricant is magnesium stearate and/or two
Silica.
Preferably, in the sustained release preparation that the present invention is provided, wetting agent is water and/or ethanol.
Preferably, the sustained release preparation that the present invention is provided, includes the component of following parts by weight：
It is further preferable that the sustained release preparation that the present invention is provided, includes the component of following parts by weight：
Preferably, the formulation for the sustained release preparation that the present invention is provided is tablet or capsule.
Preferably, when the formulation for the sustained release preparation that the present invention is provided is tablet, the component of following parts by weight is included：
It is further preferable that when the formulation for the sustained release preparation that the present invention is provided is tablet, including the component of following parts by weight：
In some embodiments of the invention, when the formulation for the sustained release preparation that the present invention is provided is tablet, including following weight
Measure the component of part：
The bromocriptine composition sustained-release tablet that specification is 5.6mg can be prepared according to pharmaceutical formulation as above.
In the other embodiment of the present invention, when the formulation for the sustained release preparation that the present invention is provided is tablet, including such as
The component of lower parts by weight：
The bromocriptine composition sustained-release tablet that specification is 17.5mg can be prepared according to pharmaceutical formulation as above.
Preferably, when the formulation for the sustained release preparation that the present invention is provided is capsule, the component of following parts by weight is included：
It is further preferable that when the formulation for the sustained release preparation that the present invention is provided is capsule, including the component of following parts by weight：
In the other embodiment of the present invention, when the formulation for the sustained release preparation that the present invention is provided is capsule, including
The component of following parts by weight：
The bromocriptine composition sustained-release capsule that specification is 35mg can be prepared according to pharmaceutical formulation as above.
Present invention also offers a kind of preparation method of bromocriptine composition sustained-release preparation, the sustained release preparation includes following weight
Measure the component of part：
10~70 parts of bromocriptine
15~60 parts of slow-release material；
The preparation method comprises the following steps：
Take above component, it is blended, formulation is made, produce.
Present invention also offers a kind of preparation method of bromocriptine composition sustained-release preparation, when the sustained release preparation is tablet,
Comprise the following steps：
Step 1：Take the component of following parts by weight：
Step 2：Take bromocriptine, slow-release material, diluent mixing after, add adhesive softwood, through pelletize, it is dry, whole
After grain, lubricant, wetting agent are added, tabletting is produced.
Preferably, the preparation method for the sustained release preparation that the present invention is provided, when the sustained release preparation is tablet, including following step
Suddenly：
Step 1：Take the component of following parts by weight：
Step 2：Take bromocriptine, slow-release material, diluent mixing after, add adhesive softwood, through pelletize, it is dry, whole
After grain, lubricant, wetting agent are added, tabletting is produced.
Preferably, in the preparation method that provides of the present invention, when the sustained release preparation is tablet, the particle diameter of bromocriptine for 30 mesh~
50 mesh.
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is tablet, the particle diameter of slow-release material is 20 mesh
~40 mesh.
Preferably, in the preparation method that provides of the present invention, when the sustained release preparation is tablet, the particle diameter of diluent for 20 mesh~
40 mesh.
Preferably, in the preparation method that provides of the present invention, when the sustained release preparation is tablet, the particle diameter of lubricant for 20 mesh~
40 mesh.
Preferably, in the preparation method that provides of the present invention, when the sustained release preparation is tablet, the particle diameter of wetting agent for 20 mesh~
40 mesh.
Preferably, in the preparation method that provides of the present invention, when the sustained release preparation is tablet, the particle diameter of adhesive for 20 mesh~
40 mesh.
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is tablet, dry temperature is 50 DEG C~70
℃。
Preferably, in the preparation method that provides of the present invention, when the sustained release preparation is tablet, dry time for 60min~
120min。
Preferably, the preparation method for the sustained release preparation that the present invention is provided, it is mixed in step 2 when the sustained release preparation is tablet
It is combined into equal proportion progressively to mix, is specially：Bromocriptine, slow-release material, diluent are uniformly divided into several parts, institute respectively according to quality
The number for obtaining the number, the number of slow-release material, diluent of bromocriptine is identical；Then the bromocriptine of equal parts is taken respectively, delayed
Release material, diluent to be mixed, this place takes the number of bromocriptine to be the 35%~45% of bromocriptine total number；It is well mixed
Afterwards, the bromocriptine, slow-release material, diluent for adding equal parts are mixed, and this place takes the number of bromocriptine hidden for bromine
The 25%~40% of booth gross score；After well mixed, the bromocriptine, slow-release material, sustained release agent for adding surplus are mixed.
In the sustained release preparation that the present invention is provided, because bromocriptine is crystalline powder, using common mixing method
Be difficult to mix, the uniformity of influence gained pharmaceutical preparation, the present invention using first bromocriptine is crushed to " 30 mesh~50 mesh " it is thin
Small powder, then progressively mixed using equal proportion, make bromocriptine and other auxiliary materials, especially slow-release material, be well mixed, more favorably
It is homogeneously dispersed in bromocriptine in sustained release preparation, to reach good sustained release performance.
Preferably, the preparation method for the sustained release preparation that the present invention is provided, when the sustained release preparation is tablet, is added in step 2
Lubricant, the method for wetting agent are：
By lubricant, wetting agent be sprayed on the surface of upper lower punch, middle mould inner surface, then add gained after whole grain and produce
Product, tabletting produces bromocriptine sustained-release tablet.
In tableting processes, traditional technique is that lubricant and wetting agent are added in whole particle, or uniform point
Cloth could be mixed around particle by long-time mixing；But mix for a long time, that is, the dissolution that have impact on medicine is held again
Easily layering, and the real lubricant and wetting agent that lubrication is played on piece surface and few, and lubricant and wetting agent
Consumption is also big, usually the 0.5%~5% of tablet gross mass.The present invention is used at the atomization that sprayer unit passes through compressed air
Reason, lubricant and wetting agent is equably sprayed on the surface of each upper lower punch and the inner surface of middle mould, in tableting processes
The frictional force of material and die surface is reduced, slice power is reduced, the quality of gained tablet is improved；Meanwhile, substantially reduce
In the consumption of lubricant and wetting agent, tablet the consumption of lubricant and wetting agent be only tablet gross mass 0.01%~
0.1%, reduce cost.
In some embodiments of the invention, lubrication is sprayed in the preparation method for the sustained release preparation that the present invention is provided, step 2
Device used in agent and wetting agent is sprayer unit.
Present invention also offers a kind of preparation method of bromocriptine composition sustained-release preparation, the sustained release preparation is capsule
When, comprise the following steps：
Step 1：Take the component of following parts by weight：
Step 2：Take bromocriptine, slow-release material, diluent mixing after, add adhesive softwood, through pelletize, it is dry, whole
After grain, fill to capsulae vacuus, produce.
Preferably, the preparation method for the sustained release preparation that the present invention is provided, when the sustained release preparation is capsule, including following step
Suddenly：
Step 1：Take the component of following parts by weight：
Step 2：Take bromocriptine, slow-release material, diluent mixing after, add adhesive softwood, through pelletize, it is dry, whole
After grain, fill to capsulae vacuus, produce.
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is capsule, the particle diameter of bromocriptine is 30 mesh
~50 mesh.
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is capsule, the particle diameter of slow-release material is 20
The mesh of mesh~40.
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is capsule, the particle diameter of diluent is 20 mesh
~40 mesh.
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is capsule, the particle diameter of lubricant is 20 mesh
~40 mesh.
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is capsule, the particle diameter of wetting agent is 20 mesh
~40 mesh.
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is capsule, the particle diameter of adhesive is 20 mesh
~40 mesh.
Preferably, the preparation method for the sustained release preparation that the present invention is provided, when the sustained release preparation is capsule, in step 2
It is mixed into equal proportion progressively to mix, is specially：Bromocriptine, slow-release material, diluent are uniformly divided into several parts respectively according to quality,
The number of gained bromocriptine, the number of slow-release material, diluent number it is identical；Then take respectively equal parts bromocriptine,
Slow-release material, diluent are mixed, and this place takes the number of bromocriptine to be the 35%~45% of bromocriptine total number；Mixing is equal
After even, the bromocriptine, slow-release material, diluent for adding equal parts are mixed, and this place takes the number of bromocriptine to be bromine
The 25%~40% of hidden booth gross score；After well mixed, the bromocriptine, slow-release material, sustained release agent for adding surplus are mixed.
Preferably, in the preparation method that provides of the present invention, when the sustained release preparation is capsule, dry temperature for 50 DEG C~
70℃。
Preferably, in the preparation method that the present invention is provided, when the sustained release preparation is capsule, the dry time is 60min
~120min.
The invention discloses a kind of bromocriptine composition sustained-release preparation and preparation method thereof.The bromocriptine composition sustained-release system
Agent includes bromocriptine, the slow-release material of 15~60 parts by weight of 10~70 parts by weight.Experimental result confirms that it is slow that the present invention is provided
Blood concentration is steady after release formulation had good sustained release effect, administration, the long period can maintain effective blood drug concentration, can significantly reduce to
Medicine number of times, improves the Compliance of patient, and its preparation method is simple, is more beneficial for the popularization of bromocriptine and uses.
Brief description of the drawings
Fig. 1 shows the release profiles for the bromocriptine composition sustained-release piece that embodiment 2 is prepared, and wherein curve 1 represents control
Group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine composition that embodiment 2 is prepared
Sustained release tablets；
Fig. 2 shows the release profiles for the bromocriptine composition sustained-release piece that embodiment 3 is prepared, and wherein curve 1 represents control
Group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine composition that embodiment 3 is prepared
Sustained release tablets；
Fig. 3 shows the release profiles for the bromocriptine composition sustained-release piece that embodiment 4 is prepared, and wherein curve 1 represents control
Group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine composition that embodiment 4 is prepared
Sustained release tablets；
Fig. 4 shows the release profiles for the bromocriptine composition sustained-release piece that embodiment 5 is prepared, and wherein curve 1 represents control
Group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine composition that embodiment 5 is prepared
Sustained release tablets；
Fig. 5 shows the release profiles for the bromocriptine composition sustained-release piece that embodiment 6 is prepared, and wherein curve 1 represents control
Group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine composition that embodiment 6 is prepared
Sustained release tablets；
Fig. 6 shows the release profiles for the bromocriptine composition sustained-release capsule that embodiment 7 is prepared, the wherein representative pair of curve 1
According to group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine combination that embodiment 7 is prepared
Thing spansule；
Fig. 7 shows the release profiles for the bromocriptine composition sustained-release capsule that embodiment 8 is prepared, the wherein representative pair of curve 1
According to group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine combination that embodiment 8 is prepared
Thing spansule；
Fig. 8 shows the release profiles for the bromocriptine composition sustained-release capsule that embodiment 9 is prepared, the wherein representative pair of curve 1
According to group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine combination that embodiment 9 is prepared
Thing spansule；
Fig. 9 shows the release profiles for the bromocriptine composition sustained-release capsule that embodiment 10 is prepared, the wherein representative pair of curve 1
According to group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine combination that embodiment 10 is prepared
Thing spansule；
Figure 10 shows the release profiles for the bromocriptine composition sustained-release capsule that embodiment 11 is prepared, and wherein curve 1 is represented
Control group 2；Curve 2 represents control group 3；Curve 3 represents control group 1；Curve 4 represents the bromocriptine group that embodiment 11 is prepared
Compound spansule；
Figure 11 shows the blood concentration-time curve for the bromocriptine composition sustained-release piece that embodiment 2 is prepared, and curve 1 is
Control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 is that embodiment 2 prepares bromocriptine composition sustained-release
Piece；
Figure 12 shows the blood concentration-time curve for the bromocriptine composition sustained-release piece that embodiment 3 is prepared, and curve 1 is
Control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 is that embodiment 3 prepares bromocriptine composition sustained-release
Piece；
Figure 13 shows the blood concentration-time curve for the bromocriptine composition sustained-release piece that embodiment 4 is prepared, and curve 1 is
Control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 is that embodiment 4 prepares bromocriptine composition sustained-release
Piece；
Figure 14 shows the blood concentration-time curve for the bromocriptine composition sustained-release piece that embodiment 5 is prepared, and curve 1 is
Control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 is that embodiment 5 prepares bromocriptine composition sustained-release
Piece；
Figure 15 shows the blood concentration-time curve for the bromocriptine composition sustained-release piece that embodiment 6 is prepared, and curve 1 is
Control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 is that embodiment 6 prepares bromocriptine composition sustained-release
Piece；
Figure 16 shows the blood concentration-time curve for the bromocriptine composition sustained-release capsule that embodiment 7 is prepared, curve 1
For control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 prepares bromocriptine composition for embodiment 7 and delayed
Release capsule；
Figure 17 shows the blood concentration-time curve for the bromocriptine composition sustained-release capsule that embodiment 8 is prepared, curve 1
For control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 prepares bromocriptine composition for embodiment 8 and delayed
Release capsule；
Figure 18 shows the blood concentration-time curve for the bromocriptine composition sustained-release capsule that embodiment 9 is prepared, curve 1
For control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 prepares bromocriptine composition for embodiment 9 and delayed
Release capsule；
Figure 19 shows the blood concentration-time curve for the bromocriptine composition sustained-release capsule that embodiment 10 is prepared, curve 1
For control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 prepares bromocriptine composition for embodiment 10 and delayed
Release capsule；
Figure 20 shows the blood concentration-time curve for the bromocriptine composition sustained-release capsule that embodiment 11 is prepared, curve 1
For control group 1；Curve 2 is control group 2；Curve 3 is control group 3；Curve 4 prepares bromocriptine composition for embodiment 11 and delayed
Release capsule.
Embodiment
The invention discloses a kind of bromocriptine composition sustained-release preparation and preparation method thereof.Those skilled in the art can join
Present disclosure is examined, the bromocriptine composition sustained-release preparation is obtained, realizes that it is applied, it is accordingly required in particular to, it is noted that all similar
Replace and change apparent to those skilled in the art, they are considered as being included in the present invention.The present invention
Preparation method and application be described by preferred embodiment, related personnel can be not substantially being departed from the present invention
Hold, this paper preparation method and application be modified in spirit and scope or suitably change is with combining, to realize and using this hair
Bright technology.
Used reagent and raw material in a kind of bromocriptine composition sustained-release preparation that the present invention is provided and preparation method thereof
It can be bought by market.
In order that those skilled in the art better understood when technical scheme, with reference to implementation
Example, is expanded on further the present invention：
The screening of the bromocriptine composition sustained-release pharmaceutical formulation of embodiment 1
In order to obtain release uniformity and the preferable sustained release preparation of stability, to slow-release material, diluent, adhesive and profit
The species of lubrication prescription has carried out screening test.Bromocriptine composition tablet obtained by being evaluated using slow release effect as reference index
Performance.
Drug release determination method：Reference《Chinese Pharmacopoeia》Two methods of annex XC second of version in 2010, in automatic digestion instrument
Carry out, dissolution medium is pH6.8 phosphate buffer, and the temperature of dissolution medium is 37 DEG C ± 5 DEG C, and rotating speed is 100rpm/
Min, using 10 point in time sampling, in regulation sampling time point, the temperature of draw solution 5mL filtrations, in time supplement same volume
The dissolution medium for 37 DEG C ± 5 DEG C is spent, should be completed from sampling to filtration in 30 seconds, sampling time point is respectively：1h、2h、
4h、8h、12h、24h、48h、72h、120h、168h.According to defined high-performance liquid chromatography method under items, calculate each
Testing sample different time burst size, and then calculate cumulative percentage release, draw release profiles.Evaluation criterion：
Discharging uniform evaluation criterion is：Medicine in sustained release preparation is slowly discharged by appropriate speed, so blood medicine is dense
Spend " peak valley " fluctuation smaller, the toxic side effect of therapeutic plasma concentrations scope can be avoided exceeding.
Discharging irregular evaluation criterion is：Sustained release rule is difficult to hold, and medicine can not slowly be discharged by appropriate speed,
Discharge too fast or excessively slow in some stage, cause blood concentration " peak valley " fluctuation larger.
The selection result of sustained release bromocriptine composition sustained-release pharmaceutical adjunct is shown in Table 1.
The specification of the bromocriptine composition sustained-release piece of screening is 17.5mg.
The formula (based on 1000 preparation units) of the bromocriptine composition sustained-release film-making is：
Preparation method is：
Main ingredient bromocriptine is taken, is crushed, 40 mesh sieve is crossed, obtains fine powder, it is standby；Slow-release material, diluent and
Lubricant, is crushed respectively, crosses 40 mesh sieve.The bromocriptine of gained after sieving is divided into 20 equal portions by uniform quality；It is sustained material
Material is divided into 20 equal portions by uniform quality；Diluent is divided into 20 equal portions by uniform quality；Lubricant is divided into by uniform quality
20 equal portions, it is standby.First take respectively bromocriptine, slow-release material and diluent divide equally gained 20 parts in 8 parts, mixing, with 20 times/
The frequency oscillation of second is well mixed for 10 minutes；Bromocriptine, slow-release material and diluent is added afterwards to divide equally in 20 parts of gained
6 parts, mixing is well mixed with the frequency oscillation 15 minutes of 20 times/second；Finally, add remaining bromocriptine, slow-release material and
Diluent, is well mixed for 20 minutes with the frequency oscillation of 20 times/second.After well mixed, add adhesive and percent by volume is
5% ethanol water (quality for the ethanol water that percent by volume is 5% is 0.2 times of adhesive quality) softwood processed,
The granulation of 30 mesh sieves is crossed, is dried 90 minutes under the conditions of 60 DEG C, 30 mesh sieve whole grains are crossed.Using lubricant mist device by lubricant and
Percent by volume is equably sprayed on the surface of each upper undershoot and the interior table of middle mould for 5% ethanol water (wetting agent)
Face, is that 25mg carries out tabletting according to every sheet weight, that is, obtains the tablet that specification is 17.5mg.
The selection result of the bromocriptine composition sustained-release pharmaceutical adjunct of table 1
It was found from the screening test result of above-mentioned table 1, in slow-release material screening test, using polyvinylpyrrolidone, card
Preferably, releasing effect is preferable for sustained release preparation release uniformity and stability prepared by ripple nurse, HPMC Methocel K4M.And adopt
The sustained release preparation insoluble drug release prepared with polypropylene glucose, Arabic gum, albumin is fast, and release uniformity and stability are not
Good, slow release effect is poor.It is preferred, therefore, that PVP, carbomer, HPMC Methocel K4M are used as slow-release material.
In adhesive screening test, the sustained release preparation prepared using gelatin, sodium carboxymethylcellulose, starch slurry discharges uniform
Property and stability preferably, releasing effect is preferable.And the sustained release preparation insoluble drug release for using syrup, hydroxypropyl cellulose to prepare is fast,
Discharge uniformity and stability is bad, slow release effect is poor.It is preferred, therefore, that gelatin, sodium carboxymethylcellulose, starch slurry are used as bonding
Agent.
In diluent screening test, the sustained release preparation prepared using mannitol, calcium sulfate, starch discharges uniformity and stably
Property preferably, releasing effect is preferable.And the sustained release preparation insoluble drug release for using magnesia, magnesium carbonate, calcium carbonate to prepare is fast, release is equal
Even property and stability are bad, and slow release effect is poor.It is preferred, therefore, that mannitol, calcium sulfate, starch are used as diluent.
In lubricant screening test, the sustained release preparation prepared using polyethylene glycol, Stepanol MG, magnesium stearate is released
Put uniformity and stability preferably, releasing effect is preferable.And the sustained release preparation medicine for using atoleine, Compritol 888 ATO to prepare
Thing release is fast, and release uniformity and stability are bad, and slow release effect is poor.It is preferred, therefore, that polyethylene glycol, Stepanol MG,
Magnesium stearate is used as lubricant.
The preparation of the bromocriptine composition sustained-release tablet of embodiment 2
Specification is the preparation of 0.7mg tablet：
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 40 mesh sieve is crossed, obtains fine powder, it is standby；Take hydroxypropyl methylcellulose (slow
Release material), ethyl cellulose, starch, microcrystalline cellulose and magnesium stearate, crush respectively, cross 40 mesh sieve.Gained after sieving
Bromocriptine be divided into 20 equal portions by uniform quality；Hydroxypropyl methylcellulose is divided into 20 equal portions by uniform quality；Starch presses quality
It is divided evenly into 20 equal portions；Microcrystalline cellulose is divided into 20 equal portions by uniform quality, standby.Bromocriptine, hydroxypropyl first are first taken respectively
Divide equally in 20 parts of gained 8 parts of cellulose, starch and microcrystalline cellulose, mixing is mixed with the frequency oscillation 10 minutes of 20 times/second
Close uniform；6 parts that bromocriptine, hydroxypropyl methylcellulose, starch and microcrystalline cellulose are divided equally in 20 parts of gained are added afterwards, are mixed
Close, be well mixed within 15 minutes with the frequency oscillation of 20 times/second；Finally, remaining bromocriptine, hydroxypropyl methylcellulose, starch are added
And microcrystalline cellulose, it is well mixed within 20 minutes with the frequency oscillation of 20 times/second.After well mixed, ethyl cellulose and nothing are added
Water-ethanol (quality of absolute ethyl alcohol is 0.2 times of ethyl cellulose quality) softwood processed, crosses the granulation of 30 mesh sieves, under the conditions of 60 DEG C
Dry 90 minutes, cross 30 mesh sieve whole grains.Using lubricant mist device by magnesium stearate and absolute ethyl alcohol (wetting agent) equably
The surface of each upper undershoot and the inner surface of middle mould are sprayed on, is that 7mg carries out tabletting according to every sheet weight, that is, obtaining specification is
0.7mg tablet.
The preparation of the bromocriptine composition sustained-release tablet of embodiment 3
Specification is the preparation of 3.5mg tablet：
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 40 mesh sieve is crossed, obtains fine powder, it is standby；Take chitosan, carboxymethyl fine
The plain sodium of dimension, pregelatinized starch and calcium stearate, crush, cross 40 mesh sieve respectively.The bromocriptine of gained after sieving is equal by quality
It is divided into 20 equal portions evenly；Chitosan is divided evenly into 20 equal portions by quality respectively；Pregelatinized starch is equably divided respectively by quality
It is standby into 20 equal portions.First take respectively bromocriptine, chitosan and pregelatinized starch divide equally gained 20 parts in 9 parts, mixing, with 20
The frequency oscillation of secondary/second is well mixed for 10 minutes；Bromocriptine, chitosan and pregelatinized starch divide gained equally 20 are added afterwards
5 parts in part, mixing is well mixed for 15 minutes with the frequency oscillation of 20 times/second；Finally, remaining bromocriptine, chitosan are added
And pregelatinized starch, it is well mixed within 20 minutes with the frequency oscillation of 20 times/second.After well mixed, sodium carboxymethylcellulose is added
(quality for the ethanol water that percent by volume is 5% is carboxymethyl cellulose with the ethanol water that percent by volume is 5%
0.0174 times of sodium quality) softwood processed, the granulation of 30 mesh sieves is crossed, is dried 90 minutes at 60 DEG C, 30 mesh sieve whole grains are crossed.Using lubrication
Calcium stearate and percent by volume are equably sprayed on above and below each by agent sprayer unit for 5% ethanol water (wetting agent)
The surface of punching and the inner surface of middle mould, are that 29.17mg carries out tabletting according to every sheet weight, that is, obtain the tablet that specification is 3.5mg.
The preparation of the bromocriptine composition sustained-release tablet of embodiment 4
Specification is the preparation of 5.6mg tablet：
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 30 mesh sieve is crossed, obtains fine powder, it is standby；Take hydroxypropyl methylcellulose (slow
Release material), sodium alginate, carbomer, starch slurry, lactose, silica and magnesium stearate, crush respectively, cross 20 mesh sieve.Will
The bromocriptine of gained is divided into 20 equal portions by uniform quality after sieving；Hydroxypropyl methylcellulose is divided into 20 equal portions by uniform quality；
Sodium alginate is divided into 20 equal portions by uniform quality；Carbomer is divided into 20 equal portions by uniform quality；Lactose is with pressing uniform quality
It is divided into 20 equal portions.Bromocriptine, hydroxypropyl methylcellulose, sodium alginate, carbomer and lactose is first taken to divide equally in 20 parts of gained respectively
8 parts, mixing is well mixed with the frequency oscillation 10 minutes of 20 times/second；Bromocriptine, hydroxypropyl methylcellulose, sea are added afterwards
Divide equally in 20 parts of gained 6 parts of mosanom, carbomer and lactose, mixing is equal with the mixing of frequency oscillation 15 minutes of 20 times/second
It is even；Finally, remaining bromocriptine, hydroxypropyl methylcellulose, sodium alginate, carbomer and lactose are added, is shaken with the frequency of 20 times/second
Swing 20 minutes and be well mixed.After well mixed, add starch slurry and ethanol water that volume ratio is 5% (volume ratio is 5%
The quality of ethanol water is 0.05 times of starch slurry quality) softwood processed, the granulation of 30 mesh sieves is crossed, is dried 120 minutes at 50 DEG C,
Cross 30 mesh sieve whole grains.Use lubricant mist device by magnesium stearate, silica and volume ratio for 5% ethanol water
(wetting agent) is equably sprayed on the surface of each upper undershoot and the inner surface of middle mould, is that 17.5mg is pressed according to every sheet weight
Piece, that is, obtain the tablet that specification is 5.6mg.
The preparation of the bromocriptine composition sustained-release tablet of embodiment 5
Specification is the preparation of 11.2mg tablet：
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 50 mesh sieve is crossed, obtains fine powder, it is standby；Take HPMC Methocel
K4M (hydroxypropyl methylcellulose, from the Dow Chemical Company), polyvinylpyrrolidone, polyethylene glycol, mannitol and dodecyl sulphate
Magnesium, is crushed respectively, crosses 40 mesh sieve, standby.The bromocriptine of gained after sieving is divided into 20 equal portions by uniform quality；HPMC
Methocel K4M are divided into 20 equal portions by uniform quality；Polyvinylpyrrolidone is divided into 20 equal portions by uniform quality；Sweet dew
Alcohol is divided into 20 equal portions by uniform quality.Bromocriptine, HPMC Methocel K4M, polyvinylpyrrolidone and sweet are first taken respectively
Reveal 7 parts that alcohol is divided equally in 20 parts of gained, mixing is well mixed for 10 minutes with the frequency oscillation of 20 times/second；Bromine is added afterwards
Hidden booth, HPMC Methocel K4M, polyvinylpyrrolidone and mannitol divide equally gained 20 parts in 8 parts, mixing, with 20
The frequency oscillation of secondary/second is well mixed for 15 minutes；Finally, remaining bromocriptine, HPMC Methocel K4M, polyethylene are added
Pyrrolidones and mannitol, are well mixed for 20 minutes with the frequency oscillation of 20 times/second.After well mixed, add polyethylene glycol and
Water (quality of water is 0.01 times of polyethylene glycol quality) softwood processed, crosses the granulation of 30 mesh sieves, is dried 80 minutes at 65 DEG C, cross 30
Mesh sieve whole grain.Stepanol MG and water (wetting agent) are equably sprayed on by each upper undershoot using lubricant mist device
Surface and middle mould inner surface, according to every sheet weight be 22.4mg carry out tabletting, that is, obtain specification be 11.2mg tablet.
The preparation of the bromocriptine composition sustained-release tablet of embodiment 6
Specification is the preparation of 17.5mg tablet：
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 50 mesh sieve is crossed, obtains fine powder, it is standby；Take HPMC Methocel
K4M (hydroxypropyl methylcellulose, from the Dow Chemical Company), starch slurry, PVP and dextrin, are crushed respectively, cross 30 mesh sieve, standby
With.The bromocriptine of gained after sieving is divided into 20 equal portions by uniform quality；HPMC Methocel K4M are divided by uniform quality
Into 20 equal portions；Dextrin is divided into 20 equal portions by uniform quality, standby.Bromocriptine, HPMC Methocel K4M and paste are first taken respectively
Divide equally in 20 parts of gained 8 parts of essence, mixing is well mixed with the frequency oscillation 10 minutes of 20 times/second；It is hidden that bromine is added afterwards
Booth, HPMC Methocel K4M and dextrin divide equally gained 20 parts in 6 parts, mixing, with 15 points of the frequency oscillation of 20 times/second
Clock is well mixed；Finally, remaining bromocriptine, HPMC Methocel K4M and dextrin are added, with the frequency oscillation of 20 times/second
It is well mixed within 20 minutes.After well mixed, the ethanol water (volume that starch slurry, PVP and percent by volume are 5% is added
The quality for the ethanol water that percentage is 5% be starch slurry, 0.0025 times of PVP quality sum) softwood processed, cross 30 mesh
Sieve series grain, is dried 60 minutes at 70 DEG C, crosses 30 mesh sieve whole grains.Using lubricant mist device by hydrogenated vegetable oil and volume hundred
Divide and be equably sprayed on the surface of each upper undershoot and the inner surface of middle mould than the ethanol water (wetting agent) for 5%, according to
It is that 25mg carries out tabletting per sheet weight, that is, obtains the tablet that specification is 17.5mg.
The preparation of the bromocriptine composition sustained-release capsule of embodiment 7
Specification is the preparation of 17.5mg capsule
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 40 mesh sieve is crossed, obtains fine powder, it is standby；Take HPMC Methocel
K4M, PVP and mannitol, are crushed respectively, cross 40 mesh sieve.The bromocriptine of gained after sieving is divided into 20 by uniform quality
Equal portions；HPMC Methocel K4M are divided into 20 equal portions by uniform quality；Mannitol is divided into 20 equal portions by uniform quality, standby
With.First take respectively bromocriptine, HPMC Methocel K4M and mannitol divide equally gained 20 parts in 8 parts, mixing, with 20 times/
The frequency oscillation of second is well mixed for 10 minutes；Bromocriptine, HPMC Methocel K4M and mannitol are added afterwards divides gained equally
20 parts in 8 parts, mixing is well mixed with the frequency oscillation 15 minutes of 20 times/second；Finally, bromocriptine, HPMC are added
Methocel K4M and mannitol, are well mixed for 20 minutes with the frequency oscillation of 20 times/second.After well mixed, addition PVP,
Starch slurry and water (quality of water is 0.01 times of PVP and starch slurry quality sum) softwood processed, cross the granulation of 30 mesh sieves, 50
Dried 120 minutes at DEG C, cross 30 mesh sieve whole grains, 31.4875mg is filled according to each capsule, filling produces specification into capsulae vacuus
For 17.5mg capsule.
The preparation of the bromocriptine composition sustained-release capsule of embodiment 8
Specification is the preparation of 35mg capsule：
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 50 mesh sieve is crossed, obtains fine powder, it is standby；Take hydroxyethyl cellulose, ring
Dextrin, sodium carboxymethylcellulose, starch and lactose, are crushed respectively, cross 30 mesh sieve.The bromocriptine of gained after sieving is pressed into quality
It is divided evenly into 20 equal portions；Hydroxyethyl cellulose is divided into 20 equal portions by uniform quality；Cyclodextrin is divided into 20 by uniform quality
Equal portions；Starch is divided into 20 equal portions by uniform quality；Lactose is divided into 20 equal portions by uniform quality, standby.First take bromine hidden respectively
Divide equally in 20 parts of gained 7 parts of booth, hydroxyethyl cellulose, cyclodextrin, starch and lactose, mixing is shaken with the frequencies of 20 times/second
Swing 10 minutes and be well mixed；Bromocriptine, hydroxyethyl cellulose, cyclodextrin, starch and lactose divide gained equally 20 are added afterwards
8 parts in part, mixing is well mixed for 15 minutes with the frequency oscillation of 20 times/second；Finally, bromocriptine, hydroxy ethyl fiber are added
Element, cyclodextrin, starch and lactose, are well mixed for 20 minutes with the frequency oscillation of 20 times/second.After well mixed, carboxymethyl is added
Sodium cellulosate and water (quality of water is 0.008 times of sodium carboxymethylcellulose quality) softwood processed, cross the granulation of 30 mesh sieves, at 60 DEG C
Lower drying 90 minutes, crosses 30 mesh sieve whole grains, and 70mg is filled according to each capsule, and filling produces the glue that specification is 35mg into capsule
Capsule.
The preparation of the bromocriptine composition sustained-release capsule of embodiment 9
Specification is the preparation of 50mg capsule
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 30 mesh sieve is crossed, obtains fine powder, it is standby；Take HPMC Methocel
K4M (slow-release material), carbomer, sodium alginate, PVP and lactose, are crushed respectively, cross 20 mesh sieve.By gained after sieving
Bromocriptine is divided into 20 equal portions by uniform quality；HPMC Methocel K4M are divided into 20 equal portions by uniform quality；Carbomer is pressed
It is divided into 20 equal portions uniform quality；Sodium alginate is divided into 20 equal portions by uniform quality；Lactose is divided into 20 etc. by uniform quality
Part, it is standby.First take respectively bromocriptine, HPMC Methocel K4M, carbomer, sodium alginate and lactose divide equally gained 20 parts
In 8 parts, mixing is well mixed with the frequency oscillation 10 minutes of 20 times/second；Bromocriptine, HPMC Methocel are added afterwards
Divide equally in 20 parts of gained 8 parts of K4M, carbomer, sodium alginate and lactose, mixing, with the frequency oscillation 15 minutes of 20 times/second
It is well mixed；Finally, bromocriptine, HPMC Methocel K4M, carbomer, sodium alginate and lactose are added, with 20 times/second
Frequency oscillation is well mixed for 20 minutes.After well mixed, (quality of water is PVP quality for addition PVP and water
0.00448 times) softwood processed, the granulation of 30 mesh sieves is crossed, is dried 60 minutes at 70 DEG C, 30 mesh sieve whole grains is crossed, is filled out according to each capsule
402.5mg is filled, filling produces the capsule that specification is 50mg into capsulae vacuus.
The preparation of the bromocriptine composition sustained-release capsule of embodiment 10
Specification is the preparation of 56mg capsule
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 40 mesh sieve is crossed, obtains fine powder, it is standby；Take hydroxypropyl cellulose, it is bright
Glue and microcrystalline cellulose, are crushed respectively, cross 40 mesh sieve, standby.The bromocriptine of gained after sieving is divided into by uniform quality
20 equal portions；Hydroxypropyl cellulose is divided into 20 equal portions by uniform quality；Microcrystalline cellulose is divided into 20 equal portions by uniform quality.First
Take respectively bromocriptine, hydroxypropyl cellulose and microcrystalline cellulose divide equally gained 20 parts in 9 parts, mixing, with the frequency of 20 times/second
Rate, which is shaken 10 minutes, to be well mixed；20 parts that bromocriptine, hydroxypropyl cellulose and microcrystalline cellulose divide gained equally are added afterwards
In 5 parts, mixing is well mixed with the frequency oscillation 15 minutes of 20 times/second；Finally, add bromocriptine, hydroxypropyl cellulose and
Microcrystalline cellulose, is well mixed for 20 minutes with the frequency oscillation of 20 times/second.After well mixed, gelatin and absolute ethyl alcohol (nothing are added
The quality of water-ethanol is 0.05 times of gelatin quality) softwood processed, the granulation of 30 mesh sieves is crossed, is dried 90 minutes at 60 DEG C, 30 mesh are crossed
Whole grain is sieved, 466.67mg is filled according to each capsule, filling produces the capsule that specification is 56mg into capsulae vacuus.
The preparation of the bromocriptine composition sustained-release capsule of embodiment 11
Specification is the preparation of 70mg capsule
Supplementary material is weighed according to following formula (based on 1000 preparation units)：
Main ingredient bromocriptine is taken, is crushed, 40 mesh sieve is crossed, obtains fine powder, it is standby；Take HPMC Methocel
K4M, sucrose and calcium sulfate, are crushed respectively, cross 40 mesh sieve, standby.The bromocriptine of gained after sieving is divided by uniform quality
Into 20 equal portions；HPMC Methocel K4M are divided into 20 equal portions by uniform quality；Sucrose is divided into 20 equal portions by uniform quality；
Calcium sulfate is divided into 20 equal portions by uniform quality.First take bromocriptine, HPMC Methocel K4M, sucrose and calcium sulfate flat respectively
8 parts in 20 parts obtained by point, mixing is well mixed for 10 minutes with the frequency oscillation of 20 times/second；Add afterwards bromocriptine,
HPMC Methocel K4M, sucrose and calcium sulfate divide equally gained 20 parts in 8 parts, mixing, with the frequency oscillation of 20 times/second
It is well mixed within 15 minutes；Finally, HPMC Methocel K4M, sucrose and calcium sulfate are added, with the frequency oscillation 20 of 20 times/second
Minute is well mixed.After well mixed, water softwood is added, the granulation of 30 mesh sieves is crossed, is dried 90 minutes at 60 DEG C, cross 30 mesh sieves
Whole grain, 350mg is filled according to each capsule, and filling produces the capsule that specification is 70mg into capsulae vacuus.
The bromocriptine composition sustained-release agent in vitro release test of embodiment 12
Bromocriptine composition sustained-release tablet that Example 2 to embodiment 6 is prepared, embodiment 7 to embodiment 11 are made
It is standby to obtain bromocriptine composition sustained-release capsule, the release of bromocriptine composition sustained-release preparation is determined, with commercially available prod
CYCLOSET tablets (0.8mg), PARLODEL tablets (2.5mg) and PARLODEL capsules (5mg) are used as control, CYCLOSET pieces
Agent (0.8mg) is that control group 1, PARLODEL tablets (2.5mg) are control group 2 and PARLODEL capsules (5mg) are control group 3.
Drug release determination method：Reference《Chinese Pharmacopoeia》Two methods of annex XC second of version in 2010, in automatic digestion instrument
Carry out, dissolution medium is pH6.8 phosphate buffer, and the temperature of dissolution medium is 37 DEG C ± 5 DEG C, and rotating speed is 100rpm/
Min, using 10 point in time sampling, in regulation sampling time point, the temperature of draw solution 5mL filtrations, in time supplement same volume
The dissolution medium for 37 DEG C ± 5 DEG C is spent, should be completed from sampling to filtration in 30 seconds, sampling time point is respectively：1h、2h、
4h、8h、12h、24h、48h、72h、120h、168h.According to defined high-performance liquid chromatography method under items, calculate each
Testing sample different time burst size, and then calculate cumulative percentage release, draw release profiles.It is prepared by each embodiment
The bromocriptine composition sustained-release preparation of acquisition is shown in Table 2 in the cumulative release percentage of different time, and each embodiment is prepared
The release profiles of bromocriptine composition sustained-release preparation see Fig. 1 to Figure 10.Fig. 1 is the bromocriptine combination that embodiment 2 is prepared
The release profiles of thing sustained release tablets, wherein curve 1 represent control group 2, i.e. PARLODEL tablets (2.5mg)；Curve 2 represents control group
3, i.e. PARLODEL capsules (5mg)；Curve 3 represents control group 1, i.e. CYCLOSET tablets (0.8mg)；Curve 4 represents embodiment 2
The bromocriptine composition sustained-release piece prepared.Fig. 2 to Figure 10 is respectively that embodiment 3 to embodiment 11 prepares bromocriptine group
The release profiles of compound sustained release preparation.
Cumulative release percentage of the bromocriptine composition sustained-release preparation of the different groups of table 2 in different time
It can be seen from experimental result in table 2 and Fig. 1 to Figure 10, control group 1 to control group 3, i.e., existing commercially available prod
CYCLOSET tablets, PARLODEL tablets, PARLODEL capsules, discharge complete, without slow release effect within 24h.It is real
The slow release effect for testing the bromocriptine composition sustained-release preparation that group, i.e. embodiment 2 to embodiment 11 are prepared is good, meets China
Requirement of the pharmacopeia to sustained release preparation, each bromocriptine composition sustained-release preparation can realize the slow releasing function of maintenance one week.Explanation
The bromocriptine composition sustained-release preparation slow release effect that the present invention is provided is good, can significantly reduce administration number of times, is conducive to improving disease
The Compliance of people, is more beneficial for the popularization of bromocriptine and uses.
The pharmacokinetic trial of embodiment 13
Bromocriptine composition sustained-release tablet that Example 2 to embodiment 6 is prepared, embodiment 7 to embodiment 11 are made
It is standby to obtain bromocriptine composition sustained-release capsule, the pharmacokinetic trial of bromocriptine composition sustained-release preparation is determined, with commercially available production
Product CYCLOSET tablets (0.8mg), PARLODEL tablets (2.5mg) and PARLODEL capsules (5mg) are used as control.
Pharmacokinetics test method is：The new zealand rabbit 84 that age, body weight are suitable is taken, 14 are randomly divided into
Group, is respectively labeled as experimental group 1 to experimental group 10, control group 1 to control group 3 and blank control group by every group 6.Blank control
Group is not administered, and experimental group 1 provides bromocriptine composition sustained-release tablet, the offer embodiment 3 of experimental group 2 that embodiment 2 is prepared
The bromocriptine composition sustained-release tablet for preparing, experimental group 3 provide the bromocriptine composition sustained-release piece that embodiment 4 is prepared
Agent, experimental group 4 provide embodiment 5 prepare bromocriptine composition sustained-release tablet, experimental group 5 provide embodiment 6 prepare obtain
The bromocriptine composition sustained-release tablet obtained；Experimental group 6 provides bromocriptine composition sustained-release capsule, the reality that embodiment 7 is prepared
Test the bromocriptine composition sustained-release capsule that 7 offer embodiments 8 are provided and prepared, experimental group 8 and the bromine that embodiment 9 is prepared is provided
Hidden booth composition sustained-release capsule, experimental group 9 provide bromocriptine composition sustained-release capsule, the experimental group 10 that embodiment 10 is prepared
The bromocriptine composition sustained-release capsule that embodiment 11 is prepared is provided；Control group 1 provides CYCLOSET tablets (0.8mg), right
PARLODEL tablets (2.5mg), control group 3 are provided according to group 2, and PARLODEL capsules (5mg) are provided.Administering mode is oral administration,
Dosage is the i.e. 0.5mg/kg per 1kg body weight 0.5mg medicines, dosage period be weekly administration once.Respectively at administration preceding 0
Hour, 1 hour after administration, 2 hours, 4 hours, 8 hours, 12 hours, 24 hours, 48 hours, 72 hours, 120 hours, it is 168 small
When extracting vein blood sample, processing blood sample after using high performance liquid chromatography detection, calculate blood concentration.
It is plotted against time with blood concentration, obtains blood concentration-time curve.The blood concentration-time curve of each group
See Figure 11 to Figure 20.Figure 11 shows the blood concentration-time curve for the bromocriptine composition sustained-release piece that embodiment 2 is prepared, bent
Line 1 is control group 1, i.e. CYCLOSET tablets (0.8mg)；Curve 2 is control group 2, i.e. PARLODEL tablets (2.5mg)；Curve 3
For control group 3, i.e. PARLODEL capsules (5mg)；Curve 4 is the blood medicine that embodiment 2 prepares bromocriptine composition sustained-release piece
Concentration time curve.Figure 12 to Figure 20 is right for the bromocriptine composition sustained-release preparation that embodiment 3 to embodiment 11 is prepared
The blood concentration-time curve answered.
It was found from Figure 11 to Figure 20, upon administration, blood concentration is quickly reached for control group 1, control group 2 and control group 3
Peak, but the maintenance of effective blood drug concentration time is shorter, whole administration process blood concentration fluctuation scope is larger；And embodiment 2
It can be realized to the bromocriptine composition sustained-release preparation that embodiment 11 is prepared and steadily be discharged in one week and maintain effective blood medicine
In concentration, whole dosage period, blood concentration fluctuation scope is small.As can be seen here, the bromocriptine composition sustained-release that the present invention is provided
Preparation can stablize sustained release drugs, can significantly reduce administration number of times, be conducive to improving the Compliance of patient, more favorably
In bromocriptine popularization and use.
It the above is only the preferred embodiment of the present invention, it is noted that above-mentioned preferred embodiment is not construed as pair
The limitation of the present invention, protection scope of the present invention should be defined by claim limited range.For the art
For those of ordinary skill, without departing from the spirit and scope of the present invention, some improvements and modifications can also be made, these change
Enter and retouch and also should be regarded as protection scope of the present invention.
Claims (5)
1. a kind of bromocriptine composition sustained-release preparation, it is characterised in that be made up of the raw material of following parts by weight：
The slow-release material is selected from one kind in hydroxypropyl cellulose or hydroxypropyl methylcellulose, or following three kinds of mixtures：
1) mixture of sodium alginate, hydroxypropyl methylcellulose and carbomer,
2) mixture of hydroxypropyl methylcellulose and polyvinylpyrrolidone,
3) mixture of hydroxyethyl cellulose and cyclodextrin；
Described adhesive is one or both of starch slurry, gelatin, sodium carboxymethylcellulose, polyethylene glycol, PVP or water
Thing mixed above；
The diluent is in starch, sucrose, lactose, pregelatinized starch, mannitol, microcrystalline cellulose, calcium sulfate or dextrin
One or both thing mixed above；
The lubricant is magnesium stearate, silica, hydrogenated vegetable oil, polyethylene glycol, calcium stearate or dodecyl sulphate
One or both of magnesium thing mixed above.
2. sustained release preparation according to claim 1, it is characterised in that the wetting agent is water and/or ethanol.
3. sustained release preparation according to claim 1, it is characterised in that its formulation is tablet or capsule.
4. a kind of preparation method of bromocriptine composition sustained-release preparation as claimed in claim 1, it is characterised in that the sustained release
When preparation is tablet, comprise the following steps：
Step 1：Take the component of following parts by weight：
Step 2：Take after the bromocriptine, the slow-release material, diluent mixing, add described adhesive softwood, warp
After granulation, dry, whole grain, the lubricant, the wetting agent are added, tabletting is produced.
5. a kind of preparation method of bromocriptine composition sustained-release preparation, it is characterised in that when the sustained release preparation is capsule, bag
Include following steps：
Step 1：Take the component of following parts by weight：
Step 2：Take after the bromocriptine, the slow-release material, diluent mixing, add described adhesive softwood, warp
After granulation, dry, whole grain, fill to capsulae vacuus, produce；
The slow-release material is selected from one kind in hydroxypropyl cellulose or hydroxypropyl methylcellulose, or following three kinds of mixtures：
1) mixture of sodium alginate, hydroxypropyl methylcellulose and carbomer,
2) mixture of hydroxypropyl methylcellulose and polyvinylpyrrolidone,
3) mixture of hydroxyethyl cellulose and cyclodextrin；
Described adhesive is one or both of starch slurry, gelatin, sodium carboxymethylcellulose, polyethylene glycol, PVP or water
Thing mixed above；
The diluent is in starch, sucrose, lactose, pregelatinized starch, mannitol, microcrystalline cellulose, calcium sulfate or dextrin
One or both thing mixed above.
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