A kind of phenylbutyrate sodium tablet and preparation method thereofTechnical field
The present invention relates to a kind of phenylbutyrate sodium tablet and preparation method thereof, belong to field of pharmaceutical preparations.
Background technology
Ornithine cycle is a kind of metabolic process, is discharged by the nitrogen of human body by this metabolism, has 6 kinds of enzymes to participate in this process, appointsWhat a kind of enzyme occurs that defect all can make this disturbed metabolic processes, in causing unnecessary nitrogen (with ammonia form) retention body.Described 6 kinds of urineElement circulatory disturbance is: carbamoyl phosphate synthetase, CPS lacks disease；N-acetyl paddy hydrogen propylhomoserin synzyme lacks disease；Ornithine ammoniaTransformylase lacks disease；Argininosuccinate synthetase lacks disease；Argininosuccinate lyase deficiency disease andArginase deficiency.
If new born baby is the one in these rare enzyme deficiency diseases during ornithine cycle, and azymia is tightIf Chong, then dead in baby being caused to go into a coma or being born several days.Phenylbutyrate sodium (Sodium Phenylbutyrate) is in vivoPhenylacetate can be become by rapid metabolization, generation phenylacetylglutamine can be combined with glutamic acid and ammonia, by renal excretion, be nitrogenous uselessOne approach of thing excretion, it can make too high blood ammonia levels and blood aminoglutaric acid concentration decline, to form phenylacetylglutamineDisplay increases the excretion of nitrogenous waste.On May 13rd, 1996, U.S. FDA by express passway ratify its be used as auxiliary treatment because ofCarbamoyl phosphate synthetase, CPS (CPS), ornithine transcarbamylase (OTC) or argininosuccinate synthetase (AS) lackAnd the hyperammonemia that the chronic uric acid circulation disorder caused causes, trade name Buphenyl, authorized rare medicine ground by FDA simultaneouslyPosition.
Phenylbutyrate sodium is ground production by Ucyclyd Pharma company of the U.S. is former, and dosage form is tablet and granule, in the U.S., EuropeAlliances etc. are multinational is widely used in neonate, infant, child and the treatment of adult's urea cycle disorder.Additionally, it is external just to benzeneSodium butyrate is studied as a kind of new drug inducing differentiation malignant tumor, and research shows, it is to glioma, carcinoma of prostate, blackMelanoma, leukemia, lymphoma and chemoprophylaxis aspect have obvious effect, are that a kind of potential efficient, low toxicity, wide spectrum lureLead differentiation new drug.So far, the approved dosage form of phenylbutyrate sodium and indication are still only tablet and granule, follow for carbamideThe auxiliary treatment of ring obstacle.
For phenylbutyrate sodium granule, its powder dose is to be measured by three different size of measuring spoons,But it is inaccurate that this mode of measuring normally results in dosage, and then cause the dosage that can not take regulation with required interval, especiallyBeing for low age group child, often can cause phenomenon of feeling sick, be unfavorable for the toleration of patient, tablet then can avoid above-mentioned askingTopic.
Summary of the invention
It is an object of the invention to provide a kind of phenylbutyrate sodium tablet and preparation method thereof, the phenylbutyrate sodium sheet that the present invention providesAgent steady quality, hardness are suitable, dissolution is high and bioavailability is high, and the preparation method that the present invention provides simply may be usedOK.
Phenylbutyrate sodium tablet provided by the present invention, is made up of phenylbutyrate sodium and diluent；
Described diluent is filler, binding agent and lubricant；
In described phenylbutyrate sodium tablet, described phenylbutyrate sodium is 1:0.2～1.5 with the mass ratio of described diluent.
In described phenylbutyrate sodium tablet, described filler is selected from microcrystalline Cellulose, mannitol, lactose, starch and dextrinIn at least one, preferably microcrystalline cellulose and lactose.
In described phenylbutyrate sodium tablet, described binding agent is selected from hydroxypropyl methyl cellulose, hydroxypropyl first carboxymethyl celluloseIn element sodium, hydroxypropyl cellulose and polyvinylpyrrolidone at least one, preferably hydroxypropyl methyl cellulose and polyvinyl pyrroleAlkanone.
In described phenylbutyrate sodium tablet, described lubricant is selected from silicon dioxide, magnesium stearate, sodium stearyl fumarate and cunningIn stone powder at least one, preferably silicon dioxide and magnesium stearate.
In described phenylbutyrate sodium tablet, it is further preferred that the mass ratio of described phenylbutyrate sodium and described diluent canFor 1:0.3～0.8, concretely 1:0.52～0.7,1:0.52,1:0.66 or 1:0.7.
In described phenylbutyrate sodium tablet, in described diluent, described filler, described binding agent and described lubricantMass ratio can be 50～25:5.5～1.5:1, concretely 29.3～36.6:1.71～4.6:1,29.3:4.6:1,30:4:1Or 36.6:1.71:1.
In described phenylbutyrate sodium tablet, described lactose includes the lactose of various model, such as spray drying lactose, directlyTabletting lactose etc..
Present invention also offers the preparation method of described phenylbutyrate sodium tablet, comprise the steps:
1) described phenylbutyrate sodium, described filler and described binding agent are mixed to get batch mixing；
2) carry out described batch mixing pelletizing and carry out to be dried to obtain phenylbutyrate sodium granule；
3) described phenylbutyrate sodium tablet is i.e. obtained by carrying out tabletting after described phenylbutyrate sodium granule and described mix lubricant.
In above-mentioned preparation method, step 1) in, described binding agent with powder or/and the form of solution adds.
In above-mentioned preparation method, described binding agent adds with the form of its ethanol water；
The weight/mass percentage composition of binding agent described in described ethanol water can be 1～10%, concretely 10%.
In above-mentioned preparation method, described dry temperature can be 40～60 DEG C, and the time is 1.5～3 hours, as at 60 DEG CUnder be dried 2 hours.
Based on phenylbutyrate sodium raw material itself to draw by force moist and specification big (principal agent ratio is big) so that there is skill on preparationArt difficulty, the invention provides that a kind of steady quality, hardness is suitable, technique simple possible, and dissolution level reaches reference preparation, biologyThe phenylbutyrate sodium tablet that availability is high, has filled up the blank of China's Buphenyl.
Detailed description of the invention
Experimental technique used in following embodiment if no special instructions, is conventional method.
Material used in following embodiment, reagent etc., if no special instructions, the most commercially obtain.
Embodiment 1, the preparation (500mg specification) of phenylbutyrate sodium tablet
The prescription of 500mg specification tablet is as shown in table 1.
The prescription of table 1 500mg specification phenylbutyrate sodium tablet
| Component | Unit (g) |
| Phenylbutyrate sodium | 100 |
| Microcrystalline Cellulose | 45.0 |
| Lactose | 15.0 |
| HPMC-K4M | 8 |
| 10% ethanol water | In right amount |
| Silicon dioxide | 2.0 |
| Tablet weight | 0.85 |
1) former, adjuvant are pulverized respectively, cross 80 mesh sieves standby；
2) phenylbutyrate sodium, microcrystalline Cellulose, lactose, hypromellose-K4M, mix homogeneously are weighed respectively by recipe quantity；
3) add appropriate 10% ethanol water (volumetric concentration) soft material processed, pelletize with 20 mesh sieves, be dried about 2 in 60 DEG C littleTime, dry granule is with 18 mesh sieve granulate；
4) weigh recipe quantity silicon dioxide, join in prepared dry granule, mix homogeneously；
5) measuring granule content, calculate tablet weight, with oval stamping, Hardness Control is at 12kg～14kg.
In phenylbutyrate sodium tablet prepared by the present embodiment, phenylbutyrate sodium and diluent (microcrystalline Cellulose, lactose, hydroxypropyl firstCellulose-K4M and silicon dioxide) mass ratio be 1:0.7, filler (microcrystalline Cellulose and lactose), binding agent (HPMC-K4M) mass ratio with lubricant (silicon dioxide) is 30:4:1.
Embodiment 2, the preparation (500mg specification) of phenylbutyrate sodium tablet
The prescription of 500mg specification tablet is as shown in table 2.
The prescription of table 2 500mg specification phenylbutyrate sodium tablet
| Component | Unit (g) |
| Phenylbutyrate sodium | 100 |
| Microcrystalline Cellulose | 48.0 |
| Lactose | 16 |
| Silicon dioxide | 0.75 |
| Magnesium stearate | 1 |
| PVPK30(10% ethanol solution) | 30 |
| Tablet weight | 0.83 |
1) former, adjuvant is crossed respectively 80 mesh sieves standby；
2) prepare 30% ethanol water (volumetric concentration), prepare 10wt%PVP with itK30Solution is in right amount as binding agentStandby；
3) phenylbutyrate sodium, microcrystalline Cellulose and lactose are weighed respectively by recipe quantity, mix homogeneously, add suitable amount of adhesive systemSoft material, pelletizes with 20 mesh sieves, is dried about 2 hours in 60 DEG C, and dry granule is with 18 mesh sieve granulate；
4) weigh recipe quantity silicon dioxide and magnesium stearate, join in prepared dry granule, mix homogeneously；
5) measuring granule content, calculate tablet weight, with oval stamping, Hardness Control is at 12kg～14kg.
In phenylbutyrate sodium tablet prepared by the present embodiment, phenylbutyrate sodium and diluent (microcrystalline Cellulose, lactose, hydroxylPVPK30, silicon dioxide and magnesium stearate) mass ratio be 1:0.66, filler (microcrystalline Cellulose and lactose), binding agent(PVPK30) it is 36.6:1.71:1 with the mass ratio of lubricant (silicon dioxide and magnesium stearate).
Embodiment 3, the preparation (500mg specification) of phenylbutyrate sodium tablet
The prescription of 500mg specification tablet is as shown in table 3.
The prescription of table 3 500mg specification phenylbutyrate sodium tablet
| Component | Unit (g) |
| Phenylbutyrate sodium | 100 |
| Microcrystalline Cellulose | 44.0 |
| HPMC-K4M | 4.4 |
| Magnesium stearate | 0.75 |
| Silicon dioxide | 0.75 |
| PVPK30(10% ethanol solution) | 25 |
| Tablet weight | 0.75 |
1) former, adjuvant is crossed respectively 80 mesh sieves standby；
2) prepare 30% ethanol solution (volumetric concentration), prepare 10wt%PVP with itK30Solution is standby as binding agent in right amountWith；
3) phenylbutyrate sodium, microcrystalline Cellulose and hypromellose-K4M are weighed respectively by recipe quantity, mix homogeneously, addSuitable amount of adhesive soft material, pelletizes with 20 mesh sieves, is dried about 2 hours in 60 DEG C, and dry granule is with 18 mesh sieve granulate；
4) weigh recipe quantity silicon dioxide and magnesium stearate, join in prepared dry granule, mix homogeneously；
5) measuring granule content, calculate tablet weight, with oval stamping, Hardness Control is at 12kg～14kg.
In phenylbutyrate sodium tablet prepared by the present embodiment, phenylbutyrate sodium and diluent (microcrystalline Cellulose, HPMC-K4M,PVPK30, silicon dioxide and magnesium stearate) mass ratio be 1:0.52, filler (microcrystalline Cellulose), binding agent (HPMC-K4MAnd PVPK30) it is 29.3:4.6:1 with the mass ratio of lubricant (silicon dioxide and magnesium stearate).
Embodiment 4, the quality research of phenylbutyrate sodium tablet
1, a plurality of stripping curve evaluation
Take phenylbutyrate sodium sheet (specification 500mg) prepared by embodiment of the present invention 1-3 and commercially available phenylbutyrate sodium sheet (Specification 500mg) each 12, respectively with 0.1M hydrochloric acid, pH4.5 acetate buffer, pH6.8 phosphate-bufferedLiquid and water are dissolution medium, rotating speed 75 revs/min, dissolution medium 1000ml, sample respectively at 5,10,20,30,45 and 60min,Centrifugal, filter membrane filtration method processes sample liquid, as need testing solution, measures ultraviolet absorptivity in 260nm, calculates its dissolution.
Result of the test is shown in Table 4, shown in table 5, table 6 and table 7.
Table 4 phenylbutyrate sodium sheet dissolution in 0.1M hydrochloric acid
| Group | 5min | 10min | 20min | 30min | 45min | 60min |
| Commercially available | 26.4 | 43.5 | 54.0 | 59.1 | 64.4 | 70.5 |
| Embodiment 1 | 27.3 | 45.8 | 55.9 | 62.7 | 66.4 | 69.9 |
| Embodiment 2 | 24.5 | 40.8 | 50.0 | 56.2 | 64.7 | 72.4 |
| Embodiment 3 | 21.2 | 33.2 | 44.6 | 61.6 | 68.8 | 73.3 |
Table 5 phenylbutyrate sodium sheet dissolution in pH4.5 acetate buffer
| Group | 5min | 10min | 20min | 30min | 45min | 60min |
| Commercially available | 29.2 | 55.5 | 88.9 | 93.8 | 96.2 | 97.3 |
| Embodiment 1 | 27.9 | 51.8 | 80.1 | 88.6 | 94.1 | 95.5 |
| Embodiment 2 | 34.4 | 54.9 | 86.7 | 92.4 | 98.8 | 100.2 |
| Embodiment 3 | 36.7 | 51.3 | 76.8 | 84.2 | 96.3 | 99.4 |
Table 6 phenylbutyrate sodium sheet dissolution in pH6.8 phosphate buffer
| Group | 5min | 10min | 20min | 30min | 45min | 60min |
| Commercially available | 19.1 | 34.3 | 60.5 | 81.6 | 98.2 | 100.4 |
| Embodiment 1 | 18.8 | 31.4 | 57.6 | 74.9 | 88.7 | 99.6 |
| Embodiment 2 | 22.7 | 35.1 | 64.8 | 80.2 | 94.4 | 100.8 |
| Embodiment 3 | 24.1 | 42.8 | 70.4 | 87.5 | 96.1 | 100.2 |
Table 7 phenylbutyrate sodium sheet dissolution in water
| Group | 5min | 10min | 20min | 30min | 45min | 60min |
| Commercially available | 18.1 | 31.1 | 59.0 | 82.0 | 99.8 | 100.8 |
| Embodiment 1 | 20.3 | 31.8 | 53.4 | 77.5 | 90.2 | 98.9 |
| Embodiment 2 | 25.9 | 40.2 | 62.8 | 80.7 | 93.3 | 100.5 |
| Embodiment 3 | 24.5 | 39.5 | 62.1 | 78.0 | 92.9 | 100.0 |
By the experimental result of table 4, table 5, table 6 and table 7 it can be seen that the phenylbutyrate sodium tablet prepared of the present invention is molten at 4 kindsThe dissolution gone out in medium does not has significant difference with commercially available product.
2, accelerated test
Tablet embodiment of the present invention 1-3 prepared, by commercially available back, (stablizes 40 respectively under acceleration conditions with commercially available productDEG C, relative humidity 75% ± 5%), place 6 months, carry out character, content and have related substance to detect, it is judged that mass change trend.
Result is as shown in table 8.
The accelerated test result of table 8 phenylbutyrate sodium sheet
By the data in table 8 it can be seen that the tablet samples prepared of embodiment of the present invention 1-3 under the conditions of accelerated test allKeep good stability.