CN101322709B - Medicament composition containing aripiprazole and preparation thereof - Google Patents
Medicament composition containing aripiprazole and preparation thereof Download PDFInfo
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Abstract
The invention discloses a pharmaceutical composition containing aripiprazole and a preparation method thereof. The formula which is suitable for preparing oral disintegrating tablets provided by the invention comprises an active component, a disintegrating agent, a diluent agent and a latent solvent, a proper amount of a corrective, a lubricant and a glidant. The composition has simple formula, mature preparation process, and successfully solves the problem that oral disintegrating tablets can not be packed by using the common equipment in a way of choosing adjuvants and the proportions of adjuvants by adopting the common tablet production equipment under the condition that the disintegration time limit is guaranteed. The preparation method of the pharmaceutical composition comprises the steps: the aripiprazole is crushed and sieved for use, the adjuvants are weighed up based on the formula and mixed thoroughly to obtain adjuvant mixture; the aripiprazole is weighed up based on the formula and evenly mixed with the adjuvant mixture based on the principle of progressively adding in equal amount to make into a mixture; the pharmaceutical content of the mixture is determined, the weight of a tablet is calculated, a tablet is obtained by being pressed directly, and the hardness of medicine tablet is 8-10kg.
Description
Invention field
The present invention relates to field of pharmaceutical preparations, be in particular a kind of pharmaceutical composition that contains Aripiprazole and preparation method thereof.
Background technology
Aripiprazole, i.e. 7-[4-[4-(2, the 3-Dichlorobenzene base)-1-piperazine] butoxy]-3,4-dihydro-2 (1)-quinolione is the atypical antipsychotic agents of Otsuka drugmaker development, referring to EP367141A, US4234585, CN1028104C etc.Aripiprazole is a (E)-3-(3-Acetyl-4-hydroxy-5-methoxy-phenyl)-N-(4-hydroxy-1-methyl-3-octyloxy-2-oxo-1,2-dihydro-quinolin-7-yl)-acrylamide, belongs to third generation atypical antipsychotic, has unique mechanism of action and pharmacological property.The basis pharmacological research shows: this product has very strong affinity to D2 and D3 and 5-HT1A and 5-HT2A receptor, and (the Ki value is respectively 0.34,0.8,1.7,3.4nmol/L), to D4,5-HT2C and 5-HT7, alpha 1-receptor and H1 receptor have stronger affinity (the Ki value is respectively 44,15,39,57 and 61nmol/L), and the reuptake point of 5-HT had stronger affinity (Ki=98nmol/L).This product is to not effect of cholinergic muscarine acceptor (IC50〉1000nmol/L).The same with other psychosis, this product antipsycholic action cutter system really is not clear fully as yet.Clinically be used for the treatment of various acute and chronic schizophrenia and schizoaffective disorders.
Oral cavity disintegration tablet is that a kind of water that do not need in the oral cavity can disintegrate or dissolved tablet, is the novel solid preparation of Recent study exploitation.Can not need the water assisting deglutition when taking, need not to chew, medicine places on the tongue, meets the rapid disintegrate of saliva, can be in the oral cavity in 30 seconds rapidly disintegrate become fine grained, finish drug administration process very easily; Also can place the Sublingual, medicine absorbs onset by mucosa after the disintegrate rapidly.It absorbs fast than the ordinary tablet preparation, bioavailability height and taking convenience.
Preparation oral cavity disintegration tablet preparation technology commonly used has freeze drying process, solid solution technology, drying process with atomizing and direct compression technology, first three plants maturation of technology, the product clinical effectiveness is more satisfactory, but cost height, complex process, need special installation, because direct compression technology is simple, existing increasing both at home and abroad oral cavity disintegration tablet adopts direct compression process to prepare.
The employing of direct compression fado has strong compressibility, the microcrystalline Cellulose of disintegrative is arranged as filler, add the stronger disintegrating agent of disintegrating property again, as direct compressions such as cross-linked carboxymethyl cellulose sodium (CCMSa), crospolyvinylpyrrolidone (PVPP), crosslinked carboxymethylstach sodium (CMSNa), low-substituted hydroxypropyl cellulose (L-HPC) and processing agar, make tablet disintegrate at short notice.The key for preparing oral cavity disintegration tablet with direct compression process is to seek the ratio of proper supplementary material and various adjuvants, and good fluidity when guaranteeing tabletting, compressibility is strong, disintegrate is fast, requires prepared tablet mouthfeel good in addition.
Disintegrate becomes fine grained because oral cavity disintegration tablet needs in the oral cavity in 30 seconds rapidly, often Ya Zhi oral cavity disintegration tablet hardness is all lower, packing needs special installation and packaging material, how in " oral cavity disintegration tablet development brief introduction " (clinical 2003 the 3rd volumes of the practical combination of Chinese and Western medicine), report earlier as Lee, such preparation Orally disintegrating effect is relatively good, but oral cavity disintegration tablet is because technologic characteristics, direct compression is with less pressure direct compression, therefore the hardness of finished product is less, general hardness is the 1-4 kilogram, crisp broken degree is higher, has the shortcoming that is difficult to guarantee its outward appearance integrity when storing and transporting.General packing adopts the plastic-aluminum blister, and this packing tool back of the body is taken off design.The oral cavity disintegration tablet hardness of report direct compression in " development progress of oral cavity disintegration tablet " (2004 the 7th volumes of Chinese pharmacist) such as Ma Ping is the 2-4 kilogram.The hardness of the oral cavity disintegration tablet of report direct compression in " development progress of oral cavity disintegration tablet " (2005 the 25th volumes of Chinese Hospitals pharmaceutical journal) such as Hu Xuelian is low, the general plastic-aluminum blister back of the body that adopts of packing is taken off package design, when using, the patient avoids damaging oral cavity disintegration tablet, and easily broken in the transportation.This shows quick releasing formulations such as oral cavity disintegration tablet, owing to need quick disintegrate, often the hardness ratio ordinary tablet is low, packaging facilities all needs to improve, and need special packing technique and material, so under the prerequisite that guarantees the quick disintegrate characteristics of oral cavity disintegration tablet, how to improve oral cavity disintegration tablet hardness and pack and solve in the transportation easily fragmentation etc. at ordinary packing equipment (as: aluminium-plastic bubble plate packing) and become the anxious technical issues that need to address of preparation research personnel to adapt to.
Existing Chinese patent application CN200410040023.1 " orally disintegrating tablet preparation of Aripiprazole and preparation method thereof " discloses the prescription and the preparation method of preparation aripiprazole orally disintegrating tablet.What this method adopted is direct powder compression.But the Aripiprazole oral cavity disintegration tablet according to this patented method preparation exists slice, thin piece hardness low, and breakable shortcoming, packing need to adopt special installation.It is mobile poor that research worker discovery simultaneously adopts this patented method amplification production Aripiprazole oral cavity disintegration tablet also to exist, and tablet weight variation is big, and yield rate is low, and the problem that production cost is high is difficult to realize industrialized big production.
Summary of the invention
For overcoming the above shortcoming that oral cavity disintegration tablet exists in the prior art, one aspect of the present invention provides a kind of pharmaceutical composition that contains Aripiprazole.The said composition prescription is simple, mature preparation process, guaranteeing to meet disintegration under the situation of oral cavity disintegration tablet prescription, adopt the aripiprazole orally disintegrating tablet hardness of common tablet manufacturing equipment preparation to reach 8-10kg, successfully solve oral cavity disintegration tablet and can not adopt the problem of general packaging facilities packing, and realized industrialized great production.
The present invention provides this preparation of drug combination method on the other hand.
The present invention is by the following technical solutions:
Aripiprazole is the active component during the present invention fills a prescription.The content of Aripiprazole accounts for the 1.0-5.0% of total formulation weight in prescription.The Aripiprazole raw material can prepare according to method described in European patent EP 367141A, U.S. Pat 4234585, the Chinese patent CN1028104C.
The pharmaceutical composition that contains Aripiprazole that the present invention relates to adopts direct powder compression, the prescription of the suitable preparation oral cavity disintegration tablet that provides is except that containing active component, also contain disintegrating agent and filler, can contain an amount of correctives, lubricant, fluidizer as required simultaneously.
Particularly, the pharmaceutical composition that contains Aripiprazole of the present invention, it contains:
Account for the Aripiprazole of pharmaceutical composition percentage by weight 1.25-5.00%
Account for the disintegrating agent of pharmaceutical composition percentage by weight 2.00-8.00%
Account for the microcrystalline Cellulose of pharmaceutical composition percentage by weight 45.00-63.43%
Account for the mannitol of pharmaceutical composition percentage by weight 20.00-41.60%;
Described disintegrating agent is selected from cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone or crosslinked carboxymethylstach sodium; The ratio of microcrystalline Cellulose and mannitol is between 1.2-3.0.
Microcrystalline Cellulose and mannitol are the filleies of pharmaceutical composition of the present invention.Can contain an amount of correctives, lubricant, fluidizer as required.Any one or more than one the mixture that for example, can contain an amount of aspartame, micropowder silica gel, magnesium stearate.
The preparation of drug combination method that more than contains Aripiprazole is: gets Aripiprazole and pulverizes, sieve, and standby; Take by weighing formula ratio adjuvant mix homogeneously, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, direct compression promptly, plain sheet hardness is the 8-10 kilogram.The oral cavity disintegration tablet that obtains has following feature simultaneously:
1, check disintegration: whole disintegrates are also by 26 mesh sieves in 30 seconds;
2, dissolution test: up to specification.
3, plain sheet hardness is the 8-10 kilogram.
Characteristics of the present invention are: filler is selected, found two kinds of proportion relations that filler is necessary, make the oral cavity disintegration tablet hardness height that is pressed into, solved the problem that normal packet installation (as: aluminium-plastic bubble plate packing) is packed; Also solve oral cavity disintegration tablet pilot scale on the conventional tablet production equipment simultaneously and amplified the problem of producing.Finishing key of the present invention is: the control of the selection of disintegrating agent, the selection of filler, microcrystalline Cellulose and mannitol ratio.
Further, preferred version of the present invention is
Comprise the pharmaceutical composition of Aripiprazole, it contains:
Account for the Aripiprazole of pharmaceutical composition percentage by weight 1.25-5.00%
Account for the polyvinylpolypyrrolidone of pharmaceutical composition percentage by weight 2.00-8.00%
Account for the microcrystalline Cellulose of pharmaceutical composition percentage by weight 45.00-63.43%
Account for the mannitol of pharmaceutical composition percentage by weight 20.00-41.60%;
The ratio of microcrystalline Cellulose and mannitol is between 1.2-3.0.Microcrystalline Cellulose and mannitol are filleies of the present invention.Can contain an amount of correctives, lubricant, fluidizer as required.Any one or more than one the mixture that for example, can contain an amount of aspartame, micropowder silica gel, magnesium stearate.
The preparation of drug combination method that more than contains Aripiprazole is: gets Aripiprazole and pulverizes, sieve, and standby; Take by weighing formula ratio adjuvant mix homogeneously, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, direct compression promptly, plain sheet hardness is the 8-10 kilogram.
The oral cavity disintegration tablet that obtains has following feature simultaneously:
1, check disintegration: whole disintegrates are also by 26 mesh sieves in 30 seconds;
2, dissolution test: up to specification.
3, plain sheet hardness is the 8-10 kilogram.
More preferably scheme of the present invention is:
Contain the pharmaceutical composition of Aripiprazole, it contains:
Account for the Aripiprazole of pharmaceutical composition percentage by weight 2.00-3.00%
Account for the polyvinylpolypyrrolidone of pharmaceutical composition percentage by weight 4.00-6.00%
Account for the microcrystalline Cellulose of pharmaceutical composition percentage by weight 45.00-55.00%
Account for the mannitol of pharmaceutical composition percentage by weight 30.00-37.50%
The ratio of microcrystalline Cellulose and mannitol is between 1.2-3.0.Microcrystalline Cellulose and mannitol are filleies of the present invention.Can contain an amount of correctives, lubricant, fluidizer as required.Any one or more than one the mixture that for example, can contain an amount of aspartame, micropowder silica gel, magnesium stearate.
The preparation of drug combination method that more than contains Aripiprazole is: gets Aripiprazole and pulverizes, sieve, and standby; Take by weighing formula ratio adjuvant mix homogeneously, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, direct compression promptly, plain sheet hardness is the 8-10 kilogram.The oral cavity disintegration tablet that obtains has following feature simultaneously:
1, check disintegration: whole disintegrates are also by 26 mesh sieves in 30 seconds;
2, dissolution test: up to specification.
3, plain sheet hardness is the 8-10 kilogram.
Most preferably one of scheme of the present invention is:
Aripiprazole 2.50%
Polyvinylpolypyrrolidone 5.17%
Microcrystalline Cellulose 50.00%
Mannitol 36.00%
Aspartame 0.33%
Micropowder silica gel 4.00%
Magnesium stearate 2.00%
The preparation of drug combination method that more than contains Aripiprazole is: gets Aripiprazole and pulverizes, sieve, and standby; Take by weighing formula ratio polyvinylpolypyrrolidone, microcrystalline Cellulose, mannitol, aspartame, micropowder silica gel, magnesium stearate mix homogeneously, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, direct compression promptly, plain sheet hardness is the 8-10 kilogram.
The oral cavity disintegration tablet that obtains has following feature simultaneously:
1, check disintegration: whole disintegrates are also by 26 mesh sieves in 30 seconds;
2, dissolution test: up to specification.
3, plain sheet hardness is the 8-10 kilogram.
Two of most preferably scheme of the present invention is:
Aripiprazole 5.00%
Polyvinylpolypyrrolidone 5.17%
Microcrystalline Cellulose 50.00%
Mannitol 33.50%
Aspartame 0.33%
Micropowder silica gel 4.00%
Magnesium stearate 2.00%
The preparation of drug combination method that more than contains Aripiprazole is: gets Aripiprazole and pulverizes, sieve, and standby; Take by weighing formula ratio polyvinylpolypyrrolidone, microcrystalline Cellulose, mannitol, aspartame, micropowder silica gel, magnesium stearate mix homogeneously, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, direct compression promptly, plain sheet hardness is the 8-10 kilogram.
The oral cavity disintegration tablet that obtains has following feature simultaneously:
1, check disintegration: whole disintegrates are also by 26 mesh sieves in 30 seconds;
2, dissolution test: up to specification.
3, plain sheet hardness is the 8-10 kilogram.
In optimized technical scheme, with reference to existing Orally disintegrating chip technology the hardness of the plain sheet of the present invention is studied, when plain sheet hardness is the 2-4 kilogram, disintegration time 15s.When plain sheet hardness is the 4-6 kilogram, disintegration time 20s.When plain sheet hardness is the 8-10 kilogram, disintegration time 25s.When hardness reached the 8-10 kilogram, the packing of oral cavity disintegration tablet can adopt common packaging facilities to carry out the packing of product fully.The solution of the technical program success the packaging Problems of common oral cavity disintegration tablet.
Oral cavity disintegration tablet is a kind of emerging dosage form, does not still have unified detection method at present.We have designed checkout gear disintegration voluntarily in line with embodying following some requirement: 1. the disintegrate medium is no more than 2 milliliters; 2. disintegrating procedue is in static state; 3. the control of granularity: the solution of disintegrate can pass through at least 26 mesh sieves in 30 seconds, and promptly particle diameter is less than 710 μ m.
Behind 30 seconds pistons of leaving behind, observe the above residue of screen cloth:
1. there are granule or bulk not to collapse the solids existence of loosing on the screen cloth, promptly are judged to and do not pass through greater than mesh;
2. do not have on the screen cloth and do not collapse the solids that looses greater than the granule of mesh or bulk and exist, promptly be judged to by, on the wax system drainage device if speckle with a little disintegration liquid, so long as not the obvious visible diffusing solids that do not collapse of naked eyes, also be judged to by.
6 of same batch sample follow-on tests, if there is more than 5 or 5 experiment all pass through, then this batch sample be judged to qualified; If have more than 1 and do not pass through, then get 6 in addition and reform, still have more than 1 by the time, then this batch sample be judged to defective, if there is more than 5 or 5 experiment pass through, then this batch sample be judged to qualified.
Dissolution test is according to 2005 editions " pertinent regulations under the Chinese pharmacopoeia appendix tablet item.
The invention will be further described below by concrete experimental program:
(1) selection of disintegrating agent
The kind of the oral cavity disintegration tablet disintegrating agent of bibliographical information is more, and the disintegrating agent that can adopt has low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, pregelatinized Starch, Sodium Hydroxymethyl Stalcs, carboxymethylcellulose calcium, cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, crosslinked carboxymethylstach sodium etc.The inventor studies above disintegrating agent, finds to adopt low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, pregelatinized Starch, Sodium Hydroxymethyl Stalcs, carboxymethylcellulose calcium to have significant difference with cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, crosslinked carboxymethylstach sodium as single disintegrating agent in the technical program as single disintegrating agent in the technical program.Concrete condition is as follows:
We adopt prescription: Aripiprazole 2.50%, disintegrating agent 5.17%, microcrystalline Cellulose 50.00%, mannitol 36.00%, aspartame 0.33%, micropowder silica gel 4.00%, magnesium stearate 2.00%.Carry out direct powder compression, plain sheet hardness is respectively 2-4 kilogram, 5-7 kilogram, 8-10 kilogram.The numbering of disintegrating agent is respectively: 1 low-substituted hydroxypropyl cellulose, 2 microcrystalline Cellulose, 3 pregelatinized Starch, 4 Sodium Hydroxymethyl Stalcses, 5 carboxymethylcellulose calciums, 6 cross-linked carboxymethyl cellulose sodium, 7 polyvinylpolypyrrolidone, 8 crosslinked carboxymethylstach sodium.
With the requirement of oral cavity disintegration tablet relatively, adopt low-substituted hydroxypropyl cellulose, microcrystalline Cellulose, pregelatinized Starch, Sodium Hydroxymethyl Stalcs, when the plain sheet hardness of carboxymethylcellulose calcium prescription is the 2-4 kilogram, disintegration time 60s is qualified.With cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone, crosslinked carboxymethylstach sodium is the plain sheet hardness of prescription of disintegrating agent when being the 2-4 kilogram, and disintegration time 15s is qualified, and when plain sheet hardness was the 5-7 kilogram, disintegration time 20s was qualified.When plain sheet hardness was the 8-10 kilogram, disintegration time 25s was qualified, and disintegration time is all within 30 seconds kinds.Concrete data see Table 1:
The disintegration time of the different disintegrating agent prescriptions of table 1 under different hardness
| Disintegrating agent | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 |
| Hardness 2-4 kilogram | 55s | 60s | 60s | 55s | 55 | 15s | 15s | 15s |
| Hardness 5-7 kilogram | 70s | 80s | 75s | 75s | 70 | 20s | 20s | 20s |
| Hardness 8-10 kilogram | 90s | 100s | 90s | 90s | 95 | 25s | 25s | 25s |
The inventor discovers to the ratio of each prescription that through concrete experiment the consumption of disintegrating agent has effect preferably when accounting between total formulation weight 2.00-8.00%.In the method that adopts direct powder compression, the content of disintegrating agent accounts for total formulation weight greater than 8.00% as the disintegrating agent of the present invention prescription, and dispersing uniformity is defective, and is also defective less than 2.00%.Exceed this scope, just do not meet the specification requirement of oral cavity disintegration tablet.Specifically see Table 2 and table 3.
Disintegrating agent can carry out equivalent to polyvinylpolypyrrolidone for two kinds with crosslinked carboxymethylstach sodium (CCMS-Na), cross-linked carboxymethyl cellulose sodium and replace.It the results are shown in Table 4 and table 5.
The prescription of table 2 different components ratio
| Component the prescription | 1 | 2 | 3 | 4 | 5 | 6 |
| Aripiprazole | 2.50 | 1.25 | 5.00 | 2.50 | 2.50 | 2.50 |
| Polyvinylpolypyrrolidone | 5.17 | 8.00 | 2.00 | 1.00 | 9.00 | 10.00 |
| Microcrystalline Cellulose | 50.00 | 63.43 | 46.90 | 60.17 | 47.00 | 60.00 |
| Mannitol | 36.00 | 21.12 | 39.10 | 30.00 | 35.17 | 21.17 |
| Aspartame | 0.33 | 0.20 | 1.00 | 0.33 | 0.33 | 0.33 |
| Micropowder silica gel | 4.00 | 4.00 | 4.00 | 4.00 | 4.00 | 4.00 |
| Magnesium stearate | 2.00 | 2.00 | 2.00 | 2.00 | 2.00 | 2.00 |
The disintegrate of table 3 various combination composition formula and the situation of relevant nature
| Project the prescription | 1 | 2 | 3 | 4 | 5 | 6 |
| Mobile | Qualified | Qualified | Qualified | Qualified | Qualified | Defective |
| Compressibility | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Tablet appearance | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Hardness | 8-10 | 8-10 | 8-10 | >12 | 5-7 | 6-8 |
| Disintegrate | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Overall merit | Qualified | Qualified | Qualified | Defective | Defective | Defective |
Table 4 is the disintegrate of composite formula of disintegrating agent and the situation of relevant nature with crosslinked carboxymethylstach sodium
| Project the prescription | 1 | 2 | 3 | 4 | 5 | 6 |
| Mobile | Qualified | Qualified | Qualified | Qualified | Qualified | Defective |
| Compressibility | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Tablet appearance | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Hardness | 8-10 | 8-10 | 8-10 | >12 | 5-7 | 6-8 |
| Disintegrate | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Overall merit | Qualified | Qualified | Qualified | Defective | Defective | Defective |
Table 5 is the disintegrate of composite formula of disintegrating agent and the situation of relevant nature with cross-linked carboxymethyl cellulose sodium
| Project the prescription | 1 | 2 | 3 | 4 | 5 | 6 |
| Mobile | Qualified | Qualified | Qualified | Qualified | Qualified | Defective |
| Compressibility | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Tablet appearance | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Hardness | 8-10 | 8-10 | 8-10 | >12 | 5-7 | 6-8 |
| Disintegrate | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Overall merit | Qualified | Qualified | Qualified | Defective | Defective | Defective |
(2) selection of filler
Filler adopts in the method for direct powder compression in the present invention, is the mixture of the mannitol of the microcrystalline Cellulose that contains total formulation weight 45.00-63.43% and total formulation weight 20-41.60%.The ratio of microcrystalline Cellulose and mannitol is between 1.2-3.0 the time, the tablet of being pressed specification requirement according to the invention.Simultaneously, lactose and xylitol can not be as the filleies of the present invention's prescription.
The inventor discovers by comparative test: lactose can not be replaced the filler of microcrystalline Cellulose as the present invention's prescription.Microcrystalline Cellulose and lactose are compared research, with the lactose is the compositions (prescription 5,6,7) of filler, its non-conformity of quality closes requirement of the present invention, and be the compositions (1,2,3,4) of filler with the microcrystalline Cellulose, the complete requirement according to the invention of its quality, whole disintegrates are also by 26 mesh sieves in 30 seconds.Concrete the results are shown in Table 6 and table 7:
The compositions of table 6 microcrystalline Cellulose and lactose
| Component the prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Aripiprazole | 2.50 | 1.25 | 5.00 | 5.00 | 2.50 | 1.25 | 5.00 |
| Polyvinylpolypyrrolidone | 5.17 | 8.00 | 2.00 | 5.17 | 5.17 | 8.00 | 2.00 |
| Microcrystalline Cellulose | 50.00 | 63.43 | 46.90 | 50.00 | - | - | - |
| Lactose | - | - | - | - | 46.90 | 63.43 | 50.00 |
| Mannitol | 36.00 | 21.12 | 39.10 | 33.50 | 39.10 | 21.12 | 38.00 |
| Aspartame | 0.33 | 0.20 | 1.00 | 0.33 | 0.33 | 0.20 | 1.00 |
| Micropowder silica gel | 4.00 | 4.00 | 4.00 | 4.00 | 4.00 | 5.00 | 1.00 |
| Magnesium stearate | 2.00 | 2.00 | 2.00 | 2.00 | 2.00 | 1.00 | 3.00 |
The disintegrate of the composite formula of the different diluent of table 7 and the situation of relevant nature
| Project the prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Mobile | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Compressibility | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Tablet appearance | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Hardness | 8-10 | 8-10 | 8-10 | 8-10 | 6-8 | 6-8 | >12 |
| Disintegrate | Qualified | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Overall merit | Qualified | Qualified | Qualified | Qualified | Defective | Defective | Defective |
The inventor discovers by comparative test: xylitol can not be replaced the filler of mannitol as the present invention's prescription.Mannitol and xylitol are compared research, with the xylitol is the compositions (prescription 5,6,7) of filler, its non-conformity of quality closes requirement of the present invention, and be the compositions (1,2,3,4) of filler with mannitol, the complete requirement according to the invention of its quality, whole disintegrates are also by 26 mesh sieves in 30 seconds.Concrete the results are shown in Table 8 and table 9:
The compositions of table 8 mannitol and xylitol
| Component the prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Aripiprazole | 2.50 | 1.25 | 5.00 | 5.00 | 2.50 | 1.25 | 5.00 |
| Polyvinylpolypyrrolidone | 5.17 | 8.00 | 2.00 | 5.17 | 5.17 | 8.00 | 2.00 |
| Microcrystalline Cellulose | 50.00 | 63.43 | 46.90 | 50.00 | 63.43 | 46.90 | 50.00 |
| Xylitol | - | - | - | - | 21.12 | 39.10 | 38.00 |
| Mannitol | 36.00 | 21.12 | 39.10 | 33.50 | - | - | - |
| Aspartame | 0.33 | 0.20 | 1.00 | 0.33 | 0.33 | 0.20 | 1.00 |
| Micropowder silica gel | 4.00 | 4.00 | 4.00 | 4.00 | 4.00 | 5.00 | 1.00 |
| Magnesium stearate | 2.00 | 2.00 | 2.00 | 2.00 | 2.00 | 1.00 | 3.00 |
The disintegrate of the composite formula of the different cosolvents of table 9 and the situation of relevant nature
| Project the prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Mobile | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Compressibility | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Tablet appearance | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Hardness | 8-10 | 8-10 | 8-10 | 8-10 | 6-8 | 6-8 | >12 |
| Disintegrate | Qualified | Qualified | Qualified | Qualified | Defective | Defective | Defective |
| Overall merit | Qualified | Qualified | Qualified | Qualified | Defective | Defective | Defective |
On the usage ratio of microcrystalline Cellulose and mannitol, the inventor finds through screening experiment: the ratio of microcrystalline Cellulose and mannitol is between 1.2-3.0 the time, the tablet of being pressed specification requirement according to the invention.In the method for employing direct powder compression of the present invention, the ratio of microcrystalline Cellulose and mannitol (prescription 4,5,6,7) its non-conformity of quality outside 1.2-3.0 closes requirement of the present invention, the ratio of microcrystalline Cellulose and mannitol is (prescription 1,2,3) within 1.2-3.0, effect is preferably arranged, the complete requirement according to the invention of its quality, all disintegrate is also by 26 mesh sieves in 30 seconds, and slice, thin piece hardness satisfies the ordinary packing equipment requirements simultaneously.Concrete the results are shown in Table 10 and table 11:
The compositions of table 10 microcrystalline Cellulose and mannitol different proportion
| Component the prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Aripiprazole | 2.50 | 1.25 | 5.00 | 2.00 | 2.50 | 1.25 | 5.00 |
| Polyvinylpolypyrrolidone | 5.17 | 8.00 | 2.00 | 7.17 | 2.17 | 8.00 | 5.00 |
| Microcrystalline Cellulose | 50.00 | 63.43 | 46.92 | 65.00 | 48.00 | 45.55 | 63.00 |
| Mannitol | 36.00 | 21.67 | 39.08 | 21.00 | 41.00 | 39.00 | 20.00 |
| Aspartame | 0.33 | 0.77 | 1.00 | 0.33 | 0.33 | 0.20 | 1.00 |
| Micropowder silica gel | 4.00 | 2.88 | 4.00 | 3.00 | 4.00 | 4.00 | 4.00 |
| Magnesium stearate | 2.00 | 2.00 | 2.00 | 1.50 | 2.00 | 2.00 | 2.00 |
The disintegrate of the composite formula of the different cosolvents of table 11 and the situation of relevant nature
| Project the prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 |
| Mobile | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Compressibility | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Tablet appearance | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified | Qualified |
| Hardness | 8-10 | 8-10 | 8-10 | 8-10 | 6-8 | 6-8 | >12 |
| Disintegrate | Qualified | Qualified | Qualified | Defective | Defective | Defective | Defective |
| Overall merit | Qualified | Qualified | Qualified | Defective | Defective | Defective | Defective |
Beneficial effect of the present invention is:
1. successfully realize industrialized great production: by to the adjuvant of aripiprazole drug substance compositions and the selection of adjuvant ratio, aripiprazole orally disintegrating tablet hardness and the contradiction of disintegration have successfully been solved, aripiprazole orally disintegrating tablet hardness of the present invention is good, and disintegrate is rapid;
2. solve the difficult problem of packing: by to the adjuvant of aripiprazole drug substance compositions and the selection of adjuvant ratio, solved the low problem that can't pack with conventional equipment of slice, thin piece hardness, reduced production cost.With respect to prior art, the equipment that technical scheme of the present invention is used is the sheeting equipment and the packaging facilities of general ordinary tablet, the slice, thin piece hardness of being pressed is at 8-10Kg, and is suitable with the hardness of ordinary tablet, successfully solves the problem that adopts common packer packing oral cavity disintegration tablet.
Be further instruction beneficial effect of the present invention, the inventor has carried out comparative study to the technical scheme of technical solution of the present invention and Chinese patent application " orally disintegrating tablet preparation of Aripiprazole and preparation method thereof " (number of patent application is CN200410040023.1), and concrete experimental result is as follows:
Reference embodiment 1 (Chinese patent application CN200410040023.1 embodiment 3)
Composition % (counting by weight percentage)
Aripiprazole 2%
Polyvinylpolypyrrolidone 5%
Microcrystalline Cellulose 40%
Mannitol 49.5%
Aspartame 0.5%
Micropowder silica gel 1.5%
Magnesium stearate 1.5%
Reference embodiment 2 (Chinese patent application CN200410040023.1 embodiment 15)
Composition % (counting by weight percentage)
Aripiprazole 2%
Cross-linked carboxymethyl cellulose sodium 5%
Microcrystalline Cellulose 40%
Mannitol 49.5%
Aspartame 0.5%
Micropowder silica gel 1.5%
Magnesium stearate 1.5%
With identical Aripiprazole raw material, adopt the reference embodiment 1,2 and the Orally disintegrating of 1 two kinds of different preparation of compositions of the embodiments of the invention sheet of determining, guarantee its of unanimity disintegration, the hardness of its plain sheet has bigger difference.The hardness of oral cavity disintegration tablet that adopts technical scheme gained of the present invention is much larger than the hardness of reference embodiment, and concrete data see Table 12
The hardness of table 12 various combination composition formula and the situation of relevant nature
| Project the prescription | Reference embodiment 1 | Reference embodiment 2 | Embodiment 1 |
| Disintegrate | 28 seconds | 30 seconds | 27 seconds |
| Mobile | 40° | 42° | 35° |
| Compressibility | It is big to lay particular stress on difference | It is big to lay particular stress on difference | It is little to lay particular stress on difference |
| Tablet appearance | Relatively poor | Relatively poor | Smooth |
| Hardness | 3-4 | 3-4 | 8-10 |
| Packing Condition | It is big to need extra package equipment slice, thin piece to damage | It is big to need extra package equipment slice, thin piece to damage | Ordinary packing equipment does not almost have damage |
From above comparative test as can be seen, the present invention passes through adjuvant, especially to the control of microcrystalline Cellulose and mannitol ratio, when guaranteeing the every index of oral cavity disintegration tablet, suitability for industrialized production and the beneficial effect that can pack with ordinary packing equipment have been realized.
The specific embodiment
Come below by embodiment that further the present invention will be described, but the present invention is not limited to following examples.
Embodiment 1-embodiment 9 sees Table 13:(and calculates by weight)
Table 13 embodiment 1-9
| Component the prescription | 1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 |
| Aripiprazole | 2.50 | 1.25 | 5.00 | 5.00 | 3.00 | 2.00 | 4.50 | 3.00 | 4.50 |
| Polyvinylpolypyrrolidone | 5.17 | 8.00 | 2.00 | 5.17 | 5.17 | 4.00 | 7.00 | 6.00 | 4.00 |
| Microcrystalline Cellulose | 50.00 | 63.43 | 46.92 | 50.00 | 55.00 | 49.90 | 60.00 | 45.00 | 49.90 |
| Mannitol | 36.00 | 21.12 | 39.08 | 33.50 | 30.00 | 41.60 | 20.00 | 37.50 | 41.60 |
| Aspartame | 0.33 | 0.20 | 1.00 | 0.33 | 0.33 | - | 0.50 | 1.00 | - |
| Micropowder silica gel | 4.00 | 4.00 | 4.00 | 4.00 | 5.00 | 2.00 | 5.00 | 4.50 | - |
| Magnesium stearate | 2.00 | 2.00 | 2.00 | 2.00 | 1.50 | 0.50 | 3.00 | 3.00 | - |
Preparation method is:
Get Aripiprazole and pulverize, sieve, standby; Take by weighing formula ratio polyvinylpolypyrrolidone, microcrystalline Cellulose, mannitol and other adjuvant mix homogeneously, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, and direct compression promptly.
The oral cavity disintegration tablet that obtains has following feature:
1, check disintegration: whole disintegrates are also by 26 mesh sieves in 30 seconds;
2, dissolution test: up to specification.
3, plain sheet hardness is the 8-10 kilogram.
Embodiment 10-embodiment 18 sees Table 14:(and calculates by weight)
Table 14 embodiment 10 to 18
| Component the prescription | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 |
| Aripiprazole | 2.50 | 1.25 | 5.00 | 5.00 | 3.00 | 2.00 | 5.00 | 3.00 | 4.50 |
| Crosslinked carboxymethylstach sodium | 5.17 | 8.00 | 2.00 | 5.17 | 5.17 | 4.00 | 8.00 | 6.00 | 4.00 |
| Microcrystalline Cellulose | 50.00 | 63.43 | 46.92 | 50.00 | 55.00 | 49.90 | 60.00 | 45.00 | 49.90 |
| Mannitol | 36.00 | 21.12 | 39.08 | 33.50 | 30.00 | 41.60 | 20.00 | 37.50 | 41.60 |
| Aspartame | 0.33 | 0.20 | - | 0.33 | 0.33 | 0.5 | 2.00 | 1.00 | - |
| Micropowder silica gel | 4.00 | 4.00 | 5.00 | 4.00 | 5.00 | - | 5.00 | 4.50 | - |
| Magnesium stearate | 2.00 | 2.00 | 2.00 | 2.00 | 1.50 | 2.00 | - | 3.00 | - |
Preparation method is:
Get Aripiprazole and pulverize, sieve, standby; Take by weighing the crosslinked carboxymethylstach sodium of formula ratio, microcrystalline Cellulose, mannitol and other adjuvant mix homogeneously, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, and direct compression promptly.
The oral cavity disintegration tablet that obtains has following feature:
1, check disintegration: whole disintegrates are also by 26 mesh sieves in 30 seconds;
2, dissolution test: up to specification.
3, plain sheet hardness is the 8-10 kilogram.
Embodiment 19 embodiment 27 see Table 15:(and calculate by weight)
Table 15 embodiment 19 to 27
| Component the prescription | 19 | 20 | 21 | 22 | 23 | 24 | 25 | 26 | 27 |
| Aripiprazole | 2.50 | 1.25 | 5.00 | 5.00 | 3.00 | 2.00 | 5.00 | 3.00 | 4.50 |
| Cross-linked carboxymethyl cellulose sodium | 5.17 | 8.00 | 2.00 | 5.17 | 5.17 | 4.00 | 8.00 | 6.00 | 4.00 |
| Microcrystalline Cellulose | 50.00 | 63.43 | 46.92 | 50.00 | 55.00 | 49.90 | 60.00 | 45.00 | 49.90 |
| Mannitol | 36.00 | 21.12 | 39.08 | 33.50 | 30.00 | 41.60 | 20.00 | 37.50 | 41.60 |
| Aspartame | 0.33 | 0.20 | 1.00 | 0.33 | 0.33 | - | 2.00 | 1.00 | - |
| Micropowder silica gel | 4.00 | 4.00 | 4.00 | 4.00 | 5.00 | 2.00 | 5.00 | 4.50 | - |
| Magnesium stearate | 2.00 | 2.00 | 2.00 | 2.00 | 1.50 | 0.50 | - | 3.00 | - |
Preparation method is:
Get Aripiprazole and pulverize, sieve, standby; Take by weighing formula ratio cross-linked carboxymethyl cellulose sodium, microcrystalline Cellulose, mannitol and other adjuvant mix homogeneously, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, and direct compression promptly.
The oral cavity disintegration tablet that obtains has following feature:
1, check disintegration: whole disintegrates are also by 26 mesh sieves in 30 seconds;
2, dissolution test: up to specification.
3, plain sheet hardness is the 8-10 kilogram.
Claims (7)
1. a pharmaceutical composition that contains Aripiprazole is characterized in that, and is composed of the following components:
Account for the Aripiprazole of pharmaceutical composition percentage by weight 1.25-5.00%
Account for the disintegrating agent of pharmaceutical composition percentage by weight 2.00-8.00%
Account for the microcrystalline Cellulose of pharmaceutical composition percentage by weight 45.00-63.43%
Account for the mannitol of pharmaceutical composition percentage by weight 20.00-41.60%
Described disintegrating agent is selected from cross-linked carboxymethyl cellulose sodium, polyvinylpolypyrrolidone or crosslinked carboxymethylstach sodium; The ratio of microcrystalline Cellulose and mannitol is between 1.2-3.0.
2. according to the pharmaceutical composition that contains Aripiprazole of claim 1, it is characterized in that also containing any one or more than one the mixture of aspartame, micropowder silica gel, magnesium stearate.
3. according to the pharmaceutical composition that contains Aripiprazole of claim 1 or 2, it is characterized in that described disintegrating agent is a polyvinylpolypyrrolidone.
4. according to the pharmaceutical composition that contains Aripiprazole of claim 1, it is characterized in that the percentage by weight of described each component is:
Account for the Aripiprazole of pharmaceutical composition percentage by weight 2.00-3.00%
Account for the polyvinylpolypyrrolidone of pharmaceutical composition percentage by weight 4.00-6.00%
Account for the microcrystalline Cellulose of pharmaceutical composition percentage by weight 45.00-55.00%
Account for the mannitol of pharmaceutical composition percentage by weight 30.00-37.50%.
5. according to the pharmaceutical composition that contains Aripiprazole of claim 3, it is characterized in that described component and percentage by weight are:
Aripiprazole 2.50%
Polyvinylpolypyrrolidone 5.17%
Microcrystalline Cellulose 50.00%
Mannitol 36.00%
Aspartame 0.33%
Micropowder silica gel 4.00%
Magnesium stearate 2.00%.
6. according to the pharmaceutical composition that contains Aripiprazole of claim 3, it is characterized in that described component and percentage by weight are:
Aripiprazole 5.00%
Polyvinylpolypyrrolidone 5.17%
Microcrystalline Cellulose 50.00%
Mannitol 33.50%
Aspartame 0.33%
Micropowder silica gel 4.00%
Magnesium stearate 2.00%.
7. each described preparation of drug combination method that contains Aripiprazole among the claim 1-6, concrete steps are: get Aripiprazole and pulverize, sieve, standby; Take by weighing the adjuvant mix homogeneously of formula ratio, get the adjuvant mixture; Take by weighing the formula ratio Aripiprazole, with equivalent progressively increase method and adjuvant mixture mix homogeneously; Measure the mixture content of dispersion, it is heavy to calculate sheet, and direct compression promptly.
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| CN102218040A (en) * | 2010-04-13 | 2011-10-19 | 齐鲁制药有限公司 | Oral disintegrating tablets of microcrystallites of aripiprazole composition and preparation method thereof |
| CN104622824A (en) * | 2015-01-27 | 2015-05-20 | 美吉斯制药（厦门）有限公司 | Aripiprazole orally disintegrating tablet and preparation method thereof |
| CN106913548A (en) * | 2015-12-28 | 2017-07-04 | 药源药物化学（上海）有限公司 | A kind of Aripiprazole oral disintegrating tablet and preparation method thereof |
| CN106389343A (en) * | 2016-09-24 | 2017-02-15 | 万全万特制药江苏有限公司 | Oral aripiprazole liquid dry suspension agent and preparation method thereof |
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| CN1317309A (en) * | 2000-04-12 | 2001-10-17 | 布里斯托尔-迈尔斯斯奎布公司 | Instant oral medincinal preparation |
| CN1561200A (en) * | 2001-10-09 | 2005-01-05 | 布里斯托尔·迈尔斯斯奎布公司 | Flashmelt oral dosage formulation |
| CN1658843A (en) * | 2002-02-15 | 2005-08-24 | 大塚制药株式会社 | Tablets having improved tabletting characteristics and process for producing the same |
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