CN101829333B - New multi-functional auxiliary material for orally disintegrating tablets and preparation method thereof - Google Patents
New multi-functional auxiliary material for orally disintegrating tablets and preparation method thereof Download PDFInfo
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- CN101829333B CN101829333B CN2010101841947A CN201010184194A CN101829333B CN 101829333 B CN101829333 B CN 101829333B CN 2010101841947 A CN2010101841947 A CN 2010101841947A CN 201010184194 A CN201010184194 A CN 201010184194A CN 101829333 B CN101829333 B CN 101829333B
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Abstract
The invention relates to a multi-functional auxiliary material for orally disintegrating tablets and a preparation method thereof, and belongs to the field of pharmacy. The preparation method comprises the following steps of: weighting and mixing mannitol, isosorbide and crospovidone; under the condition of using water as a solvent, carrying out high-shear dispersion on the obtained mixture so as to obtain solution; and then carrying out spray drying on the solution to obtain the new multi-functional auxiliary material.
Description
Technical field
The invention belongs to pharmaceutical field, relate to multi-functional auxiliary material of a kind of oral cavity disintegration tablet and preparation method thereof.
Background technology
State Food and Drug Administration (SFDA) medicine is examined the center and the definition of oral cavity disintegration tablet is meant to be defined as after taking can in the oral cavity, not be needed water or seldom water gaging can disintegrate or dissolved tablet; Can be in the oral cavity quick disintegrate or rapidly-soluble solid preparation; Oral cavity quick disintegrating slice has rapid release and takes advantage easily; Particularly the patient for old people, child and dysphagia uses traditional tablet, capsule, pill and solution to have difficulties, and oral cavity disintegration tablet is because it has the research focus that above-mentioned advantage just becomes novel form in the medicament field.Domesticly evaluate the center at national drug in 2003 and formally oral cavity disintegration tablet and oral instant-dissolving tablet are unified called after oral cavity disintegration tablet (Orally disintegrating tablets), and evaluate as new preparation formulation.It is following to the specification requirement of oral cavity disintegration tablet that country's medicine is examined the center: (1). should be in the oral cavity rapidly disintegrate, no grittiness, good mouthfeel, swallow easily, to the oral mucosa nonirritant.(2). set up suitable disintegration, and be incorporated into standard.(3) should set up suitable dissolution determination method and limit to insoluble drug.(4). the general requirement of other tablet should be met, but friability can be do not measured.
The method for preparing of oral cavity disintegration tablet has moulded tablet, lyophilization etc., but direct compression process is the development in future direction.Direct compression process technology is simple, the big production of easy realization of industrialization, but adjuvant is required high.The binding agent slice, thin piece that should be able to well bond, it is too high to be unlikely to hardness again, and can rapid expanding after the disintegrating agent that the adds suction, and it is diffusing that tablet is collapsed.Because the density of various adjuvants, flowability etc. there are differences, and often cause between the tablet widely different.Adjuvant processing back is formed premixing auxiliary material, can greatly improve the performance of adjuvant.
Wherein disintegrating agent is meant and adds in the tablet in order to overcome the required physical force of binding agent and tabletting; And can impel tablet rapid disintegrate in gastro-intestinal Fluid to become the adjuvant of small-particle; The disintegrate of tablet and stripping be the speed limit process for absorbing often, and the fine difference of dissolution in vitro may cause the significant difference of bioavailability in the body.Disintegrating agent early mainly contains surfactants such as starch, pregelatinized Starch, crystalline cellulose element, chitin and some gas-producing disintegrants (like carbonate and citric acid etc.), sodium lauryl sulphate.In recent years, some novel efficient tablet disintegrants have appearred in succession, like carboxymethyl starch sodium, low-substituted hydroxypropyl cellulose, crospolyvinylpyrrolidone, cross-linking sodium carboxymethyl cellulose etc. again.Granular sensation after the powerful disintegrating agent disintegrate commonly used is all heavier; Mouthfeel is bad, user's dysaesthesia, and also the grain density of these disintegrating agents is less; Mobile poor; Be difficult to mix homogeneously with principal agent and other adjuvants, it is big to be prone to tablet weight variation during direct compression, quality problems such as finished product disintegration time difference is big.
This laboratory is surprised to find in the oral cavity disintegration tablet research process; After in mannitol, adding an amount of isosorbide, the tablet hardness of gained is suitable, and tracing it to its cause possibly be because its fusing point is lower; Melt formation liquid bridge in the effect of the heat of compression, played the effect of binding agent.
Summary of the invention
The objective of the invention is to solve the deficiency of prior art, a kind of multi-functional auxiliary material of oral cavity disintegration tablet is provided.
According to the invention that adjuvant has good flowability and disintegrative, and have the adjuvant of certain binding agent function, this adjuvant can be widely used in various oral solid formulations, is particularly useful for direct compression process and prepares oral cavity disintegration tablet.
Adjuvant of the present invention is 11.2～20.0: 2.8～5.0 by percentage by weight mainly: 1.0 mannitol, isosorbide and polyvinylpolypyrrolidone are processed into.
Preferred adjuvant of the present invention, be 12.8～16.0: 3.2～4.0 by percentage by weight: 1 mannitol, isosorbide and polyvinylpolypyrrolidone are processed into.
Another object of the present invention is to provide the method for preparing of said excipient substance
Method for preparing of the present invention may further comprise the steps:
Get mannitol by weight ratio, isosorbide and polyvinylpolypyrrolidone mix, and are being under the condition of solvent with water, after high shear disperses, form solution, and spray drying promptly gets.
Preferably, method for preparing of the present invention may further comprise the steps:
1) take by weighing mannitol by weight, three kinds of materials of isosorbide and polyvinylpolypyrrolidone drop into retort;
2) in retort, adding weight is the deionized water of 0.2～0.8 times of three kinds of material gross weight, stirs being heated under 55～60 ℃ of conditions, forms solution;
3) solution is cooled to 26～30 ℃ with the speed of 2～4 ℃/h, makes mannitol and isosorbide crystallization form brilliant cake;
4) use centrifugal spray drier, under 60～90 ℃ of conditions of temperature, with 3) product spray drying, promptly get.
Wherein, in the above-mentioned step 2, the deionized water weight that preferably feeds intake is 0.3～0.5 of three kinds of material gross weights, and preferred crystalline condition is 58 ℃,
In above-mentioned steps 3, the speed of cooling is 3 ℃/h, and the cooling outlet temperature is 28 ℃.
In above-mentioned step 4, the centrifugal spray drying temperature is preferably 80 ℃.
The most preferred method for preparing of the present invention in an embodiment.
Pharmaceutic adjuvant of the present invention can be widely used in various oral solid formulations, is particularly useful for direct compression process and prepares oral cavity disintegration tablet.
The multi-functional auxiliary material of oral cavity disintegration tablet of the present invention is based on the efficient disintegrating agent polyvinylpolypyrrolidone basis, is main component with mannitol and isosorbide.Wherein isosorbide is a kind of low melting point adjuvant, can improve the compressibility of oral cavity disintegration tablet.On the other hand, the low melting point sugar alcohol can play the effect of binding agent under the effect of the heat of compression.Method commonly used at present is about to the direct spray drying of solution of these two kinds of compositions, and the finished particle density of gained is smaller, and is mobile poor.And by a kind of " brilliant cake " of the present invention method centrifugal spray drying technology, the products obtained therefrom grain density is big, good fluidity.This product has kept mannitol and the good mouthfeel of isosorbide, has better flowability and superior disintegrate ability.
Relatively further specify beneficial effect of the present invention through following experiment.
With the adjuvant of gained of the present invention and independent mannitol, isosorbide, polyvinylpolypyrrolidone with and the compositions that mixes carry out performance relatively, estimate by following mode.
Powder fluidity: the flowability of powder body is bigger to the weight differential and the normal running influence of preparations such as granule, capsule, tablet, as far as direct compression, more requires to have higher flowability.The flowability of powder body can't be expressed with single characteristic value, representes angle of repose commonly used.Be meant the free inclined-plane and the formed maximum angular of horizontal plane of powder body accumulation horizon angle of repose.Angle of repose is more little, and frictional force is more little, and flowability is good more, it is generally acknowledged good fluidity when θ≤30 are spent, and can satisfy the need for liquidity in the production process when θ≤40 are spent.
Disintegration time: oral cavity disintegration tablet is as a kind of special dosage form, and one of its technical essential is the disintegration time of control tablet in the oral cavity.Method commonly used at present is the dissolution improved method in the Japanese Pharmacopoeia, installs mainly by stripping rotor, and stirring arm, the disintegrate basket is formed.The screen cloth that it adopted is 10 orders, and is screen cloth all on four sides, and after the stirring, water runs through screen cloth with fast speeds, and slice, thin piece is caused bigger mechanical impulse force.The granularity that this method is used for controlling oral cavity disintegration tablet seems too loose, so we change stainless steel mesh into 30 orders with reference to the oral cavity disintegration tablet meeting summary, and with the disintegrate basket be designed to can only the bottom surface water inlet form.Concrete disintegrating method process is following: the distilled water that adds 37 ℃ of 900mL is fixed on disintegrate basket such as figure on the stripping wall of cup in stripping rotor, and its upper end flushes (water volume is 1.99mL in the disintegrate basket) with the water surface, and mixing speed is adjusted to 100r/min; Oral cavity disintegration tablet drops in the disintegrate basket, and record is the disintegration time of oral cavity disintegration tablet from dropping into tablet till the basic noresidue to the screen cloth during this period of time.The method for preparing of oral cavity disintegration tablet to be measured is: do not adding in addition under the situation of other adjuvant, adjuvant under identical compression force that each is to be compared is pressed into blank.
Mouthfeel: test the comparison mouthfeel with the volunteer, select 8 healthy volunteers, 4 male 4 woman wherein, the age was explained the purpose and the meaning of test to it between 20～32 years old.Every volunteer sucks 1 blank oral cavity disintegration tablet at every turn, normal talk and activity during the pastille, but must not drink water, to the complete disintegrate of slice, thin piece; Spue, gargle, write down every volunteer's the impression of taking with normal saline; With+represent the evaluation of volunteer to mouthfeel, be divided into level Four ,+for poor; ++ for generally, +++be better, ++ ++ for fine.
Lustrous surface: visualization
Frangible degree: get 10 of oral cavity quick disintegrating slices, place tablet friability somascope, rotate 100 times, take out and observe.Comparative result sees following table for details:
Annotate: I is identical with the ratio of this aspect adjuvant mannitol, isosorbide for the contrast adjuvant, forms through simple mix homogeneously; Contrast adjuvant II has identical component with contrast adjuvant I, is directly the solution spray drying is prepared from through routine.
Through above-mentioned test, we can draw as drawing a conclusion:
1, mannitol, isosorbide, polyvinylpolypyrrolidone are carried out the simple combination of arbitrary proportion; Its direct compression adjuvant as oral cavity disintegration tablet all is difficult to be suitable for (though disintegration time was a little less than 1 minute; But be higher than 40 its angle of repose, can't satisfy and produce required flowability basically)
What 2, contrast adjuvant II was adopted is the direct spray drying process of conventional soln, though disintegration time is compared short a little point with this aspect adjuvant, its angle of repose is very big, and is mobile very poor, can't satisfy the basic demand of adjuvant.
3, pharmaceutic adjuvant of the present invention is in angle of repose, disintegration time, and mouthfeel, aspects such as lustrous surface and frangible degree all are superior to other matched groups.
In sum, pharmaceutic adjuvant good mouthfeel of the present invention, disintegration rate is fast, good stability, and can bring into play the function of binding agent, and reduce or avoid the adding of other binding agent class adjuvant, can effectively improve the content of dispersion of preparation.The method for preparing of pharmaceutic adjuvant of the present invention is simple, and cost is low, and industrialization production feasibility is big.
The specific embodiment
Below in conjunction with specific embodiment this aspect is described, but do not play the effect of restriction for the present invention.
The preparation of embodiment 1, pharmaceutic adjuvant of the present invention
Get mannitol 56kg, isosorbide 14kg and polyvinylpolypyrrolidone 5kg and drop into retort, in retort, add the deionized water of 14L, stir being heated under 55 ℃ of conditions, form solution; Solution is cooled to 26 ℃ with the speed of 2 ℃/h makes mannitol and isosorbide partially crystallizable form " brilliant cake "; With drying machine with centrifugal spray spray drying under 60 ℃ of conditions of temperature, get finished product 58kg, yield is 82.86%.
The preparation of embodiment 2, pharmaceutic adjuvant of the present invention
Get mannitol 100kg, isosorbide 25kg and polyvinylpolypyrrolidone 5kg and drop into retort, the deionized water of 100L in retort stirs being heated under 60 ℃ of conditions, forms solution; Solution is cooled to 30 ℃ with the speed of 4 ℃/h makes mannitol and isosorbide partially crystallizable form " brilliant cake "; With drying machine with centrifugal spray spray drying under 90 ℃ of conditions of temperature, get finished product 110kg, yield is 88.00%.
The preparation of embodiment 3, pharmaceutic adjuvant of the present invention
Get mannitol 72kg, isosorbide 18kg and polyvinylpolypyrrolidone 5kg, drop into retort, the deionized water of 45L in retort stirs being heated under 58 ℃ of conditions, forms solution; Solution is cooled to 28 ℃ with the speed of 3 ℃/h makes mannitol and isosorbide partially crystallizable form " brilliant cake "; With drying machine with centrifugal spray spray drying under 80 ℃ of conditions of temperature, get finished product 85kg, yield is 94.44%.
The preparation of embodiment 4, pharmaceutic adjuvant of the present invention
Get mannitol 120kg, isosorbide 30kg and polyvinylpolypyrrolidone 5kg, drop into retort, the deionized water of 75L in retort stirs being heated under 58 ℃ of conditions, forms solution; Solution is cooled to 28 ℃ with the speed of 3 ℃/h makes mannitol and isosorbide partially crystallizable form " brilliant cake "; With drying machine with centrifugal spray spray drying under 80 ℃ of conditions of temperature, get finished product 117kg, yield is 78.00%.
The preparation of embodiment 5, pharmaceutic adjuvant of the present invention
Get mannitol 50kg, isosorbide 10kg and polyvinylpolypyrrolidone 5kg, drop into retort, the deionized water of 30L in retort stirs being heated under 58 ℃ of conditions, forms solution; Solution is cooled to 28 ℃ with the speed of 3 ℃/h makes mannitol and isosorbide partially crystallizable form " brilliant cake "; With drying machine with centrifugal spray spray drying under 80 ℃ of conditions of temperature, get finished product 45kg, yield is 75.00%.
Embodiment 6
Prepare many risperidone orally disintegrating tablets with embodiment 1 gained adjuvant, and compare with commercially available sample:
Method for preparing: get many risperidones 10 grams, add above embodiment 1 gained adjuvant 90 grams, mixing, direct compression, every heavy 0.15 gram, 646 of many risperidone orally disintegrating tablets.
Relatively see the following form:
Embodiment 7
Prepare the irsogladine maleate oral cavity disintegration tablet with embodiment 3 gained adjuvants, and compare with commercially available sample:
Method for preparing: get irsogladine maleate 100 grams, add above embodiment 3 gained adjuvants 100 grams, mixing, direct compression, every heavy 0.2 gram gets 650 of irsogladine maleate oral cavity disintegration tablets.
Relatively see the following form:
Embodiment 8
Prepare aripiprazole orally disintegrating tablet with embodiment 5 gained adjuvants, and compare with commercially available sample:
Method for preparing: get Aripiprazole 300 grams, add above embodiment 5 gained adjuvants 70 grams, mixing, direct compression, every heavy 0.4 gram gets 900 of irsogladine maleate oral cavity disintegration tablets.
Relatively see the following form:
Claims (8)
1. the multi-functional auxiliary material of an oral cavity disintegration tablet is characterized in that, is 11.2～20.0: 2.8～5.0 by weight ratio: 1 mannitol, and isosorbide and polyvinylpolypyrrolidone are processed into, and the preparation process is following:
1) take by weighing mannitol by weight, three kinds of materials of isosorbide and polyvinylpolypyrrolidone drop into retort;
2) in retort, adding weight is the deionized water of 0.2～0.8 times of three kinds of material gross weight, stirs being heated under 55～60 ℃ of conditions, forms solution;
3) solution is cooled to 26～30 ℃ with the speed of 2～4 ℃/h, makes mannitol and isosorbide crystallization form brilliant cake;
4) use centrifugal spray drier, under 60～90 ℃ of conditions of temperature, with 3) product spray drying, promptly get.
2. according to the said adjuvant of claim 1, it is characterized in that, is 12.8～16.0: 3.2～4.0 by weight ratio: 1 mannitol, isosorbide and polyvinylpolypyrrolidone are processed into.
3. the method for preparing of claim 1 or 2 said adjuvants is characterized in that step is following:
1) take by weighing mannitol by weight, three kinds of materials of isosorbide and polyvinylpolypyrrolidone drop into retort;
2) in retort, adding weight is the deionized water of 0.2～0.8 times of three kinds of material gross weight, stirs being heated under 55～60 ℃ of conditions, forms solution;
3) solution is cooled to 26～30 ℃ with the speed of 2～4 ℃/h, makes mannitol and isosorbide crystallization form brilliant cake;
4) use centrifugal spray drier, under 60～90 ℃ of conditions of temperature, with 3) product spray drying, promptly get.
4. method for preparing according to claim 3 is characterized in that, feeding intake of said deionized water heavily is 0.3～0.5 times of three kinds of material gross weights.
5. method for preparing according to claim 3 is characterized in that, the speed of programmed cooling is 3 ℃/h in the crystalline condition.
6. method for preparing according to claim 3 is characterized in that, the cooling outlet temperature is 28 ℃ in the crystalline condition.
7. method for preparing according to claim 3 is characterized in that, the centrifugal spray drying temperature is 80 ℃.
8. method for preparing according to claim 3 is characterized in that, may further comprise the steps:
1) take by weighing mannitol by weight, three kinds of materials of isosorbide and polyvinylpolypyrrolidone drop into retort;
2) in retort, adding weight is the deionized water of 0.3～0.5 times of three kinds of material gross weight, stirs being heated under 58 ℃ of conditions, forms solution;
3) solution is cooled to 28 ℃ with the speed of 3 ℃/h, makes mannitol and isosorbide crystallization form brilliant cake;
4) use centrifugal spray drier, under 80 ℃ of conditions of temperature, with 3) product spray drying, promptly get.
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| Application Number | Priority Date | Filing Date | Title |
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| CN2010101841947A CN101829333B (en) | 2010-05-27 | 2010-05-27 | New multi-functional auxiliary material for orally disintegrating tablets and preparation method thereof |
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| CN2010101841947A CN101829333B (en) | 2010-05-27 | 2010-05-27 | New multi-functional auxiliary material for orally disintegrating tablets and preparation method thereof |
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| CN101829333A CN101829333A (en) | 2010-09-15 |
| CN101829333B true CN101829333B (en) | 2012-01-25 |
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| CN105012955B (en) * | 2015-07-30 | 2017-12-22 | 湖南尔康制药股份有限公司 | A kind of premixing auxiliary material that oral disintegrating tablet is prepared for direct tablet compressing |
| FR3074423B1 (en) * | 2017-12-01 | 2020-03-06 | Roquette Freres | USE OF DINAHYDROHEXITOL IN ORAL HYGIENE TO REDUCE THE DEVELOPMENT OF BACTERIAL STRAINS |
Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1192137A (en) * | 1995-07-31 | 1998-09-02 | 格哈特·格戈里 | Chewing tablets with an effervescent action |
| CN1506043A (en) * | 2002-12-11 | 2004-06-23 | 成都博瑞医药科技开发有限公司 | Quickly disintegrating tablet containing cadotril |
| CN101365428A (en) * | 2006-01-05 | 2009-02-11 | 生命周期药物公司 | Disintegrating loadable tablets |
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Patent Citations (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1192137A (en) * | 1995-07-31 | 1998-09-02 | 格哈特·格戈里 | Chewing tablets with an effervescent action |
| CN1506043A (en) * | 2002-12-11 | 2004-06-23 | 成都博瑞医药科技开发有限公司 | Quickly disintegrating tablet containing cadotril |
| CN101365428A (en) * | 2006-01-05 | 2009-02-11 | 生命周期药物公司 | Disintegrating loadable tablets |
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