CN1767818A - Dispersible tablet comprising beta lactam antibiotics and process for preparing the same - Google Patents
Dispersible tablet comprising beta lactam antibiotics and process for preparing the same Download PDFInfo
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Abstract
The present invention relates to a dispersible tablet formulation comprising beta lactam antibiotics in which a beta lactam antibiotic is formulated with a salt of clavulanic acid in a tablet form to be easily administered upon the disintegration in water, and a process for preparing the same. The process for preparing the dispersible tablet formulation comprises the steps of: mixing a beta lactam antibiotic and a salt of clavulanic acid with a disintegrant, a lubricant and a binder and then applying the mixture to a roller compactor to obtain drytype granules; and, mixing the dry-type granules with an excipient, a disintegrant, a lubricant and a binder, and compressing the mixture to give a tablet. The dispersible tablet formulation can be practically applied for the treatment of diseases requiring beta lactam antibiotics, since it can be easily taken by the infants or older patients being troubled with oral administration with improved disintegration rate and dispersion property.
Description
Background of invention
Technical field
The present invention relates to dispersible tablet that contains beta-Lactam antibiotic and preparation method thereof, more particularly, the present invention relates to contain the dispersible tablet of beta-Lactam antibiotic, wherein beta-Lactam antibiotic and Clavulanate are mixed with tablet form, in water, take easily during disintegrate like this, and the preparation method that relates to this dispersible tablet.
Background technology
The amoxicillin, a kind of beta-Lactam antibiotic is also referred to as semisynthetic penicillin or penbritin and is widely used as antibiotic medicine most and is used for the treatment of throat pain or tonsillitis.Because the frequent amoxicillin of using has the active bacterial strain of anti-amoxicillin of beta-lactamase and catches on.Therefore, the amoxicillin is mixed with a kind of mixed type with suppressing the active Clavulanate of beta-lactamase.In the preparation of frequent use, than mixing, Amoksiklav (co-amoxiclav) preparation was commercial can having bought with 2: 1 (w/w) for amoxicillin and clavulanate potassium, and its trade mark is Augmentin
TM, prepare with forms such as film coating tablet, dry syrups.
The clavulanic acid salt pair humidity that is included in the described preparation is very responsive, and low amounts of water just can easily cause decomposition, therefore in the art, this problem has been carried out various researchs.For example, United States Patent (USP) 6,051,255 disclose a kind of tablet, and it carries out film coating by the compressed mixture to amoxicillin and Clavulanate, does not allow the dampness of outside contact with Clavulanate.This film-coated tablet does not have special problem concerning the adult, but get into trouble during still for baby or the oral administration of old people, because exotic texture, baby or old people dislike swallowing.
As a kind of selection scheme to overcome the problem that described film coating tablet brings, prepared various types of preparations wherein amoxicillin and Clavulanate be not formulated in the tablet, and to baby or gerontal patient's administration.For example, WO 01/45667 discloses water-soluble powder or the granule that contains Utimox and Clavulanate.Yet described water-soluble powder or particle formulation are suction easily, and it makes unpacked preparation directly or indirectly contact with water, finally make the Clavulanate decomposition and pass the effectiveness that medicine is not used in reduction gradually in time.In order to overcome described problem, attempt to slow down decomposition, but finally but do not address this problem by freezing unpackaged preparation.And described method makes the freezing or absorbed water recrystallization of unpackaged preparation part of this stored frozen, and the patient just can not obtain effective dose like this.
In addition, WO 00/03695 discloses and has contained Utimox, Clavulanate and as the cellulosic liquid waterborne pharmaceutical suspension preparation of filler.Prepare dry syrup by add sweeting agent in suspension formulation, it is sold in a large number as the antibiotic formulations that contains amoxicillin and Clavulanate at present.But, comprise the too moisture absorption of suspension formulation of dry syrup, moisture-proof not, its problem be Clavulanate easily decompose or since the long-time back that stores render a service and change.
Select as the another kind that overcomes aforementioned water-soluble powder, granule and suspension defective, with a kind of dispersible tablet, wherein amoxicillin and Clavulanate are prepared, and give baby or gerontal patient.For example, WO 04/06917 discloses dispersible tablet, it is prepared as follows: mix and compress with the amoxicillin with as the cross-linking sodium carboxymethyl cellulose of disintegrating agent, obtain granule, in granule, add clavulanate potassium, as the cross-linking sodium carboxymethyl cellulose of disintegrating agent, as the silicon dioxide of desiccant, as the microcrystalline Cellulose of excipient, the mixture of magnesium stearate, spice, sweeting agent and food coloring as lubricant, compress this mixture then.Yet described dispersible tablet causes some inconvenience during administration, even for example it does not contain binding agent improving dispersibility, but its disintegrate in water still needs to surpass 2 minutes, and because excessive relatively disintegrate granule, some patients may have foreign body sensation.
In order to solve described problem, carried out various researchs in the art, yet do not seen successful case up to now as yet.
Under described environment, strongly need exploitation to contain the dispersible tablet of amoxicillin and Clavulanate, this tablet can be simply under the situation of disintegration rate with improvement and dispersive property and is easily carried out administration.
Summary of the invention
The inventor develops the dispersible tablet that contains amoxicillin and Clavulanate through great efforts, this dispersible tablet can be simply and administration easily, the inventor finds, required dispersible tablet can be prepared as follows: beta-Lactam antibiotic and Clavulanate and disintegrating agent, lubricant and binding agent are mixed together, described mixture is sent in the roll squeezer (roller compactor) then, obtained the dry type granule; Then, described dry type granule is mixed with excipient, disintegrating agent, lubricant and binding agent,, obtain tablet this mixture compression.They confirm that also in fact this dispersible tablet can be used for the treatment of the disease that needs beta-Lactam antibiotic, because it can easily be taken by those oral inconvenient babies or gerontal patient.
Therefore, main purpose of the present invention provides the method that preparation contains the dispersible tablet of beta-Lactam antibiotic, and this dispersible tablet has the disintegration rate and the dispersive property of improvement.
Other purpose of the present invention provides the dispersible tablet that contains beta-Lactam antibiotic by described method preparation.
Detailed Description Of The Invention
The method that preparation contains the dispersible tablet of beta-Lactam antibiotic comprises step: (i) beta-Lactam antibiotic and Clavulanate are mixed with disintegrating agent, lubricant and binding agent, then described mixture is sent in the roll squeezer, obtain the dry type granule; Then, (ii) described dry type granule is mixed with excipient, disintegrating agent, lubricant and binding agent,, obtain tablet this mixture compression.In way of the present invention, described beta-Lactam antibiotic without limits, but Penicillin antibiotics preferably, be more preferably penicillin (penicilin), amoxicillin (amoxicillin), ampicillin (ampicillin), ciclacillin (ciclacillin), epicillin (epicillin), phenethicillin (phenethicillin) or pivampicillin (pivampicillin), described Clavulanate without limits, but clavulanate potassium preferably.
Described in the prior art of front, beta-Lactam antibiotic and Clavulanate are preferably with 2: 1-14: 1 (w/w) mixes, most preferably mix with 4: 1 (w/w), in dispersible tablet, the content of the mixture of beta-Lactam antibiotic and Clavulanate is 15-40% (w/w).
In addition, disintegrating agent in the step (i) without limits, but preferably crospovidone (crospovidone), cross-linking sodium carboxymethyl cellulose, sodium starch glycolate, carboxymethyl cellulose potassium, pregelatinized Starch or its mixture, in dispersible tablet, the content of described disintegrating agent still is preferably 3-10% (w/w) without limits.
Lubricant in the step (i) without limits, but preferably magnesium stearate, silicon dioxide, Talcum, Polyethylene Glycol, stearic acid or its mixture, in dispersible tablet, the content of described lubricant without limits, but be preferably 0.1-5% (w/w).Binding agent in the step (i) without limits, but preferably copolyvidone (copovidone), polyvidone (povidone), hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose or its mixture, in dispersible tablet, the content of described binding agent still is preferably 0.1-7.5% (w/w) without limits.
In addition, in step (i), can further desiccant or foaming agent be joined in the mixture of beta-Lactam antibiotic and Clavulanate with disintegrating agent, lubricant and binding agent, wherein said desiccant without limits, but be preferably silicon dioxide, synthetic aluminium silicate, light anhydrous silicic acid or its mixture, in dispersible tablet, described desiccant content still is preferably 0.1-10% (w/w) without limits usually.Described foaming agent without limits, but be preferably citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or its mixture, in dispersible tablet, described foaming agents content still is preferably 1-5% (w/w) without limits.
Simultaneously, step excipient (ii) without limits, but be preferably microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, lactose, calcium hydrogen phosphate, corn starch, mannitol, Sorbitol, xylitol or its mixture, in dispersible tablet, described excipient content but is preferably 30-75% (w/w) without limits.The disintegrating agent of step in (ii) without limits, but be preferably crospovidone, cross-linking sodium carboxymethyl cellulose, sodium starch glycolate, carboxymethyl cellulose potassium, pregelatinized Starch or its mixture, in dispersible tablet, the (ii) middle disintegrant content of using of step still is preferably 3-10% (w/w) without limits.The lubricant of step in (ii) without limits, but be preferably magnesium stearate, silicon dioxide, Talcum, Polyethylene Glycol, stearic acid or its mixture, in dispersible tablet, the (ii) middle lubricant content that uses of step still is preferably 0.1-5% (w/w) without limits.The binding agent of step in (ii) without limits, but be preferably copolyvidone, polyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose or its mixture, in dispersible tablet, the content of the binding agent of step in (ii) without limits, but be preferably 0.1-7.5% (w/w).
In addition, step (ii) in, described excipient, disintegrating agent, lubricant and binding agent mix with the dry type granule that obtains in one of following form and the step (i): powder type, by mixing and compress the dry type particle form of these materials acquisitions; And by these materials are mixed the wet type particle form that obtains with water.
At last, step (ii) in, can be further foaming agent be joined in the dry type granule that obtains in the step (i) with excipient, disintegrating agent, lubricant and binding agent.In this step, described foaming agent without limits, but preferably citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or its mixture, in dispersible tablet, step (ii) in employed foaming agents content without limits, but be preferably 1-5% (w/w).
In order to develop a kind of amoxicillin that can be taken by oral inconvenient baby or gerontal patient and the compound formulation of Clavulanate, the inventor has done various effort, and noticed disclosed dispersible tablet among the WO04/06917, the wet type granule that wherein contains the amoxicillin mixes with Clavulanate, compression obtains dispersive oral dispersable tablet agent in water.
The inventor attempts to improve by the following method the disintegration rate and the dispersive property of dispersible tablet: the proportion of composing that changes component and described component; Use contains the dry type granule of amoxicillin and Clavulanate, disintegrating agent, lubricant and binding agent; And the ratio of components of optimizing disintegrating agent, lubricant and binding agent, and foaming agent is as a kind of optionally component.
Usually, lubricant and binding agent should be used to prepare the dry type granule, and wherein said binding agent promotes the bonding of each component.Nature, inventor's expection uses the particulate dispersible tablet of dry type of amoxicillin and clavulanic acid salt mixture to have lower disintegration rate than the dispersible tablet among the WO 04/06917, yet, against one's expectation, preparation of the present invention shows high disintegration rate and fabulous dispersive property.
The inventor has prepared the particulate various dispersible tablets of dry type that use amoxicillin and Clavulanate, has optimized the ratio of components of disintegrating agent, lubricant, binding agent and excipient, and disintegration time and the dispersive property of having measured each preparation.The result shows, compare with the dispersible tablet among the WO 04/06917, all use the particulate various dispersible tablets of dry types to show the higher disintegration rate and the dispersive property of improvement, and the dispersible tablet that especially contains foaming agent shows disintegration rate faster than the preparation of reactive blowing agent.Therefore, can reach a conclusion, by using the dry type granule simply to take and to be absorbed by health easily, dispersible tablet of the present invention is more effective in treatment than prior art preparation.
Simultaneously, the inventor finds, lubricant should be included in and obtain dry type granule and compression and contain in two steps that the particulate mixture of described dry type obtains dispersible tablet, that is to say, the mixture of beta-Lactam antibiotic, Clavulanate, disintegrating agent, lubricant and binding agent is being sent into roll squeezer so that obtain in the particulate process of dry type, described lubricant has stoped mixture to stick on the roll squeezer, obtains the particulate continuous process of dry type otherwise will hinder.In addition, the compression of the mixture of dry type granule, excipient, disintegrating agent, lubricant and binding agent is obtained in the subsequent process of tablet, the use of lubricant has stoped mixture to stick on the drift of compressor equally, otherwise will hinder continuous compression process.Therefore, verified, lubricant should be included in simultaneously and obtain to compress with in the step for preparing dispersible tablet in the particulate step of dry type and with mixture.
As mentioned above, dispersible tablet of the present invention is prepared into inherently and comprises the amoxicillin.Yet, consider that it is designed so that preparation of the present invention can comprise various medicines with the Clavulanate of the beta-lactamase that suppresses anti-amoxicillin antibacterial, it can be used as the compound formulation that contains Clavulanate.For example, be prepared to dispersible tablet form of the present invention with Clavulanate and beta-Lactam antibiotic such as ampicillin, penicillin, ciclacillin, epicillin, phenethicillin, the blended compound formulation of pivampicillin, so described dispersible tablet can overcome the drug resistance to beta-Lactam antibiotic, and disintegration rate and dispersive property with improvement are guaranteed simple and are easily taken and absorb.In order to prove this expection, penicillin and pivampicillin mix with clavulanate potassium respectively, with each dispersible tablet disintegrate in water by method for preparing, measure disintegration time.As a result, all dispersible tablets show that in 30-40 disintegrate fully in the time of second dispersible tablet of the present invention can be applied to various beta-Lactam antibiotics and amoxicillin.
The dispersible tablet that contains beta-Lactam antibiotic that makes thus comprise 15-40% (w/w) as the beta-Lactam antibiotic of active component and the mixture of Clavulanate, and the disintegrating agent of 6-20% (w/w), the lubricant of 0.1-10% (w/w), the binding agent of 0.1-15% (w/w), the excipient of 30-75% (w/w), and foaming agent optionally, desiccant or its mixture, the content of preferred desiccant is 0.1-10% (w/w), and the content of foaming agent is 2-10% (w/w).
In fact described dispersible tablet can be used for the treatment of the disease that needs beta-Lactam antibiotic, because it has the disintegration rate and the dispersive property of improvement, and can be oral by oral inconvenient baby or gerontal patient at an easy rate.
In the following embodiments the present invention is described in more detail, but these embodiment should not be considered to limit the scope of the invention.
Embodiment 1: contain the preparation of dispersible tablet of amoxicillin and the evaluation of disintegrating property
At first, by using disclosed wet type preparation of granules dispersible tablet among the international open WO 04/06917 of PCT: 231.0g amoxicillin, 12.5mg cross-linking sodium carboxymethyl cellulose, 0.5mg pigment and some water are mixed, obtain the wet type granule.Then, in thus obtained wet type granule, add 104.4mg clavulanate potassium, 12.5mg cross-linking sodium carboxymethyl cellulose, 20mg spice, 0.5mg pigment, 5mg silicon dioxide, 10mg A Siba sweet (aspartame), 200mg microcrystalline Cellulose and 7.5mg magnesium stearate, mix, compression obtains the 600mg dispersible tablet.
Then, except that using the dry type granule to replace the wet type granule, prepare another kind of dispersible tablet as mentioned above similarly, wherein said dry type granule prepares by binding agent: that is to say, 231.0g amoxicillin, 104.4mg clavulanate potassium, 12.5mg cross-linking sodium carboxymethyl cellulose, 3.5mg magnesium stearate, 0.5mg pigment and 3mg copolyvidone are mixed with each other, with roller speed is that 5-10rpm and screw speed are that the roll squeezer of 5-10rpm compresses mixture, obtains the dry type granule.Subsequently, add in described dry type granule that 12.5mg cross-linking sodium carboxymethyl cellulose, 14mg spice, 0.5mg pigment, 3mg copolyvidone, 5mg silicon dioxide, 10mg A Siba are sweet, 200mg microcrystalline Cellulose and 4.0mg magnesium stearate, mix, compression obtains the 600mg dispersible tablet.
Each dispersible tablet disintegrate in the 5ml distilled water that will make by described two kinds of methods, measure granular size by naked eyes and reach the time required below 200 orders, measure 10 times, calculate average disintegration time, then by automatic particle size analyzer measure the disintegrate particle grain size distribution (
Referring to: table 1).
Table 1: adopt dry type granule and wet type granule disintegrating property as the dispersible tablet of intermediate preparation
| Intermediate-type | Average disintegration time (second) | d90(μm) | d50(μm) | d10(μm) |
| The wet type granule | 125 | 118.4 | 39.2 | 9.8 |
| The dry type granule | 93 | 87.4 | 21.7 | 6.4 |
As above table 1 is described, clearly illustrates that, must be fast than by the dispersible tablet disintegrate of using the wet type preparation of granules by the dispersible tablet that uses the dry type preparation of granules.These results are opposite with our expection: the dispersible tablet by using the dry type preparation of granules will must be fast than the dispersible tablet disintegrate by use wet type preparation of granules, because binding agent such as copolyvidone are generally used for bonding each component to obtain difficult disintegrating property.In addition, shown that also the dispersible tablet particle diameter after the disintegrate in water by using the dry type preparation of granules uses the dispersible tablet of wet type preparation of granules thinner than passing through.
Therefore, can draw to draw a conclusion: described result is caused by these two kinds of factors of different preparation methoies of different intermediate (being dry type granule and wet type granule) and preparation, because: two kinds of different intermediate that have same composition and amount thereof by use, except in the dry type granule, adding the binding agent, make each preparation by the amount that reduces the identical spice that disintegration rate is not influenced.
During with dry type preparation of granules dispersible tablet, because disintegrating agent and binding agent may have critical impact to disintegrating property such as disintegration rate and dispersive property, measured the disintegrating agent that shows best disintegrating property and the ratio of binding agent, whether lubricant confirms disintegrating property is influential equally in the following embodiments with the ratio of excipient.
Embodiment 2: the ratio of components that is included in each component in the dispersible tablet is optimized
In the dispersible tablet of dry type granule, measured each ratio of components of the disintegrating agent, binding agent, lubricant and the excipient that obtain best disintegration rate and dispersive property respectively as intermediate with embodiment 1 preparation.
Embodiment 2-1: the best ratio of components of measuring disintegrating agent
120mg amoxicillin, 30mg clavulanate potassium, 5mg magnesium stearate, cross-linking sodium carboxymethyl cellulose and 2mg copolyvidone are mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, in described dry type granule, add cross-linking sodium carboxymethyl cellulose, 5mg silicon dioxide, 3mg copolyvidone, microcrystalline Cellulose and 5mg magnesium stearate, mix, compression, obtain the 500mg dispersible tablet, the disintegration time by measuring each preparation as the same procedure among the embodiment 1 (
Referring to: table 2a).In the process of preparation dry type granule and preparation, as the amount of the cross-linking sodium carboxymethyl cellulose (ccs) of disintegrating agent and as the following variation of amount of the microcrystalline Cellulose (mcc) of excipient, so that in dispersible tablet, contain the disintegrating agent of 0,5,10,15,20,25 or 30% (w/w) respectively: 0mg ccs, 330mg mcc; 25mg ccs, 305mg mcc; 50mg ccs, 280mg mcc; 75mg ccs, 255mg mcc; 100mg ccs, 230mgmcc; 125mg ccs, 205mg mcc; And 150mg ccs, 180mg mcc.
Table 2a: the ratio of components of disintegrating agent is to the influence of disintegration time
| The ratio of components of disintegrating agent (%, w/w) | Disintegration time (second) |
| 0 | 300 |
| 5 | 180 |
| 10 | 70 |
| 15 | 57 |
| 20 | 45 |
| 25 | 45 |
| 30 | 45 |
As above show shown in the 2a, in the scope of disintegrating agent greater than 10% (w/w), disintegration time sharply reduces, and in the scope greater than 20% (w/w), disintegration time no longer reduces.In order to measure the ratio of components of disintegrating agent more accurately, the disintegrant content with 5,6,7,8,9,10,15,16,17,18,19 or 20% (w/w) prepares each dispersible tablet respectively, and the mensuration disintegration time (
Ginseng See: table 2b).
Table 2b: the ratio of components of disintegrating agent is to the influence of disintegration time
| The ratio of components of disintegrating agent (%, w/w) | Disintegration time (second) |
| 5 | 180 |
| 6 | 90 |
| 7 | 83 |
| 8 | 76 |
| 9 | 72 |
| 10 | 70 |
| 15 | 57 |
| 16 | 54 |
| 17 | 51 |
| 18 | 48 |
| 19 | 46 |
| 20 | 45 |
As above show shown in the 2b, in the scope of disintegrating agent greater than 6% (w/w), disintegration time sharply reduces, and in the scope greater than 20% (w/w), disintegration time no longer reduces.
Embodiment 2-2: the best ratio of components of measuring binding agent
120mg amoxicillin, 30mg clavulanate potassium, 5mg magnesium stearate, 20mg cross-linking sodium carboxymethyl cellulose and copolyvidone are mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, in described dry type granule, add 20mg cross-linking sodium carboxymethyl cellulose, 5mg silicon dioxide, copolyvidone, microcrystalline Cellulose and 5mg magnesium stearate, mix, compression, obtain the 500mg dispersible tablet, the disintegration time by measuring each preparation as the same procedure among the embodiment 1 (
Referring to: table 3a).In the process of preparation dry type granule and preparation, as the amount of the copolyvidone (" co-pvp ") of binding agent and as the following variation of amount of the microcrystalline Cellulose (" mcc ") of excipient, so that preparation contains the dispersible tablet of 0,3,6,9,12,15 or 18% (w/w) disintegrating agent respectively: 0mg co-pvp, 295mg mcc; 15mg co-pvp, 280mg mcc; 30mg co-pvp, 265mg mcc; 45mg co-pvp, 250mg mcc; 60mg co-pvp, 235mg mcc; 75mg co-pvp, 220mg mcc; With 90mg co-pvp, 205mg mcc.
Table 3a: the ratio of components of binding agent is to the influence of disintegration time
| The ratio of components of binding agent (%, w/w) | Disintegration time (second) |
| 0 | - |
| 3 | 39 |
| 6 | 40 |
| 9 | 41 |
| 12 | 43 |
| 15 | 44 |
| 18 | 73 |
As above show shown in the 3a, in the situation that does not add binding agent, fail suitably to prepare the dry type granule, fail to record disintegration time, be higher than in the situation of 15% (w/w) binding agent in adding, disintegration time sharply increases.In order to measure the ratio of components of binding agent more accurately, the binder content with 15,16,17 or 18% (w/w) has prepared dispersible tablet respectively, measure respectively disintegration time (
Referring to: table 3b).
Table 3b: the ratio of components of binding agent is to the influence of disintegration time
| The ratio of components of binding agent (%, w/w) | Disintegration time (second) |
| 15 | 44 |
| 16 | 58 |
| 17 | 66 |
| 18 | 73 |
As above show shown in the 3b, in the scope of binding agent greater than 16% (w/w), disintegration time sharply increases, and shows that it is preferred that the binding agent ratio of components is lower than 15% (w/w).
Embodiment 2-3: the best ratio of components of measuring lubricant
120mg amoxicillin, 30mg clavulanate potassium, 50mg cross-linking sodium carboxymethyl cellulose, 40mg copolyvidone and magnesium stearate are mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, in described dry type granule, add 50mg cross-linking sodium carboxymethyl cellulose, 5mg silicon dioxide, 35mg copolyvidone, microcrystalline Cellulose and magnesium stearate, mix, compression, obtain the 500mg dispersible tablet, the disintegration time by measuring each preparation as the same procedure among the embodiment 1 (
Referring to: table 4).In the process of preparation dry type granule and preparation, as the amount of the magnesium stearate (" MgSA ") of lubricant and as the following variation of amount of the microcrystalline Cellulose (" mcc ") of excipient, so that preparation contains the dispersible tablet of 0,1,5,10,15,20 or 30% (w/w) lubricant respectively: 0mg MgSA, 170mg mcc; 5mg MgSA, 165mgmcc; 25mg MgSA, 145mg mcc; 50mg MgSA, 120mg mcc; 75mgMgSA, 95mg mcc; 100mg MgSA, 70mg mcc; And 150mg MgSA, 20mg mcc.
Table 4: the ratio of components of lubricant is to the influence of disintegration time
| The ratio of components of lubricant (%, w/w) | Disintegration time (second) |
| 0 | |
| 1 | 39 |
| 5 | 40 |
| 10 | 39 |
| 15 | 41 |
| 20 | 40 |
| 30 | 42 |
As above shown in the table 4, in the situation that does not add lubricant, fail suitably to prepare the dry type granule, fail to record disintegration time, in the situation that adds at least 1% (w/w) lubricant, the amount of lubricant is to not influence of disintegration time.
Embodiment 2-4: the best ratio of components of measuring excipient
Preparation contains every kind of dispersible tablet of disintegrating agent, binding agent and the lubricant of the various ratio of componentss that record in embodiment 2-1 to 2-3 respectively.
60mg amoxicillin, 15mg clavulanate potassium, magnesium stearate (" MgSA-1 "), cross-linking sodium carboxymethyl cellulose (" ccs-1 ") and copolyvidone (" co-pvp-1 ") are mixed, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, described dry type granule is mixed with 5mg silicon dioxide, magnesium stearate (" MgSA-2 "), cross-linking sodium carboxymethyl cellulose (" ccs-2 "), copolyvidone (" co-pvp-2 ") and microcrystalline Cellulose (" mcc ") and compress, these amount of substances are as shown in following table 5a, and preparation excipient content is respectively the 500mg dispersible tablet of 0,10,20,30,40,50,60,70 or 75% (w/w).
Table 5a: each components contents (unit: mg) in the dispersible tablet
| The ratio of components of excipient (%, w/w) | MgSA-1 | ccs-1 | co-pvp-1 | MgSA-2 | ccs-2 | co-pvp-2 | mcc |
| 0 | 35 | 74 | 40 | 125 | 111 | 35 | 0 |
| 10 | 25 | 74 | 40 | 85 | 111 | 35 | 50 |
| 20 | 15 | 74 | 40 | 45 | 111 | 35 | 100 |
| 30 | 2 | 74 | 40 | 8 | 111 | 35 | 150 |
| 40 | 2 | 54 | 40 | 8 | 81 | 35 | 200 |
| 50 | 2 | 54 | 13 | 8 | 81 | 12 | 250 |
| 60 | 2 | 34 | 13 | 8 | 51 | 12 | 300 |
| 70 | 2 | 14 | 13 | 8 | 21 | 12 | 350 |
| 75 | 2 | 8 | 8 | 8 | 12 | 7 | 375 |
Disintegration time by measuring each preparation as the same procedure among the embodiment 1 (
Referring to: table 5b).
Table 5b: the ratio of components of excipient is to the influence of disintegration time
| The ratio of components of excipient (%, w/w) | Disintegration time (second) |
| 0 | - |
| 10 | - |
| 20 | - |
| 30 | 39 |
| 40 | 41 |
| 50 | 40 |
| 60 | 42 |
| 70 | 41 |
| 75 | 40 |
As above show shown in the 5b, adding above in the situation of 30% excipient, can suitably prepare dispersible tablet, add excipient and can prepare dispersible tablet suitably, the amount of excipient and disintegration time are irrelevant.
Yet the angle of the ratio of components that records from embodiment 2-1 to 2-3 considers that the ratio of components optimum of excipient is about 75% (w/w).
Sum up the result of embodiment 2-1 to 2-4, in with the dispersible tablet of dry type granule as intermediate, the ratio of greater inequality that shows best disintegration rate and dispersive property is: the binding agent of the disintegrating agent of 6-20% (w/w), 0.1-15% (w/w), the excipient of 30-75% (w/w), and the lubricant that is not particularly limited content.
Embodiment 3: preparation has the dispersible tablet of various ratio of componentss
Binding agent, disintegrating agent, lubricant, excipient or its mixture of the various ratio of componentss of determining with the dry type granule that contains amoxicillin and Clavulanate and in embodiment 2-1 to 2-4 prepare dispersible tablet, so that estimate disintegrating property.
At first, with the mixture of 75mg (15% (w/w)) amoxicillin and clavulanate potassium (4: 1, w/w), magnesium stearate (" MgSA-1 "), cross-linking sodium carboxymethyl cellulose (" ccs-1 ") and copolyvidone (" co-pvp-1 ") are mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, in described dry type granule, add 5mg (1% (w/w)) silicon dioxide, magnesium stearate (" MgSA-2 "), cross-linking sodium carboxymethyl cellulose (" ccs-2 "), copolyvidone (" co-pvp-2 ") and microcrystalline Cellulose (" mcc "), mix, compression is with preparation 500mg dispersible tablet.In the preparation process of dry type granule and preparation, the ratio of components of each component changes shown in following table 6a.
Table 6a: be included in each component in the dispersible tablet ratio of components (unit: %, w/w)
| Preparation | MgSA-1 | ccs-1 | co-pvp-1 | MgSA-2 | ccs-2 | co-pvp-2 | mcc |
| Test example 1 | 10 | 3 | 14 | 10 | 3 | 1 | 43 |
| Test example 2 | 15 | 3 | 7 | 15 | 3 | 8 | 33 |
| Test example 3 | 14 | 5 | 1 | 14 | 5 | 14 | 31 |
| Test example 4 | 0.5 | 3 | 1 | 0.5 | 3 | 1 | 75 |
| Test example 5 | 5 | 8 | 4 | 5 | 8 | 5 | 49 |
| Test example 6 | 0.1 | 8 | 5 | 0.1 | 8 | 5 | 57.8 |
| Test example 7 | 1 | 5 | 2 | 0.1 | 15 | 2 | 58.9 |
| Test example 8 | 0.1 | 10 | 1 | 1 | 10 | 1 | 60.9 |
| Test example 9 | 0.1 | 10 | 0.1 | 10 | 10 | 0.1 | 53.7 |
Average disintegration time and particle size distribution are analyzed in each dispersible tablet disintegrate in the 5ml distilled water that contains the amoxicillin that as above makes respectively, wherein the contrast with embodiment 1 in identical (
Ginseng See: table 6b).
Table 6b: the disintegration time of dispersible tablet and particle size distribution
| Preparation | Average disintegration time (second) | d90(μm) | d50(μm) | d10(μm) |
| Contrast | 123 | 118.4 | 39.2 | 9.8 |
| Test example 1 | 90 | 86.1 | 21.0 | 6.6 |
| Test example 2 | 89 | 86.2 | 21.1 | 6.5 |
| Test example 3 | 69 | 83.7 | 20.4 | 6.1 |
| Test example 4 | 91 | 82.6 | 19.9 | 6.0 |
| Test example 5 | 55 | 87.3 | 20.9 | 6.4 |
| Test example 6 | 53 | 89.7 | 20.6 | 6.5 |
| Test example 7 | 46 | 83.2 | 20.3 | 6.0 |
| Test example 8 | 44 | 84.4 | 20.2 | 6.1 |
| Test example 9 | 45 | 86.1 | 20.9 | 6.3 |
Show as above can clearly determine shown in the 6b that the disintegration time difference of each preparation be the 30-60% of contrast, and particle diameter will be compared according to thinner.
Therefore, can reach a conclusion: compare with dispersible tablet of the prior art, also show better disintegrating property with the dispersible tablet that the various ratio of componentss of determining among the embodiment 2-1 to 2-4 make with the dry type granule that contains amoxicillin and Clavulanate, disintegrating agent, binding agent, lubricant and excipient.
Embodiment 4: preparation has the dispersible tablet of various amoxicillin ratio of components
Under the situation of ratio of components of binding agent, disintegrating agent, lubricant and the excipient of test example 8, change the kind of component, preparation contains the dispersible tablet of amoxicillin, shows that the preparation disintegrate that makes is the fastest in embodiment 3, and measures their disintegrating property respectively.
At first, with the mixture of the amoxicillin of 15% (w/w) and clavulanate potassium (4: 1, w/w), the binding agent (" C1 ") of the disintegrating agent (" B1 ") of the lubricant of 0.1% (w/w) (" A1 "), 10% (w/w) and 1% (w/w) mixes, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, in described dry type granule, add the lubricant (" A2 ") of the silicon dioxide, 1% (w/w) of 1% (w/w), the disintegrating agent (" B2 ") of 10% (w/w), the binding agent (" C2 ") of 1% (w/w) and the excipient (" D ") of 60.9% (w/w), mix, compression is with preparation 500mg dispersible tablet.In the preparation process of dry type granule and preparation, the concrete component of disintegrating agent, lubricant, binding agent and excipient changes shown in following table 7a.
Table 7a: the details of disintegrating agent, lubricant, binding agent and excipient
| Preparation | A1 | B1 | C1 | A2 | B2 | C2 | D |
| Test example 1 | MgSA | cr-pvp | HPC | MgSA | cr-pvp | HPC | mcc |
| Test example 2 | tc | ccs | co-pvp | tc | ccs | co-pvp | L-HPC |
| Test example 3 | SA | Na-stg | HEC | SA | Na-stg | HEC | LA |
| Test example 4 | MgSA | K-cmc | HPMC | tc | K-cmc | HPMC | CHP |
| Test example 5 | tc | pgst | co-pvp | SA | pgst | HEC | cst |
| Test example 6 | SA | cr-pvp | HPMC | MgSA | Na-stg | HEC | Ma |
| Test example 7 | MgSA | ccs | co-pvp | SA | K-cmc | HPMC | mcc |
| Test example 8 | tc | Na-stg | HEC | MgSA | pgst | co-pvp | L-HPC |
| Test example 9 | SA | K-cmc | HPMC | tc | cr-pvp | HEC | LA |
*Abbreviation: Cr-pvp, crospovidone; Ccs, cross-linking sodium carboxymethyl cellulose; Na-stg, sodium starch glycolate; K-cmc, carboxymethyl cellulose potassium; Pgst, pregelatinized Starch; MgSA, magnesium stearate; Tc, Talcum; PEG, Polyethylene Glycol; SA, stearic acid; Co-pvp, copolyvidone; Pvp, polyvidone; HPC, hydroxypropyl cellulose; HPMC, hydroxypropyl emthylcellulose; HEC, hydroxyethyl-cellulose; Mcc, microcrystalline Cellulose; L-HPC, low-substituted hydroxypropyl cellulose; LA, lactic acid; CHP, calcium hydrogen phosphate; Cst, corn starch; Ma, mannitol.
Average disintegration time and particle size distribution (d90, d50 and d10) are analyzed in the dispersible tablet that contains the amoxicillin that as above makes disintegrate in the distilled water in 5ml respectively, wherein the contrast with embodiment 1 in identical (
Referring to: table 7b).
Table 7b: the disintegration time of dispersible tablet and particle size distribution
| Preparation | Average disintegration time (second) | d90(μm) | d50(μm) | d10(μm) |
| Contrast | 123 | 118.4 | 39.2 | 9.8 |
| Test example 1 | 46 | 86.1 | 21.0 | 6.6 |
| Test example 2 | 45 | 86.2 | 21.1 | 6.5 |
| Test example 3 | 45 | 83.7 | 20.4 | 6.1 |
| Test example 4 | 46 | 82.6 | 19.9 | 6.0 |
| Test example 5 | 44 | 87.3 | 20.9 | 6.4 |
| Test example 6 | 45 | 89.7 | 20.6 | 6.5 |
| Test example 7 | 46 | 83.2 | 20.3 | 6.0 |
| Test example 8 | 45 | 84.4 | 20.2 | 6.1 |
| Test example 9 | 44 | 86.1 | 20.9 | 6.3 |
As above show shown in the 7b, the disintegration time in each preparation does not show difference, shows that disintegrate does not change with disintegrating agent, lubricant, binding agent and excipient type change.
Embodiment 5: by the prepared in various methods dispersible tablet
Result based on embodiment 3 and 5 shows, the dispersible tablet that contains amoxicillin, binding agent, disintegrating agent, lubricant and excipient that ratio of components such as embodiment 2 determine shows identical disintegrating property, and the change of component is to not influence of disintegrating property, checks that binding agent, disintegrating agent, lubricant and excipient have same composition and ratio of components and whether the dispersible tablet that contains the amoxicillin by prepared in various methods shows similar disintegrating property.
Embodiment 5-1: the dispersible tablet that contains the amoxicillin by the dry type preparation of granules of using two types
At first, with the mixture of the amoxicillin of 15% (w/w) and clavulanate potassium (4: 1, w/w), the copolyvidone of the cross-linking sodium carboxymethyl cellulose and 1% (w/w) of the magnesium stearate of 0.1% (w/w), 10% (w/w) is mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.
Subsequently, the microcrystalline Cellulose of copolyvidone and 60.9% (w/w) of cross-linking sodium carboxymethyl cellulose, 1% (w/w) of magnesium stearate, 10% (w/w) that in described dry type granule, adds the silicon dioxide, 1% (w/w) of 1% (w/w), be mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, to prepare another kind of dry type granule.
Described two kinds of dry type granules are mixed with each other compression, preparation 500mg dispersible tablet (" test example 1 ").
Simultaneously, in order to prepare dispersible tablet in contrast, with the mixture of the amoxicillin of 15% (w/w) and clavulanate potassium (4: 1, w/w), the copolyvidone of the cross-linking sodium carboxymethyl cellulose and 1% (w/w) of the magnesium stearate of 0.1% (w/w), 10% (w/w) is mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, the microcrystalline Cellulose of copolyvidone and 60.9% (w/w) of cross-linking sodium carboxymethyl cellulose, 1% (w/w) of magnesium stearate, 10% (w/w) that in described dry type granule, adds the silicon dioxide, 1% (w/w) of 1% (w/w), mix, compression is with preparation 500mg dispersible tablet.
Embodiment 5-2: use dry type granule and wet type preparation of granules to contain the dispersible tablet of amoxicillin
At first, with the mixture of the amoxicillin of 15% (w/w) and clavulanate potassium (4: 1, w/w), the copolyvidone of the cross-linking sodium carboxymethyl cellulose and 1% (w/w) of the magnesium stearate of 0.1% (w/w), 10% (w/w) is mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.
Subsequently, the microcrystalline Cellulose of copolyvidone and 60.9% (w/w) of cross-linking sodium carboxymethyl cellulose, 1% (w/w) of magnesium stearate, 10% (w/w) that in described dry type granule, adds the silicon dioxide, 1% (w/w) of 1% (w/w), be mixed with each other, the copolyvidone that then in mixture, adds some distilled water and 1% (w/w), then described mixture is carried out a series of fusion, pelletize, drying and standardization, obtain the wet type granule.
To be mixed with each other by thus obtained dry type granule of top method and wet type granule, compression, preparation 500mg dispersible tablet (" test example 2 ") is wherein identical among contrast and the embodiment 5-1.
Embodiment 5-3: use wet type granule and dry type preparation of granules to contain the dispersible tablet of amoxicillin
At first, the copolyvidone of the cross-linking sodium carboxymethyl cellulose and 1% (w/w) of the magnesium stearate, 10% (w/w) of the amoxicillin, 0.1% (w/w) of 12% (w/w) is mixed with each other, the copolyvidone that in mixture, adds some distilled water and 1% (w/w), then described mixture is carried out fusion, pelletize, drying and standardization, obtain the wet type granule.
Subsequently, the microcrystalline Cellulose of copolyvidone and 60.9% (w/w) of cross-linking sodium carboxymethyl cellulose, 1% (w/w) of magnesium stearate, 10% (w/w) of silicon dioxide, 1% (w/w) that in described dry type granule, adds the clavulanate potassium, 1% (w/w) of 3% (w/w), be mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.
Thus obtained wet type granule and dry type granule are mixed with each other, compression, preparation 500mg dispersible tablet (" test example 3 ") is wherein identical among contrast and the embodiment 5-1.
Embodiment 5-4: the dispersible tablet that contains the amoxicillin by the wet type preparation of granules of using two types
At first, the copolyvidone of the cross-linking sodium carboxymethyl cellulose and 1% (w/w) of the magnesium stearate, 10% (w/w) of the amoxicillin, 0.1% (w/w) of 12% (w/w) is mixed with each other, then described mixture is carried out fusion, pelletize, drying and standardization, obtain the wet type granule.
Subsequently, the microcrystalline Cellulose of cross-linking sodium carboxymethyl cellulose and 60.9% (w/w) of magnesium stearate, 10% (w/w) that in described dry type granule, adds the silicon dioxide, 1% (w/w) of 1% (w/w), be mixed with each other, the copolyvidone that adds some distilled water and 1% (w/w) in mixture is with the top wet type granule that obtains similarly.
Thus obtained two kinds of wet type granules are mixed with the clavulanate potassium of 3% (w/w), compression, preparation 500mg dispersible tablet (" test example 4 ") is wherein identical among contrast and the embodiment 5-1.
Embodiment 5-5: the comparison of dispersive property
With each dispersible tablet disintegrate in the 5ml distilled water among the routine 1-4 of the test of contrast and embodiment 5-1 to 5-4 preparation, by the method described in the embodiment 1 analyze respectively average disintegration time and particle size distribution (d90, d50 and d10) (
Referring to: table 8).
Table 8: the disintegration time of dispersible tablet and particle size distribution
| Preparation | Average disintegration time (second) | d90(μm) | d50(μm) | d10(μm) |
| Contrast | 46 | 83.2 | 20.3 | 6.0 |
| Test example 1 | 46 | 86.1 | 21.0 | 6.6 |
| Test example 2 | 45 | 86.2 | 21.1 | 6.5 |
| Test example 3 | 120 | 103.7 | 37.4 | 9.1 |
| Test example 4 | 125 | 105.6 | 40.9 | 9.5 |
As above shown in the table 8, the dispersible tablet that makes with the dry type granule that contains amoxicillin and clavulanate potassium (promptly, test example 1 and 2) shows and contrast identical disintegrating property, and make with the wet type granule that contains the amoxicillin those (promptly, test example 3 and 4) significantly increased disintegration time and reduced dispersive property, shown that they have and the similar disintegrating property of preparation described in the international open WO 04/06917 of PCT.
Therefore, can draw to draw a conclusion: in order to prepare the dispersible tablet of the present invention that shows fabulous disintegrating property, should use the dry type granule that contains amoxicillin and clavulanate potassium, and process subsequently can be different.
Embodiment 6: preparation contains the dispersible tablet of amoxicillin and foaming agent
Based on following knowledge, promptly foaming agent influences disintegration time and dispersive property with disintegrating agent and binding agent, has checked the disintegrating property of foaming agent to dispersible tablet of the present invention.
Embodiment 6-1: preparation contains the dispersible tablet of amoxicillin and foaming agent
At first, with the mixture of the amoxicillin of 15% (w/w) and clavulanate potassium (4: 1, w/w), the copolyvidone of the sodium bicarbonate and 1% (w/w) of the citric acid, 2% (w/w) of the cross-linking sodium carboxymethyl cellulose, 2% (w/w) of the magnesium stearate of 0.1% (w/w), 10% (w/w) is mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, the microcrystalline Cellulose of sodium bicarbonate and 72.9% (w/w) of citric acid, 2% (w/w) of copolyvidone, 2% (w/w) of cross-linking sodium carboxymethyl cellulose, 1% (w/w) of magnesium stearate, 10% (w/w) that in described dry type granule, adds the silicon dioxide, 1% (w/w) of 1% (w/w), be mixed with each other, compression, preparation 500mg dispersible tablet (" test example ").
Simultaneously, in contrast, with the mixture of the amoxicillin of 15% (w/w) and clavulanate potassium (4: 1, w/w), the copolyvidone of the cross-linking sodium carboxymethyl cellulose and 1% (w/w) of the magnesium stearate of 0.1% (w/w), 10% (w/w) is mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, the microcrystalline Cellulose of copolyvidone and 60.9% (w/w) of cross-linking sodium carboxymethyl cellulose, 1% (w/w) of magnesium stearate, 10% (w/w) that in described dry type granule, adds the silicon dioxide, 1% (w/w) of 1% (w/w), mix compression, preparation 500mg dispersible tablet.
Each dispersible tablet disintegrate in the 5ml distilled water in the example with contrast and test, by the method described in the embodiment 1 analyze respectively average disintegration time and particle size distribution (d90, d50 and d10) (
Referring to: table 9a).
Table 9a: the disintegration time of dispersible tablet and particle size distribution
| Preparation | Average disintegration time (second) | d90(μm) | d50(μm) | d10(μm) |
| Contrast | 46 | 83.2 | 20.3 | 6.0 |
| The test example | 30 | 86.1 | 21.0 | 6.6 |
As above show shown in the 9a, when compared with the control, show disintegration time and significantly reduce, on dispersive property, do not have difference although contain the dispersible tablet (i.e. test example) of foaming agent.
Embodiment 6-2: the best ratio of components of determining foaming agent
Result based on embodiment 6-1 shows that foaming agent has promoted the disintegrate of dispersible tablet, by following test determination obtain the ratio of components of the foaming agent of best disintegrating property.
At first, with the mixture of the amoxicillin of 15% (w/w) and clavulanate potassium (4: 1, w/w), the cross-linking sodium carboxymethyl cellulose of the magnesium stearate of 0.1% (w/w), 10% (w/w), foaming agent (1: 1 (w/w) mixture of citric acid powder and sodium bicarbonate) and the copolyvidone of 1% (w/w) are mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, copolyvidone, foaming agent and the microcrystalline Cellulose of cross-linking sodium carboxymethyl cellulose, 1% (w/w) of magnesium stearate, 10% (w/w) that in described dry type granule, adds the silicon dioxide, 1% (w/w) of 1% (w/w), be mixed with each other compression, preparation 500mg dispersible tablet.In the process of preparation dry type granule and preparation, the amount of foaming agent (" SHC ") and as the following variation of amount of the microcrystalline Cellulose (" mcc ") of excipient, so that preparation contains the dispersible tablet of 0-15% (w/w) foaming agent respectively, and by embodiment 1 described method measure disintegration time (
Referring to: table 9b): 60.9% (w/w) mcc; 1% (w/w) SHC, 59.9% (w/w) mcc; 2% (w/w) SHC, 58.9% (w/w) mcc; 3% (w/w) SHC, 57.9% (w/w) mcc; 4% (w/w) SHC, 56.9% (w/w) mcc; 5% (w/w) SHC, 55.9% (w/w) mcc; 6% (w/w) SHC, 54.9% (w/w) mcc; 7% (w/w) SHC, 53.9% (w/w) mcc; 8% (w/w) SHC, 52.9% (w/w) mcc; 9% (w/w) SHC, 51.9% (w/w) mcc; 10% (w/w) SHC, 50.9% (w/w) mcc; 11% (w/w) SHC, 49.9% (w/w) mcc; 12% (w/w) SHC, 48.9% (w/w) mcc; 13% (w/w) SHC, 47.9% (w/w) mcc; 14% (w/w) SHC, 46.9% (w/w) mcc; With 15% (w/w) SHC, 45.9% (w/w) mcc.
Table 9b: the ratio of components of foaming agent is to the influence of disintegration time
| The ratio of components of foaming agent (%, w/w) | Disintegration time (second) |
| 0 | 48 |
| 1 | 47 |
| 2 | 40 |
| 3 | 39 |
| 4 | 38 |
| 5 | 36 |
| 6 | 34 |
| 7 | 32 |
| 8 | 30 |
| 9 | 29 |
| 10 | 28 |
| 11 | 28 |
| 12 | 28 |
| 13 | 28 |
| 14 | 28 |
| 15 | 28 |
As above show shown in the 9b, the dispersible tablet that contains foaming agent is faster than the preparation disintegrate that does not have foaming agent.In particular, add the foaming agent that is higher than 2% (w/w), disintegration time descends rapidly, adds the foaming agent that is higher than 10% (w/w) and finds that disintegration time no longer reduces.
Embodiment 6-3: prepare the different dispersible tablet that contains the amoxicillin of each ratio of components
In the scope of determined each ratio of components, preparation contains the dispersible tablet of amoxicillin when changing the foaming agent ratio of components, and checks the disintegrating property of each preparation respectively in embodiment 6-2.
At first, with the mixture of the amoxicillin of 15% (w/w) and clavulanate potassium (4: 1, w/w), the cross-linking sodium carboxymethyl cellulose of the magnesium stearate of 0.1% (w/w), 10% (w/w), foaming agent (1: 1 (w/w) mixture of citric acid powder and sodium bicarbonate) (" A1 ") and the copolyvidone of 1% (w/w) are mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, copolyvidone, foaming agent (" A2 ") and the microcrystalline Cellulose (" B ") of cross-linking sodium carboxymethyl cellulose, 1% (w/w) of magnesium stearate, 10% (w/w) that in described dry type granule, adds the silicon dioxide, 1% (w/w) of 1% (w/w), mix, compression, preparation 500mg dispersible tablet.Wherein the ratio of components of foaming agent (A1, A2) and microcrystalline Cellulose (B) is illustrated among the following table 9c.
Table 9c: the ratio of components of foaming agent and microcrystalline Cellulose (unit: %, w/w)
| Preparation | A1 * | A2 * | B |
| Test example 1 | 0 | 0 | 60.9 |
| Test example 2 | 0 | 10 | 50.9 |
| Test example 3 | 10 | 0 | 50.9 |
| Test example 4 | 5 | 4 | 51.9 |
| Test example 5 | 2 | 1 | 57.9 |
| Test example 6 | 0 | 5 | 59.9 |
| Test example 7 | 3 | 7 | 50.9 |
| Test example 8 | 7 | 2 | 51.9 |
| Test example 9 | 5 | 0 | 55.9 |
*The composition of A1 and A2 is mutually the same.
To contain each dispersible tablet disintegrate in the 5ml distilled water of amoxicillin, analyze average disintegration time and particle size distribution (d90, d50 and d10) respectively, wherein the contrast with embodiment 1 in identical (
Referring to: table 9d).
Table 9d: the disintegration time of dispersible tablet and particle size distribution
| Preparation | Average disintegration time (second) | d90(μm) | d50(μm) | d10(μm) |
| Test example 1 | 48 | 86.1 | 21.0 | 6.6 |
| Test example 2 | 28 | 86.2 | 21.1 | 6.5 |
| Test example 3 | 27 | 83.7 | 20.4 | 6.1 |
| Test example 4 | 29 | 82.6 | 19.9 | 6.0 |
| Test example 5 | 39 | 87.3 | 20.9 | 6.4 |
| Test example 6 | 36 | 89.7 | 20.6 | 6.5 |
| Test example 7 | 28 | 83.2 | 20.3 | 6.0 |
| Test example 8 | 29 | 84.4 | 20.2 | 6.1 |
| Test example 9 | 36 | 86.1 | 20.9 | 6.3 |
As above show shown in the 9d, disintegration time does not depend on the time that adds foaming agent, and disintegration time changes with the ratio of components of foaming agent.
Embodiment 7: preparation contains the dispersible tablet of various beta-Lactam antibiotics and estimates disintegrating property
Preparation contains for example dispersible tablet of penicillin or pivampicillin rather than amoxicillin of beta-Lactam antibiotic respectively, and analyzes the disintegration time and the particle size distribution (d90, d50 and d10) of described preparation.
Embodiment 7-1: preparation contains the dispersible tablet of penicillin and estimates disintegrating property
With the mixture of 188mg penicillin and clavulanate potassium (2: 1, w/w), 30mg crospovidone, 8mg copolyvidone, 23mg silicon dioxide, 8mg magnesium stearate, 9mg citric acid and 11mg sodium bicarbonate are mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, in described dry type granule, add 15mg low-substituted hydroxypropyl cellulose, 145mg microcrystalline Cellulose, 47mg crospovidone, 9mg magnesium stearate and 7mg polyvidone, mix, compression, preparation 500mg dispersible tablet.Analyze respectively the disintegration time of described preparation and particle size distribution (d90, d50 and d10) (
Referring to: table 10a).
Table 10a: the disintegration time and the particle size distribution that contain the dispersible tablet of penicillin
| Average disintegration time (second) | 35 |
| d90(μm) | 102.4 |
| d50(μm) | 38.2 |
| d10(μm) | 8.7 |
Embodiment 7-2: preparation contains the dispersible tablet of pivampicillin and estimates disintegrating property
With the mixture of 156mg pivampicillin and clavulanate potassium (4: 1, w/w), 48mg crospovidone, 9mg copolyvidone, 25mg silicon dioxide, 7mg magnesium stearate, 9mg citric acid and 11mg sodium bicarbonate are mixed with each other, then mixture is sent in the roll squeezer that fast 5-10rpm of being of roller and screw speed are 5-10rpm and compressed, obtain the dry type granule.Subsequently, in described dry type granule, add 113mg microcrystalline Cellulose, 60mg lactic acid, 42mg crospovidone, 12mg magnesium stearate and 8mg polyvidone, mix, compression, preparation 500mg dispersible tablet.Analyze respectively the disintegration time of described preparation and particle size distribution (d90, d50 and d10) (
Referring to: table 10b).
Table 10b: the disintegration time and the particle size distribution that contain the dispersible tablet of pivampicillin
| Average disintegration time (second) | 38 |
| d90(μm) | 92.4 |
| d50(μm) | 35.1 |
| d10(μm) | 8.1 |
Shown in embodiment 7-1 and 7-2 result, can clearly determine, except that the amoxicillin, the method for preparing dispersible tablet of the present invention can comprise various beta-Lactam antibiotics for example penicillin or pivampicillin equally, preparation by this method preparation can reduce average disintegration time and show fabulous dispersive property, and it shows that method of the present invention can be actually used in the preparation of various beta-Lactam antibiotics.
Purposes
The dispersible tablet that contains beta-Lactam antibiotic of the present invention can be with the concentration of 20-50mg/mL (being dispersed in the water) dosed administration with 5-20mg/ body weight (kg), and dosage is decided with patient's age, sex, symptom, administering mode or prevention purpose.For the patient who shows specific symptoms, those skilled in the art can change discrete dosage according to the order of severity of patient's body weight, age, sex, health status, diet, administration time, administering mode, discharge rate, disease etc.
Clearly explain and show as top, the invention provides the dispersible tablet that contains beta-Lactam antibiotic, wherein beta-Lactam antibiotic and Clavulanate are prepared with tablet form, and it is easy to take during disintegrate in water, and the present invention also provides the method for this dispersible tablet of preparation.Dispersible tablet of the present invention can be used for the treatment of the disease that needs beta-Lactam antibiotic in practice, because it can easily be taken by oral inconvenient baby or gerontal patient, and has the disintegration rate and the dispersive property of improvement.
Being appreciated that top explanation only is the description to preferred embodiment, is not to limit the invention to the particular form of being set forth, and by contrast, present invention resides in these changes, variant and equivalent in the spirit and scope of determining in the claim.
Claims (32)
1. preparation contains the method for the dispersible tablet of beta-Lactam antibiotic, comprises step:
(i) beta-Lactam antibiotic and Clavulanate are mixed with disintegrating agent, lubricant and binding agent, then described mixture is sent in the roll squeezer, obtain the dry type granule; Then,
(ii) the dry type granule that will obtain in step (i) mixes with excipient, disintegrating agent, lubricant and binding agent, and to this mixture compression, obtains dispersible tablet.
2. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, and wherein beta-Lactam antibiotic is a Penicillin antibiotics.
3. the preparation of claim 2 contains the method for the dispersible tablet of beta-Lactam antibiotic, and wherein Penicillin antibiotics is penicillin, amoxicillin, ampicillin, ciclacillin, epicillin, phenethicillin or pivampicillin.
4. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, and wherein Clavulanate is a clavulanate potassium.
5. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, and wherein the mixture of beta-Lactam antibiotic in the step (i) and Clavulanate is included in the dispersible tablet with the ratio of components of 15-40% (w/w).
6. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein the disintegrating agent in the step (i) is crospovidone, cross-linking sodium carboxymethyl cellulose, sodium starch glycolate, carboxymethyl cellulose potassium, pregelatinized Starch or its mixture, and is included in the dispersible tablet with the ratio of components of 3-10% (w/w).
7. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein the lubricant in the step (i) is magnesium stearate, silicon dioxide, Talcum, Polyethylene Glycol, stearic acid or its mixture, and is included in the dispersible tablet with the ratio of components of 0.1-5% (w/w).
8. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein the binding agent in the step (i) is copolyvidone, polyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose or its mixture, and is included in the dispersible tablet with the ratio of components of 0.1-7.5% (w/w).
9. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein in the process of step (i) desiccant or foaming agent is further joined in the mixture of beta-Lactam antibiotic and Clavulanate, disintegrating agent, lubricant and binding agent.
10. the preparation of claim 9 contains the method for the dispersible tablet of beta-Lactam antibiotic, and wherein desiccant is silicon dioxide, synthetic aluminium silicate, light anhydrous silicic acid or its mixture, and is included in the dispersible tablet with the ratio of components of 0.1-10% (w/w).
11. the preparation of claim 9 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or its mixture, and is included in the dispersible tablet with the ratio of components of 1-5% (w/w).
12. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein the excipient of step in (ii) is microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, lactose, calcium hydrogen phosphate, corn starch, mannitol, Sorbitol, xylitol or its mixture, and is included in the dispersible tablet with the ratio of components of 30-75% (w/w).
13. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein the disintegrating agent of step in (ii) is crospovidone, cross-linking sodium carboxymethyl cellulose, sodium starch glycolate, carboxymethyl cellulose potassium, pregelatinized Starch or its mixture, and is included in the dispersible tablet with the ratio of components of 3-10% (w/w).
14. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein the lubricant of step in (ii) is magnesium stearate, silicon dioxide, Talcum, Polyethylene Glycol, stearic acid or its mixture, and is included in the dispersible tablet with the ratio of components of 0.1-5% (w/w).
15. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein the binding agent of step in (ii) is copolyvidone, polyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose or its mixture, and is included in the dispersible tablet with the ratio of components of 0.1-7.5% (w/w).
16. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein excipient, disintegrating agent, lubricant and the binding agent of step in (ii) mixes with the dry type granule that obtains in powder type and the step (i).
17. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein excipient, disintegrating agent, lubricant and the binding agent of step in (ii) is to mix with the dry type granule of acquisition in the step (i) by mixing and compress the dry type particle form that these materials obtain.
18. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein excipient, disintegrating agent, lubricant and the binding agent of step in (ii) is to mix with the dry type granule of the middle acquisition of step (i) by these materials are mixed the wet type particle form that obtains with water.
19. the preparation of claim 1 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein in step process (ii) foaming agent is further joined in the mixture of the middle dry type granule that obtains of step (i) and excipient, disintegrating agent, lubricant and binding agent.
20. the preparation of claim 19 contains the method for the dispersible tablet of beta-Lactam antibiotic, wherein foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or its mixture, and is included in the dispersible tablet with the ratio of components of 1-5% (w/w).
21. the dispersible tablet that contains beta-Lactam antibiotic by claim 1 preparation, it comprises the mixture of the beta-Lactam antibiotic of 15-40% (w/w) and Clavulanate as active component in dispersible tablet, and the disintegrating agent of 6-20% (w/w), the lubricant of 0.1-10% (w/w), the binding agent of 0.1-15% (w/w), the excipient of 30-75% (w/w).
22. the dispersible tablet that contains beta-Lactam antibiotic of claim 21, wherein beta-Lactam antibiotic is a Penicillin antibiotics.
23. the dispersible tablet that contains beta-Lactam antibiotic of claim 22, wherein Penicillin antibiotics is penicillin, amoxicillin, ampicillin, ciclacillin, epicillin, phenethicillin or pivampicillin.
24. the dispersible tablet that contains beta-Lactam antibiotic of claim 21, wherein Clavulanate is a clavulanate potassium.
25. the dispersible tablet that contains beta-Lactam antibiotic of claim 21, wherein disintegrating agent is crospovidone, cross-linking sodium carboxymethyl cellulose, sodium starch glycolate, carboxymethyl cellulose potassium, pregelatinized Starch or its mixture.
26. the dispersible tablet that contains beta-Lactam antibiotic of claim 21, wherein lubricant is magnesium stearate, silicon dioxide, Talcum, Polyethylene Glycol, stearic acid or its mixture.
27. the dispersible tablet that contains beta-Lactam antibiotic of claim 21, wherein binding agent is copolyvidone, polyvidone, hydroxypropyl cellulose, hydroxypropyl emthylcellulose, hydroxyethyl-cellulose or its mixture.
28. the dispersible tablet that contains beta-Lactam antibiotic of claim 21, wherein excipient is microcrystalline Cellulose, low-substituted hydroxypropyl cellulose, lactose, calcium hydrogen phosphate, corn starch, mannitol, Sorbitol, xylitol or its mixture.
29. the dispersible tablet that contains beta-Lactam antibiotic of claim 21 wherein further comprises foaming agent, desiccant or its mixture in dispersible tablet.
30. the dispersible tablet that contains beta-Lactam antibiotic of claim 29, wherein foaming agent is citric acid, tartaric acid, alginic acid, malic acid, sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate or its mixture, and is included in the dispersible tablet with the ratio of components of 2-10% (w/w).
31. the dispersible tablet that contains beta-Lactam antibiotic of claim 29, wherein desiccant is silicon dioxide, synthetic aluminium silicate, light anhydrous silicic acid or its mixture, and is included in the dispersible tablet with the ratio of components of 0.1-10% (w/w).
32. contain the dispersible tablet of amoxicillin, it comprises the mixture (4: 1 of the amoxicillin of 15-40% (w/w) and Clavulanate in dispersible tablet, w/w), and the disintegrating agent of 6-20% (w/w), the lubricant of 0.1-10% (w/w), the binding agent of 0.1-15% (w/w), the foaming agent of the excipient of 30-75% (w/w), 2-10% (w/w) and the desiccant of 0.1-10% (w/w).
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| KR1020040039302 | 2004-05-31 | ||
| KR20040039302 | 2004-05-31 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN1767818A true CN1767818A (en) | 2006-05-03 |
Family
ID=36743272
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNA2004800089274A Pending CN1767818A (en) | 2004-05-31 | 2004-12-09 | Dispersible tablet comprising beta lactam antibiotics and process for preparing the same |
Country Status (4)
| Country | Link |
|---|---|
| JP (1) | JP2006527064A (en) |
| KR (1) | KR100515311B1 (en) |
| CN (1) | CN1767818A (en) |
| WO (1) | WO2005115347A1 (en) |
Families Citing this family (7)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SI21912A (en) * | 2004-12-24 | 2006-06-30 | Lek Farmacevtska Druzba D.D. | Stable pharmaceutical forms containing amoxicillin and clavulanic acid |
| US9198862B2 (en) | 2005-07-22 | 2015-12-01 | Rubicon Research Private Limited | Dispersible tablet composition |
| KR100589483B1 (en) * | 2005-11-10 | 2006-06-14 | 지엘팜텍 주식회사 | A dispersible tablet comprising the mixture of amoxicillin and clavulanic acid or its salts and processes for preparing the same |
| WO2007058397A1 (en) * | 2005-11-17 | 2007-05-24 | Gl Pharmtech Corp. | A dispersible tablet comprising the mixture of amoxicillin and clavulanic acid or its salts and processes for preparing the same |
| TR201010860A2 (en) * | 2010-11-05 | 2012-05-21 | Bi̇lgi̇ç Mahmut | Production method for cefdinir formulations. |
| TR201009167A2 (en) * | 2010-11-05 | 2012-05-21 | Bi̇lgi̇ç Mahmut | Pharmaceutical granules containing cephalosporin. |
| EP4331667A3 (en) | 2012-03-22 | 2024-05-08 | Novo Nordisk A/S | Compositions comprising a delivery agent and preparation thereof |
Family Cites Families (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3266580D1 (en) * | 1981-12-02 | 1985-10-31 | Beecham Group Plc | Pharmaceutical formulation comprising beta-lactam antibiotics |
| GB9109862D0 (en) * | 1991-05-08 | 1991-07-03 | Beecham Lab Sa | Pharmaceutical formulations |
| AU4818393A (en) * | 1992-09-18 | 1994-04-12 | Unilever Plc | Production of desired proteins or polypeptides by culturing a transformed lactic acid bacterium |
| DK0890359T3 (en) * | 1996-02-29 | 2002-07-01 | Fujisawa Pharmaceutical Co | Beta-Lactam antibiotic-containing tablets and method of preparation thereof |
-
2004
- 2004-12-09 CN CNA2004800089274A patent/CN1767818A/en active Pending
- 2004-12-09 JP JP2006520128A patent/JP2006527064A/en not_active Withdrawn
- 2004-12-09 WO PCT/KR2004/003228 patent/WO2005115347A1/en not_active Application Discontinuation
- 2004-12-11 KR KR10-2004-0104661A patent/KR100515311B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| KR100515311B1 (en) | 2005-09-16 |
| WO2005115347A1 (en) | 2005-12-08 |
| KR20050002738A (en) | 2005-01-10 |
| JP2006527064A (en) | 2006-11-30 |
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