CN105377241A

CN105377241A - Super quick disintegrating tablet formula for api miglitol

Info

Publication number: CN105377241A
Application number: CN201480040954.3A
Authority: CN
Inventors: T.莱希
Original assignee: Bayer Pharma AG
Current assignee: Bayer Pharma AG
Priority date: 2013-07-19
Filing date: 2014-07-14
Publication date: 2016-03-02
Also published as: JP2016533383A; JP6506752B2; EP3021837A1; WO2015007676A1; HK1221915A1

Abstract

The invention relates to a tablet containing 20% to 30% miglitol, 65% to 78% insoluble constituents and tableting auxiliaries.

Description

The supper-fast disintegrating tablet formula of API miglitol

Miglitol is used to the oral medication of diabetes.It is by Inhibiting α-glucosidase, the rising of blood sugar level after the supply of the food of suppression containing carbohydrate.For optimum efficiency, active component being uniformly distributed in food is favourable.In order to realize it, there is the probability using oral cavity disintegration tablet.Then this allow the effective mixing in itself chyme under one's belt.

Be, in the tablet art of fater disintegration or dissolving in oral cavity, to there is a large amount of prior aries.A noticeable example is herein a similar preparation, and it is described by very upper, and has the wide claimed scope (JP2009114069A) relevant with the dissolubility of used active component.

The production of novel formulation should not make any professional technique become required, and the cost of the composition used should be low.But this special challenge is the acquisition of tablet short disintegration time (softening time) in the oral cavity.Target number is for being less than 100 seconds.Due to the relative low capacity of liquid in the oral cavity, and equally due to the viscosity (it has been increased compared with the viscosity of water) of saliva, this becomes and more difficult for.

The mouthfeel obtained should be pleasant, especially for patient/consumer, to increase acceptability and the treatment compliance of preparation.

Surprisingly, described compositions achieves (37 ° of C have the PhEU device of disk) and the tablet disintegration times in the oral cavity in water that are less than 100 seconds.The active component mark (being greater than 25% (m/m)) of said preparation is sufficiently high for allowing to produce for attractive little tablet.Meanwhile, the mechanical strength (breaking load is greater than 50N, and wearing and tearing are less than 0.5%) of tablet is sufficiently high for permission tablet is processed normally and packs.

Soluble carrier (it is insoluble for adding up at least 70% (m/m)) result in disintegrate fast and pleasant mouthfeel together with the combination of thick API granularity, and different from having easily of using under other circumstances and carrier/active component solvable rapidly and/or the technology of high porosity medicament forms as lyophilisation product.In addition, as the result of used production technology, the tablet obtained is more cheap significantly.

Surprising factor is the relation between the granularity of measured disintegration time and active pharmaceutical ingredient (API).Favourable active component aggregate is fine and close (preferred crystallization), and be also by conventional method of granulating (preferred aqueous fluid bed agglomeration and dry-pressing) or crystallization attainable.Find that the particle mean size of finer and close active component aggregate and the increase of being on the increase result in shorter disintegration time.

Fig. 1 illustrates the example of API granularity to the impact of disintegration time (Ph.EU device, water, 37 DEG C).The post of left-hand side illustrates the disintegration time of the miglitol of crystallization, and second post illustrates the disintegration time of the miglitol of the classification of the granularity with <400 micron.3rd post illustrates the disintegration time of the miglitol of the classification of the granularity with >400 micron, and dexter post illustrates the disintegration time of the miglitol of granulation.Granulate and undertaken by fluid bed agglomeration, and crystalline product classification by screening.

Surprisingly, although there is restrictive boundary condition (method and composition), achieve successfully in the process of exploitation preparation: described preparation is equal to or is better than many professional techniques of describing in the literature and/or composition.

Tablet of the present invention containing have an appointment 20% to 30% miglitol.The miglitol of 25% to 28% is preferred.In addition, tablet of the present invention contains 65% to 78%, preferably insoluble composition of 68% to 75%.Supplied by compression aids with the difference of 100%, described compression aids is such as disintegrate auxiliary agent, excipient, filler, lubricant and optional correctives.

The production technology adopted is the quite conventional standard method of the tablet manufacturing in pharmaceuticals industry.

Tablet can obtain preferably by the method for direct compression.In the method, only component is mixed, and optionally sieve, then the mixture obtained is carried out tabletting by compression.The method is noticeable, particularly for low production cost.

Equally likely by some components or all components mixing, and with the form dry-pressing of such mixture or part mixes.So-called " spreading granule (rollgranules) " is like this cheap equally, and easily produces.After dry-pressing, compact is sieved also optionally component remaining with other and mix, to obtain the flowable mixture for tabletting.Subsequently this mixture is compressed into tablet form.

In order to utilize granularity for active component on the positive impact described by disintegration time, also can in the mode forming larger active component aggregate or the aggregate containing active component separately or process active component together with other component of described compositions.Here, above-mentioned dry-pressing or other common granulation technique, granulate as fluid bed agglomeration or high-speed mixer and also have fitness.The granulation liquid used in such a case is preferably water or suitable organic solvent.

If, due to any special reason (such as, the availability of miglitol medicine or the shortage of technical equipment), must by fine granularity grade (such as particle mean size x ₅₀be 3 μm-80 μm, 10 μm-50 μm or 15 μm-30 μm) miglitol medicine be used in described compositions, then the flowing property of obtained mixture reduces significantly.Thus, the physical property of the tablet obtained can change, but still remains within scope desired for enough short disintegration time and sufficiently high mechanical resistance.But the manufacture method step of tablet press be have impact on negatively.The use of the miglitol (little crystal or the material ground) of fine granularity grade causes powder segregation (powdersegregation), which results in unacceptable content uniformity result (content uniformity test is that all main pharmacopeia are as the conventional methods of PhEU, PhJap, USP) for some time points in sheeting operation.Due to this discordance of the bonding code of the usual employing with content uniformity test, such method have produce can not discharge/for the excessive risk of the tablet of market supply.

Although be not understood (such as at viewed powder segregation precise mechanism behind, the difference of the granularity of component of mixture, the difference of the density of component of mixture, the irregular flow of powder etc. caused due to shunting (bridging)), by being used as the flexible foil-pipeline (flexiblefoil-tubing) of the connection between container (containing mixture namely for compressing) and tablet machine feeder, the output of tabletting method and robustness can be improved surprisingly (with regard to regard to the content uniformity result of tablet of producing).The material that this flexible foil-pipeline uses must be enough flexible (changing with flow of powder to allow pipe diameter), and must by for directly contacting with food and pharmaceutical preparation suitable material (such as, polyethylene LDPE or HDPE, polypropylene PP, polyvinylchloride, polyethylene terephthalate (Polyetylenterephtalat) PET, cellulose, silicon, polystyrene PS, polytetrafluoroethylene PTFE or its combine) make.The maximum gauge of this flexible foil-pipeline is the scope at 75mm-400mm, 100mm-350mm, 150mm-300mm.This described simple flexible foil-pipeline is for replacing the metallic conduit of standard (normally rustless steel) and all parts inside tablet machine, on feeder (forced feeder or gravity-feeder).Thus, give there is directly flexibly connecting of the probability that changes diameter between its container at tablet machine and feeder.This equipment ensure that acceptance criteria that the powder segregation of mixture is reduced to content uniformity test is met and the degree that is greatly improved of the robustness of tabletting method safely.

Described the method equipment simple and effective improvement helps avoid other technology commercially available work (such as, fixed amount feed unit, the mixture of powders of little determined amounts is supplied in the feeder of tablet machine by it), allow the vertical transmitting range of the length of mixture of powders, eliminate clean needs (because it can be discarded after a procedure, and needing considerably less investment).The tabletting method of this improvement can run when having the robustness improved significantly (or even when using the miglitol of fine granularity grade, it will be impossible in other cases).

The embodiment of tablet composition

	[%]	Mg/ sheet
			Miglitol *)	27.778	50.000
Corn starch	42.842	77.115
			Magnesium trisilicate	16.700	30.060
Crospolyvinylpyrrolidone	11.100	19.980
			Lubricant * *)	1.500	2.700

			Sucralose	0.080	0.144

				100.000	180.0
180	mg
			8.5mm FF

(facet) the flat tablet with facet, the breaking load that are compressed to 8.5mm are 50-70N (Schleuniger6D)

*) miglitol can alternately be used or directly use (because do not have extra operating procedure, it is particularly preferred) after crystallisation with the form of dry-pressing (spreading granule) as fluid bed granulate product.

*) lubricant suitable is especially magnesium stearate or sodium stearyl fumarate (PRUV).

Under be classified as insoluble: corn starch, magnesium trisilicate, PVPCL.

By the embodiment that direct compression is produced

Embodiment by the reunion of the part mixes of dry-pressing:

Claims

1. tablet, it contains the miglitol of 20% to 30%, insoluble component of 65% to 78% and compression aids.

2. tablet according to claim 1, it contains the miglitol of 25% to 28%, insoluble component of 68% to 75% and compression aids.

3., according to the tablet of claim 1 and 2, described insoluble component is corn starch, magnesium trisilicate and crospolyvinylpyrrolidone.

4. according to the tablet of claim 1-3, it has the disintegration time being less than 100 seconds, is the miglitol of 100-800 μm containing particle mean size.

5. tablet according to claim 4, it has the average miglitol granularity of 150-600 μm.

6. tablet according to claim 4, it has the average miglitol granularity of 160-500 μm.

7. according to the tablet of claim 1-3, it has the disintegration time being less than 100 seconds, is the miglitol of 3-80 μm containing particle mean size.

8. according to the tablet of claim 1-3, it has the disintegration time being less than 100 seconds, is the miglitol of 10-50 μm containing particle mean size.

9. according to the tablet of claim 1-3, it has the disintegration time being less than 100 seconds, is the miglitol of 15-30 μm containing particle mean size.

10. according to the tablet of claim 1-9, it can obtain as follows: mix each component, and passes through mixture tabletting without the compression of other intermediate steps.

11. according to the tablet of claim 1-9, and it can obtain as follows: mix each component, makes mixture experience initial compacting and by compression by its tabletting.

12. according to the tablet of claim 1-11, and described active component miglitol uses with the form of reuniting.

13. according to the tablet of claim 1-11, and described active component directly uses after crystallisation.

14. prepare the method for the tablet any one of claim 1-13 with tablet machine, wherein flexible foil-pipeline are used as the connection containing being namely used between the container of the mixture compressed and tablet machine feeder.