Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2059—Starch, including chemically or physically modified derivatives; Amylose; Amylopectin; Dextrin
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K31/00—Medicinal preparations containing organic active ingredients
  • A61K31/33—Heterocyclic compounds
  • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
  • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
  • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
  • A61K31/445—Non condensed piperidines, e.g. piperocaine
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/0012—Galenical forms characterised by the site of application
  • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
  • A61K9/0056—Mouth soluble or dispersible forms; Suckable, eatable, chewable coherent forms; Forms rapidly disintegrating in the mouth; Lozenges; Lollipops; Bite capsules; Baked products; Baits or other oral forms for animals
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2009—Inorganic compounds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
  • A61P3/00—Drugs for disorders of the metabolism
  • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
  • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

• Miglitol is employed for the oral therapy of diabetes mellitus. It inhibits the rise in blood sugar level following supply of carbohydrate-containing food, by inhibiting alpha-glucosidase. For an optimum effect, the uniform distribution of the active ingredient in the food is advantageous. In order to achieve this, the possibility exists of using an orally disintegrating tablet. This then allows effective mixing in the chyme in the stomach itself.
• the mouth feel obtained is to be pleasant especial ly for the patient, consumer, in order to increase the acceptance of the formulation and the therapeutic compliance.
• the composition described surprisingly, achieves a tablet disintegration time in water (37°C, PhEU apparatus with disc) and in the mouth of less than 100 seconds.
• the activ e ingredient fraction of the formulation at more than 25% (m/m), is high enough to allow production of appealingly small tablets.
• insoluble vehicle a good 70% (m/m) overall is insoluble
• coarse API particle size results in rapid disintegration with pleasant mouth feel and contrasts with the otherwise used technology with easily and quickly soluble vehicle/active ingredients and/or high- porosity drug forms such as freeze-dried products.
• the tablets obtained are significantly less expensive.
• a surprising factor is the relationship between the disintegration times measured and the particle size of the active pharmaceutical ingredient (API).
• Favourable active ingredient agglomerates are compact (preferably crystallized) and are also achievable by customary granulation methods (preferably aqueous fluid-bed agglomeration and dry compacting) or crystallization. It is found that increasingly more compact active ingredient agglomerates with increasing average particle size lead to shorter disintegration times.
• Figure 1 shows an example of the effect of the API particle size on the disintegration time (Ph. EU apparatus, water, 37°C).
• the left-hand column shows the disintegration time of crystalline miglitol, the second column that of fractionated miglitol with a particle size of ⁇ 400 micrometers.
• the third column shows the disintegration time with fractionated miglitol, with a particle size of >400 micrometes, and the right-hand column shows that of granulated miglitol. Granulation took place by fluid-bed agglomeration, and the crystalline product was fractionated by sieving.
• a tablet of the invention contains about 20% to 30% miglitol. 25% to 28% miglitol is preferred. Moreover, the tablet of the invention contains 65% to 78%, preferably 68% to 75%, of insoluble ingredients. The difference to 100% is made up by tableting auxiliaries such as, for example, disintegration assistants, excipients, fillers, lubricants and optionally flavours.
• the tablets can be obtained preferably by the method of direct tableting. In this method the components are merely mixed and optionally sieved, and the resulting mixture is then tableted by compression. This method is notable in particular for low production costs.
• the active ingredient can also be processed, alone or in combination with other components of the composition described, in such a way as to form larger active ingredient agglomerates or active ingredient-containing agglomerates.
• Suitabi lity here as well is possessed by the above-described dry compacting or other common granulation techniques, such as fluid-bed agglomeration or high-speed mixer granulat ion.
• Granulating liquids used in such cases are preferably water or suitable organic solvents. i f, for any particular reason (e.g.
• M iglitol drug substance of a fine part icle size grade (for example mean particle size x 50 at 3 ⁇ m-80 ⁇ m, 10 ⁇ m- 50 ⁇ m or 15 ⁇ m -30 ⁇ m ) has to be used in the described compositions, the flow properties of the resulting mixtures is markedly decreased. As a consequence the physical properties of the resulting tablets do change, but still remain within the desired range for sufficiently short disintegration time and sufficiently high mechanical resistance. The manufacturing process step of tablet compression however is negatively affected.
• the tableting process output and robustness can be surprisingly improved with respect to the content uniformity results of the produced tablets by using a flexible foil-tubing as a connection between the container (containing the ready-to-press mixture) and the tablet press feeder.
• the used material of this flexible foil-tubing has to be flexible enough to allow for a change in tube-diameter depending on powder flow and has to be made of suitable material for direct contact with food and pharmaceutical preparations (e.g.
• the maximum diameter of the flexible foil-tubing is in the range of 75mm-400mm, 100mm-350mm, 150mm-300mm.
• This described simple flexible foil-tubing is used to replace the standard metal tubing (usually stainless steel ) and all part inside the tablet press above the feeder ( forced feeder or gravity feeder).
• This set-up ensures that powder segregat ion of the mixture is reduced to an extent, that acceptance criteria for content uniformity testing are safely met and robustness of the tableting process is greatly improved.
• the described simple and effective modification of the process equipment helps to av oid other technical efforts that are commercially av ailable (e.g. fixed quantity supplying units, that supply small defined quantities of powder mixture to the feeder of the tablet press), allows for long v ertical transport distances for powder mixture, eliminates the need for cleaning as it can be disposed after use and needs very low investment.
• the modified tableting process can be run with markedly improved robustness even with the fine particle size grade of Miglitol, which otherwise would not be possible.
• M iglitol may be used alternatively as a fluid-bed granule product, in dry-compacted form (roll granules) or directly after crystallization (particularly preferred on account of no additional operating step).
• Particularly suitable lubricants are magnesium stearate or sodium stearylfumaratc (PRUV).

Landscapes

• Health & Medical Sciences (AREA)
• Veterinary Medicine (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Public Health (AREA)
• General Health & Medical Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Diabetes (AREA)
• Hematology (AREA)
• Engineering & Computer Science (AREA)
• Organic Chemistry (AREA)
• General Chemical & Material Sciences (AREA)
• Chemical Kinetics & Catalysis (AREA)
• Obesity (AREA)
• Bioinformatics & Cheminformatics (AREA)
• Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
• Endocrinology (AREA)
• Zoology (AREA)
• Nutrition Science (AREA)
• Physiology (AREA)
• Emergency Medicine (AREA)
• Inorganic Chemistry (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Priority Applications (4)

Applications Claiming Priority (2)

Publications (1)

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Citations (4)

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• 2014
  • 2014-07-14 CN CN201480040954.3A patent/CN105377241A/zh active Pending
  • 2014-07-14 WO PCT/EP2014/065016 patent/WO2015007676A1/en active Application Filing
  • 2014-07-14 EP EP14738534.8A patent/EP3021837A1/en not_active Withdrawn
  • 2014-07-14 JP JP2016526560A patent/JP6506752B2/ja active Active
• 2016
  • 2016-08-29 HK HK16110220.3A patent/HK1221915A1/zh unknown

Patent Citations (4)

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