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
  • A61K9/2009—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
  • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
  • A61K9/4841—Filling excipients; Inactive ingredients
  • A61K9/485—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
  • A61K9/2013—Organic compounds, e.g. phospholipids, fats
  • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
• • 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
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

• the present invention relates to a sustained release formulation for peroral administration together with a meal containing at least one active ingredient and optionally one or more pharmaceutically acceptable excipients and an amount of gas generator which allows a substantially homogeneous mixing of the active ingredient with the stomach contents and thus a continuous flooding of the active ingredient ,
• delays in the systemic tsunami often occur, which are usually characterized by the fact that, compared to fasting administration, the maximum systemic active substance levels are lowered and the time to onset the maximum drug level is prolonged.
• sustained-release preparations with or after a meal a prolonged phase until the onset of first measurable systemic drug concentrations is often observed in comparison to fasting.
• the known effervescent mixtures to be taken perorally when used as intended ie the ingestion after disintegration of the effervescent preparation in a suitable liquid, which is mostly water, lead to a particularly rapid onset of the drug.
• gas developers as solid-delivery excipients is sometimes also suggested as a disintegrants for the preparation of peroral oral tablets or chewable tablets, described, for example, in Oral tablet disintegrant of nimodipine for treating dementia, Faming Zhuanli Shenqing Gongkai Shuomingshu, 6 pp.
• CODES CNXXEV; Chinese; CN1394605, where gas evolution does not occur until it is taken in the mouth or in the stomach, but the amounts of gas generators incorporated in such dosage forms are too low to prevent the discontinuation of the corresponding active ingredient.
• DE 691 25 619 T2 relates to controlled release structures achieved by coating an elongated extruded core with a water-insoluble material.
• Calcium carbonate is mentioned as a possible additive and is unrelated to the controlled release, on the contrary, the presence of calcium carbonate causes just no retardation but a faster release, as shown in the figures of this document. It is the object of the present invention to find dosage forms which avoid the problem of the occurrence of undesirable plasma peak levels as well as delays in the onset of peroral drug administration with or after the meal.
• the dosage forms are furthermore intended to bring about as uniform as possible a concentration course of the drug in the systemic circulation.
• gas developers as adjuvants in solid peroral administration forms undesirably low plasma peak levels and delays in the influx in the peroral administration of drugs with or after the meal occur significantly reduced. This is probably due to the fact that due to the amounts of gas developer contained in the dosage forms according to the invention, a preferably homogeneous mixing of the active ingredients also contained or the active ingredient-containing components of the dosage form with the stomach contents occurs.
• the active ingredient contained in the dosage form can also be completely or partially present in slowly releasing form of the active ingredient.
• Gastro-resistant forms are also conceivable, in which case the drug can be protected from the stomach environment.
• sustained-release formulations and / or enteric coatings depending on the active substance, or the like.
• Conceivable here are, for example, coated or constructed from an excipient matrix particles, such as granules or pellets, or microparticles.
• an excipient matrix particles such as granules or pellets, or microparticles.
• Suitable gas developers are substances that release carbon dioxide. Preference is given to sodium bicarbonate, sodium carbonate, calcium carbonate and
• Magnesium carbonate or mixtures thereof In this case, it is conceivable to mix two or more of the mentioned gas images in any desired ratios.
• the person skilled in the art will select a suitable composition of gas developer, depending on the active ingredient or combination of active ingredients. As stated above, other substances that release carbon dioxide may also be considered here.
• such an amount of gas developer is used per single dose, which is a substantially homogeneous
• this may be at least 50 mg of a gas developer per single dose.
• these are at least 100 to 150 mg of gas developer per ingestion, more preferably at least 250 mg, more preferably 300 mg, if appropriate administered 500 mg and also up to 1000 mg of gas developer per ingestion.
• the person skilled in the art will, depending on the active substance and the present galenics, select the required amount of gas developer and determine it in such a way that the effect according to the invention of homogeneous mixing with the gastric contents is achieved.
• the acid required for the carbon dioxide release which is preferred according to the invention for the gas developers may originate from the gastric contents or may be contained in the dosage form. All non-physiologically acceptable acids are suitable for admixing, and preferred auxiliaries are acid components such as citric acid, tartaric acid and ascorbic acid or mixtures thereof. Particularly preferred is ascorbic acid.
• the acid or acids according to preferred embodiments of the invention in amounts of 100 to 300 mg, more preferably from 100 to 200 mg, more preferably in an amount of about 200 mg in the dosage form of the invention. The person skilled in the art will choose an appropriate amount of acid, depending on the dosage form.
• the dosage forms according to the invention are particularly suitable for the following systemically acting drugs: tricyclic antidepressants, such as amitryptiline, doxepin, and imipramine; non-steroidal anti-inflammatory drugs, such as in particular indomethacin, diclofenac and ketoprofen; Analgesics such as oxycodone, orphin, tramadol and tilidine; Anti-epileptic drugs such as carbamazepine, oxcarbazepine, valproic acid, phenytoin and gabapentin; Anti-parkinson agents, such as levodopa and enthacapone; Alpha-Receptor Blockers, such as Doxazosin; Beta-blockers such as bisoprolol, atenolol and metoprolol; Spasmolytics, such as oxybutynin; Anti-dementia drugs such as memantine and donepizil; Thyroid hormones, such as levo
• the dosage forms of the invention are also particularly suitable for administration of the active ingredients acarbose, miglitol, pancreatic enzymes, ezetemibe, statins, such as atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and orlistat.
• statins such as atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and orlistat.
• statins such as atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and orlistat.
• statins such as atorvastatin, fluvastatin, lovastatin, pravastatin, simvastatin and orlistat.
• the active ingredient acarbose is particularly suitable for administration of the active ingredients acarbose.
• Dosage forms according to the invention may be coated or uncoated tablets, chewable tablets, capsules, coated or uncoated granules, coated or uncoated powders or suspensions.
• the required dose of active ingredient per administration may be divided into several individually divided forms, for example two or three tablets or capsules.
• the required amount of gas developer then refers to the total amount of active ingredient dose taken.
• Tablet consisting of 500 mg of sodium bicarbonate, 100 mg of acarbose, 100 mg of microcrystalline cellulose, 10 mg of magnesium stearate.
• Sodium bicarbonate, acarbose and microcrystalline cellulose are mixed in a free-fall mixer, magnesium stearate is added and mixed again briefly.
• the powder is compressed on a tablet press into a tablet.
• Tablet consisting of 400 mg sodium bicarbonate, 100 mg citric acid, 50 mg acarbose, 100 mg microcrystalline cellulose, 10 mg magnesium stearate.
• Sodium bicarbonate, citric acid, acarbose and microcrystalline cellulose are mixed in a free-fall mixer, magnesium stearate is added and mixed again briefly.
• the powder is compressed on a tablet press into a tablet.
• Sodium bicarbonate and acarbose are mixed in a free-fall mixer, magnesium stearate is added and mixed again briefly.
• the powder is filled into a hard gelatin capsule.
• Example 4 Capsule containing 250 mg of sodium bicarbonate, 50 mg of citric acid, 25 mg of acarbose, 5 mg of magnesium stearate. Sodium bicarbonate, citric acid and acarbose are mixed in a free-fall mixer, magnesium stearate is added and mixed again briefly. The powder is filled into a hard gelatin capsule.
• Example 5
• omeprazole consisting of 10 mg omeprazole as pellets in enteric-coated form (omeprazole, Stada), 300 mg sodium bicarbonate, 50 mg ascorbic acid, 5 mg magnesium stearate. Sodium bicarbonate and citric acid are mixed in a free-fall mixer, magnesium stearate and the enteric-coated pellets (omeprazole, stada) are added. It is mixed again. The mixture is filled into a hard gelatin capsule.
• Example 6 Capsule consisting of 10 mg of omeprazole as pellets in enteric-coated form (omeprazole, Stada), 300 mg of sodium bicarbonate, 50 mg of ascorbic acid, 50 mg of microcrystalline cellulose, 5 mg of magnesium stearate. Sodium bicarbonate, citric acid and microcrystalline cellulose are mixed in a free-fall mixer, after addition of magnesium stearate, the powder is compacted and then coarsely crushed into granules. The granules and the enteric pellets (omeprazole, stada) are mixed. The mixture is filled into a hard gelatin capsule.
• Example 7 50 mg each of acarbose were mixed with 406 mg of ascorbic acid and 194 mg of sodium bicarbonate in a mortar and filled into a size 1 hard gelatin capsule.
• Blood samples (1.5 ml each) were obtained at the following time points: 5 min before the start of the breakfast, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, 40 min, 45 min, 50 min , 55 min, 60 min, 1 h 10min, 1 h 20min, 1 h 30min, 1h 40min, 1h 50min, 2h, 2h 15min, 2h 30min, 2h 45min, 3h, 3h 15min, 3h 30min, 3h 45min, 4h , 4h 20min, 4h 40min, 5h, 5h 20min, 5h 40min, 6h, 6h 20min, 6h 40min, 7h, 7h 20min, 7h 40min, 8h after the start of the breakfast.
• the blood samples were analyzed for glucose content.
• FIG. 1 For the glucose blood levels, the result shown in FIG. 1 was obtained.
• the figure shows that by using the preparation according to the invention, which was applied in this case as a hard gelatin capsule, a significantly flatter and thus advantageous course of the plasma glucose level is achieved. It clearly comes to a long-lasting and uniform effect of acarbose and unwanted "peak concentrations" of the drug can be avoided.

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• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Life Sciences & Earth Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Inorganic Chemistry (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
• Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

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• 2004
  • 2004-08-31 DE DE102004042139A patent/DE102004042139B4/de not_active Expired - Fee Related
• 2005
  • 2005-08-30 EP EP05775898A patent/EP1814512A2/de not_active Withdrawn
  • 2005-08-30 EA EA200700524A patent/EA013429B1/ru not_active IP Right Cessation
  • 2005-08-30 JP JP2007528874A patent/JP2008511585A/ja active Pending
  • 2005-08-30 UA UAA200703512A patent/UA94031C2/ru unknown
  • 2005-08-30 WO PCT/EP2005/054260 patent/WO2006024638A2/de not_active Ceased
  • 2005-08-30 US US11/574,317 patent/US20090010906A1/en not_active Abandoned

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