DE102011051308A1 - Manufacturing process and dosage form - Google Patents

Abstract

This invention relates to a manufacturing method for dosage forms. The manufacturing process makes pharmaceutical forms accessible that also help poorly soluble active ingredients to have good bioavailability when taken orally. Another important advantage of the method is that the pharmaceutical forms thus produced have good storage stability. The pharmaceutical forms thus produced have several subunits. The dosage forms and uses of the dosage forms are also described.

Description

The present invention relates to a manufacturing method for a drug form and drug forms that can be prepared by the method.

In pharmaceutical technology, there is a continuing need for dosage forms that allow a targeted release characteristics of drugs in the human gastrointestinal tract. Therefore, a variety of different dosage forms are already known in the art. For example, there are monolithic dosage forms containing active ingredients in a polymeric matrix. After entry of such a dosage form into the gastrointestinal tract of humans, the active ingredient dissolves in a controlled manner. In particular, the dissolution rate can be controlled by selecting a matrix polymer which gradually dissolves in the gastrointestinal tract. By dissolving the matrix, the active substance is released piece by piece, dissolves in the existing fluid and is absorbed. Another approach is to use a matrix polymer that does not dissolve but releases the drug through pores. Still other concepts make use of osmotic systems that control the drug release of membranes.

However, the drug forms just mentioned assume that the active ingredient dissolves rapidly both in the acidic pH of the stomach and in the intestine, where pH values of typically greater than 6 predominate. If the active ingredient dissolves more slowly than, for example, an eroding matrix polymer dissolves, it is no longer the erosion of the matrix polymer that determines the release of the active ingredient but the dissolution rate of the active ingredient. Similar considerations apply to dosage forms that have porous matrices or are based on osmotic systems.

Particularly problematic is the controlled release of those drugs that are weak bases. Weak bases are protonated in the acidic environment of the stomach and thus normally positively charged. In this cationic form, the weakly basic active ingredient is readily soluble in water. After the active ingredient dissolves easily in this environment, it can be rapidly absorbed. However, when the conventional controlled release dosage form enters the intestine, it is in a less acidic environment. Consequently, the weakly basic active substance is no longer present in the protonated form but as an uncharged molecule. In this form, the active ingredient is only poorly soluble in water. In addition, the amount of fluid that is available in the intestine to dissolve the drug is much lower than in the stomach. This means that the drug, as soon as the drug form has arrived in the intestine, only very poorly dissolves, so that the dissolution rate of the drug determines the release of the drug from the drug form and thus the rate of absorption.

In order to improve the dissolution of the active ingredients, the particle size of the active ingredient of a dosage form is usually reduced. As a result, the surface of the drug particles increases and their dissolution rate is increased.

Due to the larger surface of the drug particles but also the oxidation of oxidation-sensitive drugs is accelerated. As a result, on the one hand reduces the amount of active ingredient in the dosage form and on the other hand accumulate oxidation products of the drug, which can be harmful at worst. This is a serious disadvantage of such dosage forms.

Furthermore, as a result of the reduction in the particle sizes of active ingredients, agglomerates increasingly occur, which in turn have a larger surface area and thus adversely affect both the further processing and the dissolution rate of the active ingredient.

It is therefore the object of this invention to provide a manufacturing method which makes it possible to prepare dosage forms which are superior to the forms of the prior art in terms of bioavailability and in terms of durability.

The object is achieved by the subject-matter of the patent claims, in particular by a production method for a pharmaceutical form which has at least two and preferably at least three subunits.

Each of the subunits preferably comprises at least one carrier and at least one drug. The manufacturing process is divided into two phases, a first phase in which the subunits are provided, and a second phase in which the subunits are optionally combined to form the drug using other ingredients.

The subunits of the dosage form are identified in this application as "subunit I", "subunit II" and "subunit III". It is meant to express that the subunits differ from each other. The dosage form may each comprise one of these subunits so that the entire dosage form contains exactly three subunits; but it can also be present in the drug form of the respective subunits more. Because the production process according to the invention is very complex, an addition in the form of Roman numerals I, II or III is made to facilitate the understanding in the designation of ingredients or intermediates in the preparation of the various subunits. This indicates the affiliation to the corresponding subunit.

The first phase of preparation preferably comprises the preparation of subunit I and subunit II, preferably also of a subunit III.

The fact that the different subunits differ from each other, the drug form can be flexibly adapted to the requirements that the active ingredient provides to the pharmaceutical formulation.

The dosage form of this invention is preferably an oral dosage form, which means that the dosage form is intended for oral administration. Therefore, these may be, in particular, powders, tablets, coated tablets, granules, capsules or pellets. Preferred are solid oral forms.

In the following three preferred subunits and their preparation are presented. The production method of this invention enables the preparation of a dosage form comprising an active ingredient in a matrix. The matrix is suitable for promoting the solubility of the active ingredient.

1 subunit I

Subunit I comprises at least one excipient I and at least one active ingredient I. Optionally, additional ingredients may be used. The additional ingredients may also include one or more other active ingredients Ib. The subunit I preferably consists of at least one excipient I, at least one active ingredient I and the additional ingredients.

1.1 Mixing

• I. Wälzmischer, insbesondere Fall-, Trommel-, Schüttel- und Rotationsmischer; unter den Rotationsmischern sind V-Mischer, Taumelmischer und Rhönradmischer besonders bevorzugt. Wälzmischer sorgen für eine besonders schonende Vermischung des Mischgutes. Hierbei ist vorzugsweise darauf zu achten, dass der Füllungsgrad des Mischbehälters dieser Mischgeräte einen Anteil von 60 Vol.-%, vorzugsweise 50 Vol.-% und besonders bevorzugt 40 Vol.-% nicht übersteigt.
• II. Schermischer, insbesondere Pflugscharmischer;
• III. Mischkneter, insbesondere Planeten-Mischkneter und Sigmakneter;
• IV. Fluidmischer

The provision of subunit I preferably comprises mixing the carrier I with the active ingredient I and the optional additional ingredients. Among the additional ingredients may be further active ingredients Ib. The mixing can be done in different ways. Preferably, a mixing device is used for mixing carrier I, active ingredient I and optional additional ingredients for preparing subunit I. The following mixing devices are suitable:

• I. rolling mats, in particular falling, tumbling, shaking and rotary mixers; among the rotary mixers V-mixers, tumble mixers and Rhönradmischer are particularly preferred. Rolling mills ensure a particularly gentle mixing of the mix. It should preferably be ensured that the degree of filling of the mixing container of these mixing devices does not exceed a proportion of 60% by volume, preferably 50% by volume and particularly preferably 40% by volume.
• II. Shear mixers, especially plowshare mixers;
• III. Mixing kneader, in particular planetary mixing kneader and sigma kneader;
• IV. Fluid mixer

From this preparation step of mixing, a mixture I is obtained which consists of carrier I, active ingredient I and the optional additional ingredients.

The mixture I preferably has the following composition in percent by weight: Carrier I 0 to 99% Active substance I 0.01 to 100% additional ingredients 0 to 50%

The required quality of mixing is achieved in carrying out the method according to the invention, if the mixing time during the first mixing is preferably at least 5 minutes. Too long a mixing can lead to an undesirable segregation due to the associated shocks. Therefore, the mixing time in this step is preferred in the invention limited to at most 60 minutes, more preferably at most 25 minutes, and most preferably at most 15 minutes.

In order to counteract segregation and to ensure the required mixing quality, it is preferred if the particle sizes of all ingredients of the mixture I vary in a range from 90% to 100%, preferably 95% to 105%, by the mean value of the particle sizes. This quality of mixing is achieved by adhering to the parameters described above.

1.2 Crushing

Preferably, carrier I, active ingredient I and the optional additional ingredients are comminuted before mixing.

It is preferably to be comminuted such that the average particle size of the active ingredient I is a value of at most 2 mm, in particular at most 1.2 mm, particularly preferably at most 0.8 mm and in particular at most 0.3 mm. This ensures that the dissolution rate of the active ingredient I is improved compared to large particles. However, in order not to increase the risk of oxidation of the active substance I too much and to suppress the agglomeration of the active ingredient particles into larger agglomerates, the particle size should preferably be at least 50 μm, more preferably at least 100 μm and particularly preferably at least 185 μm. Preferably, at least 90% of the particles are smaller than 250 microns.

The comminution of the active ingredient I is preferably carried out by dry comminution or wet comminution. If dry grinding is used, preferably hammer mills, pin mills, mortar mills, ball mills or air jet mills are used. In the case of wet comminution, stirred ball mills or colloid mills are preferably used. Also suitable are screen mills, rotating and oscillating screening machines.

The average particle size of the active ingredient I can be determined by light microscopy in the case of the large particles preferred here. Meant here is the average Ferret diameter of at least 100 particles.

For carrier I and the additional ingredients of subunit I, the same preferred comminution types and particle sizes apply as for active ingredient I.

In order to prevent segregation during further processing, the average particle sizes of active ingredient I, carrier I and additional ingredients of subunit I should preferably not deviate more than 10% from the average of the average particle sizes of the other components of mixture I.

To ensure this, the individual components of the mixture I are screened, if necessary, before mixing but after optional comminution. This is preferably done with a sieve having a mesh size of at most 2 mm. Particularly preferably, the mesh size should be at least 0.5 and at most 1.1 mm.

1.3 Seven

After the first mixing, the mixture I is preferably sieved. This is preferably done with a sieve having a mesh size of at most 2 mm. Particularly preferably, the mesh size should be at least 0.5 and at most 1.1 mm. This ensures that large particles are screened out. Large particles could lead to variations in the homogeneity of the content of active ingredient I in the dosage forms during further processing.

1.4 Addition of additional ingredients

Optionally, additional ingredients are added to the mixture I after the first mixing. Among the additional ingredients may be lubricants. Preferred lubricants are metal soaps, in particular alkaline earth metal soaps. Particularly preferred lubricants are fumarates, stearates, especially magnesium stearate.

As additional ingredients granulating aids, flow agents, disintegrants, binders, antioxidants, complexing agents and mixtures thereof can be added at this point. The granulation aids can be binders and / or solvents.

1.5 granulation

Optionally, the mixture I is granulated to obtain a granule I. Granules are well suited for further processing, because they are readily flowable in the inventive preparation and also can be pressed well into tablets.

The granules are produced by methods known to the person skilled in the art, in particular by extrusion or compaction.

1.6 Carrier

The carrier I used in subunit I is preferably selected from celluloses, in particular microcrystalline cellulose. Further preferred carriers are calcium hydrogen phosphate, bolus alba, mannitol, talc, sorbitol, lactose (H 2 O or anhydrous), sucrose and starch.

1.7 Active substance I

In principle, according to the invention, virtually any active substance can be incorporated into subunit I. The preferred active ingredient content of subunit I depends strongly on the planned indication of a corresponding drug form and thus on the active ingredient used. However, it is preferred according to the invention that the active ingredient content is at least 0.01% by weight, more preferably at least 0.25% by weight and particularly preferably at least 1% by weight, based on the subunit I. In particularly preferred embodiments, the active agent matrix may even contain at least 8% by weight, more preferably at least 12% by weight, and most preferably at least 18% by weight of active ingredient I. However, in order that the promotion of the dissolution of the active ingredient I can take place sufficiently, the proportion of active ingredient should preferably not be higher than 60% by weight, based on the subunit I. The proportion of active ingredient is particularly preferably at most 50% by weight, more preferably at most 40% by weight and particularly preferably at most 30% by weight. In particular embodiments, the proportion of the active ingredient I in the subunit I can be up to 80 wt .-%.

In preferred embodiments, the active ingredient I contained in subunit I is poorly water-soluble. Poorly water-soluble active ingredients particularly benefit from the advantageous properties of the subunit I according to the invention. This applies in particular to active ingredients which, although sufficiently soluble in the stomach with sufficient liquid supply, are not adequately absorbed in the intestine due to the small amount of liquid present there.

The active ingredient I preferably has at least one amino group. As a result, the active ingredient I in the stomach is usually protonated and thus water-soluble in this acidic environment. At higher pH levels in the intestine, however, the active ingredient I can not dissolve. The active ingredient I used according to the invention has a solubility of preferably less than 10 mg / ml at a pH of 1.1.

The active ingredient I used according to the invention preferably has an n-octanol-water partition coefficient (logP _OW ) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5. This distribution coefficient is a measure of the lipophilicity of a substance. As previously mentioned, particularly lipophilic drugs benefit from subunit I of this invention. The advantage for such agents is also particularly high because usually the absorption of lipophilic drugs works very well, as soon as these substances are dissolved. In other words, the dissolution of these drugs from a dosage form is the rate-limiting step in the uptake of the drug into the body. Nevertheless, there are also active substances whose lipophilicity is so pronounced that the subunit I proposed here is not sufficient to ensure sufficient bioavailability. Therefore, the active ingredient I used in the invention has an n-octanol-water partition coefficient (log P _OW ) at 20 ° C. of preferably at most 100, more preferably at most 50, especially at most 30, particularly preferably at most 15 and especially at most 7 on.

Examples of active ingredients and active ingredient classes which can be used advantageously as active ingredient I in subunit I of the present invention are:
Medicines for the treatment of pain and pain therapy with peripherally acting analgesics, centrally acting analgesics and adjuvant non-analgesics. These are the following analgesics and adjuvants:
Drugs for the treatment of dizziness of various origins, in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.

Acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, naproxen, piroxicam, paracetamol, metamizole, celecoxib, parecoxib, tramadol, pethidine, codeine, dihydrocodeine, piritramide, tilidine, morphine, hydromorphone, oxycodone, levomethadone, fentanyl, sufentanil, buprenorphine, pentazocine, naloxone, Flupirtine, carbamazepine, metoprolol, metoclopramide, amitryptiline, doxepin, clomipramine, mianserin, maprotiline, triptans such as Naratriptan, rizatriptan, sumatriptan, zolmitriptan, calcium antagonists such as: flunarizine, topiramate, valproic acid, phenytoin, baclofen, other agents such as: botulinum toxin, ergotamine, lisuride, methysergide, pizotifen, oxcarbazepine, gabapentin and lamotrigine, dexamethaone, methylprednisolone, prednisolone, triamcinolone, Diazepam, tetrazepam, tizanidine, butylscopolamine, combination of tilidine and naloxone.

Drugs for the treatment of the nervous system, alone or in combination, e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline, dihydroergocriptine, lisuride, pergolide mesilate, pramipexole, ropinirole, apomorphine, biperiden, metixene hydrochloride, trihexphenidyl, entacapone, amantadine, bupidine, selegiline, apomorphine), stroke (acetylsalicylic acid, clopidogrel, dipyridamole, ticlopidine, heparin, phenprocoumon , Warfarin, protamine, phytomenadione, nimodipine, paracetamol, tramadol, buprenorphine), intracranial pressure (furosemide), tremor (propranolol, clozapine, alprazolam, primidone).

Drugs for the treatment of phytochemical disorders such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thioridazine, flupentixol, fluspirilene, etc.), depression (imipramine, amitripytline, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine, trazodone , Moclobemide, miratazepam, etc.), psychoses and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, temazepam, Zolpidem tartrate, zopiclone, promethazine, chlorprothixene, pipamperone, thioridazine, chloral hydrate, etc.) Restlessness and confusion (alprazolam, oxazepam, doxepin, clomipramine, imipramine, thioridazine, perazine, etc.), dementia of the Alzheimer's type (donepezil, rivastigmine, tacrine , Memantine, nimodipine, selegiline etc.).

Drugs for the treatment of cardiovascular diseases, such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem, verapamil , Benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan, losartan, chlorthalidone, xipamide, hydrochlorothiazide, furosemide, Piretanide, triamterene, digitalis glycosides, carvedilol, metoprolol, prazosin, etc.), cardiac arrhythmias (ajmaline, quinidine, disopyramide, flecainide, propafenone, propranolol, carvedilol, amiodarone, verapamil, diltiazem, etc.), hypertension (metoprolol, atenolol, urapidil, Clonidine, dihydralazine, chlorthalidone, hydrochlorothiazide, furosemide, felodipine, israpidine, lacidipine, diltiazem, Captopril, enalapril, fosinopril, lisinopril, ramipril, verapamil, candesartan, eprosartan, irbesatan, losartan, doxazosin, bunazosin, prazosin, terazosin, moxonidine, dihydralazine, minoxidil).

Drugs, alone or in combination, for the treatment of the respiratory tract and lungs (Theophylline, Methylprednisolone, Flucorton, Dexamethasone, Montelukast, Roxithromycin, Erythromycin, Azithromycin, Ciprofloxacin, Clarithromycin, Levofloxacin, Ofloxacin, Doxycycline, Ampicillin and Sulbactam, Amoxicillin, Cefuroxime, Clindamycin , Cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).

Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride, dimenhydrinate, cinnarizine, flunarizine, levomeprazine, ondansetron, betahistine, aprepitant, etc.).

Anti-infective drugs with antibiotics or antivirally active substances (acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazolin, cefixime, cefprozil, ceftriaxone, chloroquine, ciprofloxacin, clotrimazole, dicloxacillin, doxycycline, econazole, erythromycin, ethambutol, fosfomycin, flucloxacillin, fluconazole, Fusidic acid, gramicidin, idoxuridine, indinavir, interferon, itraconazole, isoniazid, josamycin, ketoconazole, lamivudine, lomefloxacin, mafenide, mebendazole, mesalazine, mezlozillin, mupirocin, miconazole, naftifine, nalidixic acid, norfloxacin, ofloxacin, oxacillin, oxytetracycline, piperacillin, praziquantel, Primaquine, proguanil, ribavirin, rifabutin, rimantadine, roxithromycin, saquinavir, spectinomycin, spriramycin, stavudine, sulbactam, teicoplanin, terbinafine, tetracycline, tetroxoprim, ticarcillin, tinidazole, tromantadine, tolnaftate, vancomycin, zidovudine, zalcitabine, etc.).

Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).

A preferred active ingredient I is cinnarizine and / or a cinnarizine salt.

1.8 Additional ingredients

Lubricants, lubricants, binders, other active ingredients, disintegrants, antioxidants, complexing agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers and pigments are particularly suitable as additional ingredients.

Preferably, the subunit I comprises at least one lubricant I. As a preferred lubricant I are in particular metal soaps and talc in question, especially alkaline earth metal soaps. Particularly preferred lubricants I are stearates, in particular magnesium stearate. Preferred embodiments of this invention include both talc and at least one alkaline earth metal soap as a lubricant combination, with talc preferably being in a mass-to-mass fraction than the alkaline earth metal soap.

The additional ingredients are present in a proportion of at most 50 wt .-%, more preferably at most 40 wt .-% and particularly preferably at most 32 wt .-% in the subunit I. In certain embodiments, subunit I is free of additional ingredients. However, the additional ingredients are preferably present in subunit I in a content of at least 10% by weight, more preferably at least 15% by weight and particularly preferably at least 20% by weight.

The subunit I preferably comprises a further active ingredient Ib, which is preferably selected from the active ingredients mentioned above for active ingredient I. For the other properties, the same applies preferably as stated above for active ingredient I. Particularly preferred is the further active ingredient Ib Dimenhydrinat.

1.9 Completion of subunit I

• • optionaler Zerkleinerung des Trägerstoffes I, Wirkstoffes I und optionaler zusätzlicher Inhaltsstoffe,
• • optionalem Sieben des Trägerstoffes I, Wirkstoffes I und optionaler zusätzlicher Inhaltsstoffe,
• • Mischen des Trägerstoffes I, Wirkstoffes I und optionaler zusätzlicher Inhaltsstoffe, um eine Mischung I zu erhalten,
• • optionalem Sieben der Mischung I,
• • optionaler Zugabe zusätzlicher Inhaltsstoffe,
• • optionaler Granulierung, um ein Granulat I zu erhalten, und
• • optionalem weiteren Sieben des Granulates I oder der Mischung I,

schließt sich die Fertigstellung der Untereinheit I an. Im einfachsten Fall ist hierfür kein weiterer Bearbeitungsschritt nötig, nämlich dann, wenn die Untereinheit I selbst aus dem Produkt der oben stehenden Herstellungsschritte, also dem Granulat I oder der Mischung I, besteht. So kann die Untereinheit I beispielsweise ein Pulver sein oder ein Granulat, wie es bei Beachtung der oben stehenden Anweisungen erhalten wird. After performing the above steps, namely

• Optional comminution of carrier I, active ingredient I and optional additional ingredients,
• Optional screening of the carrier I, active ingredient I and optional additional ingredients,
• Mixing the carrier I, drug I and optional additional ingredients to obtain a mixture I,
• Optional sieving of the mixture I,
• Optional addition of additional ingredients,
• • optional granulation to obtain a granulate I, and
• Optional further sieving of granulate I or mixture I,

joins the completion of subunit I on. In the simplest case, no further processing step is necessary for this purpose, namely when the subunit I itself consists of the product of the above-mentioned production steps, that is to say the granulate I or the mixture I. For example, subunit I may be a powder or granules, as obtained following the above instructions.

When subunit I is a tablet, granule I or mixture I is compressed into tablets. Preferred embodiments provide that the subunit I consists of powder, granules, tablets or pellets.

The preparation of tablets or pellets of granules I and I is carried out by methods familiar to the person skilled in the art.

2 subunit II

Subunit II comprises at least one carrier II and at least one active ingredient II and optionally additional ingredients. The additional ingredients of subunit II preferably include at least one complexing agent II and at least one antioxidant II. Further, at least one further active ingredient IIb is among the additional ingredients.

Lubricants, lubricants, binders, other active ingredients, disintegrants, antioxidants, complexing agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers and pigments are particularly suitable as additional ingredients.

2.1 Mixing

The provision of subunit II preferably comprises mixing the carrier II with the active ingredient II and the optional additional ingredients.

The mixing preferably comprises dissolving the carrier II in a solvent IIa. Further, the mixing preferably comprises dissolving additional ingredients, in particular the antioxidant II and the complexing agent II, in at least one solvent. These solutions are preferably combined to form a premix II. The active ingredient II is preferably added to the premix II so that a mixture II is obtained.

In preferred embodiments, in which the optional additional ingredients comprise complexing agent II and antioxidants II, first at least complexing agent II is dissolved in a solvent IIb and at least antioxidant II in a solvent IIc. These are then combined as described above with the solution of the carrier II and are then part of the premix II.

The solvents IIb and IIc may be the same or different, preferably they are different.

Solvent IIa is preferably an alkanol, ketone, alkyl halide, ester or glycol. Best choosen alkanols. Particularly preferred are short-chain alkanols having carbon chain lengths of 1 to 5, in particular 1 to 3 and preferably 1 or 2.

Solvent IIb is preferably water or a water-miscible organic solvent. Water is preferred.

Solvent IIc is preferably an alkanol, ketone, alkyl halide, ester or glycol. Best choosen alkanols. Particularly preferred are short-chain alkanols having carbon chain lengths of 1 to 5, in particular 1 to 3 and preferably 1 or 2.

2.2 Drying

The mixture II prepared as just described is dried. This is preferably done by freeze drying, tray drying, vacuum drying, drum drying or spray drying, spray drying being preferred.

In the case of spray drying, it is preferable to proceed in such a way that the gas stream introduced into the spray-drying device has temperatures of at least 100 ° C. Too low temperatures would not ensure sufficient drying. Preferably, the introduced gas stream should have temperatures of at least 110 ° C and more preferably at least 120 ° C. In order to keep the energy consumption low, this gas flow should not exceed temperatures of at most 180 ° C, more preferably 170 ° C and most preferably 160 ° C. If the temperature is too high, it can easily lead to agglomeration of the drug particles, which is urgently to be avoided.

In the gas stream, the solvent or the solvent mixture evaporates, the exhaust gas temperature is therefore below the temperature of the introduced gas stream. The drying process should preferably be carried out so that the exhaust gas temperature is at most 110 ° C. If the exhaust gas temperature is higher, that is Energy consumption too high, the process may be uneconomical. Preferably, the exhaust gas temperature is at most 99 ° C. So that no condensation of the solvent or solvent mixture occurs in the spray drying plant, the exhaust gas temperature should preferably not fall below a value of 75 ° C. Preferably, the exhaust gas temperature should be at least 80 ° C.

By drying, a drying material II is obtained, which has a solvent content of less than 5000 ppm.

This drying material II consists of an active ingredient matrix II, which consists of carrier II, active ingredient II and optional additional ingredients, in particular complexing agent II and / or antioxidant II. Preferably, the carrier II is chosen so that the drying material II is a solid dispersion of the active ingredient II in the active ingredient matrix II. This Trocknungsgut II is particularly important to promote the dissolution of drug II in the gastrointestinal tract.

The particle size of the material to be dried II should have a value of at most 0.8 mm, preferably at most 0.6 mm. In order to avoid agglomeration, the particle size of the material to be dried II should be at least 200 μm. This is preferably ensured by sieving.

The particle size is preferably determined by light microscopic methods which have already been mentioned above.

2.3 Completion of subunit II

The completion of the subunit II preferably provides that either the drying material II is already used as subunit II or the subunit II is produced using the material to be dried II. Using the material to be dried II, it is possible to produce granules, tablets, coated tablets or pellets, in particular microtablets or pellets.

In order to solve the problem of the invention, the individual ingredients of the material to be dried II were matched with respect to their nature and quantity.

The desiccant II comprises at least one carrier II, at least one active ingredient II, and preferably additional ingredients, including preferably at least one antioxidant II and at least one complexing agent II. According to the invention, the active ingredient II is embedded in a matrix II (active ingredient matrix II), which is the carrier II and additional ingredients. As a result, among other things, the agglomeration of the drug particles is suppressed. The material to be dried II is preferably a solid dispersion of the active ingredient II, which also positively influences the dissolution of the active ingredient II.

The preferred combination of antioxidant II and complexing agent II achieves a unique improvement in the shelf life of the active ingredient II in the matrix II. Particularly pronounced is the antioxidant effect of this combination in a drying material II, which contains the following ingredients in the indicated amounts: Active ingredient II 0.01% by weight to 50% by weight Carrier II 20% by weight to 99% by weight Antioxidant II 0.1% by weight to 5% by weight Complexing agent II 0.1% by weight to 5% by weight additional ingredients 0% by weight to 50% by weight

It has been found that the effect is particularly evident when a phenol ether is used as antioxidant II and an acetic acid derivative as complexing agent II. The molar ratio of antioxidant II to complexing agent II should be at least 0.5 to 1 and at most 10 to 1. Agents that are prone to undesirable oxidation when used in a solid dispersion are cinnarizine and its salts. Therefore, these active ingredients particularly benefit from the matrix II according to the invention in the drying material II.

The material to be dried II, in addition to the components carrier II, active ingredient II, antioxidant II and complexing II also contain additional ingredients. These additional ingredients may include solubilizers. Preferred solubilizers are cyclodextrins, sugar esters and other surfactants. Particularly preferred are sucrose fatty acid esters and / or sodium lauryl sulfate. The solubilizers may be used in a proportion of at least 1% by weight and preferably in amounts of at most 20% by weight, more preferably at most 10% by weight, in the drying stock II.

2.4 The carrier of subunit II

The carrier II used according to the invention must be present in the drying material II in a sufficient proportion. If the carrier II is used in too low a proportion in the drying material II, it can not adequately support the dissolution of the active ingredient. The upper limit of the proportion of carrier II in the material to be dried II is usually given by the limited volume of appropriate dosage forms. It has proved to be advantageous to use the carrier II in a proportion of at least 20 wt .-% in the drying material II. The content of carrier II in the material to be dried II is particularly preferably at least 30% by weight, more preferably at least 40% by weight and particularly preferably at least 45% by weight. In particular embodiments, the content of carrier II on the drying material II is at least 50% by weight, more preferably at least 60% by weight. Usually, the carrier II is used in amounts of at most 99% by weight, more preferably at most 95% by weight and particularly preferably at most 90% by weight, in the drying stock II. Particularly preferred embodiments contain the carrier II in amounts of at most 80 wt .-%, more preferably at most 70 wt .-% and particularly preferably at most 68 wt .-%. The carrier II is preferably a polymer.

The carrier II is preferably water-soluble. This ensures that the material to be dried II rapidly dissolves after entering the gastrointestinal tract and it allows the drug to dissolve upon contact with the liquid contained in the gastrointestinal tract. The water solubility of the carrier II is preferably at least 1 g / 100 ml, more preferably at least 5 g / 100 ml and particularly preferably at least 10 g / 100 ml.

Preferred carriers II have a glass transition temperature of at least 85 ° C and more preferably at least 100 ° C. If the glass transition temperature of the carrier materials II is below these values, the processability of the carrier materials II in the context of the production process of the material to be dried II is made more difficult. Carriers II which can be used according to the invention have in particular a glass transition temperature of at most 225 ° C., more preferably at most 190 ° C. It has been found that the use of such excipients II suppresses the agglomeration of the active ingredient particles in the matrix II.

The substances preferably used as carriers II are predominantly amorphous. In particular, the carriers II have crystalline proportions of at most 20% by volume. Crystallinity delays the dissolution rate of the carrier II, which in turn hinders the dissolution of the active ingredient II and thus impairs its absorption.

When a polymer is used as the carrier II, it preferably has a number average molecular weight (M _N ) of at least 5,000, more preferably at least 12,000, and particularly preferably at least 20,000. Polymers with smaller average molecular weights often do not have the necessary strengths to be able to produce stable and abrasion-resistant dosage forms with the item to be dried II. On the other hand, polymers having too high average molecular weights often dissolve poorly, so that the carriers II preferably have average molecular weights of at most 200,000, more preferably at most 100,000, and most preferably at most 50,000. Convincing results were obtained with polyvinylpyrrolidone having an average molecular weight of 35,000 to 45,000 as the carrier II.

The carrier II is preferably selected from the group consisting of polyvinylpyrrolidones, cellulose derivatives, polyethers, poloxamers, urea, sugars, sugar alcohols, sugar derivatives, succinic acid and mixtures thereof.

Among the sugar alcohols, mannitol is particularly preferred, among the sugar derivatives dextrin.

The carrier II may comprise or consist of a polymer. The carrier II is preferably water-soluble and in particular a water-soluble polymer. Preferred water-soluble polymers are polyvinylpyrrolidone, water-soluble celluloses, polyethylene glycols and poloxamers. Preferred polymers are hydroxypropylmethylcellulose and polyethylene glycols having average molecular weights of 6,000 to 20,000.

Among the cellulose derivatives, particularly preferred are those having hydroxyl groups. Particularly preferred is hydroxypropylmethylcellulose. Among the polyethers, poloxamers and polyethylene glycols are particularly preferred. A particularly preferred carrier II is polyvinylpyrrolidone.

The carrier II in the desiccant II of this invention is preferably solid at room temperature.

In order to allow sufficient solubility in water and promotion of the rate of dissolution of the active ingredient II, the carrier II has a water storage capacity of preferably at least 10 wt .-%, more preferably at least 20 wt .-% and particularly preferably at least 30 wt .-%. This means the water storage capacity at a relative humidity of 75% and a temperature of 23 ° C. Nevertheless, the water storage capacity should preferably not exceed a value of at most 50% by weight and in particular not more than 45% by weight in order not to jeopardize the stability of the material to be dried II and in particular of the active substance.

The person skilled in the art expediently uses those excipients II which are physiologically harmless and inert to the active compounds.

2.5 Antioxidant II Subunit II

The antioxidant II in the drying material II serves to control the oxidation of the active ingredient II. This is particularly important if the active ingredient II is present in small particles. For this purpose, the proportion of antioxidant II in the drying material II is preferably at least 0.1 wt .-%, more preferably at least 0.2 wt .-% and particularly preferably at least 0.3 wt .-%. The amount of antioxidant II is subject to legal limits. Therefore, the amount should not be too high. It is an advantage of this invention that the content of the antioxidant II can be kept low. The content of the antioxidant II on the material to be dried II is preferably at most 5% by weight, more preferably at most 3% by weight, in particular at most 2% by weight and particularly preferably at most 1.1% by weight.

The antioxidant II serves primarily to prevent the oxidation of the active ingredient II. Since the active ingredient II is advantageously used in small particle sizes, the surface of the active ingredient particles is very large and exposed to the attacks of oxidatively active substances. Therefore, the amount of the antioxidant II is based on the amount of active ingredient. The molar ratio of antioxidant II to active ingredient II should preferably be at least 1 to 50, more preferably at least 1 to 30 and particularly preferably at least 1 to 15. This ensures that the antioxidant activity is sufficient to effectively prevent oxidation. This molar ratio should preferably be at most 1 to 5, more preferably at most 1 to 7 and particularly preferably at most 1 to 10.

The antioxidant II acts synergistically with the complexing agent II preferably used according to the invention. Therefore, the amount of the antioxidant II is also based on the amount of complexing agent II used in the active ingredient matrix II. The molar ratio of antioxidant II to complexing agent II should preferably be at least 0.5 1, more preferably at least 1 to 1, more preferably at least 1.15 to 1, and especially at least 1.18 to 1. It has proven to be advantageous to comply with an upper limit of this molar ratio of preferably at most 10 to 1, more preferably at most 5 to 1, particularly preferably at most 3 to 1 and in particular at most 2 to 1. If these conditions are met, the synergistic effect of these two additional ingredients in the drying material II is particularly pronounced.

Preferred antioxidants II are ascorbic acid, hydrogen sulfites, sulfites, disulfite, cysteine, butylhydroxyanisole (BHA), tocopherols, nordihydroguiaretic acid (NDGA), coniferyl benzoate, isoascorbic acid, gallates (ester of gallic acid), t-butylhydroquinone (TBHQ), butylhydroxytoluene (BHT)

In preferred embodiments, the antioxidants II are used in combination with acids, in particular citric acid, tartaric acid and / or fumaric acid or salts thereof. Through this combination, the effect of the antioxidants II can be further improved.

The antioxidant II is preferably a radical scavenger or an easily oxidizable substance, whereby combinations of several antioxidants and also combinations of free-radical scavengers with easily oxidisable substance can be used. Easily oxidizable substances include hydrogen sulfites, sulfites, disulfite, ascorbic acid and isoascorbic acid. Radical scavengers include BHA, BHT, NDGA, TBHQ, tocopherols, coniferyl benzoate, and gallates.

The antioxidant II is preferably a radical scavenger. In particular, the antioxidant II is selected from phenol derivatives. Phenol derivatives are in particular substituted and unsubstituted phenol ethers and substituted phenols. Preferred are alkyl-substituted phenol derivatives such as BHA, BHT and TBHQ. In particularly preferred embodiments, the antioxidant is BHA.

2.6 Complexing Agent II Subunit II

The complexing agent II in the drying material II acts synergistically with the antioxidant II, especially when it is used in the ratios described above. In order to ensure that the effect of the complexing agent II is sufficient, its content should preferably be at least 0.1% by weight, more preferably at least 0.2% by weight and more preferably at least 0.3% by weight, based on the material to be dried II amount. Particularly good effect is achieved if the content of complexing agent II is not more than 5% by weight, in particular not more than 3% by weight, more preferably not more than 2% by weight and particularly preferably not more than 1% by weight.

The synergistic effect of antioxidant II and complexing agent II is most pronounced when complexing agents are used which form stable complexes with divalent metal ions. Particularly suitable are chelating agents. Preferably, the complexing agent II in the drying material II is an organic molecule. The complexing agent II preferably has at least 2 carboxyl groups and more preferably at least 3 carboxyl groups per molecule. The preferred complexing agent II is an acetic acid derivative. Particularly preferred substances are nitrilotriacetic acid (NTA), ethylene glycol bis (aminoethyl ether) -N, N'-tetraacetic acid (EGTA), ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), citric acid, polycarboxylates and mixtures thereof. The best results are achieved with EDTA.

If the item to be dried II itself is not the subunit II, the item to be dried II is preferably further processed with additional ingredients.

The additional ingredients will depend on the form in which subunit II is to be used. Possible forms include tablets, coated tablets, pellets, powders, granules and MUPS. A preferred form are tablets, especially microtablets. Another preferred form is pellets.

2.7 Active ingredient II

In principle, according to the invention, virtually any active substance can be incorporated into subunit II. The preferred active ingredient content of subunit II depends strongly on the planned indication of a corresponding dosage form and thus on the active ingredient II used. However, it is preferred according to the invention that the active ingredient content is at least 0.01% by weight, more preferably at least 0.25% by weight and particularly preferably at least 1% by weight, based on the subunit II. In particularly preferred embodiments, the subunit II may even contain at least 4% by weight, more preferably at least 5% by weight, and most preferably at least 7% by weight of the active ingredient. However, in order that the promotion of the dissolution of the active ingredient II can take place sufficiently, the proportion of active ingredient should preferably not be higher than 40% by weight, based on the subunit II. The proportion of active ingredient is particularly preferably at most 30% by weight, more preferably at most 20% by weight and particularly preferably at most 10% by weight. In particular embodiments, the proportion of the active ingredient II at the subunit II can be up to 50% by weight.

If the manufacturing instructions described herein are adhered to, the active ingredient II is present in small particle sizes in the active substance matrix of the material to be dried II. It is important to comply with the regulations regarding the production and the composition of the material to be dried II, so that the particle sizes remain even after prolonged storage of the drug forms prepared therefrom.

In order to simplify the dissolution, the active ingredient II is preferably present in small particle sizes of at most 1000 nm, in particular at most 800 nm, more preferably at most 500 nm and in particular at most 300 nm. This increases the specific surface area of the active ingredient II and facilitates the dissolution. However, in order not to increase the risk of oxidation of the active ingredient II too much and to suppress the agglomeration of the active ingredient particles into larger agglomerates, the particle size should preferably be at least 50 nm, more preferably at least 100 nm and particularly preferably at least 150 nm.

The mean particle size of drug II in the drug matrix is determined as follows: the carrier is dissolved in a medium in which the drug particles are insoluble. From this suspension, the particle size distribution is determined by means of laser diffraction. All other particle sizes and mean particle sizes mentioned in this specification are determined in an analogous manner unless otherwise described.

An important influencing factor on the dissolution rate of the active ingredient II is the mass ratio of active ingredient II to carrier II. This is preferably at least 1 in 1000, more preferably at least 1 in 100, particularly preferably at least 1 in 50 and especially at least 1 in 30. In particularly preferred Embodiments, this mass ratio is at least 1 to 15 and in particular at least 1 to 10. Too low an active ingredient content of the subunit II can cause a drug form containing the subunit II would take too large a volume of sufficient amount of drug and thus the ingestion is affected by the patient. Therefore, the mass ratio of active ingredient II to carrier II in the subunit II of the invention is preferably at most 1 to 1, in particular 1 to 2, particularly preferably at most 1 to 4, more preferably at most 1 to 5 and particularly preferably at most 1 to 6.

In preferred embodiments, drug II, which is contained in subunit II, is poorly water-soluble. Poorly water-soluble active ingredients particularly benefit from the advantageous properties of the subunit II according to the invention. This is particularly true for active ingredients which, although sufficiently soluble in the stomach with sufficient liquid supply, are not adequately absorbed in the intestine due to the small amount of liquid present there.

The active ingredient II preferably has at least one amino group. As a result, the active ingredient II is usually protonated in the stomach and thus water-soluble in this acidic environment. At higher pH levels in the intestine, however, the active ingredient II can not dissolve. The active compound II used according to the invention has a solubility of preferably less than 10 mg / ml at a pH of 1.1. This active substance II needs the technological support of the matrix II according to the invention for adequate absorption, in particular in prolonged-release dosage forms.

The active ingredient II used according to the invention preferably has an n-octanol-water partition coefficient (logP _OW ) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5. This distribution coefficient is a measure of the lipophilicity of a substance. As previously mentioned, particularly lipophilic drugs benefit from subunit II of this invention. The advantage for such agents is also particularly high because usually the absorption of lipophilic drugs works very well, as soon as these substances are dissolved. In other words, the dissolution of these drugs from a dosage form is the rate-limiting step in the uptake of the drug into the body. Nevertheless, there are also active substances whose lipophilicity is so pronounced that the subunit II proposed here is not sufficient to ensure sufficient bioavailability. Therefore, the active substances which are used according to the invention in the subunit II n-octanol-water partition coefficient (logP _OW ) at 20 ° C of preferably at most 100, more preferably at most 50, in particular at most 30, more preferably at most 15 and in particular at most 7th on.

Examples of active ingredients and active ingredient classes which can be used advantageously as active ingredient II in the context of the present invention are:
Medicines for the treatment of pain and pain therapy with peripherally acting analgesics, centrally acting analgesics and adjuvant non-analgesics. These are the following analgesics and adjuvants:
Drugs for the treatment of dizziness of various origins, in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.

Acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, naproxen, piroxicam, paracetamol, metamizole, celecoxib, parecoxib, tramadol, pethidine, codeine, dihydrocodeine, piritramide, tilidine, morphine, hydromorphone, oxycodone, levomethadone, fentanyl, sufentanil, buprenorphine, pentazocine, naloxone, Flupirtine, carbamazepine, metoprolol, metoclopramide, amitryptiline, doxepin, clomipramine, mianserin, maprotiline, triptans such as naratriptan, rizatriptan, sumatriptan, zolmitriptan, calcium antagonists such as: flunarizine, topiramate, valproic acid, phenytoin, baclofen, other agents such as: botulinum toxin, ergotamine , Lisurid, Methysergide, Pizotifen, oxcarbazepine, gabapentin and lamotrigine, dexamethaone, methylprednisolone, prednisolone, triamcinolone, diazepam, tetrazepam, tizanidine, butylscopolamine, combination of tilidine and naloxone.

Drugs for the treatment of the nervous system, alone or in combination, e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline, dihydroergocriptine, lisuride, pergolide mesilate, pramipexole, ropinirole, apomorphine, biperiden, metixene hydrochloride, trihexphenidyl, entacapone, amantadine, bupidine, selegiline, apomorphine), stroke (acetylsalicylic acid, clopidogrel, dipyridamole, ticlopidine, heparin, phenprocoumon , Warfarin, protamine, phytomenadione, nimodipine, paracetamol, tramadol, buprenorphine), intracranial pressure (furosemide), tremor (propranolol, clozapine, alprazolam, primidone).

Drugs for the treatment of phytochemical disorders such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thioridazine, flupentixol, fluspirilene, etc.), depression (imipramine, amitripytline, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine, trazodone , Moclobemide, miratazepam, etc.), psychoses and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, temazepam, Zolpidem tartrate, zopiclone, promethazine, chlorprothixene, pipamperone, thioridazine, chloral hydrate, etc.) Restlessness and confusion (alprazolam, oxazepam, doxepin, clomipramine, imipramine, thioridazine, perazine, etc.), dementia of the Alzheimer's type (donepezil, rivastigmine, tacrine , Memantine, nimodipine, selegiline etc.).

Drugs for the treatment of cardiovascular diseases, such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem, verapamil , Benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan, losartan, chlorthalidone, xipamide, hydrochlorothiazide, furosemide, Piretanide, triamterene, digitalis glycosides, carvedilol, metoprolol, prazosin, etc.), cardiac arrhythmias (ajmaline, quinidine, disopyramide, flecainide, propafenone, propranolol, carvedilol, amiodarone, verapamil, diltiazem, etc.), hypertension (metoprolol, atenolol, urapidil, Clonidine, dihydralazine, chlorthalidone, hydrochlorothiazide, furosemide, felodipine, israpidine, lacidipine, diltiazem, Captopril, enalapril, fosinopril, lisinopril, ramipril, verapamil, candesartan, eprosartan, irbesatan, losartan, doxazosin, bunazosin, prazosin, terazosin, moxonidine, dihydralazine, minoxidil).

Drugs, alone or in combination, for the treatment of the respiratory tract and lungs (Theophylline, Methylprednisolone, Flucorton, Dexamethasone, Montelukast, Roxithromycin, Erythromycin, Azithromycin, Ciprofloxacin, Clarithromycin, Levofloxacin, Ofloxacin, Doxycycline, Ampicillin and Sulbactam, Amoxicillin, Cefuroxime, Clindamycin , Cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).

Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride, dimenhydrinate, cinnarizine, flunarizine, levomeprazine, ondansetron, betahistine, aprepitant, etc.).

Anti-infective drugs with antibiotics or antivirally active substances (acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazolin, cefixime, cefprozil, ceftriaxone, chloroquine, ciprofloxacin, clotrimazole, dicloxacillin, doxycycline, econazole, erythromycin, ethambutol, fosfomycin, flucloxacillin, fluconazole, Fusidic acid, gramicidin, idoxuridine, indinavir, interferon, itraconazole, isoniazid, josamycin, ketoconazole, lamivudine, lomefloxacin, mafenide, mebendazole, mesalazine, mezlozillin, mupirocin, miconazole, naftifine, nalidixic acid, norfloxacin, ofloxacin, oxacillin, oxytetracycline, piperacillin, praziquantel, Primaquine, proguanil, ribavirin, rifabutin, rimantadine, roxithromycin, saquinavir, spectinomycin, spriramycin, stavudine, sulbactam, teicoplanin, terbinafine, tetracycline, tetroxoprim, ticarcillin, tinidazole, tromantadine, tolnaftate, vancomycin, zidovudine, zalcitabine, etc.).

Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).

Preferred active ingredient II is cinnarizine and / or a cinnarizine salt.

2.8 tablets

As mentioned above, the item to be dried II is further processed depending on the desired form of subunit II. A preferred option for further processing is the preparation of tablets containing the material to be dried II.

For the preparation of tablets, the material to be dried II is preferably mixed with additional ingredients.

The excipients which are used for the production of tablets from the drying material II, are preferably selected from flow agents, other active ingredients, binders, disintegrants, fillers, lubricants, lubricants, humectants, antioxidants, complexing agents, coating agents, flow agents, preservatives, surfactants, plasticizers and Pigments and mixtures thereof.

Preferred flow agent is fumed silica. The content of superplasticizer should preferably be at least 1% by weight and preferably at most 7% by weight, in particular at least 2% by weight and at most 5% by weight, based on the subunit II.

Preferred lubricants are hydrogenated vegetable oil and metal soaps. The content of lubricant should preferably be at least 0.5% by weight and preferably at most 5% by weight, in particular at least 1% by weight and at most 3% by weight, based on subunit II. Preferred lubricant is talc.

Examples of further active ingredients and active ingredient classes which can be used advantageously as further active ingredient IIb in the context of subunit II are:
Medicines for the treatment of pain and pain therapy with peripherally acting analgesics, centrally acting analgesics and adjuvant non-analgesics. These are the following analgesics and adjuvants:
Drugs for the treatment of dizziness of various origins, in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.

Acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, naproxen, piroxicam, paracetamol, metamizole, celecoxib, parecoxib, tramadol, pethidine, codeine, dihydrocodeine, piritramide, tilidine, morphine, hydromorphone, oxycodone, levomethadone, fentanyl, sufentanil, buprenorphine, pentazocine, naloxone, Flupirtine, carbamazepine, metoprolol, metoclopramide, amitryptiline, doxepin, clomipramine, mianserin, maprotiline, triptans such as Naratriptan, rizatriptan, sumatriptan, zolmitriptan, calcium antagonists such as: flunarizine, topiramate, valproic acid, phenytoin, baclofen, other agents such as: botulinum toxin, ergotamine, lisuride, methysergide, pizotifen, oxcarbazepine, gabapentin and lamotrigine, dexamethaone, methylprednisolone, prednisolone, triamcinolone, Diazepam, tetrazepam, tizanidine, butylscopolamine, combination of tilidine and naloxone.

Drugs for the treatment of the nervous system, alone or in combination, e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline, dihydroergocriptine, lisuride, pergolide mesilate, pramipexole, ropinirole, apomorphine, biperiden, metixene hydrochloride, trihexphenidyl, entacapone, amantadine, bupidine, selegiline, apomorphine), stroke (acetylsalicylic acid, clopidogrel, dipyridamole, ticlopidine, heparin, phenprocoumon , Warfarin, protamine, phytomenadione, nimodipine, paracetamol, tramadol, buprenorphine), intracranial pressure (furosemide), tremor (propranolol, clozapine, alprazolam, primidone).

Drugs for the treatment of phytochemical disorders such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thioridazine, flupentixol, fluspirilene, etc.), depression (imipramine, amitripytline, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine, trazodone , Moclobemide, miratazepam, etc.), psychoses and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, temazepam, Zolpidem tartrate, zopiclone, promethazine, chlorprothixene, pipamperone, thioridazine, chloral hydrate, etc.) Restlessness and confusion (alprazolam, oxazepam, doxepin, clomipramine, imipramine, thioridazine, perazine, etc.), dementia of the Alzheimer's type (donepezil, rivastigmine, tacrine , Memantine, nimodipine, selegiline etc.).

Drugs for the treatment of cardiovascular diseases, such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem, verapamil , Benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan, losartan, chlorthalidone, xipamide, hydrochlorothiazide, furosemide, Piretanide, triamterene, digitalis glycosides, carvedilol, metoprolol, prazosin, etc.), cardiac arrhythmias (ajmaline, quinidine, disopyramide, flecainide, propafenone, propranolol, carvedilol, amiodarone, verapamil, diltiazem, etc.), hypertension (metoprolol, atenolol, urapidil, Clonidine, dihydralazine, chlorthalidone, hydrochlorothiazide, furosemide, felodipine, israpidine, lacidipine, diltiazem, Captopril, enalapril, fosinopril, lisinopril, ramipril, verapamil, candesartan, eprosartan, irbesatan, losartan, doxazosin, bunazosin, prazosin, terazosin, moxonidine, dihydralazine, minoxidil).

Drugs, alone or in combination, for the treatment of the respiratory tract and lungs (Theophylline, Methylprednisolone, Flucorton, Dexamethasone, Montelukast, Roxithromycin, Erythromycin, Azithromycin, Ciprofloxacin, Clarithromycin, Levofloxacin, Ofloxacin, Doxycycline, Ampicillin and Sulbactam, Amoxicillin, Cefuroxime, Clindamycin , Cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).

Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride, dimenhydrinate, cinnarizine, flunarizine, levomeprazine, ondansetron, betahistine, aprepitant, etc.).

Anti-infective drugs with antibiotics or antivirally active substances (acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazolin, cefixime, cefprozil, ceftriaxone, chloroquine, ciprofloxacin, clotrimazole, dicloxacillin, doxycycline, econazole, erythromycin, ethambutol, fosfomycin, flucloxacillin, fluconazole, Fusidic acid, gramicidin, idoxuridine, indinavir, interferon, itraconazole, isoniazid, josamycin, ketoconazole, lamivudine, lomefloxacin, mafenide, mebendazole, mesalazine, mezlozillin, mupirocin, miconazole, naftifine, nalidixic acid, norfloxacin, ofloxacin, oxacillin, oxytetracycline, piperacillin, praziquantel, Primaquine, proguanil, ribavirin, rifabutin, rimantadine, roxithromycin, saquinavir, spectinomycin, spriramycin, stavudine, sulbactam, teicoplanin, terbinafine, tetracycline, tetroxoprim, ticarcillin, tinidazole, tromantadine, tolnaftate, vancomycin, zidovudine, zalcitabine, etc.).

Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).

Preferred further active ingredient IIb in subunit II is dimenhydrinate.

The content of further active ingredient IIb on subunit II is preferably at least 1% by weight and preferably at most 35% by weight, in particular at least 10% by weight and preferably at most 25% by weight.

The additional ingredients are mixed with the drying material II and optionally sieved. The mixture thus obtained is compressed on a tablet press.

It has proven advantageous to design the small diameter subunit II to increase the subunit II contact area with the existing liquid in the gastrointestinal tract. To facilitate the release of drug II, the diameter of subunit II should preferably not exceed 7.5 mm. Preferably, the diameter of the subunit II is not more than 5.5 mm, and more preferably not more than 3 mm. In particular, subunits II are preferred which have diameters of not more than 2 mm and more preferably not more than 1.8 mm.

Unless otherwise indicated, "diameter" means the diameter which subunit II has at its thickest point.

If the subunit II too small, the manufacture and handling is difficult. Therefore, the diameter of subunit II is preferably at least 0.1 mm, more preferably at least 0.2 mm, more preferably at least 0.5 mm, and further preferably at least 1 mm. Due to this small diameter of the subunit II it is achieved that the active ingredient II as well as the optionally contained further active ingredients dissolve better where little fluid is available, especially in the intestine.

Subunit II preferably has a surface area of at least 5 mm ² and preferably at most 2000 mm ² . In particular, the subunit II has a surface area of at least 25 mm ² , more preferably at least 50 mm ² and especially at most 1500 mm ² and more preferably at most 1000 mm ² . Large surfaces facilitate the resolution of subunit II and thus the dissolution and absorption of the active ingredient II or the active ingredients.

Basically, subunit II can have any shape. However, it has been found to be advantageous to make subunit II in spherical (e.g., pellets) or cylindrical (e.g., tablets) shapes. The production of pellets and tablets from the material to be dried II is preferably carried out by methods known in the art. It is preferable to add the further active ingredient IIb to the material to be dried II before the preparation of the pellets or tablets.

In particular, the subunit II is preferably a solid body of a volume of at least 1 mm ³ , preferably at least 3 mm ³ and more preferably at least 5 mm ³ . The minimum size should be adhered to in order to allow good processability. In order to ensure good dissolution behavior, the volume of subunit II should not exceed a value of preferably 20 mm ³ , more preferably 10 mm ^3, and more preferably 8.5 mm ³ .

2.9 pellets

From the drying material II pellets can be produced. For this purpose, the item to be dried II is optionally mixed with other ingredients and formed into pellets using known methods. Suitable pelleting machines which can be used are coating bowls, drum coater, coating layer overdrawers and pelletizing plates, also fluidized bed devices in combination with extruding devices and extruding devices in combination with pelletizing plates.

2.10 coating

Both the pellets and the powders, granules and tablets, which were prepared using the material to be dried II, in turn can be provided with a coating. The coating applied to Subunit II is called Coating II.

The coating II is preferably designed such that the subunit II coated therewith does not dissolve in the gastric juice, ie an enteric coating is produced.

Preferably, the coating II comprises at least one coating polymer II.

The coating II preferably comprises a coating polymer II which has acid groups which are charged in the deprotonated state. Coating polymers containing such acid groups dissolve better in the basic environment of the gut than other polymers. Furthermore, they do not dissolve in the acidic environment of the stomach, they are insoluble in gastric juice. Preferably, the coating polymer II has at least 0.3 acid functions per monomer. The acid function may be a carboxylic acid group. In particularly preferred embodiments, the coating polymer II is a polymer containing methacrylic acid monomers include, in particular Eudragit ^® L-100-55.

Further preferred coating polymers II are cellulose derivatives, in particular those which have been esterified with organic acids. The organic acids may be aromatic and / or aliphatic, wherein in a preferred embodiment, a cellulose derivative is used, which is esterified both aromatic and aliphatic. The organic acids should preferably have not more than 10 carbon atoms, but preferably they should comprise at least 2 carbon atoms. In one embodiment of the invention, the coating polymer II is cellulose acetate phthalate.

Furthermore, cellulose ethers can also be used as cellulose derivatives. In this case, it is preferable to use cellulose etherified with short-chain alkyl groups. "Short chain" means that the alkyl radicals preferably have up to four carbon atoms. The alkyl radicals are furthermore preferably unbranched. A particularly preferred cellulose ether is ethylcellulose.

Furthermore, shellac can be used as coating polymer II.

The coating polymer II is preferably added a plasticizer II, which may be glycerol triacetate.

Coating polymer II preferably dissolves in the upper intestinal tract at a pH of at least 6. Those skilled in such coating polymers are known. In one embodiment, a coating polymer II is used, which is a copolymer of methacrylic acid and alkyl methacrylate monomers. In this case, the molar ratio of acid monomers to ester monomers, which preferably represent the starting materials of this coating polymer II, preferably at least 45:55 and particularly preferably at most 70:30.

This coating polymer II ensures that the subunit II dissolves only at a pH of at least 6. Such a pH typically prevails in the upper intestinal tract (jejunum).

According to the invention, the coating of subunit II is preferably at least 90% by weight of the coating polymer II and the plasticizer II. The subunit II coating is preferably at least 95% by weight, more preferably at least 98% by weight two components.

The process step in which subunit II is provided with a coating II preferably comprises the provision of a coating mixture. The coating mixture comprises at least a coating polymer II, a plasticizer II and a solvent. This solvent is preferably an alcohol and / or water. In particular, this solvent is a mixture of an alcohol and water. The alcohol is preferably isopropanol. In addition, talc is preferably dispersed in the coating mixture.

This coating mixture is then preferably sprayed onto subunit II, for example with a sausage coater known to the person skilled in the art.

3 subunit III

Subunit III comprises at least one carrier III and at least one drug III and optionally additional ingredients. The additional ingredients of subunit III preferably include at least one complexing agent III and at least one antioxidant III. Further preferably, at least one further active ingredient IIIb is among the additional ingredients.

Lubricants, lubricants, binders, other active ingredients, disintegrants, antioxidants, complexing agents, coating agents, flow agents, preservatives, fillers, surfactants, plasticizers and pigments are particularly suitable as additional ingredients.

3.1 mixing

Provision of subunit III preferably comprises mixing carrier III with drug III and the optional additional ingredients.

The mixing preferably comprises dissolving the carrier III in a solvent IIIa. Furthermore, the mixing preferably comprises dissolving additional ingredients, in particular the antioxidant III and the complexing agent III, in at least one solvent. These solutions are preferably combined to form a premix III. The active ingredient III is preferably added to the premix III so that a mixture III is obtained.

In preferred embodiments, in which the optional additional ingredients comprise complexing agent III and antioxidants III, first at least complexing agent III is dissolved in a solvent IIIb and at least antioxidant III in a solvent IIIc. These are then combined as described above with the solution of the carrier III and are then part of the premix III.

The solvents IIIb and IIIc may be the same or different, preferably they are different.

Solvent IIIa is preferably an alkanol, ester or glycol. Best choosen alkanols. Particularly preferred are short-chain alkanols having carbon chain lengths of 1 to 5, in particular 1 to 3 and preferably 1 or 2.

Solvent IIIb is preferably water or a water-miscible organic solvent. Water is preferred.

Solvent IIIc is preferably an alkanol, ester or glycol. Best choosen alkanols. Particularly preferred are short-chain alkanols having carbon chain lengths of 1 to 5, in particular 1 to 3 and preferably 1 or 2.

3.2 Drying

The mixture III prepared just described is dried. This is preferably done by freeze drying, tray drying, vacuum drying, drum drying, fluidized bed drying or spray drying, spray drying being preferred.

In the case of spray drying, it is preferable to proceed in such a way that the gas stream introduced into the spray-drying apparatus has temperatures of at least 100 ° C. Too low temperatures would not ensure sufficient drying. Preferably, the introduced gas stream should have temperatures of at least 110 ° C and more preferably at least 120 ° C. In order to keep energy consumption low, this gas flow should not exceed temperatures of at most 180.degree. C., more preferably 170.degree. C. and particularly preferably 160.degree.

In the gas stream, the solvent or the solvent mixture evaporates, the exhaust gas temperature is therefore below the temperature of the introduced gas stream. The drying process should preferably be carried out so that the exhaust gas temperature is at most 110 ° C. If the exhaust gas temperature is higher, the energy consumption is too high, the process may be uneconomical. Preferably, the exhaust gas temperature is at most 99 ° C. So that no condensation of the solvent or solvent mixture occurs in the spray drying plant, the exhaust gas temperature should preferably not fall below a value of 75 ° C. Preferably, the exhaust gas temperature should be at least 80 ° C.

By drying, a drying material III is obtained, which has a solvent content of less than 5000 ppm.

This material to be dried III consists of an active substance matrix III, which preferably consists of carrier III, active ingredient III and optional additional ingredients, in particular complexing agent III and / or antioxidant III. Preferably, the carrier III is selected so that the material to be dried III represents a solid dispersion of the active ingredient III in the active ingredient matrix III. This Trocknungsgut III is particularly important to promote the dissolution of the active ingredient III in the gastrointestinal tract.

The particle size of the material to be dried III should have a value of at most 0.8 mm, preferably at most 0.6 mm. To avoid agglomeration, the particle size of the material to be dried III should be at least 200 μm. This is preferably ensured by sieving.

The particle size is preferably determined by light microscopic methods which have already been mentioned above.

3.3 Completion of subunit III

The completion of the subunit III preferably provides that either the material to be dried III is already used as subunit III or the subunit III is prepared using the material to be dried III. Using the material to be dried III granules, tablets, coated tablets or pellets, in particular microtablets or pellets can be produced preferably.

In order to solve the problem of the invention, the individual ingredients of the material to be dried III were matched with respect to their nature and quantity.

The drying material III comprises at least one carrier III, at least one active ingredient III, and preferably additional ingredients, including preferably at least one antioxidant III and at least one complexing agent III. According to the invention, the active ingredient III is embedded in a matrix III (active substance matrix III) which comprises the carrier III and additional ingredients. As a result, among other things, the agglomeration of the drug particles is suppressed. The material to be dried III is preferably a solid dispersion of the active ingredient III, which also positively influences the dissolution of the active ingredient III.

The preferred combination of antioxidant III and complexing agent III achieves a unique improvement in the shelf life of drug III in matrix III. Particularly pronounced is the antioxidant effect of this combination in a drying material III, which contains the following ingredients in the indicated amounts: Active ingredient III 0.01% by weight to 50% by weight Carrier III 20% by weight to 99% by weight Antioxidant III 0.1% by weight to 5% by weight Complexing agent III 0.1% by weight to 5% by weight additional ingredients 0% by weight to 50% by weight

It has been found that the effect is particularly evident when a phenol ether is used as antioxidant III and an acetic acid derivative as complexing agent III. The molar ratio of antioxidant III to complexing agent III should be at least 0.5 to 1 and at most 10 to 1. Agents that are prone to undesirable oxidation when used in a solid dispersion are cinnarizine and its salts. Therefore, these active ingredients particularly benefit from the matrix III according to the invention in the drying material III.

The material to be dried III, in addition to the components carrier III, active ingredient III, antioxidant III and complexing III also contain additional ingredients. These additional ingredients may include solubilizers. Preferred solubilizers are cyclodextrins, sugar esters and other surfactants. Particularly preferred are sucrose fatty acid esters and / or sodium lauryl sulfate. The solubilizers may be used in a proportion of at least 1 wt .-% and preferably in amounts of at most 20 wt .-%, more preferably at most 10 wt .-% in the drying material III.

3.4 The carrier of subunit III

The carrier III used according to the invention must be present in the drying material III in a sufficient proportion. If the carrier III is used in too low a proportion in the drying material III, it can not adequately support the dissolution of the active ingredient. The upper limit of the proportion of carrier III in the material to be dried III is usually given by the limited volume of appropriate dosage forms. It has proved to be advantageous to use the carrier III in a proportion of at least 20 wt .-% in the drying material III. The content of carrier III in the material to be dried III is particularly preferably at least 30% by weight, more preferably at least 40% by weight and particularly preferably at least 45% by weight. In particular embodiments, the content of carrier III on the material to be dried III is at least 50% by weight, more preferably at least 60% by weight. Usually, the carrier III is used in amounts of at most 99 wt .-%, more preferably at most 95 wt .-% and particularly preferably at most 90 wt .-% in the drying material III. Particularly preferred embodiments contain the carrier III in amounts of at most 80% by weight, more preferably at most 70% by weight and particularly preferably at most 68% by weight. The carrier III is preferably a polymer.

The carrier III is preferably water-soluble. This ensures that the material to be dried III dissolves rapidly after entering the gastrointestinal tract and it allows the drug to dissolve upon contact with the liquid contained in the gastrointestinal tract. The water solubility of the carrier III is preferably at least 1 g / 100 ml, more preferably at least 5 g / 100 ml and particularly preferably at least 10 g / 100 ml.

Preferred carriers III have a glass transition temperature of at least 85 ° C and more preferably at least 100 ° C. If the glass transition temperature of the carriers III is below these values, the processability of the carriers III in the context of the production process of the material to be dried III is made more difficult. Carriers III which can be used according to the invention have, in particular, a glass transition temperature of at most 225 ° C., more preferably at most 190 ° C. It has been found that the use of such carriers III suppresses the agglomeration of the active ingredient particles in the matrix III.

The substances preferably used as carriers III are predominantly amorphous. In particular, the carriers III have crystalline contents of at most 20% by volume. Crystallinity delays the dissolution rate of the carrier III, which in turn hinders the dissolution of the active ingredient III and thus impairs its absorption.

When a polymer is used as the carrier III, it preferably has a number average molecular weight (M _N ) of at least 5,000, more preferably at least 12,000, and particularly preferably at least 20,000. Polymers with smaller average molecular weights often do not have the necessary strength to be able to produce stable and abrasion-resistant drug forms with the material to be dried III. On the other hand, polymers having too high average molecular weights often dissolve poorly, so that the carriers III preferably have average molecular weights of at most 200,000, more preferably at most 100,000, and most preferably at most 50,000. Convincing results were obtained with polyvinylpyrrolidone having an average molecular weight of 35,000 to 45,000 as the carrier III.

The carrier III is preferably selected from the group consisting of polyvinylpyrrolidones, cellulose derivatives, polyethers, poloxamers, urea, sugars, sugar alcohols, sugar derivatives, succinic acid and mixtures thereof.

Among the sugar alcohols, mannitol is particularly preferred, among the sugar derivatives dextrin.

The carrier III may comprise or consist of a polymer. The carrier III is preferably water-soluble and in particular a water-soluble polymer. Preferred water-soluble polymers are polyvinylpyrrolidone, water-soluble celluloses, polyethylene glycols and poloxamers. Preferred polymers are hydroxypropylmethylcellulose and polyethylene glycols having average molecular weights of 6,000 to 20,000.

Among the cellulose derivatives, particularly preferred are those having hydroxyl groups. Particularly preferred is hydroxypropylmethylcellulose. Among the polyethers, poloxamers and polyethylene glycols are particularly preferred. A particularly preferred carrier III is polyvinylpyrrolidone.

The carrier III in the dry matter III of this invention is preferably solid at room temperature.

In order to allow sufficient solubility in water and promotion of the rate of dissolution of the active ingredient III, the carrier III has a water storage capacity of preferably at least 10 wt .-%, more preferably at least 20 wt .-% and particularly preferably at least 30 wt .-%. This means the water storage capacity at a relative humidity of 75% and a temperature of 23 ° C. Nevertheless, the water storage capacity should preferably not exceed a value of at most 50% by weight and in particular not more than 45% by weight in order not to endanger the stability of the material to be dried III and in particular of the active substance.

The person skilled in the art expediently uses those excipients III which are physiologically harmless and inert to the active compounds.

3.5 Antioxidant III Subunit III

The antioxidant III in the drying material III serves to contain the oxidation of the active ingredient III. This is especially important when the drug III is present in small particles. For this purpose, the proportion of antioxidant III in the drying material III is preferably at least 0.1 wt .-%, more preferably at least 0.2 wt .-% and particularly preferably at least 0.3 wt .-%. The amount of antioxidant III is subject to legal limits. Therefore, the amount should not be too high. It is an advantage of this invention that the content of the antioxidant III can be minimized. The content of the antioxidant III on the drying material III is preferably at most 5% by weight, more preferably at most 3% by weight, in particular at most 2% by weight and particularly preferably at most 1.1% by weight.

The antioxidant III serves primarily to prevent the oxidation of the active ingredient III. Since the active ingredient III is advantageously used in small particle sizes, the surface of the active ingredient particles is very large and exposed to the attacks of oxidatively active substances. Therefore, the amount of antioxidant III is based on the amount of active ingredient. The molar ratio of antioxidant III to active ingredient III should preferably be at least 1 in 50, more preferably at least 1 in 30, and most preferably at least 1 in 15. This ensures that the antioxidant activity is sufficient to effectively prevent oxidation. This molar ratio should preferably be at most 1 to 5, more preferably at most 1 to 7 and particularly preferably at most 1 to 10.

The antioxidant III acts synergistically with the complexing agent III used according to the invention. Therefore, the amount of the antioxidant III is also based on the amount of complexing agent III used in the active substance matrix III. The molar ratio of antioxidant III to complexing agent III should preferably at least 0.5 to 1, more preferably at least 1 to 1, particularly preferably at least 1.15 to 1 and in particular at least 1.18 to 1. It has proven to be advantageous to comply with an upper limit of this molar ratio of preferably at most 10 to 1, more preferably at most 5 to 1, particularly preferably at most 3 to 1 and in particular at most 2 to 1. If these conditions are met, the synergistic effect of these two additional ingredients in the drying material III is particularly pronounced.

Preferred antioxidants III are ascorbic acid, hydrogen sulfites, sulfites, disulfite, cysteine, butylhydroxyanisole (BHA), tocopherols, nordihydroguiaretic acid (NDGA), coniferyl benzoate, isoascorbic acid, gallates (ester of gallic acid), t-butylhydroquinone (TBHQ), butylhydroxytoluene (BHT).

The antioxidant III can also be used in combination with acids, in particular citric acid, tartaric acid, fumaric acid and their salts. It has been found that this further enhances the oxidation inhibition.

The antioxidant III is preferably a radical scavenger or a readily oxidizable substance, whereby combinations of several antioxidants and also combinations of free-radical scavengers with easily oxidisable substance can be used. Easily oxidizable substances include hydrogen sulfites, sulfites, disulfite, ascorbic acid and isoascorbic acid.

Radical scavengers include BHA, BHT, NDGA, TBHQ, tocopherols, coniferyl benzoate, and gallates.

The antioxidant III is preferably a radical scavenger. In particular, the antioxidant III is selected from phenol derivatives. Phenol derivatives are in particular substituted and unsubstituted phenol ethers and substituted phenols. Preferred are alkyl-substituted phenol derivatives such as BHA, BHT and TBHQ. In particularly preferred embodiments, the antioxidant is BHA.

3.6 complexing agent III subunit III

The complexing agent III in the drying material III acts synergistically with the antioxidant III, especially when it is used in the ratios described above. In order to ensure that the effect of the complexing agent III is sufficient, its content should preferably be at least 0.1% by weight, more preferably at least 0.2% by weight and more preferably at least 0.3% by weight, based on the material to be dried III amount. A particularly good effect is achieved if the content of complexing agent III is not more than 5% by weight, in particular not more than 3% by weight, more preferably not more than 2% by weight and particularly preferably not more than 1% by weight.

The synergistic effect of antioxidant III and complexing agent III is most pronounced when complexing agents are used which form stable complexes with divalent metal ions. Particularly suitable are chelating agents. Preferably, the complexing agent III in the drying material III is an organic molecule. The complexing agent III preferably has at least 2 carboxyl groups and more preferably at least 3 carboxyl groups per molecule. The preferred complexing agent III is an acetic acid derivative. Particularly preferred substances are nitrilotriacetic acid (NTA), ethylene glycol bis (aminoethyl ether) -N, N'-tetraacetic acid (EGTA), ethylenediamine disuccinic acid (EDDS), ethylenediaminetetraacetic acid (EDTA), citric acid, polycarboxylates and mixtures thereof. The best results are achieved with EDTA.

If the material to be dried III itself is not the subunit III, the material to be dried III is preferably further processed with additional ingredients.

The additional ingredients are dependent upon the form in which subunit III is to be used. Possible forms include tablets, coated tablets, pellets, powders, granules and MUPS. A preferred form are tablets, especially microtablets. Another preferred form is pellets.

3.7 Active substance III

In principle, according to the invention, virtually any active substance can be incorporated into subunit III. The preferred active ingredient content of subunit III depends strongly on the planned indication of a corresponding dosage form and thus on the active ingredient III used. However, it is preferred according to the invention that the active ingredient content is at least 0.01% by weight, more preferably at least 0.25% by weight and especially preferably at least 1 wt .-% based on the subunit III. In particularly preferred embodiments, the active substance matrix III may even contain at least 4% by weight, more preferably at least 5% by weight and most preferably at least 7% by weight of active ingredient. However, in order that the promotion of the dissolution of the active ingredient III can take place sufficiently, the proportion of active ingredient should preferably not be higher than 40% by weight, based on the subunit III. The proportion of active ingredient is particularly preferably at most 30% by weight, more preferably at most 20% by weight and particularly preferably at most 10% by weight. In particular embodiments, the proportion of the active ingredient III at the subunit III can be up to 50 wt .-%.

If the manufacturing instructions described herein are adhered to, the active ingredient III is present in small particle sizes in the active ingredient matrix of the material to be dried III. It is important to comply with the regulations regarding the production and composition of the material to be dried III, so that the particle sizes are retained even with prolonged storage of the drug forms prepared therefrom.

In order to simplify the dissolution, the active ingredient III is preferably present in small particle sizes of at most 1000 nm, in particular at most 800 nm, particularly preferably at most 500 nm and in particular at most 300 nm. As a result, the specific surface area of the active ingredient III is increased and the dissolution is facilitated. However, in order not to increase the risk of oxidation of the active ingredient III too much and to suppress the agglomeration of the active ingredient particles into larger agglomerates, the particle size should preferably be at least 50 nm, more preferably at least 100 nm and particularly preferably at least 150 nm.

The mean particle size of drug III in the drug matrix is determined as follows: the carrier is dissolved in a medium in which the drug particles are insoluble. From this suspension, the particle size distribution is determined by means of laser diffraction. All other particle sizes and mean particle sizes mentioned in this specification are determined in an analogous manner unless otherwise described.

Decisive for the rate of dissolution of the active ingredient III is in addition to the particle size and the mass ratio of active ingredient III to carrier III. This is preferably at least 1 to 1000, more preferably at least 1 to 100, more preferably at least 1 to 50 and especially at least 1 to 30. In particularly preferred embodiments, this mass ratio is at least 1 to 15 and especially at least 1 to 10. An excessively low proportion of active ingredient at the subunit III can lead to a drug form containing the subunit III would take a sufficient amount of active substance too large a volume and thereby the intake is impaired by the patient. Therefore, the mass ratio of active ingredient III to carrier III in the subunit III of the invention is preferably at most 1 to 1, in particular 1 to 2, more preferably at most 1 to 4, further preferably at most 1 to 5 and particularly preferably at most 1 to 6.

In preferred embodiments, drug III, which is contained in subunit III, is poorly water-soluble. Poorly water-soluble active ingredients profit particularly from the advantageous properties of the subunit III according to the invention. This is especially true for active ingredients, which are still sufficiently soluble in the stomach with sufficient liquid supply, but are not sufficiently absorbed in the intestine due to the small amount of liquid present there.

The active ingredient III preferably has at least one amino group. As a result, the active ingredient III is usually protonated in the stomach and thus water-soluble in this acidic environment. At higher pH levels in the intestine, however, the active ingredient III can not dissolve. The active ingredient III used according to the invention has a solubility of preferably less than 10 mg / ml at a pH of 1.1. This active substance III needs the technological support of the matrix III according to the invention for sufficient absorption, in particular in prolonged-release dosage forms.

The active ingredient III used according to the invention preferably has an n-octanol-water partition coefficient (logP _OW ) at 20 ° C. of more than 1, preferably more than 2, more preferably more than 3 and particularly preferably more than 4, in particular more than 5. This distribution coefficient is a measure of the lipophilicity of a substance. As mentioned previously, particularly lipophilic drugs benefit from subunit III of this invention. The advantage for such agents is also particularly high because usually the absorption of lipophilic drugs works very well, as soon as these substances are dissolved. In other words, the dissolution of these drugs from a dosage form is the rate-limiting step in the uptake of the drug into the body. Nevertheless, there are also active substances whose lipophilicity is so pronounced that the subunit III proposed here is insufficient to ensure adequate bioavailability to deliver. Therefore, the active substances which are used according to the invention in the subunit III n-octanol-water partition coefficient (logP _OW ) at 20 ° C of preferably at most 100, more preferably at most 50, in particular at most 30, more preferably at most 15 and in particular at most 7th on.

Examples of active ingredients and active ingredient classes which can be advantageously used as active ingredient III in the context of the present invention are:
Medicines for the treatment of pain and pain therapy with peripherally acting analgesics, centrally acting analgesics and adjuvant non-analgesics. These are the following analgesics and adjuvants:
Drugs for the treatment of dizziness of various origins, in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.

Acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, naproxen, piroxicam, paracetamol, metamizole, celecoxib, parecoxib, tramadol, pethidine, codeine, dihydrocodeine, piritramide, tilidine, morphine, hydromorphone, oxycodone, levomethadone, fentanyl, sufentanil, buprenorphine, pentazocine, naloxone, Flupirtine, carbamazepine, metoprolol, metoclopramide, amitryptiline, doxepin, clomipramine, mianserin, maprotiline, triptans such as Naratriptan, rizatriptan, sumatriptan, zolmitriptan, calcium antagonists such as: flunarizine, topiramate, valproic acid, phenytoin, baclofen, other agents such as: botulinum toxin, ergotamine, lisuride, methysergide, pizotifen, oxcarbazepine, gabapentin and lamotrigine, dexamethaone, methylprednisolone, prednisolone, triamcinolone, Diazepam, tetrazepam, tizanidine, butylscopolamine, combination of tilidine and naloxone.

Drugs for the treatment of the nervous system, alone or in combination, e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline, dihydroergocriptine, lisuride, pergolide mesilate, pramipexole, ropinirole, apomorphine, biperiden, metixene hydrochloride, trihexphenidyl, entacapone, amantadine, bupidine, selegiline, apomorphine), stroke (acetylsalicylic acid, clopidogrel, dipyridamole, ticlopidine, heparin, phenprocoumon , Warfarin, protamine, phytomenadione, nimodipine, paracetamol, tramadol, buprenorphine), intracranial pressure (furosemide), tremor (propranolol, clozapine, alprazolam, primidone).

Drugs for the treatment of phytochemical disorders such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thioridazine, flupentixol, fluspirilene, etc.), depression (imipramine, amitripytline, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine, trazodone , Moclobemide, miratazepam, etc.), psychoses and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, temazepam, Zolpidem tartrate, zopiclone, promethazine, chlorprothixene, pipamperone, thioridazine, chloral hydrate, etc.) Restlessness and confusion (alprazolam, oxazepam, doxepin, clomipramine, imipramine, thioridazine, perazine, etc.), dementia of the Alzheimer's type (donepezil, rivastigmine, tacrine , Memantine, nimodipine, selegiline etc.).

Drugs for the treatment of cardiovascular diseases, such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem, verapamil , Benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan, losartan, chlorthalidone, xipamide, hydrochlorothiazide, furosemide, Piretanide, triamterene, digitalis glycosides, carvedilol, metoprolol, prazosin, etc.), cardiac arrhythmias (ajmaline, quinidine, disopyramide, flecainide, propafenone, propranolol, carvedilol, amiodarone, verapamil, diltiazem, etc.), hypertension (metoprolol, atenolol, urapidil, Clonidine, dihydralazine, chlorthalidone, hydrochlorothiazide, furosemide, felodipine, israpidine, lacidipine, diltiazem, Captopril, enalapril, fosinopril, lisinopril, ramipril, verapamil, candesartan, eprosartan, irbesatan, losartan, doxazosin, bunazosin, prazosin, terazosin, moxonidine, dihydralazine, minoxidil).

Drugs, alone or in combination, for the treatment of the respiratory tract and lungs (Theophylline, Methylprednisolone, Flucorton, Dexamethasone, Montelukast, Roxithromycin, Erythromycin, Azithromycin, Ciprofloxacin, Clarithromycin, Levofloxacin, Ofloxacin, Doxycycline, Ampicillin and Sulbactam, Amoxicillin, Cefuroxime, Clindamycin , Cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).

Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride, dimenhydrinate, cinnarizine, flunarizine, levomeprazine, ondansetron, betahistine, aprepitant, etc.).

Anti-infective drugs with antibiotics or antivirally active substances (acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazolin, cefixime, cefprozil, ceftriaxone, chloroquine, ciprofloxacin, clotrimazole, dicloxacillin, doxycycline, econazole, erythromycin, ethambutol, fosfomycin, flucloxacillin, fluconazole, Fusidic acid, gramicidin, idoxuridine, indinavir, interferon, itraconazole, isoniazid, josamycin, ketoconazole, lamivudine, lomefloxacin, mafenide, mebendazole, mesalazine, mezlozillin, mupirocin, miconazole, naftifine, nalidixic acid, norfloxacin, ofloxacin, oxacillin, oxytetracycline, piperacillin, praziquantel, Primaquine, proguanil, ribavirin, rifabutin, rimantadine, roxithromycin, saquinavir, spectinomycin, spriramycin, stavudine, sulbactam, teicoplanin, terbinafine, tetracycline, tetroxoprim, ticarcillin, tinidazole, tromantadine, tolnaftate, vancomycin, zidovudine, zalcitabine, etc.).

Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).

Preferred active ingredient III is cinnarizine and / or a cinnarizine salt.

3.8 tablets

As mentioned above, the drying material III is further processed depending on the desired form of the subunit III. A preferred option for further processing is the preparation of tablets containing the material to be dried III.

For the preparation of tablets, the material to be dried III is preferably mixed with additional ingredients.

The auxiliaries which are used for the production of tablets from the material to be dried III are preferably selected from flow agents, other active ingredients, binders, disintegrants, fillers, lubricants, lubricants, humectants, antioxidants, complexing agents, coating agents, flow agents, preservatives, surfactants, plasticizers and Pigments and mixtures thereof.

Preferred flow agent is fumed silica. The content of superplasticizer should preferably be at least 1% by weight and preferably at most 7% by weight, in particular at least 2% by weight and at most 5% by weight, based on the subunit III.

Preferred lubricants are hydrogenated vegetable oil and metal soaps. The content of lubricant should preferably be at least 0.5% by weight and preferably at most 5% by weight, in particular at least 1% by weight and at most 3% by weight, based on subunit III. Preferred lubricant is talc.

Examples of further active ingredients and active ingredient classes which can be used advantageously as further active ingredient IIIb in the context of subunit III are:
Medicines for the treatment of pain and pain therapy with peripherally acting analgesics, centrally acting analgesics and adjuvant non-analgesics. These are the following analgesics and adjuvants:
Drugs for the treatment of dizziness of various origins, in particular cinnarizine, scopolamine, promethazine, dimenhydrinate, betahistine, flunarizine, sulpiride and combinations of these active substances, in particular combinations of cinnarizine with dimenhydrinate.

Acetylsalicylic acid, ibuprofen, diclofenac, indomethacin, naproxen, piroxicam, paracetamol, metamizole, celecoxib, parecoxib, tramadol, pethidine, codeine, dihydrocodeine, piritramide, tilidine, morphine, hydromorphone, oxycodone, levomethadone, fentanyl, sufentanil, buprenorphine, pentazocine, naloxone, Flupirtine, carbamazepine, metoprolol, metoclopramide, amitryptiline, doxepin, clomipramine, mianserin, maprotiline, triptans such as naratriptan, rizatriptan, sumatriptan, zolmitriptan, calcium antagonists such as: flunarizine, topiramate, valproic acid, phenytoin, baclofen, other agents such as: botulinum toxin, ergotamine , Lisurid, Methysergide, Pizotifen, oxcarbazepine, gabapentin and lamotrigine, dexamethaone, methylprednisolone, prednisolone, triamcinolone, diazepam, tetrazepam, tizanidine, butylscopolamine, combination of tilidine and naloxone.

Drugs for the treatment of the nervous system, alone or in combination, e.g. Seizure disorders (clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetrazetam, mesuximide, primidone, nitrazepam, vigabatrin), Parkinson's disease (levodopa, with Benserazide / carbidopa, bromocriptine, cabergoline, dihydroergocriptine, lisuride, pergolide mesilate, pramipexole, ropinirole, apomorphine, biperiden, metixene hydrochloride, trihexphenidyl, entacapone, amantadine, bupidine, selegiline, apomorphine), stroke (acetylsalicylic acid, clopidogrel, dipyridamole, ticlopidine, heparin, phenprocoumon , Warfarin, protamine, phytomenadione, nimodipine, paracetamol, tramadol, buprenorphine), intracranial pressure (furosemide), tremor (propranolol, clozapine, alprazolam, primidone).

Drugs for the treatment of phytochemical disorders such as anxiety disorders (alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thioridazine, flupentixol, fluspirilene, etc.), depression (imipramine, amitripytline, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine, trazodone , Moclobemide, miratazepam, etc.), psychoses and schizophrenia (sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, oxazepam, flurazepam, nitrazepam, temazepam, Zolpidem tartrate, zopiclone, promethazine, chlorprothixene, pipamperone, thioridazine, chloral hydrate, etc.) Restlessness and confusion (alprazolam, oxazepam, doxepin, clomipramine, imipramine, thioridazine, perazine, etc.), dementia of the Alzheimer's type (donepezil, rivastigmine, tacrine , Memantine, nimodipine, selegiline etc.).

Drugs for the treatment of cardiovascular diseases, such as coronary heart disease / angina pectoris (acetylsalicylic acid, clopidrogel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem, verapamil , Benazepril, lisinopril, ramipril, fosinopril, enalapril, etc.), myocardial infarction and heart failure (isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captopril, ramipril, lisinopril, candesartan, eprosartan, irbesatan, losartan, chlorthalidone, xipamide, hydrochlorothiazide, furosemide, Piretanide, triamterene, digitalis glycosides, carvedilol, metoprolol, prazosin, etc.), cardiac arrhythmias (ajmaline, quinidine, disopyramide, flecainide, propafenone, propranolol, carvedilol, amiodarone, verapamil, diltiazem, etc.), hypertension (metoprolol, atenolol, urapidil, Clonidine, dihydralazine, chlorthalidone, hydrochlorothiazide, furosemide, felodipine, israpidine, lacidipine, diltiazem, Captopril, enalapril, fosinopril, lisinopril, ramipril, verapamil, candesartan, eprosartan, irbesatan, losartan, doxazosin, bunazosin, prazosin, terazosin, moxonidine, dihydralazine, minoxidil).

Drugs, alone or in combination, for the treatment of the respiratory tract and lungs (Theophylline, Methylprednisolone, Flucorton, Dexamethasone, Montelukast, Roxithromycin, Erythromycin, Azithromycin, Ciprofloxacin, Clarithromycin, Levofloxacin, Ofloxacin, Doxycycline, Ampicillin and Sulbactam, Amoxicillin, Cefuroxime, Clindamycin , Cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin, moxifloxacin, etc.).

Drugs for the treatment of the gastrointestinal tract and the pancreas (fluconazole, mesalazine, sulfasalazine, budesonide, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine , Ranitidine, nizatidine, sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride, dimenhydrinate, cinnarizine, flunarizine, levomeprazine, ondansetron, betahistine, aprepitant, etc.).

Anti-infective drugs with antibiotics or antivirally active substances (acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazolin, cefixime, cefprozil, ceftriaxone, chloroquine, ciprofloxacin, clotrimazole, dicloxacillin, doxycycline, econazole, erythromycin, ethambutol, fosfomycin, flucloxacillin, fluconazole, Fusidic acid, gramicidin, idoxuridine, indinavir, interferon, itraconazole, isoniazid, josamycin, ketoconazole, lamivudine, lomefloxacin, mafenide, mebendazole, mesalazine, mezlozillin, mupirocin, miconazole, naftifine, nalidixic acid, norfloxacin, ofloxacin, oxacillin, oxytetracycline, piperacillin, praziquantel, Primaquine, proguanil, ribavirin, rifabutin, rimantadine, roxithromycin, saquinavir, spectinomycin, spriramycin, stavudine, sulbactam, teicoplanin, terbinafine, tetracycline, tetroxoprim, ticarcillin, tinidazole, tromantadine, tolnaftate, vancomycin, zidovudine, zalcitabine, etc.).

Drugs for the treatment of erectile dysfunction (sildenafil, tadalafil, vardenafil, theobromine, caffeine, theophylline, etc.).

Preferred further active ingredient IIIb in subunit III is dimenhydrinate.

The content of further active ingredient IIIb at subunit III is preferably at least 1% by weight and preferably at most 35% by weight, in particular at least 10% by weight and preferably at most 25% by weight.

The additional ingredients are mixed with the material to be dried III and optionally sieved. The mixture thus obtained is compressed on a tablet press.

It has proven advantageous to design the small diameter subunit III in order to increase the contact area of subunit III with the existing liquid in the gastrointestinal tract. In order to facilitate the release of the active ingredient III, the diameter of the subunit III should preferably not exceed 7.5 mm. Preferably, the diameter of the subunit III is not more than 5.5 mm, and more preferably not more than 3 mm. In particular, subunits III are preferred which have diameters of not more than 2 mm, and more preferably not more than 1.8 mm.

Unless otherwise indicated, "diameter" means the diameter which subunit III has at its thickest point.

If the subunit III is too small, the manufacture and handling is difficult. Therefore, the diameter of subunit III is preferably at least 0.1 mm, more preferably at least 0.2 mm, more preferably at least 0.5 mm, and further preferably at least 1 mm. As a result of this small diameter of the subunit III, it is achieved that the active ingredient III and the optionally contained further active substances dissolve better where little fluid is available, in particular in the intestine.

Subunit III preferably has a surface area of at least 5 mm ² and preferably at most 2000 mm ² . In particular, the subunit III has a surface area of at least 25 mm ² , more preferably at least 50 mm ² and especially at most 1500 mm ² and more preferably at most 1000 mm ² . Large surfaces facilitate the resolution of subunit III and thus the dissolution and absorption of the active ingredient III or the active ingredients.

Basically, subunit III can take any conceivable form. However, it has been found to be advantageous to design subunit III in spherical (e.g., pellets) or cylindrical (e.g., tablets) form. The preparation of pellets and tablets from the material to be dried III is preferably carried out by methods known in the art. Preferably, the III further material IIIb is added to the material to be dried III before the preparation of the pellets or tablets.

In particular, the subunit III is preferably a solid body of a volume of at least 1 mm ³ , preferably at least 3 mm ³ and more preferably at least 5 mm ³ . The minimum size should be adhered to in order to allow good processability. In order to ensure good dissolution behavior, the volume of subunit III should not exceed a value of preferably 20 mm ³ , more preferably 10 mm ³ and more preferably 8.5 mm ³ .

3.9 pellets

From the drying material III pellets can be produced. For this purpose, the material to be dried III is optionally mixed with other ingredients and formed into pellets using known methods. Suitable pelleting machines which can be used are coating pans and pelletizing plates.

3.10 coating

Both the pellets and the powders, granules and tablets, which were prepared using the material to be dried III, can in turn be provided with a coating. The coating applied to subunit III is called Coating III.

The coating III is preferably designed such that the subunit III coated therewith does not dissolve in the gastric juice, ie an enteric coating is produced.

Preferably, the coating III has a coating polymer III.

The coating III preferably comprises a coating polymer III which has acid groups which are charged in the deprotonated state. Coating polymers containing such acid groups dissolve better in the basic environment of the gut than other polymers. Furthermore, they do not dissolve in the acidic environment of the stomach, they are insoluble in gastric juice. The acid function may be a carboxylic acid group. In particularly preferred embodiments, the coating polymer III is a polymer comprising methacrylic acid monomers, in particular Eudragit ^® L 100-55, Eudragit ^® S 100 and Eudragit ^® L 100th

Further preferred coating polymers III are cellulose derivatives, in particular those which have been esterified with organic acids. The organic acids may be aromatic and / or aliphatic, wherein in a preferred embodiment, a cellulose derivative is used that is both aromatic and aliphatic esterified. The organic acids should preferably have not more than 10 carbon atoms, but preferably they should comprise at least 2 carbon atoms. In one embodiment of the invention, the coating polymer III is cellulose acetate phthalate.

Furthermore, cellulose ethers can also be used as cellulose derivatives. In this case, it is preferable to use cellulose etherified with short-chain alkyl groups. "Short chain" means that the alkyl radicals preferably have up to four carbon atoms. The alkyl radicals are furthermore preferably unbranched. A particularly preferred cellulose ether is ethylcellulose.

Furthermore, shellac can be used as coating polymer III.

The coating polymer III is preferably added a plasticizer III, which may be glycerol triacetate.

Preferably, the coating III has a coating polymer III. The coating polymer III is preferably chosen so that it dissolves only in lower intestine sections. In the lower part of the intestine there are higher pH values than in the upper part of the intestine. Therefore, the coating III is designed so that it dissolves only at pH values of at least 7. Those skilled in such coatings are known. In particular, the coating III may be a polymeric coating. Preferably, this coating is prepared by mixing Eudragit ^® L100 and Eudragit ^® S100. The mixing ratio is preferably 1 to 10 to 5 to 10 based on the mass.

Eudragit ^® L100 corresponds to poly (methacrylic acid-co-methyl methacrylate) 1: 1 (CAS 25086-15-1). Eudragit ^® S100 corresponds to poly (methacrylic acid-co-methyl methacrylate) 1: 2 (CAS 25086-15-1). Eudragit ^® L100-55 corresponds to poly (methacrylic acid-co-ethyl acrylate) 1: 1 (CAS 25212-88-8).

According to the invention, the coating of the subunit III is preferably at least 90% by weight of the coating polymer III and the plasticizer III. The coating of subunit III preferably consists of at least 95% by weight, more preferably at least 98% by weight, of these two components.

The process step in which the subunit III is provided with a coating III preferably comprises the provision of a coating mixture. The coating mixture comprises at least a coating polymer III, a plasticizer III and a solvent. This solvent is preferably an alcohol and / or water. In particular, this solvent is a mixture of an alcohol and water. The alcohol is preferably isopropanol. In addition, talc is preferably dispersed in the coating mixture.

This coating mixture is then preferably sprayed onto subunit III, for example with a sausage coater known to the person skilled in the art.

4 dosage form

Also contemplated by the invention is a dosage form comprising at least subunit I and subunit II, and preferably also subunit III.

Preferably, the active ingredients I, II and III are the same. Preferably, carrier II and carrier III are the same. Preferably, carrier I is different from carrier II and III. Antioxidant II is preferably antioxidant III. Preferably, complexing agent II is the same as complexing agent III.

In order to provide the largest possible surface area and thus to increase the dissolution rates of the subunits and thus of the active ingredient or of the active ingredients, the inventive Dosage form preferably at least 10 subunits in total, selected from subunits I, II and optionally III. Preferably, the dosage form according to the invention even contains at least 20, more preferably at least 30, and most preferably at least 40 subunits. There are also embodiments according to the invention, which have at least 100 subunits. However, it must be taken into account that the dosage form according to the invention must not be too large, since otherwise the intake could be made more difficult. Therefore, the dosage form according to the invention preferably contains at most 500 subunits. Preferably, the dosage form contains at most 400, more preferably at most 200, and most preferably at most 150 subunits. For example, the dosage form may contain a plurality of subunits II in the form of pellets or microtablets, a plurality of subunits III in the form of pellets or microtablets and a subunit I in the form of powder. A quantum of a powder is understood according to the invention as a unit.

The dosage form according to the invention is preferably designed such that it releases the subunits after taking the dosage form through the patient. This can basically be achieved in various ways. The pharmaceutical form may, for example, have a carrier matrix in which the subunits are embedded. The carrier matrix is then preferably selected so that it dissolves very rapidly on contact with the gastric juice. The expert is familiar with corresponding matrix materials, in particular, these may be water-soluble polymers. For example, these may be polymers that have been described above as being water-soluble.

In a preferred embodiment according to the invention, the drug form has a shell which encloses the subunits. The sheath is preferably designed so that it dissolves very quickly on contact with the gastric juice. In particular, the sheath may be the sheath of a hard capsule commonly used in pharmaceutical technology. Preferred materials from which the shell can be made are water-soluble polymers, especially gelatin.

There are also drug forms according to the invention, which have no shell. In particular, the subunits may be contained in a bag which is opened by the patient and the contents of which can be taken. The dosage form may also be in the form of sticks containing the subunits.

Furthermore, the subunits can also be compressed to a body, so that the drug form is in the form of a MUPS (Multiple Unit Pellet System).

With the dosage form according to the invention, a sequential release of active substance can be achieved, wherein a multiple daily intake is simulated. This improves the compliance of patients who are treated with such a dosage form compared to those who need to take a fast-releasing form several times a day. The combination of various small subunits which release one or more active substances in different sections of the gastrointestinal tract with an active ingredient finely dispersed in a matrix makes it possible to achieve adequate bioavailability even in the case of poorly soluble active substances. The type of active ingredient is not critical to the success of the invention. In fact, this invention can also be used in drugs that dissolve poorly both in the stomach and in the intestine. In this case, it would be particularly advantageous in all three subunits to disperse the active ingredient in a matrix, so that its dissolution is already supported in the stomach.

The dosage forms of this invention are oral dosage forms. This means that they are intended for oral use. The dosage forms according to the invention may be, for example, capsules, powders, tablets, coated tablets, granules, sachets, sachets, pellets or sticks.

Due to the preferably simpler structure of subunit I compared to subunits II and III, less auxiliaries are needed in this unit. Therefore, the proportion by weight of subunit I in the dosage form is preferably relatively low. Thus, the proportion by weight of subunit I in the dosage form is usually less than 25% by weight, preferably even less than 20% by weight. According to the invention, the proportion of subunit I will preferably be at least 8% by weight and more preferably at least 12% by weight.

The proportion by weight of subunit II in the dosage form according to the invention should preferably be at least 30% by weight, more preferably at least 40% by weight and preferably at most 60% by weight, more preferably at most 50% by weight. If subunit III is not present, the content may also be higher, in particular up to 80% by weight or up to 75% by weight.

The proportion by weight of the optional subunit III in the pharmaceutical form should preferably be at least 30% by weight, more preferably at least 40% by weight and preferably at most 60% by weight, more preferably at most 50% by weight.

The usefulness of this dosage form according to the invention may consist, for example, in subunit I immediately releasing an active substance in the stomach, subunit II releasing a further portion of an active substance in the small intestine and an optional subunit III releasing a further portion of an active substance in the large intestine. This dosage form is then no sustained release dosage form in the conventional sense, because the active ingredient, once arrived at the site of release, not slowed down, but released immediately. Poorly soluble active substances can be released according to the invention in this way. With a conventional retarded form, this effect could not be achieved. The sequential release can be achieved by the choice of coating polymers.

According to the invention, therefore, is a dosage form which quickly releases an active substance at several different locations in the gastrointestinal tract and thus enables the absorption of poorly soluble active ingredients.

Also according to the invention is a dosage form prepared by the method according to the invention. Also according to the invention is the use of the dosage form for the treatment of dizziness. 5 Examples Examples Preparation of a Drug Form with Microtablets ingredient Quantity per dosage form function monograph drugs dimenhydrinate 120.00 mg Active ingredient Ib, IIb, IIIb Ph. Eur. cinnarizine 60.00 mg Active ingredient I, II, III Ph. Eur. Other ingredients Povidone K30 40.00 mg Carrier II, III Ph. Eur. Silica, highly dispersed 2.00 mg superplasticizer Ph. Eur. microcrystalline cellulose 252.00 mg Filler, disintegrant Ph. Eur. Vegetable oil, hydrogenated 8.00 mg lubricant BP talc 20.20 mg lubricant Ph. Eur. magnesium stearate 1.00 mg lubricant Ph. Eur. Methacrylic Acid Ethyl Acrylate Copolymer (1: 1) 17.20 mg Coating polymer II Ph. Eur. Methacrylic acid-methyl methacrylate copolymer (1: 2) 3.44 mg Coating polymer III Ph. Eur. Methacrylic acid-methyl methacrylate copolymer (1: 1) 13.76 mg Coating polymer III Ph. Eur. triacetin 10.32 mg softener Ph. Eur. Isopropanol ¹⁾ (550.00 mg) solvent Ph. Eur. Methanol ¹⁾ (4260.00 mg) solvent Ph. Eur. purified water ¹⁾ (47.60 mg) solvent Ph. Eur. Total mass Capsule content 529.92 mg capsule Hard capsule size 00eL

A dosage form according to the invention with the active ingredient cinnarizine (active ingredient I, II and III) and the further active ingredient dimenhydrinate (active ingredient Ib, IIb and IIIb) was prepared. Cinnarizine is a weak base that has a water solubility of 1.55 mg / ml at pH 1.1. At pH 3.0 the solubility is only about 0.05 mg / ml, at pH 6.5 still about 0.00025 mg / ml. Thus, cinnarizine is the ideal drug to demonstrate the benefits of the present invention.

First, a molecular disperse mixture of cinnarizine with the carrier (II and III) polyvinylpyrrolidone (PVP) was prepared. The cinnarizine was thus dispersed in a matrix of a water-soluble polymer. In this dispersion, the active ingredient is present in particles below the visible limit (<150 nm) or partially dissolved. The dispersion was prepared as follows: Cinnarizine was treated with PVP having an average molecular weight of about 40,000 in acetone and sprayed in a spray drying plant. The product obtained had an average grain size of 10-25 microns and a cinnarizine content of 12.38 wt .-% in a PVP matrix.

As subunits II and III, microtablets having a diameter of 1.7 mm and an average height of 1.7 mm were prepared. These microtablets can be produced very well on a rotary press with multiple tools, especially if the above recipe is complied with. It is the resulting granules are compressed with the above-mentioned excipients to form a tablet.

The microtablets were prepared as follows: 161.6 mg of the cinnarizine dispersed in PVP matrix were mixed with 40 mg of dimenhydrinate and some adjuvants to control flow and to prevent sticking and on a multi-tool rotary press to 1.7 mm diameter and 1 microtiter tablets , 7 mm height pressed.

The coatings were applied to the microtablets in a fluidized bed system with sausage insert.

For the preparation of the subunit II, the micro-tablets were coated with a coating of Eudragit ^® L100-55 with an appropriate amount of plasticizer (glycerol triacetate). The coating is stable for at least 60 minutes at a pH of 1.2.

The coating is dissolved at a pH of 6.0 to 6.5, the micro-tablets disintegrate and release the active ingredients.

To produce the subunit III micro-tablets were coated with a coating of Eudragit ^® L100 and S100 in a mass ratio of 2 to 8 and glycerol as a plasticizer. The microtablets have a resistance of at least 60 minutes in the stomach, but do not decompose at a pH of 6.0 to 6.5 but the coating dissolves from a pH of 7.0. Here, too, the multicompartments disintegrate and release the active ingredients.

In addition, a subunit I was prepared in the form of a powder. This first drug-containing unit contained 20 mg cinnarizine and 40 mg dimenhydrinate and excipients.

Then, a capsule machine (Zanasi 48E) with a powder dosing station and two microtablets was set up to fill the subunits in size 00eL capsules. These capsules were each filled with 246 mg of subunits II and III and 80 mg of subunit I.

Thus, three subunit drug forms were obtained in one capsule. Each subunit comprised 20 mg cinnarizine and 40 mg dimenhydrinate.

The dosage form should release 25-45% of both drugs within 60 minutes in 0.1 N HCl. Within a further 60 minutes at pH 6.5 a total of 60-80% should be released and after a further 120 minutes more than 80% should be released.

5.1.1 Oxidation experiments

The following examples are intended to show the effect according to the invention of the oxidation suppression in the active substance matrix by the combination of antioxidant and complexing agent. For this purpose, several text matrices were prepared and stored at room temperature for an extended period of time.

The table shows that a synergistic effect on storage stability occurs, which increases the longer the samples are stored. This effect is most pronounced with the combination EDTA + BHA, but also disulfite and cysteine in combination with EDTA clearly show the effect. This improvement is still possible Total contamination in mole% relative to drug after days 3 d 10 d 14 d 21 d 24 d 28 d 56 d 90 d BHA 0.5% 0.06 0.08 0.08 0.15 0.14 0.16 0.37 0.37 EDTA 0.5% 0.33 0.46 0.58 0.88 1.12 1.09 2.28 2.66 Disulfite 0.5% 0.43 0.59 0.58 0.95 1.02 1.06 1.66 2.31 EDTA 0.5% disulfite 0.5% 0.44 0.54 0.56 0.84 0.98 0.99 1.49 1.89 EDTA 0.5% cysteine 1.0% 0.15 0.27 0.33 0.50 0.48 0.60 1.16 1.56 EDTA 0.5% BHA 0.5% 0.04 0.07 0.06 0.07 0.08 0.08 0.24 0.22 increase by using higher levels of antioxidant.

Description of the pictures

shows a theoretical release profile of a commercial drug form that releases an active ingredient over a prolonged period.

shows the plasma levels of a poorly soluble drug, which are achieved with such a conventional preparation in vivo using the example of cinnarizine. As discussed above, this conventional dosage form is not suitable for simulating three times a day administration of a weakly basic, poorly water-soluble drug.

shows the release course of a dosage form according to the invention. The inventive form releases the active ingredient gradually, so that the three times daily intake is simulated. Due to the special design of the subunits a good release profile is achieved. It is to be expected that this will also be confirmed in vivo.

Claims (10)

Preparation process for a dosage form comprising at least one subunit I and at least one subunit II, comprising the steps of: providing subunit I; providing subunit II; assembling the subunits, optionally with further ingredients, subunit II comprising an active ingredient II in a matrix comprising a carrier II and the active ingredient II, characterized in that the mass ratio of active ingredient II to carrier II is at most 1 to 1 and providing the subunit II comprises the following step • mixing of active ingredient II and carrier II in a solvent to obtain a mixture II and drying the mixture II. The production method according to claim 1, wherein the carrier II is a polymer. The preparation process according to claim 1, wherein the carrier II is selected from polyvinylpyrrolidones, cellulose derivatives, polyethers, poloxamers, urea, sugars, sugar alcohols, sugar derivatives, succinic acid and mixtures thereof. Manufacturing method according to at least one of the preceding claims, the method comprising the following further step • Provision of a subunit III. Preparation process according to at least one of the preceding claims, wherein the subunit II comprises at least one antioxidant II and at least one complexing agent II. The production method according to at least one of the preceding claims, wherein the provision of the subunit II comprises coating the subunit II with a coating polymer II. Production process according to at least one of the preceding claims, wherein the drying of the mixture II takes place by means of spray-drying. Production process according to at least one of the preceding claims, wherein the subunit II comprises an enteric coating. Preparation process according to at least one of the preceding claims, wherein the carrier II is a polyvinylpyrrolidone and the active ingredient II is present in a particle size of less than 1000 nm. Pharmaceutical form, produced by a process according to at least one of the preceding claims.

Images