DE102011051304A1 - drug matrix - Google Patents

Abstract

An active ingredient matrix is presented which comprises an active ingredient dispersed in a carrier. In spite of the fact that the active substance is present in the matrix in fine dispersion, it hardly tends to oxidize and pharmaceutical forms produced using the matrix have a good shelf life. A production method for the active substance matrix and its uses are also according to the invention.

Description

This invention relates to a drug release matrix (drug matrix) and to a dosage form containing said drug matrix, and to a method of preparation.

Many pharmaceutical agents have poor water solubilities. As a result, these drugs show poor bioavailabilities when used perorally. In order for an active substance to be able to be absorbed from the gastrointestinal tract, it must first dissolve.

Particularly difficult is the drug dissolution in the intestine. While in the stomach still relatively large amounts of liquid are available for dissolution, the supply of liquid in the intestine is very limited.

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, the amount of active ingredient in the dosage form is rapidly reduced during storage and, on the other hand, oxidation products of the active substance accumulate, which in the worst case may even be harmful to health. 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.

Against the background of the problems described, it is the object of this invention to provide a drug matrix which improves the dissolution of drugs both in the stomach and in the intestine and has a significantly improved resistance to oxidation compared to conventional drug matrices. It is a further object of the invention to provide a pharmaceutical form which makes use of the advantages of the active ingredient matrix and to make available a preparation process with which the active ingredient matrix can be prepared.

In order to achieve the object according to the invention, the individual constituents of the active ingredient matrix have been matched with regard to their type and amount and, with an advantageous production process, a matrix which can be further processed into a suitable dosage form. The object is solved by the subject matters of the claims.

The drug matrix of this invention comprises at least one carrier, at least one drug, at least one antioxidant and at least one complexing agent. According to the invention, the active ingredient is embedded in the matrix. As a result, among other things, the agglomeration of the drug particles is suppressed. The active ingredient matrix is preferably a solid dispersion of the active ingredient, which also positively influences the dissolution of the active ingredient.

The combination of antioxidant and complexing agent provides a unique improvement in the shelf life of the active ingredient in the matrix. Particularly pronounced is the antioxidant effect of this combination in a drug matrix containing the following ingredients in the indicated amounts: active substance 0.01% by weight to 50% by weight excipient 20% by weight to 99% by weight antioxidant 0.1% by weight to 5% by weight complexing 0.1% by weight to 5% by weight

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

In addition to the components carrier, active substance, antioxidant and complexing agent, the active ingredient matrix may also contain further ingredients. These other ingredients may include a solubilizer. Preferred solubilizers are cyclodextrins, sugar esters and other surfactants. Particularly preferred are sucrose fatty acid esters and / or sodium lauryl sulfate. These further ingredients 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.

The other ingredients may also include other excipients, other agents and various excipients.

The carrier

The carrier used according to the invention must be present in the drug matrix in a sufficient proportion, because it contributes significantly to the fact that poorly soluble drugs can be brought to absorption. If the carrier is used in too low a proportion of the drug matrix, it can not adequately support the dissolution of the drug. The upper limit of the proportion of carrier in the drug matrix is usually given by the limited volume of appropriate drug forms. It has proved to be advantageous to use the carrier in a proportion of at least 20% by weight in the active substance matrix. The content of carrier in the active substance matrix 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 substance in the active substance matrix is at least 50% by weight, more preferably at least 60% by weight. Usually, the carrier 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 active ingredient matrix. Particularly preferred embodiments contain the carrier in proportions of at most 80% by weight, more preferably at most 70% by weight and particularly preferably at most 68% by weight, based on the active ingredient matrix.

The carrier is preferably a polymer. Polymers make it possible to adapt the properties of the carrier to the requirements imposed by the active ingredient. This can be done for example by a suitable choice of the average molecular weight or the degree of branching of the polymer.

The carrier is preferably water-soluble. This ensures that the active ingredient matrix rapidly dissolves after entry into the gastrointestinal tract and allows the active ingredient to dissolve on contact with the liquid contained in the gastrointestinal tract. The water solubility of the carrier is preferably at least 1 g / 100 ml, more preferably at least 5 g / 100 ml, and most preferably at least 10 g / 100 ml.

Preferred carriers 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 is below these values, the processability of the carrier substances is made more difficult in the context of the production process of the active substance matrix. Carriers 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 polymers suppresses the agglomeration of the drug particles in the matrix during the manufacturing process.

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

When a polymer is used as the carrier, it preferably has a number average molecular weight (M _N ) of at least 5,000, more preferably at least 12,000, and most 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 active substance matrix. On the other hand, polymers having too high average molecular weights often dissolve poorly, so that the carriers of this invention 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 a carrier.

It should be noted that the average molecular weights of the carriers have an influence on the solubility of the active ingredient in the carrier. According to the invention, it is preferred that the active ingredient matrix is a solid dispersion of the active ingredient. Therefore, the active ingredient should not dissolve in the carrier. When the above average molecular weight values of the carrier are maintained, the preferred solid dispersions become available. This is especially true when agents are used whose lipophilicity - expressed by the n-octanol-water partition coefficient (logP _OW ) at 20 ° C - in the scope of the invention.

The carriers are 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 can comprise or consist of a polymer. The carrier 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 is polyvinylpyrrolidone.

The carrier in the drug matrix of this invention is preferably solid at room temperature.

In order to allow sufficient solubility in water and promotion of the dissolution rate of the active ingredient, the carrier has a water storage capacity of preferably at least 10 wt .-%, more preferably at least 20 wt .-% and particularly preferably at least 30 wt .-% to. 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 active substance matrix and in particular of the active substance.

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

The active substance

In principle, according to the invention, virtually any active substance can be incorporated into the active ingredient matrix. It is preferable to ensure that the active ingredient in the carrier matrix does not dissolve or only to a very limited extent.

The preferred active substance content of the active substance matrix depends strongly on the planned indication of a corresponding dosage form and thus on the active ingredient used. Experiments have shown that drug matrices according to the invention can be prepared with the following amounts of active ingredient. 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 active ingredient matrix. In particularly preferred embodiments, the drug matrix may even contain at least 4 wt%, more preferably at least 5 wt%, and most preferably at least 7 wt% of active ingredient. However, in order that the promotion of the dissolution of the active ingredient can take place sufficiently, the proportion of active ingredient should preferably not be higher than 40% by weight, based on the active ingredient matrix. 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 active ingredient in the drug matrix may be up to 50% by weight.

Crucial for the dissolution rate of the active ingredient is the mass ratio of active ingredient to carrier. 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 drug matrix can lead to a drug form, which contains the drug matrix, would take too large a volume with sufficient amount of drug and thereby the intake is affected by the patient. Therefore, the mass ratio of active substance to carrier in the active substance matrix according to 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, the drug contained in the drug matrix is poorly water-soluble. Poorly water-soluble active ingredients profit particularly from the advantageous properties of the active substance matrix 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 preferably has at least one amino group. As a result, the active ingredient 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 can not dissolve. The active compounds used according to the invention have a solubility of preferably less than 10 mg / ml at a pH of 1.1. These agents need the technological support of the matrix of the present invention for adequate absorption, especially in prolonged release dosage forms.

The active ingredient 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 Partition coefficient is a measure of the lipophilicity of a substance. As previously mentioned, particularly lipophilic drugs benefit from the drug matrix 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 active substance matrix proposed here is not sufficient to ensure adequate bioavailability. Therefore, the active compounds used according to the invention have n-octanol-water partition coefficients (logP _OW ) at 20 ° C. of preferably at most 100, more preferably at most 50, in particular at most 30, particularly preferably at most 15 and in particular at most 7.

Examples of active ingredients and active ingredient classes which can be advantageously used as active ingredient 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.).

In very particularly preferred embodiments, the active ingredient is cinnarizine and / or a cinnarizine salt. The active substance matrix can have a further active ingredient in addition to this active substance. The further active ingredient is preferably dimenhydrinate.

The active ingredient, in order to simplify the dissolution, 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. This increases the specific surface area of the active substance and facilitates the dissolution. However, in order not to increase the risk of oxidation of the active substance 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 the drug 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 is by means of Laserdiffraction determines the particle size distribution. All other particle sizes and mean particle sizes mentioned in this specification are determined in an analogous manner unless otherwise described.

The antioxidant

The antioxidant in the drug matrix of this invention serves to control the oxidation of the drug. This is especially important if the drug is present in small particles. For this purpose, the proportion of antioxidant to the drug matrix 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 is subject to legal limits. Therefore, the amount should not be too high. It is a merit of this invention that the content of the antioxidant can be kept low. Preferably, the content of the antioxidant to the active ingredient matrix is at most 5 wt .-%, more preferably at most 3 wt .-%, in particular at most 2 wt .-% and particularly preferably at most 1.1 wt .-%.

The antioxidant serves primarily to prevent the oxidation of the active ingredient. Since the active ingredient is used in small particle sizes, the surface of the drug particles is very large and exposed to the attacks of oxidatively active substances. Therefore, the amount of the antioxidant based on the amount of active ingredient. The molar ratio of antioxidant to active ingredient should preferably be at least 1 to 50, more preferably at least 1 to 30, and most 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 acts synergistically with the complexing agent used according to the invention. Therefore, the amount of antioxidant 'is also based on the amount of complexing agent used in the drug matrix. The molar ratio of antioxidant to complexing agent should preferably be 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 ingredients of the drug matrix is particularly pronounced. It should be noted that the synergistic effect is particularly useful during prolonged storage. With a short storage time of just a few days, the combination of antioxidant and complexing agent is only slightly superior to the antioxidant as the only agent, only after a few weeks, the pronounced synergy occurs.

Preferred antioxidants are ascorbic acid, hydrogen sulphites, sulphites, disulphite, cysteine, butylhydroxyanisole (BHA), tocopherols, nordihydroguiaretic acid (NDGA), coniferyl benzoate, isoascorbic acid, gallates (esters of gallic acid), t-butylhydroquinone (TBHQ), butylhydroxytoluene (BHT) and mixtures thereof ,

The antioxidant 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 is preferably a radical scavenger. In particular, the antioxidant is selected from phenolic 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 butylhydroxyanisole.

The complexing agent

The complexing agent in the drug matrix of this invention acts synergistically with the antioxidant, particularly when used in the proportions described above. To ensure that the effect of the complexing agent is sufficient, its content should preferably be at least 0.1% by weight, more preferably at least 0.2% by weight and most preferably at least 0.3% by weight. be based on the drug matrix. A particularly good effect is achieved if the content of complexing agent is at most 5% by weight, in particular at most 3% by weight, more preferably at most 2% by weight and particularly preferably at most 1% by weight.

The synergistic effect of antioxidant and complexing agent is most pronounced when complexing agents are used which form stable complexes with divalent metal ions, especially iron and / or copper. Particularly suitable are chelating agents. Preferably, the complexing agent in the drug matrix is an organic molecule. The complexing agent preferably has at least 2 carboxyl groups and more preferably at least 3 carboxyl groups per molecule. The preferred complexing agent 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 were achieved with EDTA.

The drug form

Also according to the invention is a dosage form which comprises the active substance matrix according to the invention. The dosage form is intended for oral use. The dosage form is preferably a solid form, in particular a capsule, a tablet, a coated tablet, pellets, a granulate, a powder or a Multi Unit Pellet System (MUPS). The use of the active substance matrix in a dosage form for oral administration is also according to the invention.

The active ingredient, which is arranged in the active ingredient matrix, is preferably present in a proportion of at least 30 mg and more preferably at least 50 mg in the dosage form according to the invention. The maximum amount of this active ingredient in the dosage form according to the invention is preferably at most 100 mg and in particular at most 75 mg.

If the dosage form is not in monolithic form (capsule, tablet, coated tablet, MUPS), the amounts given here in the dosage form are based on a single dose.

The dosage form may contain further adjuvants such as lubricants, disintegrants, release agents, flow agents and / or binders.

By using the drug matrix, the bioavailability of the active ingredients in the oral dosage form can be significantly improved. For this purpose it is preferred that the dosage form comprises the active ingredient matrix in a proportion of at least 40% by weight and more preferably at least 50% by weight. The proportion of the active ingredient matrix in the dosage form should preferably be at most 90% by weight, more preferably at most 75% by weight and particularly preferably at most 60% by weight. This is especially true if the drug form, as preferred according to the invention, in addition to the active ingredient in the drug matrix comprises at least one additional active ingredient, which may be located in the drug matrix and / or outside. This active substance is referred to below as "additional active ingredient".

The additional active ingredient may preferably be contained in proportions of at least 50 mg and more preferably at least 100 mg in the dosage form. The maximum amount of the additional active ingredient in the dosage form is preferably at most 200 mg and in particular at most 150 mg.

Examples of active ingredients and active ingredient classes which can be used advantageously as an additional active ingredient in the dosage form 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.).

It is particularly preferred that the dosage form comprises dimenhydrinate as additional active ingredient. A particularly preferred dosage form comprises the active substance cinnarizine or a cinnarizine salt in the active substance matrix and as additional active substance dimenhydrinate, the latter may preferably be present outside the active substance matrix. The cinnarizine or the salt of cinnarizine may additionally be present outside the active substance matrix but within the dosage form. As a result, the poorly soluble active ingredient cinnarizine can be excellently absorbed.

There are those dosage forms particularly preferred in which the drug matrix is arranged in pellets or microtablets within the drug form. In this case, the pharmaceutical form itself may preferably be in the form of a capsule or a MUPS which contains a plurality of pellets or microtablets, each comprising the active substance matrix according to the invention.

The dosage form preferably comprises at least one disintegrant in addition to the active substance matrix. This disintegrant is preferably selected from starch and starch derivatives as well as cellulose and cellulose derivatives. The disintegrant is preferably used in proportions of at least 1% by weight, in particular at least 2% by weight, based on the mass of the pharmaceutical form. The disintegrant ensures the timely and rapid disintegration of the drug form, so that the drug matrix can be released quickly and difficult to dissolve active ingredients for absorption. The disintegrant is usually preferably used in a content of at most 30 wt .-% and particularly preferably at most 15 wt .-%.

Particularly preferred is a dosage form which comprises the active ingredient in at least two portions, which release the active ingredient in each case at different locations. For this purpose, the dosage form contains a first active substance portion, which is arranged outside the matrix according to the invention, and a second active ingredient portion, which is arranged within the matrix.

The matrix is preferably present in pellets or tablets, in particular microtablets, which are provided with a gastric juice-insoluble coating. The enteric-insoluble coating may comprise a polymer comprising acrylic acid and alkyl acrylate monomers. The polymer is preferably chosen so that it dissolves at about pH 6. The skilled person such polymers are known, an example is Eudragit ^® L100-55; this corresponds to poly (methacrylic acid-co-ethyl acrylate) 1: 1 (CAS 25212-88-8).

According to the invention, therefore, a dosage form which contains the active substance matrix according to the invention in the form of coated pellets or tablets and additionally comprises a portion of the active substance outside the active substance matrix, wherein the coating of the tablets or pellets is selected so that it is insoluble in gastric juice and at about pH 6 dissolves. The tablets are preferably microtablets. In preferred embodiments, the additional active ingredient or a portion of the additional active ingredient is present outside the active ingredient matrix but within the pellets or tablets.

Furthermore, the pharmaceutical form may contain a third active ingredient portion, which is likewise arranged in a drug matrix according to the invention. Also, this matrix is in the form of pellets or tablets provided with a gastric juice-insoluble coating. This enteric-insoluble coating may comprise a polymer comprising acrylic acid and alkyl methacrylate monomers. The polymer is preferably chosen so that it dissolves at about pH 7. The skilled person such polymers are known, an example is a mixture of Eudragit ^® L100 and Eudragit ^® S100 corresponds to a mass ratio of at least 1 to 6 and at most 1 ^® to 3. Eudragit L100 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).

By such an embodiment of the drug form, a poorly soluble drug can be released in several phases. This has so far been thwarted by the fact that poorly soluble drugs have hardly dissolved in the intestine and thus were not absorbed even when dissolution of a corresponding coating in the intestine.

Production of the active ingredient matrix

• • Mischen von Wirkstoff, Trägerstoff, Antioxidans und Komplexbildner und optional weiteren Inhaltsstoffen in einem Lösungsmittel oder Lösungsmittelgemisch und
• • Trocknen der Mischung.

The preparation of the active substance matrix comprises the following steps:

• Mixing of active substance, carrier, antioxidant and complexing agent and optionally further ingredients in a solvent or solvent mixture and
• • drying the mixture.

• • Mischen des Trägerstoffs mit einem ersten Lösungsmittel (Mischung I),
• • Mischen des Antioxidans‘ mit einem zweiten Lösungsmittel (Mischung II),
• • Mischen des Komplexbildners mit einem dritten Lösungsmittel (Mischung III),
• • Zusammenführen der so erhaltenen Mischungen zu einer vereinigten Mischung (Mischung IV),
• • Hinzufügen des Wirkstoffes zu dieser Mischung IV.

The method steps of mixing the individual matrix components are preferably divided into

• Mixing the carrier with a first solvent (mixture I),
• Mixing the antioxidant with a second solvent (mixture II),
• Mixing the complexing agent with a third solvent (mixture III),
• Combining the mixtures thus obtained into a combined mixture (mixture IV),
• Adding the active ingredient to this mixture IV.

The mixtures may each independently be solutions, emulsions or suspensions. Preferably, in any case, mixture IV is a solution, preferably all mixtures are solutions.

The other ingredients can be added depending on the solubility in one of the mixing steps.

The solutions are preferably prepared in the absence of light.

The solvents used may be the same or different. In preferred embodiments, the first solvent is an alkanol. Preferably, the second solvent is an alkanol. The third solvent is preferably water.

• • Trocknen der Mischung IV

The preparation of the mixture IV follows as mentioned above:

• • drying the mixture IV

Drying is preferably carried out by means of spray drying, fluidized bed drying, vacuum drying, drum drying or tray drying.

Spray drying is particularly preferred because it surprisingly further improves the dissolution of the active ingredient. The spray drying preferably takes place with an inlet temperature of between 110 ° C and 175 ° C, bes onders preferably between 125 ° C and 155 ° C instead. The outlet temperature is preferably between 80 ° C and 98 ° C, more preferably between 85 ° C and 95 ° C.

The dried product is the drug matrix of this invention. The proportions of the constituents are to be observed as described above.

The above-described mixture I of the carrier with the first solvent preferably has a polymer concentration of at least 3% by weight, in particular at least 5% by weight and particularly preferably at least 6% by weight. The polymer concentration should preferably not exceed 10% by weight, in particular 8% by weight. The first solvent is preferably methanol. Due to the high polymer concentrations in the mixture I, the solvent consumption is kept low. The above-mentioned drying method ensures that the content of this solvent in the final matrix is not more than 5000 ppm, especially not more than 3000 ppm.

The mixture II of the antioxidant with the second solvent preferably has a concentration of antioxidant of at least 4 wt .-%, preferably at least 7 wt .-%, on. The maximum concentration should not exceed 12% by weight and preferably 9% by weight. The second solvent is preferably methanol.

The mixture III of the complexing agent with the third solvent preferably has a concentration of complexing agent of at least 3 wt .-%, in particular at least 6.8 wt .-%, on. The mixture III should preferably contain not more than 11% by weight and more preferably not more than 9.5% by weight of complexing agent. The third solvent is preferably water.

The targeted selection of solvents and concentrations of the individual ingredients in the solvent solvent consumption is kept low.

To produce a dosage form according to the invention, the active substance matrix can be filled, for example, into a capsule or further processed into tablets or pellets. The active substance matrix can also first be processed into tablets, coated tablets or pellets and then processed with further ingredients to form a drug.

Before further processing into a pharmaceutical form, the tablets or pellets containing the active substance matrix can be provided with coatings. The coatings are described above. So it can a dosage form comprising the active substance in three portions, two of which comprise the active substance matrix according to the invention and are provided with gastric juice-insoluble coatings as described above. In this case, an active ingredient portion is preferably arranged outside the active ingredient matrix. This ensures that the drug is released in three phases, which is a three times daily intake is simulated.

The gastric juice-insoluble coating can be applied in conventional processes, in particular with coating layer coating devices (Wurster coater) and drum coaters.

Examples

Production of a Drug Matrix According to the Invention

A dosage form according to the invention with the active ingredient cinnarizine and the active ingredient dimenhydrinate 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 drug matrix of this invention.

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

Then, 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 compositions of matrix and pharmaceutical form are 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.

In a fluidized bed system with Wurstereinsatz coatings were applied to the microtablets.

For the production of coated units, 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.

For the preparation of other coated units, the 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 powder was prepared. This powder contained 20 mg cinnarizine and 40 mg dimenhydrinate and excipients.

Then, a capsule machine (Zanasi 48E) was equipped with a powder dosing station and two microtablets to fill the drug-containing units in capsules of size 00eL. These capsules were filled with 246 mg each of the various microtablets and 80 mg of the powder.

Thus, dosage forms were obtained in the form of capsules.

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

oxidation tests

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 can be further increased by using higher levels of antioxidant. Total contamination in mole% relative to drug after days 3 d 7 d 10 d 14 d 17 d 21 d 24 d 28 d 56 d 90 d BHA 0.5% 0.06 0.04 0.08 0.08 0.05 0.15 0.14 0.16 0.37 0.37 EDTA 0.5% 0.33 0.30 0.46 0.58 0.62 0.88 1.12 1.09 2.28 2.66 Disulfite 0.5% 0.43 0.61 0.59 0.58 0.64 0.95 1.02 1.06 1.66 2.31 EDTA 0.5% 0.44 0.54 0.54 0.56 0.61 0.84 0.98 0.99 1.49 1.89 Disulfite 0.5% EDTA 0.5% 0.15 0.27 0.27 0.33 0.36 0.50 0.48 0.60 1.16 1.56 Cysteine 1.0% EDTA 0.5% 0.04 0.03 0.07 0.06 0.04 0.07 0.08 0.08 0.24 0.22 BHA 0.5%

Description of the pictures

shows a theoretical release profile of a commercial drug form that releases an active ingredient over a prolonged period. It would be desirable to have such a release profile even with poorly soluble drugs in vivo.

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 drug form according to the invention with drug matrix and distributed on three portions of active ingredient. The inventive form releases the active ingredient gradually, so that the three times daily intake is simulated. Due to the special design of the drug matrix, a good release profile is achieved. It is to be expected that this will also be confirmed in vivo.

Claims (11)

Containing drug matrix a. at least one carrier in an amount of at least 20% by weight, b. at least one active ingredient, c. at least one antioxidant and d. at least one complexing agent, wherein the molar ratio of antioxidant to complexing agent is at least 0.5 to 1 and at most 10 to 1. The drug matrix of claim 1, wherein the carrier is a water-soluble polymer. Active ingredient matrix according to claim 1, wherein the carrier is selected from polyvinylpyrrolidones, cellulose derivatives, polyethers, poloxamers, urea, sugars, sugar alcohols, sugar derivatives, succinic acid and mixtures thereof. Active ingredient matrix according to at least one of the preceding claims, wherein the active ingredient is present in a proportion of at least 1 to 1000 and at most 1 to 1 in the mass ratio to the carrier. Active ingredient matrix according to at least one of the preceding claims, wherein the active substance has an n-octanol-water partition coefficient of more than 1. Active ingredient matrix according to at least one of the preceding claims, wherein the active ingredient is present in an average particle size of at most 1000 nm. Active ingredient matrix according to at least one of the preceding claims, wherein the antioxidant in a molar ratio to the active ingredient of at least 1 to 50 and at most 1 to 5 is included. Active ingredient matrix according to at least one of the preceding claims, wherein the antioxidant is a radical scavenger. Active ingredient matrix according to at least one of the preceding claims, wherein the complexing agent is EDTA. Pharmaceutical form for oral administration comprising an active substance matrix according to at least one of the preceding claims in a proportion of at least 40% by weight. A process for preparing a drug matrix according to at least one of claims 1 to 9 comprising the steps Mixing of active ingredient, carrier, antioxidant and complexing agent as well as optional further ingredients in a solvent or solvent mixture and • drying the mixture.

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