WO2012175737A1

WO2012175737A1 - Active ingredient matrix

Info

Publication number: WO2012175737A1
Application number: PCT/EP2012/062235
Authority: WO
Inventors: Gernot Francas; Karl-Heinz PRZYKLENK
Original assignee: Hennig Arzneimittel Gmbh & Co. Kg
Priority date: 2011-06-24
Filing date: 2012-06-25
Publication date: 2012-12-27
Also published as: DE102011051304A1

Abstract

The invention relates to an active ingredient matrix, which comprises an active ingredient dispersed in a carrier substance. Although the active ingredient is present in the matrix in a fine dispersion, the active ingredient hardly tends toward oxidation, and dosage forms produced by using the matrix have a long shelf life. The invention further relates to a production method for the active ingredient matrix and to uses of the active ingredient matrix.

Description

Active ingredient matrix

This invention relates to a drug delivery matrix (drug matrix) as well as to a dosage form containing this drug delivery matrix and 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 area of the active substance particles, however, the oxidation of oxidation-sensitive active substances is also 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. This effect of enhanced oxidation occurs not only in drugs that are finely dispersed in small particles, but also in drugs that are present, for example, dissolved in a matrix.

Furthermore, due to the reduction in the particle sizes of active ingredients, agglomerates increasingly occur, which in turn have a lower surface area and thus adversely affect both the further processing and the dissolution rate of the active ingredient. In addition, it can happen that active ingredients dissolved in a matrix agglomerate or crystallize, especially during prolonged storage. This also leads to problems with the absorption.

Against the background of the problems described, it is the object of this invention to provide an active ingredient matrix which improves the dissolution of active ingredients 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 ingredients of the active ingredient matrix have been matched with regard to their type and quantity and, with an advantageous production method, a matrix is produced 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 optionally 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 and crystallization 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 active ingredient is thus present in the matrix either suspended and / or dissolved. In preferred embodiments, the active ingredient is dissolved in the matrix.

The combination of antioxidant, carrier and advantageously complexing agent achieves 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 ingredient 0.01% by weight to 50% by weight

Carrier 20 wt% to 99 wt%

Antioxidant 0.1% by weight to 5% by weight of complexing agent (optional) 0.1% by weight to 5% by weight

It has been found that the effects according to the invention, in particular the improvement in durability, are particularly evident when a phenol ether is used as antioxidant and optionally as complexing agent an acetic acid derivative. The molar ratio of antioxidant to complexing agent 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 according to the invention.

In addition to the components carrier, active substance, antioxidant and optional complexing agent, the active substance matrix may also contain further ingredients, in particular at least one emulsifier. 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 can 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 preferably contained emulsifier supports the release of the active ingredient. This is particularly important to ensure that at least part of the active substance is absorbed as quickly and evenly as possible after me a drug form containing the matrix already dissolves in the stomach. In fact, the pH of the stomach decreases slowly after taking a meal. However, it is necessary that the active ingredient already dissolves in the stomach so that it is mixed with the chyme. The mixing is done by the stomach movement. In order for the improvement in the release to be particularly pronounced, the emulsifier should preferably have an HLB value of at least 1 and at most 16, in particular at least 9 and at most 14. The emulsifier is preferably nonionic.

It has been found that such emulsifiers achieve particularly advantageous results which have a specific structural motif. This structural motif is a polyethylene glycol chain. It was found that emulsifiers with this structural motif have a dual function. On the one hand, at high pH values from about pH 4, they lead to an improvement in the solubility of the active ingredient. On the other hand, at low pH, namely when the first active is very soluble, they lead to a delay in release.

The polyethylene glycol chain is the hydrophilic part of the emulsifier and is linked to a lipophilic part. The lipophilic part may advantageously be a glyceride residue or another polyalkylene oxide chain.

Suitable glyceride residues are mono- and diglyceride residues, diglyceride residues being preferred. Monoglyceride residues may not be lipophilic enough, depending on the chain length of the fatty acid residues involved. Suitable polyalkylene oxide chains are, in particular, polyalkylene oxides which have uninterrupted carbon chains of at least 3 carbon atoms. A preferred example of a polyalkylene oxide chain in the emulsifier of this invention is polypropylene oxide.

These emulsifiers can be obtained by methods known to those skilled in the art. Polyethylene glycol glycerides can be prepared, for example, by reaction of the corresponding glycerides with polyethylene glycol. Commercially available polyethylene glycol glycerides include Gelucire® 43/01 and Gelucire® 50/13.

In other words, the emulsifiers which are preferably used in the matrix according to the invention have the following structural element:

R ¹ -O- [CH ₂ -CH ₂ -O] "- R ² (Formula I) In which R ¹ and R ^{2 are the} same or different. R ¹ and R ² are independently hydrogen, alkyl, glyceride or polyalkylene oxide. Alkyl is preferably short-chain, ie it has a maximum chain length 6 carbon atoms. Preferably, R ¹ and R ^{2 are} independently hydrogen, glyceride or polyalkylene oxide.

When a radical R ¹ or R ^{2 is} hydrogen, the radicals R ¹ and R ^{2 are} different, ie the other radical is not hydrogen; and when R ¹ or R ^{2 is} alkyl, the radicals R ¹ and R ^{2 are} different, ie the other radical is not alkyl. Otherwise, the molecule would not have the required emulsifying effect. Preferably, R ¹ and R ^{2 are} neither hydrogen nor alkyl when the other is hydrogen or alkyl. n is the number of chain links in the polyethylene oxide chain. n is preferably an integer of at least 4, more preferably at least 10 and particularly preferably at least 20. If n is smaller, the effect desired according to the invention is not very pronounced, because the lipophilic part of the emulsifier is too small. In preferred embodiments, n is not greater than 100, more preferably not greater than 50 or 40. Larger chain lengths have been found to cause the emulsifier of pancreatin and lipases to degrade more slowly. This allows the prolonged release to be controlled. But if the chain is too long, the dosage form will not release the drug fast enough.

When R ¹ and / or R ^{2 are} a polyalkylene oxide radical, the radical has the following general formula:

-0- [Y-0] _m -R ³ (Formula II)

Therein R ^{3 is} hydrogen or alkyl, in particular short-chain alkyl (to Ce). Y is an alkylene group having a carbon chain length of at least C3, and preferably at most Ce, more preferably at most C4. m denotes the number of chain links in the polyalkylene oxide chain. m is preferably an integer of at least 3, in particular at least 5 and particularly preferably at least 10. m should preferably not exceed an integer of 50, in particular 40 and particularly preferably 30. In preferred embodiments, R ¹ and R ^{2 are} polyalkylene oxide radicals.

When R ¹ and / or R ^{2 are} glyceride radicals, the radical has the following general formula:

(Formula III)

In this case, the formula III is linked to the structural element of the formula I at one of the sites R ⁴ , R ⁵ or R ⁶ . It is irrelevant according to the invention at which point the structure of the formula III with the Structure of the formula I is linked. It is therefore one of the radicals R ⁴ , R ⁵ or R ^6, the structure of formula I. For the other two radicals then applies the following:

R ⁴ is preferably hydrogen or a fatty acid residue. The fatty acid radical R ⁴ has a chain length of preferably at least Ce, more preferably at least Ce and particularly preferably at least C10. A minimum chain length should be maintained so that the glyceride residue is sufficiently lipophilic. The number of carbon atoms in the fatty acids is preferably even. The chain length should preferably not exceed a value of C22, more preferably C18 and particularly preferably C16, because otherwise the solubility of the emulsifier could be impaired.

R ⁵ is preferably hydrogen or a fatty acid residue. The fatty acid radical R ⁵ has a chain length of preferably at least Ce, more preferably at least Ce and particularly preferably at least C10. A minimum chain length should be maintained so that the glyceride residue is sufficiently lipophilic. The number of carbon atoms in the fatty acids is preferably even. The chain length should preferably not exceed a value of C22, more preferably C18 and particularly preferably C16, because otherwise the solubility of the emulsifier could be impaired. R ⁶ is preferably hydrogen or a fatty acid residue. The fatty acid residue R ⁶ has a chain length of preferably at least Ce, more preferably at least Ce and particularly preferably at least C10. A minimum chain length should be maintained so that the glyceride residue is sufficiently lipophilic. The number of carbon atoms in the fatty acids is preferably even. The chain length should preferably not exceed a value of C22, more preferably C18 and particularly preferably C16, because otherwise the solubility of the emulsifier could be impaired.

Preferably, two of R ⁴ , R ⁵ and R ^{6 are} fatty acid residues. Accordingly, it is then a diglyceride group.

It should be noted that the correct chain length of the fatty acid residues corresponds strongly with the number of chain links in the polyethylene oxide chain (s). If the polyethylene oxide chain is longer, the fatty acid chain may be longer.

The emulsifiers described here can be prepared by reaction of corresponding mono-, di- and / or triglycerides with corresponding polyalkylene oxides. These starting materials are commercially available. The emulsifiers are preferably mixtures of the substances mentioned.

In preferred embodiments, the emulsifier is selected from Gelucire® 50/13, Gelucire® 43/01, Poloxamer 407, and mixtures thereof.

A good solubilization is achieved when the ratio of the masses of active ingredient to emulsifier is at least 1 to 30, more preferably at least 1 to 20 and particularly preferably 1 to 10. The said ratio is at most 1 to 1, more preferably at most 1 to 4, and particularly preferably In general, it is true that a larger amount of emulsifier enables a better solubilization. However, it must be remembered that a dosage form should not exceed certain maximum volumes, so that the intake is not unnecessarily unpleasant. In addition, an excessive amount of emulsifier can also lead to the release of the drug is hindered. The active substance matrix preferably contains the emulsifier in a proportion of at least 10% by weight, more preferably at least 15% by weight and particularly preferably at least 20% by weight. The proportion of the emulsifier should preferably not exceed a proportion of 50 wt .-%, more preferably 40 wt .-% and particularly preferably 32 wt .-%. When trying to determine the optimal ratio of solubilization and volume of the drug matrix, these amounts have proven to be advantageous. In particularly preferred embodiments, at least one phospholipid is used instead of the abovementioned substances or in addition to the abovementioned substances. The phospholipid is preferably selected from phosphatidylcholines (lecithins), phosphatidylethanolamines (cephalins), phosphatidylserines, sphingomyelins and mixtures thereof. Particularly preferred are phosphatidylcholines (lecithins). It has surprisingly been found that phospholipids also produce the advantageous effects described above, like the other emulsifiers mentioned above.

The emulsifier can therefore be a phospholipid. Preferably, the emulsifier comprises the phospholipid in addition to at least one of the above-mentioned substances. The phospholipid thereby enhances the beneficial effects of the above-mentioned substances.

The carrier used according to the invention must be present in the active ingredient matrix in a sufficient proportion, because it contributes significantly to the fact that poorly soluble active ingredients can be brought to absorption. If the carrier is used in too low a proportion of the drug matrix, it can not sufficiently 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 wt .-% in the drug matrix. The content of carrier substance 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 upon 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, then the processability of the carriers in the context of the production process of the active ingredient matrix is made more difficult. 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 active ingredient particles in the matrix during the production 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. If a polymer is used as the carrier, it preferably has a number average molecular weight (MN) 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 preferable for the active ingredient matrix to be 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 (logPow) at 20 ° C - within 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. Particularly preferred polymers are polyvinylpyrrolidone, polyethylene glycols and poloxamers.

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. Polyethers also include esterification products of polyethers, especially with glycerides and / or fatty acids.

The carrier in the drug matrix of this invention is preferably solid at room temperature. This is particularly important if the matrix has a relatively high proportion of emulsifier and / or triglyceride. Because then the carrier is needed as a structuring component.

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% by weight, more preferably at least 20% by weight, and most preferably at least 30% by weight. This means the water storage capacity at a relative humidity of 75% and a temperature of 23 ° C. However, the water storage capacity should preferably not exceed a value of at most 50 wt .-% and in particular at most 45 wt .-%, in order not to endanger the stability of the active ingredient matrix and in particular the active ingredient.

For particularly preferred carriers, the following applies:

Preferred carriers are selected from polymeric organic substances, in particular those which are capable of swelling. Preferred excipients are acrylate polymers, methacrylate polymers and their copolymers and mixtures thereof. Other preferred carriers are celluloses, especially high viscosity celluloses. The carrier of the drug matrix of this invention is preferably a polymer, especially a polysaccharide. Preference is given to cellulose, cellulose derivatives, alginates and mixtures thereof and their hydrates, but there are also polyacrylates, polymethacrylates and their Copolymers and mixtures in question. Particularly preferred cellulose derivatives are methylcellulose and hydroxypropylmethylcellulose.

Preferably, a carrier is used which has a viscosity of at least 1500 mPas in an aqueous solution in a proportion of 2 wt .-% at a temperature of 20 ° C and a pressure of 101, 325 kPa. The viscosity is measured with a falling ball viscometer (DIN 53015). Depending on the desired prolongation of the release of the first active ingredient, it may be desirable to also choose higher viscosities. The higher the viscosity of the carrier, the stronger will be the prolongation of the release. In particularly preferred embodiments, the viscosity of the carrier is even at least 2500 mPas and more preferably at least 3500 mPas. However, if the viscosity is too high, the drug will be released too slowly. This would result in the drug not being completely released during its passage through the gastrointestinal tract. Therefore, the viscosity should be limited to at most 200,000 mPas, more preferably at most 120,000 mPas.

The proportion of this carrier to the active substance matrix should preferably be at least 10% by weight, more preferably at least 20% by weight and particularly preferably at least 30% by weight. If too small an amount of the carrier used, the effect of the invention is not achieved. Too large amounts of the drug will not release fast enough. Therefore, the proportion of carrier substance in the active substance matrix should not exceed a value of 60% by weight, more preferably 50% by weight and particularly preferably 40% by weight. In the mass ratio to the active ingredient, the content of carrier should preferably be at least 3 to 1, more preferably at least 5 to 1 and particularly preferably at least 7 to 1. However, this ratio should not exceed 20 to 1, more preferably 15 to 1, and most preferably 10 to 1.

In alternative embodiments, the carrier is a polyol, especially mannitol or lactose. Especially in combination with an emulsifier, the use of sugars, sugar alcohols and sugar derivatives has proven itself.

Thus, the carrier or excipients are preferably selected from: polyvinylpyrrolidone, cellulose derivatives, polyethers, poloxamers, urea, sugars, sugar alcohols, sugar derivatives, succinic acid, polyacrylates, polymethacrylates and their copolymers, as well as mixtures of the substances listed here. A particularly preferred group of carriers consists of polyvinylpyrrolidone, polyethers, poloxamers, polyacrylates, polymethacrylates and their copolymers, as well as mixtures of the listed substances. The person skilled in the art expediently uses those excipients which are physiologically harmless and inert to the active compounds.

Further, the drug matrix may be added to a fatty alcohol. The fatty alcohol is preferably an alcohol having a chain length of at least 10 carbon atoms, more preferably at least 12 Carbon atoms, and more preferably at least 14 carbon atoms. However, the chain length should not exceed a value of preferably 20 carbon atoms, more preferably 18 and especially 16 carbon atoms. It has been found that the addition of a fatty alcohol is suitable for delaying the release of the active ingredient. By delaying the release, it is possible to control the release of active ingredient. Thus, on the one hand, the release of the active ingredient can be supported and, on the other hand, the release can be extended. This is particularly advantageous in modified release dosage forms.

The proportion by weight of the long-chain alcohol in the active substance matrix is preferably at least 5 wt .-%, more preferably at least 10 wt .-% and particularly preferably at least 18 wt .-%. If the content of the long-chain alcohol on the matrix is too low, the effect according to the invention is not achieved. Too much content may affect the structural identity of the matrix. Therefore, the content of the long-chain alcohol in the matrix is preferably at most 40% by weight, more preferably at most 35% by weight, and particularly preferably at most 30% by weight.

In principle, according to the invention, virtually any active substance can be incorporated into the active substance 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 ingredient 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 inventively preferred that the active ingredient content is at least 0.01 wt .-%, more preferably at least 0.25 wt .-% and particularly preferably at least 1 wt .-% based on the active ingredient matrix. In particularly preferred embodiments, the drug matrix may even contain at least 4% by weight, more preferably at least 5% 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 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 the active substance in the active substance matrix can 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 On the drug matrix can cause a drug form containing the drug matrix, take in sufficient amount of active substance too large a volume and thereby the intake by the patient is impaired. Therefore, the mass ratio of active ingredient to carrier in the active ingredient matrix according to the invention is preferably at most 1 to 1, in particular 1 to 2, more 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 Active substance, which is contained in the active substance matrix, 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 substance therefore preferably has no carboxyl group. Carboxyl groups are deprotonated in an alkaline medium and thus charged. They therefore do not benefit to the extent of the release-improving properties of the matrix according to the invention.

The active ingredient used according to the invention preferably has an n-octanol-water partition coefficient (logPow) 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 the drug matrix of this invention. The advantage for such active ingredients is also particularly high because usually the absorption of lipophilic active ingredients 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 ingredient matrix proposed here is not sufficient to ensure sufficient bioavailability. Therefore, the active compounds used according to the invention, n-octanol-water partition coefficient (logPow) at 20 ° C of preferably at most 100, more preferably at most 50, especially at most 30, more 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 e.g. 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, thi-oridazine, flupentixol, fluspirilen, etc.), depression (imipramine, amitripytine, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine, trazodone, moclobemide, miratazepam, etc.), psychosis 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, nitroglycerine, 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.).

Antiinfective drugs with antibiotics or antivirally active substances (acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazolin, cefixime, cef-prozil, 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,

Meziozillin, 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 preferred embodiments, the active substance matrix according to the invention comprises no antibiotics in a pharmaceutically effective amount, in particular no representative of the active substance class of the tetracyclines. Antibiotics affect the intestinal flora by killing important bacteria in the gut. In the drug matrix of this invention, this effect would lead to severe side effects. In preferred embodiments, the active substance matrix according to the invention does not comprise proton pump inhibitors. Proton pump inhibitors increase the pH in the stomach and thus interfere with the dissolution of many drugs from the drug matrix, especially the weakly basic drugs.

In very particularly preferred embodiments, the active ingredient is cinnarizine and / or a cinnarizine salt. The active ingredient matrix may have a further active ingredient besides this active ingredient. 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 active ingredient may also be in dissolved form. In dissolved form, the active ingredient has a particle size of less than 50 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, 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.

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 in 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 drug 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 is 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, 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 ingredients of the active ingredient 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 (ester of gallic acid), f-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 optional complexing agent in the drug matrix of this invention acts synergistically with the antioxidant, particularly when used in the proportions described above were. 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 particularly preferably at least 0.3% by weight, based on the active ingredient 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. In preferred embodiments, the drug matrix further contains at least one surfactant. The surfactant serves to enhance the solubilization mediated by the emulsifier and / or the carrier. If a mixture of emulsifier and / or carrier and surfactant is used, these two substances act synergistically. As a result, the total mass of emulsifier, carrier and surfactant can be reduced in relation to the active ingredient. As mentioned above, for optimum solubilization, it may be necessary to choose a very large amount of emulsifier relative to the active ingredient. This large amount can be reduced by the use of a surfactant.

Preferred surfactants are ionic surfactants, especially anionic surfactants. Metal soaps have proven to be particularly advantageous. Metal soaps are preferably understood to mean substances which comprise an organic acid as the anionic component and a metal cation as the cationic component. The metal cation is preferably selected from alkali and alkaline earth metal ions. Particularly preferred are alkali metal ions and especially sodium and potassium. Among the alkaline earth metal ions, magnesium and calcium are particularly preferred.

Preferred organic acids which may be present as anionic component in the surfactants are acids having at least 6 carbon atoms. Organic acids with shorter carbon chain lengths have been found to be less effective. However, the organic acids should preferably not exceed chain lengths of 22 carbon atoms. With longer carbon chains, the synergistic effect in combination with the emulsifier is not strong enough. Particularly preferably, the organic acids in the surfactants have chain lengths of at least 10 and at most 18, more preferably at least 12 and at most 16 carbon atoms. The organic acids may have branched or unbranched carbon chains, preferably the carbon chains are unbranched. A particularly preferred surfactant is sodium myristate.

The surfactants of the invention also have the task of slowing the gastrointestinal passage of the chyme and thus the absorption of the first active ingredient. Interestingly, it has been found that this can be achieved especially by the metal soaps described herein.

The proportion of the surfactant in the active substance matrix according to the invention should preferably be at least 2% by weight, preferably at least 7% by weight, more preferably at least 12% by weight and particularly preferably at least 17% by weight. It has been shown that the effects of the surfactant are so particularly pronounced. However, an amount of preferably 35% by weight, more preferably 25% by weight and especially preferably 20% by weight should not be exceeded. This would hinder the release of the drug too much. The absolute mass of the surfactant in the active ingredient matrix should not exceed a value of 300 mg, more preferably 250 mg and more preferably 200 mg. The minimum amount of the surfactant should preferably not fall below a value of 10 mg, more preferably 50 mg and particularly preferably 100 mg. The content of surfactant in the mass ratio to the active ingredient should not fall below a proportion of 1 to 1, more preferably 1, 5 to 1 and particularly preferably 2 to 1. Preferably, this ratio should not exceed a value of 5 to 1, more preferably 4 to 1 and in particular 3 to 1. Taking these values into account, the advantageous effect outlined above can be optimally utilized.

In a preferred embodiment, the drug matrix of this invention has at least one triglyceride. The triglyceride serves to slow down the gastrointestinal passage of the drug form. The triglyceride can also be used in combination with the surfactant to further slow down the release of the active ingredient.

The triglyceride preferably comprises a fatty acid residue having at least 10 carbon atoms, more preferably at least 12 carbon atoms, and most preferably at least 16 carbon atoms. This minimum chain length is desirable because it makes the prolongation of the residence time of the drug matrix in the stomach as part of a drug form particularly pronounced and the release of the active ingredient can be particularly efficiently supported. However, the chain length should preferably not exceed a value of 22 carbon atoms, more preferably 20 carbon atoms. In particularly preferred embodiments, all fatty acid residues in the triglyceride meet these requirements.

The triglyceride may preferably be used in a proportion of at least 10% by weight, more preferably at least 15% by weight and particularly preferably at least 20% by weight in the active substance matrix according to the invention. A maximum content of preferably 40% by weight, more preferably 30% by weight and more preferably 25 wt .-% should not be exceeded, because otherwise the release of the active ingredient would be too limited.

The absolute mass of the triglyceride in the active substance matrix should not exceed a value of 500 mg, more preferably 400 mg and most preferably 300 mg. The minimum amount of the triglyceride should preferably not fall below a value of 50 mg, more preferably 100 mg and particularly preferably 150 mg.

The content of triglyceride in the mass ratio to the active ingredient should not fall below a proportion of 2 to 1, more preferably 3 to 1 and particularly preferably 3.5 to 1. Preferably, this ratio should not exceed a value of 20 to 1, more preferably 10 to 1 and in particular 7 to 1. Taking these values into account, the advantageous effect outlined above can be optimally utilized.

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 ingredient matrix in a dosage form for oral administration is also according to the invention. The dosage forms are preferably not oral dispersible forms, in particular not buccal tablets, sublingual tablets or wafers. In preferred embodiments, the dosage form is a shift tablet or a sheath-core tablet. 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 active ingredient 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 pharmaceutical 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 pharmaceutical 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:

Diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thi-oridazine, flupentixol, fluspirilen, etc.), depression (imipramine, amitripytine, desipramine, maprotiline, mianserin, citalopram, fluoxetine, paroxetine, trazodone, moclobemide, miratazepam, etc.), psychosis and schizophrenia (sulpiride,

Promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine, risperidone, etc.), sleep disorders (triazolam, Brotizolam, Oxazepam, Flurazepam, Nitrazepam, Temazepam, Zolpidemtartrat, 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, nitroglycerine, 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,

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 in addition to the active ingredient matrix at least one disintegrant. 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 timely and rapid disintegration of the dosage form, so that the active substance matrix can be rapidly released and poorly soluble active substances are absorbed. 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 pharmaceutical form contains a first active ingredient 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. Those skilled in the art are familiar with such polymers

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 of 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 an active substance 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. Such polymers are known to those skilled in the art, an example being a mixture of Eudragit® L100 and Eudragit® S100 in a mass ratio of at least 1 to 6 and at most 1 to 3. Eudragit® L100 corresponds to poly (methacrylic acid-co-methyl methacrylate) 1: 1 (CAS 25086-15-1). Eudragit® S100 corresponds to poly (methacrylic acid-co-methylmethacrylate) 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. 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.

The method steps of mixing the individual matrix constituents 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.

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. Spray-drying preferably takes place with an inlet temperature of between 110 ° C and 175 ° C, more preferably between 125 ° C and 155 ° C. The outlet temperature is preferably between 80 ° C and 98 ° C, more preferably between 85 ° C and 95 ° C.

The dried product is the active ingredient 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.

For the preparation of 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 drug matrix can also be processed into tablets, coated tablets or pellets and then processed with other 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. Thus, it is possible to prepare a pharmaceutical form which comprises the active ingredient 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

1. Preparation 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 a pH of 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 μίη 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 multi-purpose rotary press, especially if the above compositions of matrix and drug form be respected. 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 prevent sticking, and to 1, 7 mm diameter and 1 microtablets on a multi-tool rotary tablet press , 7 mm height pressed.

In a fluidized bed system with Wurstereinsatz coatings were applied to the microtab-Ietten.

To prepare coated units, the microtablets 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 prepare further coated units, the microtablets were coated with a coating of Eudragit® L100 and S100 in a mass ratio of 2 to 8 and glycerol triacetate 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 OOeL. 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 in 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.

2. Active substance matrix with emulsifier Example A

Dosage forms of the following compositions were prepared:

The specified ingredients were mixed and then processed by means of a conventional melt granulation to a granulate and then pressed into tablets.

Example B

The following example shows the effect of a triglyceride on drug release of the drug. The experiment was carried out at a pH of 5.5 in a paddle apparatus.

1st compartment Ex.4 Ex.5 Purpose

Cinnarizine 60 60 active ingredient

Gelucire® 50/13 240 240 emulsifier

Dynasan 118 0 240 triglyceride

Pharmatose 480 480 Carrier

Description of the pictures

Figure 1 shows a theoretical release profile of a commercially available drug form, which 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. Figure 2 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.

Figure 3 shows the course of release from a drug form according to the invention with active ingredient 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.

Figure 4 shows the influence of the relative amount of emulsifier on the drug matrix on the solution behavior. The ordinate shows the released amount of active ingredient in%, the abscissa the past minutes. It can be seen that the amount of emulsifier also increases the amount of active ingredient released.

Figure 5 shows the effect of the triglyceride in the drug matrix on the dissolution behavior of the first drug. The ordinate shows the released amount of active ingredient in%, the abscissa the past minutes. It can be seen that the amount of emulsifier also increases the amount of active ingredient released.

Claims

claims

1. Active substance matrix containing a. at least one carrier in a proportion of at least 20% by weight and at most 95% by weight, b. at least one active ingredient in a proportion of at least 1 wt .-% and at most 40 wt .-% and c. at least one antioxidant; wherein the active ingredient has an n-octanol-water partition coefficient (logPow) at 20 ° C of more than 1.

The drug matrix of claim 1, wherein the carrier is a water-soluble polymer.

3. The drug 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.

4. Active substance matrix according to at least one of the preceding claims, wherein the active ingredient is present in a particle size of at most 1000 nm.

5. Active substance matrix according to at least one of the preceding claims, wherein the active ingredient matrix has 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.

6. active ingredient matrix according to at least one of the preceding claims, wherein the active ingredient is contained in a proportion of at least 1 to 1000 and at most 1 to 1 in the mass ratio to the carrier.

7. Active substance matrix according to at least one of the preceding claims, wherein said at least one emulsifier having a structural motif of the following formula

R ¹ -O- [CH ₂ -CH ₂ -O] "- R ² wherein R ¹ and R ^{2 are} independently hydrogen, alkyl, glyceride or polyalkylene oxide and n is an integer of at least 4 and wherein the mass ratio of active ingredient to Emulsifier at least 1 to 30 and at most 1 to 1.

8. Active substance 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.

9. Active substance 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.

10. Active substance matrix according to at least one of the preceding claims, wherein the antioxidant is a radical scavenger.

11. Dosage form for oral administration comprising a drug matrix according to at least one of the preceding claims in a proportion of at least 40 wt .-%.

12. A method for producing a drug matrix according to at least one of claims 1 to 9 with 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.