AU2013283474A1 - Pharmaceutical form for extended release of active substances - Google Patents

Pharmaceutical form for extended release of active substances Download PDF

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Publication number
AU2013283474A1
AU2013283474A1 AU2013283474A AU2013283474A AU2013283474A1 AU 2013283474 A1 AU2013283474 A1 AU 2013283474A1 AU 2013283474 A AU2013283474 A AU 2013283474A AU 2013283474 A AU2013283474 A AU 2013283474A AU 2013283474 A1 AU2013283474 A1 AU 2013283474A1
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Australia
Prior art keywords
active substance
pharmaceutical form
compartment
emulsifier
form according
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AU2013283474A
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AU2013283474B2 (en
Inventor
Gernot Francas
Karl-Heinz PRZYKLENK
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Hennig Arzneimittel GmbH and Co KG
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Hennig Arzneimittel GmbH and Co KG
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0002—Galenical forms characterised by the drug release technique; Application systems commanded by energy
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146—Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2013—Organic compounds, e.g. phospholipids, fats
    • A61K9/2018—Sugars, or sugar alcohols, e.g. lactose, mannitol; Derivatives thereof, e.g. polysorbates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2031—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer

Abstract

A pharmaceutical form is described, which makes it possible to uniformly release an active substance over an extended period of time. The pharmaceutical form comprises an emulsifier with a polyalkylene oxide structural motif. The pharmaceutical form is suitable for releasing a second active substance alongside the first active substance. A uniform release is achieved even if the two active substances have completely different properties in terms of solubility. A production method for the pharmaceutical form and the use thereof are also described.

Description

1 Pharmaceutical form for extended release of active substances This invention relates to pharmaceutical forms for extended release of active substances, in particular of active substances with bad solubility at high pH values. A special embodiment relates to such a pharmaceutical form which does not only release a first active substance with 5 bad solubility at high pH values in an extended manner, but does also release a second active substance in a retarded manner, in particular a second active substance with a better solubility at high pH values than the first active substance. For this purpose embodiments of this invention comprise several compartments which may contain one active substance each. Such a pharmaceutical form according to the present invention may for example have the design of a 10 layer tablet. A lot of pharmaceutically active substances are organic bases, i.e. they comprise functional groups with a pKB value of lower than 7, in particular lower than 5. Such active substances show bad solubility in the milieu of the intestine. The reason for that is that the intestine is characterized by an alkaline pH value. Thus, there the organic bases are not protonated and so 15 they are not charged. Then these molecules show bad solubility. But the intestine, in particular the small intestine, is the place at which typically the resorption of the active substances takes place and should take place. So that an active substance can be resorbed, it has to be dissolved before. When it does not dissolve, then it is not released from its pharmaceutical form. 20 For the above mentioned organic bases it is true that they typically show better solubility in acidic milieu. The reason for that is that the basic group in the respective molecule is protonated in the acidic milieu so that the organic base is positively charged. Such an acidic milieu can typically be found in the fasting human stomach. The above mentioned circumstances of a better solubility in the fasting stomach on the one 25 hand and a worse solubility in the intestine on the other hand result in problems, when pharmaceutical forms are formulated, in particular in the case, when extended release is desired. It has to be considered that the pH value in the human stomach is not always extremely acidic. After the ingestion of a meal the pH value may also reach neutral values, generally values of between about pH 4 and 6. Only with time the pH value becomes lower and lower again. 30 Generally, a pH value of < 2 is reached again only after 90 to 120 minutes. This means that the active substance with the above described properties at first shows bad solubility in the 2 stomach, when it is taken after a meal, and that this bad solubility improves only gradually, when the pH value in the stomach becomes more acidic again. It is particularly difficult to achieve an extended release of such active substances with bad solubility. One idea for solving the mentioned problem is the formulation of pharmaceutical 5 forms with extended release. This is often achieved with a pharmaceutical form having a coating which releases the active substance only slowly, or in that the active substance is dispersed in a matrix which only slowly erodes. But here again the problem arises that the active substance shows bad solubility in the alkaline milieu of the intestine. But for the extended, preferably linear release it is required that the 10 active substance is continuously dissolved. In practice this results in pharmaceutical forms which should release a basic active substance with bad solubility in the intestine in an extended manner, and they are indeed successful in fulfilling this requirement at first (in the stomach), but when the pharmaceutical form reaches the intestine it results in such a bad release that its use in total is not expedient. 15 A further problem arises, when two active substances with different solubility behavior should be released from one pharmaceutical form in the same kind. In the case of better soluble active substances, in particular such ones with permanent charge, the problem arises that these better soluble active substances are allowed only to be released in a retarded manner. So with respect to the first active substance a stimulation of the release has to be achieved, at least in the 20 intestine, and with respect to the second active substance retardation has to be achieved. It is an object of the present invention to provide pharmaceutical forms enabling an extended release of an active substance with bad solubility at high pH values. Certain embodiments in addition solve the object of extendedly releasing an active substance with bad solubility at high pH values and an active substance with higher solubility in an equal manner. "Releasing" in this 25 connection means that the active substance is made available at the site of resorption, thus in the small intestine. The pharmaceutical forms according to the present invention are characterized by a long residence time in the stomach so that they are present in the stomach for such a long time that a significant proportion of the first active substance can be dissolved. The above described objects are solved by the subject matter of the patent claims. 30 The pharmaceutical form of this invention contains at least one first active substance and at least one emulsifier, wherein the emulsifier has a structural motif of the following formula 3
R
1
-O-[CH
2
-CH
2
-O]-R
2 wherein R 1 and R 2 independently from each other are selected from hydrogen, alkyl, glyceride and polyalkylene oxide, and n is an integer of at least 4, wherein the mass ratio of active substance to emulsifier is at least 1 to 30 and at most 1 to 1. 5 The pharmaceutical form according to the present invention may comprise either only one compartment with the first active substance or several compartments which may contain further active substances. In a preferable embodiment the pharmaceutical form comprises at least one first compartment and one second compartment. In exceptionally preferable embodiments the pharmaceutical form according to the present invention consists of the first compartment 10 containing active substance and the second compartment containing active substance. The pharmaceutical form of this invention is preferably a solid oral pharmaceutical form. The design of the pharmaceutical form according to the present invention is preferably such that its mass does not exceed a value of 1750 mg, preferably 1500 mg, further preferably 1400 mg, still further preferably 1200 mg and particularly preferably 1000 mg. According to the conditions of 15 its formulation its mass is preferably at least 700 mg, further preferably at least 800 mg. Here, the mass of the second compartment, if present, is preferably at least 150 mg, further preferably at least 200 mg and in particularly at most 500 mg, preferably at most 400 mg and further preferably at most 350 mg. The pharmaceutical form of this invention may have the design of a monolithic pharmaceutical 20 form, in particular the form of a tablet. A capsule is also possible. Preferable forms are tablets, in particular layer tablets. The pharmaceutical form according to the present invention is preferably a layer tablet comprising at least two layers, wherein the first layer is the above described first compartment and the second layer is the above described second compartment. Furthermore, such a layer tablet may also contain further layers. Exceptionally preferably, the 25 pharmaceutical form according to the present invention is a layer tablet consisting of two layers, wherein one layer is the first compartment and the other layer is the second compartment. The layer tablet may also be a shell-core tablet. In this case one layer is disposed in the core and a further layer forms the shell. In other words, the design of the layer tablet may be such that 30 one layer completely surrounds the other layer. But preferable is an embodiment in which the layers are adjacent, wherein however the one layer does not completely surround the other 4 layer. The one layer does "not completely" surround the other layer, when preferably not more than 70 %, further preferably at most 62 % and exceptionally preferably at most 52 % of the total outer surface of the one layer are covered with the other layer. In particularly preferable embodiments the pharmaceutical form which is described here is a 5 form with long residence time in the stomach. This means that the pharmaceutical form is not so strongly dissolved in the stomach that it can quickly leave the stomach through the pylorus sphincter. Preferably, the pharmaceutical form according to the present invention resides in the stomach of the patient for at least 2 hours, further preferably at least 3 hours, before it enters the intestine. According to the present invention this is achieved by designing the pharmaceutical 10 form such that it is dissolved very slowly. So over a longer period of time the size of it is such that it cannot leave the stomach. The pharmaceutical form preferably at at least one site has a diameter of more than 2 mm, in particularly more than 4 mm and particularly preferably at least 5 mm. So it is guaranteed that the pharmaceutical form cannot leave the stomach through the pylorus sphincter, but still stays 15 in the stomach for a period of time. After the food intake the stomach is not emptied immediately, but it step by step releases the chyme into the small intestine. This physiological fact can be used with the pharmaceutical form according to the present invention. As described above, the first active substance is preferably an active substance with a solubility which is better at a low pH value, thus in an 20 acidic milieu, than in an alkaline milieu. Typically, in the stomach the pH value is low. But after a meal the pH increases to higher values, e.g. about pH 5. Only after a certain time the pH gradually decreases to lower values again. This means that the first active substance after food intake would at first be dissolved worse, because the pH value is too high. But the pharmaceutical form according to the present 25 invention enables the dissolution of a part of the first active substance by the measures which are described here. Through the motion of the stomach the released first active substance is mixed with the chyme and is then gradually released into the small intestine. Then the active substance is resorbed in the proximal small intestine, thus a short time after leaving the stomach. So the stomach serves 30 as a retardation means for the first active substance. At the same time also the second active substance, if present, is dissolved, wherein this second active substance preferably shows a 5 higher solubility than the first active substance. The second active substance preferably has higher solubility, when its solubility is at least one decimal power higher than the solubility of the first active substance. When the pH value in the stomach has reached a lower value, e.g. about pH 3, then the first 5 active substance is dissolved better. Lest the total residual content of the first active substance is released at once, the emulsifier is preferably selected such that it can slow down the release of the first active substance. For that optionally at least one surfactant, at least one triglyceride and/or at least one retarding agent are present for further support. In the second compartment no emulsifier is required, so that preferably no emulsifier is present 10 there. Instead of preferably at least one retarding agent is present there which is suitable for slowing down the release of the second active substance so that here an extended release can be achieved. Since the pharmaceutical form is only dissolved very slowly, it preferably stays in the stomach until it is nearly emptied. Then a great proportion of the chyme has entered the small intestine 15 via the pylorus sphincter. In such a moment the stomach is emptied by means of so-called housekeeper contractions. In this way also bodies which normally do not enter the small intestine via the pylorus sphincter are yet able to get there. Then the pharmaceutical form will further release the active substances in the small intestine. So a nearly linear release of both active substances becomes possible. 20 The first active substance is preferably an active substance with bad solubility in basic milieu. This means in particular that the first active substance in an aqueous solution with a pH value of 7 has a solubility of lower than 0.5 mol/l, in particular lower than 0.1 mol/1 as well as preferably lower than 0.01 mol/l. Unless otherwise stated, the solubility is determined at standard conditions (DIN 1343), and this is also true for all other parameters in this description. 25 This regularly applies to active substances with at least one functional group having a pKB value of at most 5, in particular at most 4, wherein the first active substance of this invention preferably comprises such a functional group. This preferably may be a functional group which is selected from amino groups, guanidine groups and nitrogen-containing heterocyclic groups. Amino groups are particularly preferable. Thus, the first active substance comprises at least one 30 functional group being selected from amino group, guanidine group and nitrogen-containing heterocyclic group. Here according to the present invention the term "amino group" comprises 6 primary, secondary and tertiary amines, including nitrogen atoms in saturated or partially unsaturated cyclic hydrocarbons. It is exceptionally preferable, when the first active substance comprises at least one amino group, further preferably at least two amino groups. Nevertheless according to the present invention not the molecular structure of the first active 5 substance is very important, but rather its solubility behavior. Therefore, also active substances which do not comprise an above mentioned functional group according to the present invention may be first active substances, when in the stomach at an acidic pH value they show good solubility and at an alkaline pH value they show bad solubility. According to the present invention "good soluble" or "good solubility" means that the such 10 characterized substance can be dissolved in the respective milieu and/or solvent in an amount of higher than 0.5 mol/l. "Bad soluble" or "bad solubility" means that the such characterized substance can be dissolved in the respective milieu and/or solvent in an amount of at most 0.5 mol/l, in particular at most 0.1 mol/1 and preferably at most 0.01 mol/l. The first active substance being used according to the present invention has preferably an 15 n-octanol/water distribution coefficient (logPow) at 20'C of higher than 1, preferably higher than 2, more preferably higher than 3 and particularly preferably higher than 4, in particular higher than 5. This distribution coefficient is a measure for the lipophilic property of a substance. As already mentioned above, in particular lipophilic active substances profit from the active substance matrix of this invention. The advantage for such active substances is also 20 particularly great, because normally the resorption of lipophilic active substances functions very well, when these substances are dissolved. In other words, the dissolution of these active substances from a pharmaceutical form is the rate-determining step of the assimilation of the active substance into the body. But there are also active substances, the lipophilic property of which is so strong that the active 25 substance matrix which is proposed here is not sufficient for guaranteeing a sufficient bioavailability. Therefore, the first active substances which are used according to the present invention have n-octanol/water distribution coefficients (logPow) at 20'C of preferably at most 100, further preferably at most 50, in particularly preferably at most 30, particularly preferably at most 15 and in particularly at most 7. 30 For improving the solubility of the first active substance after application it is preferable according to the present invention to use the first active substance in small particle size.
7 Therefore, the first active substance in the pharmaceutical form of this invention has preferably mean particle sizes of at most 1000 nm, further preferably at most 600 nm and particularly preferably at most 300 nm. Preferably according to the present invention the mean particle size is determined by the analysis method of dynamic light scattering. 5 The small particle size is especially important, when the active substance does not or hardly dissolve in the emulsifier. This is often true, when the emulsifier comprises a particularly large hydrophilic proportion, such as a lot of poloxamers, and/or the active substance is especially lipophilic. According to the present invention it is preferable that the active substance can nearly completely, preferably completely, be dissolved in the emulsifier. So an improved 10 release is achieved. This effect can simply be achieved, when the lipophilic proportion of the emulsifier is adjusted to the lipophilic property of the active substance. How this can be achieved can be followed from the explanations about the emulsifier and its molecular structure which can be found below. 15 The pharmaceutical form according to the present invention is particularly well suitable for the administration of active substances which at least comprise one amino group. It is advantageous, when these active substances do not comprise hydroxyl groups and/or carboxyl groups. In any case, such active substances especially profit from the design of the pharmaceutical form according to the present invention. So the first active substance preferably 20 does not comprise any hydroxyl group and/or carboxyl group. In a preferable embodiment the first active substance according to the present invention is selected from the following active substances and their salts: * antihistamines, in particular diphenhydramine, chlorphenoxamine, doxylamine, carbinoxamine, phenyltoloxamine, diphenylpyralin, clemastine, pheniramine, 25 brompheniramine, dexchlorpheniramine, triprolidine, dimetinden, promethazine, mequitazine, oxatomid, meclozine, hydroxyzine, bamipin, cyproheptadine, ketotifen, pizotifen, emedastine, azelastine, ebastine, loratadine, desloratadine, ranitidine, nizatidine, roxatidine acetate, cimetidine; e neuroleptics, in particular promazine, chlorpromazine, triflupromazine, prothipendyl, 30 alimemazine, levomepromazine, thioridazine, periciazine, perazine, trifluoperazine, fluphenazine decanoate, chlorprothixene, haloperidol decanoate, melperone, 8 pipamperone, benperidol, pimozide, fluspirilene, clozapine, olanzapine, zotepine, quetiapine, sulpiride, amisulpiride, risperidone, ziprasidone, aripiprazole; * antidepressants, in particular imipramine, desipramine, clomipramine, trimipramine, lofepramine, amitriptyline, nortriptyline, doxepin, dosulepin, dibenzepin, mianserin, 5 maprotiline, fluoxetine, paroxetine, citalopram, sertraline, fluvoxamine, reboxetine, viloxazine, atomoxetine, venlafaxine, duloxetine, mirtazapine, trazodone, nefazodone, tranylcypromine, moclobemide; * triptans, in particular sumatriptan, zolmitriptan, almotriptan, rizatriptan, naratriptane, eletriptan, frovatriptan; 10 e antiemetics, in particular cinnarizine, betahistine, tropisetron, granisetron, dolasetron, ondansetron, aprepitant; * tranquilizers, in particular chlordiazepoxide, nordazepam, diazepam, prazepam, flurazepam, nitrazepam, clonazepam, flunitrazepam, tetrazepam, bromazepam, clotiazepam, alprazolam, triazolam, midazolam, brotizolam, zopiclon, zaleplon, 15 zolpidem; * agents against Parkinson disease, in particular pergolide, cabergoline, lisuride, ropinirole, pramipexole, selegiline, rasagiline, amantadine, memantine, budipine, benzatropin, bornaprin, metixene; * spasmolytic agents, in particular papaverine, ethaverine, moxaverine; 20 e antidementives, in particular tacrine, donepezil, rivastigmine, nimodipine; * sympatholytic agents, in particular prazosine, terazosine, doxazosine, alfuzosine, bunazosine, tamsulosin, urapidil, dapiprazole, indoramine; * diuretics, in particular hydrochlorothiazide, butizide, trichlormethiazide, polythiazide, bendroflumethiazide, bemetizide, metolazone, clopamid, indapamid, azosemid, 25 amiloride, triamteren, dorzolamide, brinzolamide; * calcium canal blockers, in particular nitrendipine, nisoldipine, nimodipine, isradipine, felodipine, nicardipine, nilvadipine, barnidipine, amlodipine, lacidipine, lercanidipine, verapamil, gallopamil, diltiazem, flunarizine, bencyclan * antiestrogens, in particular clomifene, tamoxifene, toremifene; 30 e antidiabetics, in particular pioglitazone, rosiglitazone. The above mentioned active substances all comprise at least one amino group which is typically protonated in the milieu of the stomach and typically deprotonated in the milieu of the intestine so that the solubility of the active substances is substantially characterized by this functional 9 group. Furthermore, these active substances do not comprise neither hydroxyl nor carboxyl groups. In a particularly preferable embodiment the first active substance is cinnarizine, a salt of cinnarizine and/or a cinnarizine derivative, in particular a pro-drug. It is exceptionally 5 preferable, when the first active substance is cinnarizine. The first active substance is preferably used in an amount of at least 10 mg and further preferably at least 20 mg or especially preferably at least 40 mg in the pharmaceutical form. The amount of the first active substance should preferably not exceed a value of 200 mg, further preferably 100 mg and especially preferably 80 mg. 10 The emulsifier supports the release of the first active substance. This is especially important so that at least a part of the first active substance is dissolved as quick as possible and uniformly already in the stomach. As described above, the pH value in the stomach after the intake of a meal is only lowered slowly. But it is required that the first active substance is already dissolved now in the stomach so that it is mixed with the chyme. The mixing is conducted by 15 the motion of the stomach. The use of an emulsifier according to the present invention in the pharmaceutical forms according to the present invention in particular enables an improvement of the solubility of the first active substance at higher pH values. The emulsifier according to the present invention contributes to the release of the first active substance, ideally already in dissolved form, and subsequently to the possibility of a resorption thereof. 20 So that the improvement of the release is especially distinct, 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. Preferably, the emulsifier is not an ionic one. It has been shown that such emulsifiers having a certain structural motif achieve particularly advantageous results. This structural motif is a polyethylene glycol chain. It was found that 25 emulsifiers with this structural motif are characterized by a double function. On the one hand, at high pH values starting at about pH 4 they result in an improvement of the solubility of the first active substance. On the other hand, at low pH values, namely when the first active substance shows better solubility, they result in retardation of the release. This is a desired behavior according to the present invention, because the release of the first active substance should 30 happen as continuously as possible over a long period of time.
10 The polyethylene glycol chain is the hydrophilic part of the emulsifier and is connected with a lipophilic part. The lipophilic part may advantageously be a glyceride group or another polyalkylene oxide chain. As glyceride groups mono- and diglyceride groups can be used, wherein diglyceride groups are 5 preferable. According to the chain lengths of the used fatty acid groups monoglyceride groups may optionally be not lipophilic enough. As polyalkylene oxide chains in particular polyalkylene oxides with uninterrupted carbon chains of at least 3 carbon atoms may be used. A preferable example of a polyalkylene oxide chain in the emulsifier of this invention is polypropylene oxide. 10 These emulsifiers can be obtained according to methods which are known by a person skilled in the art. Polyethylene glycol glycerides can for example be prepared by reaction of respective glycerides with polyethylene glycol. Commercially available polyethylene glycol glycerides are for example Gelucire* 43/01 and Gelucire* 50/13. In other words: the emulsifiers which are used in the pharmaceutical form according to the 15 present invention comprise the following structural element: R -O-[CH 2
-CH
2 -O],-R2 (formula 1) In this formula R and R2 are the same or different. R and R2 independently from each other are hydrogen, alkyl, glyceride or polyalkylene oxide. Alkyl is preferably a short-chain alkyl, i.e. its chain length amounts to at most 6 carbon atoms. Preferably, R and R2 independently from 20 each other are hydrogen, glyceride or polyalkylene oxide. When one group R or R 2 is hydrogen, then the groups R and R2 are different, i.e. the respective other group is not hydrogen; and when R or R2 is alkyl, then the groups R and R2 are different, i.e. the respective other group is not alkyl. Otherwise, the molecule would not have the required emulsifying effect. Preferably, R and R2 are neither hydrogen nor alkyl, 25 when the respective other group is hydrogen or alkyl. n is the number of the chain members in the polyethylene oxide chain. Preferably, n is an integer of at least 4, further preferably at least 10 and particularly preferably at least 20. When n is lower, then the desired effect according to the present invention is not very strong, because the lipophilic part of the emulsifier is too small. In preferable embodiments n is not higher than 30 100, in particular not higher than 50, further preferably not higher than 40 or not higher than 30.
11 It has been shown that longer chains result in slower degradation of the emulsifier by pancreatin and lipases. With that the extended release can be controlled. But when the chain is too long, then the pharmaceutical form does not release the first active substance fast enough. When R and/or R2 are a polyalkylene oxide group, then the residue has the following general 5 formula: -0-[Y-O]m-R 3 (formula II) In this formula R3 is hydrogen or alkyl, in particular short-chain alkyl (up to C 6 ). Y is an alkylene group having a carbon chain length of at least C 3 and preferably at most C 6 , further preferably at most C 4 . 10 m is the number of the chain members 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. Preferably, m should not exceed an integer of 50, in particular 40 and particularly preferably 30 or 20. In preferable embodiments R and R2 are polyalkylene oxide groups. When R and/or R2 are glyceride groups, then the glyceride group has the following general 15 formula: R 5 R 0 R (formula III) Here formula III at one of the positions R 4, R or R is connected with the structural element of 20 formula I. According to the present invention it is irrelevant at which position the structure of formula III is connected with the structure of formula I. So one of the groups R 4, R or R is the structure of formula I. For the remaining two groups the following is true:
R
4 is preferably hydrogen or a fatty acid group. The fatty acid group R 4 has a chain length of preferably at least C 6 , further preferably at least Cs and particularly preferably at least C 10 . A 25 minimum chain length should be satisfied, so that the lipophilic property of the glyceride group is sufficient. The number of the carbon atoms in the fatty acids is preferably even. Preferably, the chain length should not exceed a value of C 22 , further preferably C 18 and particularly preferably C 16 , because otherwise the solubility of the emulsifier may be compromised.
12
R
5 is preferably hydrogen or a fatty acid group. The fatty acid group R 5 has a chain length of preferably at least C 6 , further preferably at least C 8 and particularly preferably at least Cio. A minimum chain length should be satisfied, so that the lipophilic property of the glyceride group is sufficient. The number of the carbon atoms in the fatty acids is preferably even. Preferably, 5 the chain length should not exceed a value of C 22 , further preferably C 18 and particularly preferably C 16 , because otherwise the solubility of the emulsifier may be compromised. R is preferably hydrogen or a fatty acid group. The fatty acid group R has a chain length of preferably at least C 6 , further preferably at least C 8 and particularly preferably at least Cio. A minimum chain length should be satisfied, so that the lipophilic property of the glyceride group 10 is sufficient. The number of the carbon atoms in the fatty acids is preferably even. Preferably, the chain length should not exceed a value of C 22 , further preferably C 18 and particularly preferably C 16 , because otherwise the solubility of the emulsifier may be compromised. 4 5 6 Preferably, two of the groups R4, R and R are fatty acid groups. So then it is a diglyceride group. 15 It has to be considered that the correct chain length of the fatty acid groups strongly corresponds with the number of the chain members in the polyethylene oxide chain (n). When the polyethylene oxide chain is longer, then also the fatty acid chains may be longer. The emulsifiers described here can be produced by reaction of respective mono-, di- and/or triglycerides with respective polyalkylene oxides. These educts are commercially available. The 20 emulsifiers according to the present invention are preferably mixtures of the mentioned substances. In preferable embodiments the emulsifier is selected from Gelucire* 50/13, Gelucire* 43/01, Poloxamer 407 and mixtures thereof. Good solubilization is achieved, when the ratio of the masses of active substance to emulsifiers 25 is at least 1 to 30, further preferably at least 1 to 20 and particularly preferably at least 1 to 10 and still further preferably at least 1 to 8. The mentioned ratio is at most 1 to 1, preferably lower than 1 to 1, further preferably at most 1 to 2, still further preferably at most 1 to 3 and still further preferably at most 1 to 4 and particularly preferably at most 1 to 6. Basically it is true, that a higher amount of emulsifier enables better solubilization. But it has to be considered that 30 a pharmaceutical form should not exceed a certain maximum volume, so that the intake thereof is not unnecessarily unpleasant. In addition, a too high amount of an emulsifier may also result 13 in hindrance of the release of the first active substance. It has been shown that a mass ratio of active substance to emulsifier of at least 1 to 10 and at most 1 to 2 is particularly suitable, wherein a mass ratio of at least 1 to 8 and at most 1 to 2 is an ideal one. When these mass ratios were fulfilled, then this resulted in a particularly advantageous release acceleration together 5 with an especially favorable size of the pharmaceutical form. The pharmaceutical form or the first compartment contains the emulsifier preferably in a proportion of at least 7 % by weight, preferably at least 10 % by weight, further 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 % by weight, further preferably 40 10 % by weight and particularly preferably 32 % by weight. In tests for determining the optimum ratio of solubilization and volume of the pharmaceutical form it has been shown that these amounts are advantageous. In particularly preferable embodiments instead of the above mentioned substances or in addition to the above mentioned substances at least one phospholipid is used. The phospholipid 15 is preferably selected from phosphatidylcholines (lecithins), phosphatidylethanolamines (kephalins), phosphatidylserines, sphingomyelins and mixtures thereof. Especially preferable are phosphatidylcholines (lecithins). It has surprisingly been found that phospholipids also result in the above described advantageous effects, like the above mentioned emulsifiers. Thus, the emulsifier may be a phospholipid. Preferably, the emulsifier comprises the 20 phospholipid in addition to at least one of the above mentioned substances. In such a case the phospholipid strengthens the advantageous effects of the above mentioned substances. In preferable embodiments the pharmaceutical form in addition contains at least one surfactant. The purpose of the surfactant is the strengthening of the solubilization imparted by the emulsifier. Namely, when a mixture of emulsifier and surfactant is used, then the effect of these 25 substances is a synergistic one. So the total mass of emulsifier and surfactant in relation to the active substance can be reduced. As mentioned above, for optimum solubilization it may be necessary to choose a very high amount of emulsifier in relation to the active substance. This high amount can be reduced by the use of a surfactant. Preferable surfactants are ionic surfactants, in particular anionic surfactants. Metal soaps have 30 shown to be particularly advantageous. Metal soaps preferably means substances comprising as anionic component an organic acid and as cationic component a metal cation. The metal cation 14 is preferably selected from alkali and alkaline earth metal ions. Especially preferable are alkali metal ions and in particular sodium and potassium. Under the alkaline earth metal ions magnesium and calcium are especially preferable. Preferable organic acids which can be used as anionic component in the surfactants are acids 5 with at least 6 carbon atoms. It has been shown that organic acids with shorter carbon chain lengths have lower efficacy. But the organic acids should preferably not exceed chain lengths of 22 carbon atoms. In the case of longer carbon chains the synergistic effect in connection with the emulsifier is not very strong. It is particularly preferable, when the organic acids in the surfactants have chain lengths of at least 10 and at most 18, further preferably at least 12 and at 10 most 16 carbon atoms. The organic acids may comprise branched or unbranched carbon chains, but preferably the carbon chains are unbranched. A particularly preferable surfactant is sodium myristate. A further purpose of the surfactants according to the present invention is the slowing of the stomach-intestine passage of the chyme and thus the resorption of the first active substance. It 15 has interestingly been found that this can be achieved especially with the metal soaps described here and that they can have a direct effect onto the control of the gastrointestinal passage, with the result that in total a higher amount of the first active substance can be resorbed. The proportion of the surfactant in the pharmaceutical form according to the present invention should preferably be at least 2 % by weight, preferably at least 7 % by weight, further 20 preferably at least 12 % by weight and particularly preferably at least 17 % by weight. It has been shown that so the effects of the surfactant are especially more distinct. But an amount of preferably 35 % by weight, further preferably 25 % by weight and particularly preferably 20 % by weight should not be exceeded. Because otherwise the release of the first active substance would be hindered too much. The absolute mass of the surfactant in the pharmaceutical form 25 should not exceed a value of 300 mg, further preferably 250 mg and particularly preferably 200 mg. The minimum amount of the surfactant should preferably not fall below a value of 10 mg, further preferably 50 mg and particularly preferably 100 mg. The content of the surfactant as a mass ratio to the first active substance should not fall below a proportion of 1 to 1, further preferably 1.5 to 1 and particularly preferably 2 to 1. Preferably, 30 this ratio should not exceed a value of 5 to 1, further preferably 4 to 1 and in particular 3 to 1.
15 When these values are fulfilled, then the above described advantageous effect can be optimally used. In a preferable embodiment the pharmaceutical form of this invention comprises at least one triglyceride. The purpose of the triglyceride is the slowing of the stomach-intestine passage of 5 the pharmaceutical form. The triglyceride can also be used in combination with the surfactant for additionally slowing down the release of the first active substance. The triglyceride preferably comprises a fatty acid group with at least 10 carbon atoms, further preferably at least 12 carbon atoms and particularly preferably at least 16 carbon atoms. This minimum length of the chain is desired, because so the extension of the residence time of the 10 pharmaceutical form in the stomach is especially distinct and the release of the first active substance can be supported in a particularly efficient manner. But the chain length should preferably not exceed a value of 22 carbon atoms, further preferably 20 carbon atoms. In particularly preferable embodiments at least two and exceptionally preferably all fatty acid groups in the triglyceride fulfill these prerequisites. 15 The triglyceride may preferably be used in the pharmaceutical form according to the present invention in a proportion of higher than 5 % by weight, preferably at least 7 % by weight, further preferably at least 10 % by weight, still further preferably at least 15 % by weight and particularly preferably at least 20 % by weight. But a maximum proportion of preferably 40 % by weight, further preferably 30 % by weight and particularly preferably 25 % by weight should 20 not be exceeded, because otherwise the release of the first active substance would be restricted too much. The absolute mass of the triglyceride in the pharmaceutical form should not exceed a value of 500 mg, further preferably 400 mg and particularly preferably 300 mg. The minimum amount of the triglyceride should preferably not fall below a value of 50 mg, further preferably 25 100 mg and particularly preferably 150 mg. The content of the triglyceride as a mass ratio to the first active substance is preferably higher than 1 to 1. The content of the triglyceride as a mass ratio to the first active substance should further preferably not fall below a proportion of 2 to 1, still further preferably 3 to 1 and particularly preferably 3.5 to 1. Preferably, this ratio should not exceed a value of 20 to 1, 30 further preferably 10 to 1, still further preferably 7 to 1 and in particular 6 to 1. When these values are fulfilled, then the above mentioned advantageous effect can be optimally used.
16 The first compartment may comprise a compression aid. The compression aid is preferably selected from lactose and corn starch. Further preferably, the compression aid is corn starch. In another embodiment lactose is used as a compression aid. The purpose of the compression aid is inter alia the increase of the melting point of a mixture of active substance and emulsifier 5 during the production so that a further processing of this mixture is possible. The proportion of this compression aid in the pharmaceutical form or, when the pharmaceutical form comprises several compartments, in the first compartment should preferably be at least 10 % by weight, further preferably at least 20 % by weight and particularly preferably at least 30 % by weight. When the amount of the compression aid used is too low, then the desired effect 10 cannot be achieved. An amount of the compression aid which is too high increases the size of the pharmaceutical form and is thus not desired. Therefore the proportion of the compression aid in the pharmaceutical form or, when the pharmaceutical form comprises several compartments, in the first compartment should not exceed a value of 65 % by weight, preferably 60 % by weight, further preferably 50 % by weight and particularly preferably 40 % 15 by weight. The pharmaceutical form of this invention may also contain a retarding agent. The retarding agent is preferably selected from polymeric organic substances, in particular such ones which are swellable. Preferable retarding agents are acrylate polymers, methacrylate polymers and their copolymers as well as mixtures thereof. Other preferable retarding agents are celluloses, in 20 particular highly viscous celluloses. The retarding agent of the pharmaceutical form of this invention is preferably a polymer, in particular a polysaccharide. Preferred are cellulose, cellulose derivatives, alginates and mixtures thereof as well as their hydrates, but also polyacrylates, polymethylacrylates and their copolymers and mixtures can be used. Especially preferable cellulose derivatives are methylcellulose and hydroxypropylmethylcellulose. 25 Preferably a retarding agent is used which in an aqueous solution in a proportion of 2 % by weight at a temperature of 20'C and a pressure of 101.325 kPa results in a viscosity of at least 1500 mPas. The viscosity is measured with a falling sphere viscosimeter (DIN 53015). According to the desired extension of the release of the first active substance is may be desired, also to choose higher viscosities. The higher the viscosity of the retarding agent, the higher is 30 the extension of the release. In especially preferable embodiments the viscosity of the retarding agent is even at least 2500 mPas and particularly preferably at least 3500 mPas. But when the viscosity is too high, then the release of the first active substance is too slow. This would have 17 the result that the first active substance during its passage through the gastrointestinal tract may possibly not be completely released. Therefore, the viscosity should be restricted to a value of at most 200.000 mPas, further preferably at most 120.000 mPas. The proportion of this retarding agent in the pharmaceutical form or, when the pharmaceutical 5 form comprises several compartments, in the first compartment should preferably be at least 10 % by weight, further preferably at least 20 % by weight and particularly preferably at least 30 % by weight. When the amount of the retarding agent used is too low, then the desired effect is not achieved. When the amounts are too high, then the release of the first active substance is too slow. Therefore, the proportion of the retarding agent in the pharmaceutical form or, when the 10 pharmaceutical form comprises several compartments, in the first compartment should not exceed a value of 60 % by weight, further preferably 50 % by weight and particularly preferably 40 % by weight. The content of the retarding agent as the mass ratio to the first active substance should preferably be at least 3 to 1, further preferably at least 5 to 1 and particularly preferably at least 7 to 1. But this ratio should not exceed a value of 20 to 1, further 15 preferably 15 to 1 and particularly preferably 10 to 1. Furthermore, to the first and/or the second compartment a fatty alcohol can be added. In this case the fatty alcohol is preferably an alcohol with a chain length of at least 10 carbon atoms, further preferably at least 12 carbon atoms and particularly preferably at least 14 carbon atoms. But the chain length should preferably not exceed a value of 20 carbon atoms, further 20 preferably 18 carbon atoms and in particular 16 carbon atoms. It has been shown that the addition of a fatty alcohol is suitable for retarding the release of the active substances, in particular the second active substance. The weight proportion of the fatty alcohol in the pharmaceutical form or the first compartment (when the pharmaceutical form comprises several compartments) is preferably at least 5 % by 25 weight, further preferably at least 10 % by weight and particularly preferably at least 18 % by weight. When the proportion of the fatty alcohol in the pharmaceutical form or the first compartment (when the pharmaceutical form comprises several compartments) is too low, then the effect according to the present invention may be compromised. In the case of a content which is too high, the structural identity of the pharmaceutical form may be compromised. 30 Therefore, the content of the fatty alcohol in the pharmaceutical form or the first compartment (when the pharmaceutical form comprises several compartments) is preferably at most 40 % by 18 weight, further preferably at most 35 % by weight and particularly preferably at most 30 % by weight. The pharmaceutical form of this invention may comprise further pharmaceutical adjuvants. These adjuvants may preferably be selected from anti-blocking agents, lubricants, binders, 5 disintegrants, antioxidants, complex-forming agents, coating agents, flow promoters, preservatives, fillers, plasticizers, pigments and mixtures of such substances. A preferred adjuvant in the pharmaceutical form is a pharmaceutically acceptable carrier. Preferred carriers are polysaccharides, in particular cellulose and/or lactose. The carrier results in sufficient stability of the pharmaceutical form. Because, the pharmaceutical form contains a 10 high proportion of emulsifier. The emulsifier supports the structural integrity of the pharmaceutical form only in a very limited extent. Preferably, the pharmaceutical form contains the carrier in a weight proportion of at least 10 % by weight, further preferably at least 20 % by weight and particularly preferably at least 30 % by weight. In summary, the pharmaceutical form or the first compartment, when the pharmaceutical form 15 comprises several compartments, may inter alia contain: a. a first active substance, b. an emulsifier for improving the solubility of the first active substance at high pH values and for slowing down the dissolution of the first active substance at low pH values; c. optionally a surfactant for improving the solubility of the first active substance and for 20 slowing down the transport of the first active substance from the stomach into the intestine; d. optionally a triglyceride, also for improving the solubility of the first active substance and for slowing down the transport of the first active substance from the stomach into the intestine; 25 e. optionally a retarding agent for slowing down the dissolution of the first active substance at low pH values; f. optionally a compression aid for supporting the processing of a mixture of the first active substance and the emulsifier during the production; g. optionally a fatty alcohol for slowing down the dissolution of the first active substance 30 at low pH values; h. optionally further adjuvants.
19 In a preferable embodiment of this invention the pharmaceutical form comprises at least two compartments which preferably contain different active substances. In this case the first compartment comprises the above mentioned substances, namely the first active substance and the emulsifier and also optionally the surfactant, triglyceride, retarding agent, compression aid, 5 fatty alcohol and optionally further adjuvants. It is exceptionally preferable, when the pharmaceutical form consists of two compartments containing active substances, wherein these active substances are different active substances and wherein the first compartment comprises the above mentioned substances. According to the present invention "different active substances" means that the active substances of the compartments are different, thus one and 10 the same active substance is not contained in different compartments. The first compartment at least comprises the first active substance, the second compartment at least comprises one second active substance. Besides the first and second active substances in the pharmaceutical form also further active substances may be contained. Thus, besides the first and/or second active substances the first and at least the second compartment may contain 15 further active substances. However, exceptionally preferably the active substance proportion of the pharmaceutical form consists of the first and the second active substances. The weight proportion of the first compartment in the pharmaceutical form according to the present invention is preferably 45 to 100 % by weight, further preferably 55 to 87.5 % by weight. The reason for that is that the first compartment is not only responsible for the extended 20 release, but also for the solubilization of the first active substance which normally can be formulated only with difficulties. A second compartment of the pharmaceutical form comprises at least the second active substance. The second active substance is preferably an active substance with higher water solubility than the first active substance which thus dissolves better in the stomach and also in 25 the intestine than the first active substance. So the second active substance preferably has a higher solubility than the first active substance, at least in an extent of one decimal power, in particular at pH 7. The second compartment may in particular contain: a. a second active substance, 30 b. optionally a retarding agent for slowing down the release of the second active substance, 20 c. optionally a long-chain alcohol for slowing down the release of the second active substance, d. optionally a surfactant as described above for slowing down the transport of the active substance from the stomach into the intestine; 5 e. optionally a triglyceride as described above for slowing down the transport of the active substance from the stomach into the intestine; f. optionally further adjuvants. In prior art no satisfying pharmaceutical form is proposed which enables in one pharmaceutical form a retarded release of an active substance with bad solubility (here: first active substance) 10 and also of a second active substance each, in particular when the second active substance shows higher solubility than the first active substance. Because the release of the active substance with bad solubility has to be supported and in the case of a second active substance with better solubility at the same time the release of the second active substance has to be suppressed. This invention provides a solution for this problem by providing a pharmaceutical 15 form according to the present invention which preferably comprises two compartments, wherein the first compartment contains the first active substance and the second compartment contains the second active substance. In the context of the pharmaceutical form described here it is a challenge to retard the release of the second active substance. One reason for that is that for the solubilization of the first active 20 substance a relatively high amount of emulsifier is necessary. This results in the fact that due to the necessary solubility-enhancing measure with respect to the first active substance the volume of the pharmaceutical form is already nearly completely exhausted. So the release-retarding measure with respect to the second active substance must be possible in a minimum volume. Thus, a simple coating of the whole pharmaceutical form is not preferred, because this coating 25 would suppress the release of both active substances. So according to the present invention it is preferable, that the pharmaceutical form comprises two compartments, wherein the first compartment at least comprises the first active substance and at least one emulsifier. The second compartment comprises the second active substance. So that the second active substance is extendedly released, the second compartment preferably contains a retarding agent. 30 In a preferred embodiment of this invention the pharmaceutical form comprises at least two compartments in the form of layers. Here preferably one of the layers is the first compartment 21 and another one of the layers is the second compartment. The pharmaceutical form may also comprise further layers, in particular a third layer. In an embodiment of this invention the pharmaceutical form of this invention comprises a shell and a core. In this case the core may be a compartment of this invention, in particular the first 5 compartment. The shell may be another compartment, in particular the second compartment. In this case the shell preferably completely surrounds the core. In other words, the core is completely embedded within the shell. Basically each active substance can profit from the presentation form of the pharmaceutical form according to the present invention which should be administered over a longer period of 10 time in an extended manner. Examples of such active substances and classes of active substances which can advantageously be used as a second active substance in the context of the present invention are: Pharmaceutical products for the treatment of pain and for pain therapy with peripherally acting analgesics, centrally acting analgesics and adjuvant non-analgesics. Preferably, those concerned 15 here are the following analgesics and adjuvant substances: 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, 20 amitriptyline, 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, dexamethasone, methylprednisolone, prednisolone, triamcinolone, diazepam, tetrazepam, tizanidine, 25 butylscopolamine and/or combination of tilidine and naloxone. Drugs for the treatment of the nervous system, alone or in combination, e.g. seizure disorders (in particular clonazepam, diazepam, lorazepam, midazolam, clobazam, phenytoin, clomethiazole, valproic acid, phenobarbital, gabapentin, lamotrigine, oxcarbazepine, pregabalin, topiramate, ethosuximide, levetracetam, mesuximide, primidone, nitrazepam and/or 30 vigabitrine), Parkinson syndrome (in particular levodopa, with benserazide/carbidopa, bromocriptine, cabergoline, dihydroergocriptine, lisuride, pergolide mesylate, pramipexole, 22 ropinirole, apomorphine, biperidene, metixene hydrochloride, trihexphenidyl, entacapone, amantadine, budidine, selegiline and/or apomorphine), stroke (in particular acetylsalicylic acid, clopidogrel, dipyridamole, ticlopidine, heparin, phenprocoumon, warfarin, protamine, phytomenadione, nimodipine, paracetamol, tramadol and/or buprenorphine), intracranial 5 pressure (in particular furosemide and/or mannitol), tremor (in particular propranolol, clozapine, alprazolam and/or primidone). Drugs for the treatment of psychiatric diseases such as anxiety disorders (in particular alprazolam, diazepam, fluoxetine, paroxetine, chlorprothixene, levomepromazine, thioridazine, flupentixol and/or fluspirilene), depressions (in particular imipramine, amitriptyline, 10 desipramine, maprotiline, minaserine, citalopram, fluoxetine, paroxetine, trazodone, moclobemide and/or miratazepam), psychoses and schizophrenias (in particular sulpiride, promazine, melperone, thioridazine, chlorprothixene, perazine, pimozide, fluphenazine, olanzapine and/or risperidone), sleep disorders (in particular triazolam, brotizolam, oxazepam, flurazepam, nitrazepam, temazepam, zolpidem tartrate, zopiclon, promethazine, 15 chlorprothixene, pipamperone, thioridazine and/or chloral hydrate), conditions of restlessness and disorientation/confusion (in particular alprazolam, oxazepam, doxepin, clomipramine, imipramine, thioridazine and/or perazine), dementia of the Alzheimer type (in particular donepezil, rivastigmine, tacrine, memantine, nimodipine and/or seleginine). Drugs for the treatment of cardiovascular diseases, such as coronary heart disease/angina 20 pectoris (in particular acetylsalicylic acid, clopidogrel, ticlopidine, isosorbide dinitrate, isosorbide mononitrate, nitroglycerin, molsidomine, trapidil, metoprolol, bisoprolol, atenolol, acebutolol, carvedilol, nitrendipine, nifedipine, diltiazem, verapamil, benazepril, lisinopril, ramipril, fosinopril and/or enalapril), cardiac infarction and cardiac insufficiency (in particular isosorbide mono- and dinitrate, clopidogrel, ticlopidine, captoprol, ramipril, lisinopril, 25 candesartan, eprosartan, irbesatan, losartan, chlortalidone, xipamide, hydrochlorothiazide, furosemide, piretanide, triameterene, digitalis glycosides, carvedilol, metoprolol and/or prazosine), cardiac arrhythmia (in particular ajmaline, quinidine, disopyramide, flecainide, propafenone, propranolol, carvedilol, amiodarone, verapamil and/or diltiazem), hypertension (in particular metoprolol, atenolol, urapidil, clonidine, dihydralazine, chlortalidone, 30 hydrochlorothiazide, furosemide, felodipine, israpidine, lacidipine, diltiazem, captopril, enalapril, fosinopril, lisinopril, ramnipril, verapamil, candesartan, eprosartan, irbesatan, losartan, doxazosine, bunazosine, prazosine, terazosine, moxonidine, dihydralazine and/or minoxidil).
23 Drugs, alone or in combination, for the treatment of the respiratory tract and the lung (in particular theophylline, methylprednisolone, flucortone, dexamethasone, montekulast, roxithromycin, erythromycin, azithromycin, ciprofloxacin, clarithromycin, levofloxacin, ofloxacin, doxycycline, ampicillin and sulbactam, amoxicillin, cefuroxime, clindamycin, 5 cefotiam, cefuroxime, ceftazidime, ceftriaxone, piperacillin and/or moxifloxacin). Drugs for the treatment of the gastrointestinal tract and the pancreas (in particular fluconazole, mesalazine, sulfasalazine, budenoside, azathioprine, prednisone, metronidazole, infliximab, loperamide, cotrimoxazole, ciprofloxacin, metronidazole, vancomycin, esomeprazole, lansoprazole, pantoprazole, rabeprazole, cimetidine, famotidine, ranitidine, nizatidine, 10 sucralfate, misoprostol, metoclopramide, pirenzepine, bisacodyl, domperidone, sulpiride, alizapride, dimenhydrinate, cinnarizine, flunarizine, levomeprazine, ondansetron, betahistine and/or aprepitant). Drugs for infection defense with antibiotics or antivirally active substances (in particular acyclovir, amantadine, azithromycin, bacampicillin, cefaclor, cefazoline, cefixime, cefprozil, 15 ceftriaxone, chloroquine, ciprofloxacin, clotrimazole, dicloxacillin, doxycyclline, econazole, erythromycin, ethambutol, fosfomycin, flucloxacillin, fluconazole, fusidic acid, gramicidin, idoxuridine, indinavir, interferon, itraconazole, isoniazide, josamycin, ketoconazole, lamivudine, lomefloxacin, mafenide, mebendazole, mesalazine, mezlozillin, mupirocine, miconazole, naftifine, nalidixic acid, norfloxacin, ofloxacin, oxacillin, oxytetracycline, 20 piperacillin, praziquantel, primaquim, proguanil, ribavirine, rifabutine, rimantadine, roxothromycin, saquinavir, spectinomycin, spriramycin, stavudine, sulbactam, teiucoplanin, terbinafin, tetracycline, tetroxoprim, ticarcillin, tinidazole, tromantadine, tolnaftate, vancomycin, zidovudine and/or zalcitabine). Drugs for the treatment of erectile dysfunction (in particular sildenafil, tadalafil, vardenafil, 25 theobromine, caffeine and/or theophylline). In preferable embodiments the pharmaceutical form according to the present invention does not comprise antibiotics in pharmaceutically active amounts, in particular no representative of the class of active substances of tetracyclines. Antibiotics compromise the flora of the intestine by killing important bacteria in the intestine. In the case of the pharmaceutical form of this 30 invention this effect would result in strong adverse effects, since partially the pharmaceutical form is dissolved only very late.
24 In preferable embodiments the pharmaceutical form according to the present invention does not comprise proton pump inhibitors. Proton pump inhibitors increase the pH value in the stomach and thus disturb the dissolution of many drugs from the first unit containing active substance, in particular the weakly basic active substances. 5 Preferably, the second active substance is contained in the second compartment in the form of small particles. This means that the mean particle size of the second active substance preferably does not exceed 1000 nm. Further preferably, the mean particle size of the second active substance is not higher than 300 nm. The particle size of the active substance will be determined by means of laser diffraction. 10 The second active substance may be an active substance with good water-solubility. The second active substance is in particular an active substance which comprises at least one hydroxyl group, at least one carboxyl group and/or at least one permanent charge. A preferable active substance is dimenhydrinate. The second active substance is preferably used in the pharmaceutical form in an amount of at 15 least 50 mg and further preferably at least 80 mg or particularly preferably at least 100 mg. The amount of the second active substance should preferably not exceed a value of 400 mg, further preferably 300 mg and particularly preferably 200 mg. The retarding agent in the second compartment of the pharmaceutical form of this invention is preferably a polymer, in particular a polysaccharide. Preferred are celluloses, cellulose 20 derivatives, alginates or mixtures thereof, but also polyacrylates, polymethacrylates and their copolymers and mixtures can be used. Especially preferable cellulose derivatives are methylcellulose and hydroxypropylmethylcellulose. Such cellulose derivatives enable a particularly preferable release of the second active substance and do not show an unfavourable pH dependent behavior. 25 Preferably a retarding agent is used which in aqueous solution in a proportion of 2 % by weight at a temperature of 20'C and a pressure of 101.325 kPa results in a viscosity of at least 1500 mPas. The viscosity is measured with a falling sphere viscosimeter (DIN 53015). According to the desired retardation of the release of the second active substance it may be desired, also to choose higher viscosities. The higher the viscosity of the retarding agent, the stronger is the 30 retardation of the release. In especially preferable embodiments the viscosity of the retarding agent is even at least 2500 mPas and particularly preferably at least 3500 mPas. But when the 25 viscosity is too high, then the release of the second active substance is too slow. This would have the result that the second active substance during its passage through the gastrointestinal tract may possibly not be completely released. Therefore, the viscosity should be restricted to a value of at most 200.000 mPas, further preferably at most 120.000 mPas. 5 The proportion of this retarding agent in the second compartment should preferably be at least 10 % by weight, further preferably at least 20 % by weight and particularly preferably at least 30 % by weight. When the amount of the retarding agent used is too low, then the effect according to the present invention is not achieved. When the amount is too high, then the release of the second active substance is too slow. Therefore, the proportion of the retarding 10 agent in the second compartment should not exceed a value of 60 % by weight, further preferably 50 % by weight and particularly preferably 40 % by weight. Furthermore, to the first and/or the second compartment a long-chain alcohol can be added. Here "long-chain" alcohol means an alcohol with a chain length of at least 10 carbon atoms, further preferably at least 12 carbon atoms and particularly preferably at least 14 carbon atoms. 15 But the chain length should preferably not exceed a value of 20 carbon atoms, further preferably 18 and in particularly 16 carbon atoms. It has been shown that the addition of a long chain alcohol is suitable for retarding the release of the active substances, in particular of the second active substance. The weight proportion of the long-chain alcohol in the second compartment of the invention is 20 preferably at least 5 % by weight, further preferably at least 10 % by weight and particularly preferably at least 18 % by weight. When the proportion of the long-chain alcohol in the second compartment is too low, then the desired effect is not achieved. When the content is too high, then the structural integrity of the pharmaceutical form may be compromised. Therefore, the content of the long-chain alcohol in the second compartment is preferably at most 40 % by 25 weight, further preferably at most 35 % by weight and particularly preferably at most 30 % by weight. Furthermore, the second compartment in the pharmaceutical form according to the present invention may contain further adjuvants. These adjuvants may preferably be selected from anti blocking agents, lubricants, binders, disintegrants, antioxidants, complex-forming agents, 30 coating agents, flow promoters, preservatives, fillers, plasticizers, pigments and mixtures of such substances.
26 An especially preferable embodiment of the pharmaceutical form according to the present invention comprises as the first active substance cinnarizine, wherein it is exceptionally preferable that the first active substance is cinnarizine and the second active substance is dimenhydrinate. The pharmaceutical form is suitable for use in therapy of dizziness of any 5 origin. Therefore, also the use of this pharmaceutical form for the treatment of dizziness of any origin is according to the present invention. A great advantage of the pharmaceutical form according to the present invention is that it can be produced in a cost-effective way. Preferably, the method for the production of the pharmaceutical form comprises the steps: 10 a. mixing the constituents of the pharmaceutical form, b. granulating the mixture and c. preparing a monolithic pharmaceutical form from the granules. The mixing of the constituents of the pharmaceutical form is conducted in embodiments in which the pharmaceutical form comprises at least two compartments, preferably by mixing the 15 constituents of each single compartment so that at least two compartment mixtures are obtained. The granulation of the mixture comprises in embodiments in which the pharmaceutical form comprises at least two compartments preferably the granulation of the at least two compartment mixtures, so that at least two compartment granulates are obtained. The production of a monolithic pharmaceutical form from the granules comprises in embodiments in which the 20 pharmaceutical form comprises at least two compartments preferably the compression of the at least two compartment granulates. The ingredients of the compartment each are preferably mixed and subjected to melting granulation. Preferably, the pharmaceutical form according to the present invention does not comprise a coating. In alternative embodiments the pharmaceutical form comprises a coating 25 with good solubility. When two compartments have to be produced, then preferably the constituents of the first compartment are mixed together and melting granules are produced thereof. The same is preferably conducted with the constituents of the second compartment. But also with the help of a spray method granules may be produced.
27 Then from the granulates a pharmaceutical form is produced. In the case of a layer tablet the granules are compressed in a tablet-compressing machine. In preferred embodiments of the production method the first active substance is mixed with the emulsifier for the production of the first compartment. Preferably, the active substance is 5 dissolved in the emulsifier. Optionally, a solvent can be used. Then active substance, emulsifier and solvent are mixed. According to the exact nature of active substance and emulsifier different solvents may be considered. Preferably, in the pharmaceutical technology common adjuvants are used, in particular alcohols, esters and/or ketones, in particular acetone. This mixture is then preferably sprayed onto a carrier. The carrier may be the above mentioned 10 compression aid and/or the retarding agent. The spraying operation may preferably be conducted in a fluidized bed facility. In an alternative embodiment the active substance is mixed with the emulsifier, in particular in a compulsory mixer, and melted. Then this mixture is applied onto the carrier which may be the compression aid and/or the retarding agent. 15 Before compression, to the granulates being prepared by the melting method or the alternative spray method adjuvants such as lubricants and flow promoters can be added and then they can directly be compressed to the desired compartments. If required, the active substance can be comminuted before, in particular in a nano mill. The powder thus obtained is preferably incorporated into the emulsifier. For the incorporation a 20 solvent is used in which the active substance is not soluble, in particular water. The incorporation prevents the reagglomeration of the active substance particles. The second compartment can be prepared in the same way. Preferably, granules of active substance and retarding agent are prepared, for example by way of wet granulation, wherein these granules are then compressed to the second compartment, optionally together with 25 adjuvants. Examples Example 1 Pharmaceutical forms with the following compositions were prepared (quantities in mg each): 28 First compartment Ex. 1 Ex. 2 Ex. 3 Purpose Cinnarizine 60 60 60 first active substance Gelucire' 50/13 120 240 480 emulsifier Pharmatose 480 480 480 compression aid Here the mentioned ingredients were mixed and then processed into granules by way of a common melting granulation method and subsequently compressed to tablets. The release was measured at a pH of 5.5 with a paddle apparatus. 5 Figure 1 shows the influence of the relative amount of the emulsifier in the pharmaceutical form onto the dissolution behavior. The ordinate shows the released amount of active substance in percent, the abscissa shows the elapsed minutes. It can be seen that the amount of emulsifier also increases the amount of released active substance. Example 2 10 A pharmaceutical form with the following composition was prepared: First compartment Amount in mg Purpose Cinnarizine 60 first active substance Gelucireo 50/13 240 emulsifier Dynasan" 118 240 triglyceride Pharmatose 480 compression aid Sum 1020 Second compartment Dimenhydrinate 120 second active substance Nacol 16-98 80 long-chain alcohol Methocel E4M (4000 cP) 120 retarding agent Sum 320 Here at first the ingredients of the first compartment were mixed together and processed into granules by means of melting granulation. Thereafter also the ingredients of the second 15 compartment were processed in the same way into melting granules. Thereafter both granulates 29 together were compressed in a tablet-compressing machine to a pharmaceutical form with two compartments. Example 3 The following example shows the influence of a triglyceride onto the release of the active 5 substance with bad solubility. The test was conducted at a pH value of 5.5 in a paddle apparatus. The quantities of the constituents are given in mg. First compartment Ex. 4 Ex. 5 Purpose Cinnarizine 60 60 first active substance Gelucireo 50/13 240 240 emulsifier Dynasan 118 0 240 triglyceride Pharmatose 480 480 compression aid Figure 2 shows the influence of the triglyceride in the pharmaceutical form onto the dissolution behavior of the first active substance. It can be seen that the triglyceride enhances the release of 10 cinnarizine. So according to Ex. 5 after 480 min already 23.6 mg of cinnarizine were dissolved. This is a surprising and advantageous fact, because cinnarizine at a pH value of 5.5 (aqueous buffer) only dissolves in a maximum amount of 1 to 2 mg. The ordinate shows the amount of the released active substance in percent, the abscissa shows the elapsed minutes. Example 4 15 The following example shows further tests for determining the influence of the emulsifier onto the amount of dissolved active substance with bad solubility. For that the following compositions were compressed to tablets (quantities are in mg each). The test was conducted at pH 5.5 in a Bio-Dis facility (30 minutes with 15 dip/minute). After 30 minutes each the vessel was exchanged. The solutions were analyzed in a photometric manner. First compartment Ex. 6 Ex. 7 Purpose Cinnarizine 20 60 first active substance Gelucireo 50/13 160 480 emulsifier Pharmatose, anhydrous 160 480 compression aid 20 For the amount of dissolved cinnarizine the following values were obtained: 30 t [minutes] Ex. 6 Ex. 7 30 2.14 3.92 60 1.12 2.15 90 1.27 2.26 120 0.85 2.36 150 - 2.07 180 0.45 1.57 Total: 5.83 14.33 It is a surprising fact that with the increase of the total amount of active substance also the absolute amount of substance which dissolves is increased. So it becomes clear that the amount of released cinnarizine is influenced by the emulsifier and is not restricted by a limiting 5 concentration. Example 5 The following example shows tests for the formation of an optional second compartment of the pharmaceutical form according to the present invention. For that with the following compositions (quantities in mg each) using the production method according to the present 10 invention layer tablets with dimensions of 18x8 mm were prepared, wherein for the first compartment a placebo mixture was used. Second compartment Ex. 8 Purpose Dimenhydrinate 120 second active substance Nacol 16-98 80 long-chain alcohol Methocel E4M 120 retarding agent Figure 3 shows the release of dimenhydrinate from the pharmaceutical form. The ordinate shows the amount of released active substance in percent, the abscissa shows the elapsed 15 minutes. It can be seen that at first within 60 minutes dimenhydrinate is quickly released from the second compartment, wherein subsequently the active substance is released slower and nearly linear. A retardation of the active substance in the second compartment over 10 hours was achieved.

Claims (15)

1. A pharmaceutical form with at least one first active substance and at least one emulsifier, wherein the emulsifier has a structural motif with the following formula 5 R 1 -O-[CH 2 -CH 2 -Ob-R 2 wherein R and R2 independently from each other are hydrogen, alkyl, glyceride or polyalkylene oxide and n is an integer of at least 4 and wherein the mass ratio of active substance to emulsifier is at least 1 to 30 and at most 1 to 1. 10
2. The pharmaceutical form according to claim 1, wherein the mass ratio of active substance to emulsifier is lower than 1 to 1.
3. The pharmaceutical form according to at least one of the preceding claims, wherein the 15 pharmaceutical form comprises at least one triglyceride.
4. The pharmaceutical form according to at least one of the preceding claims, wherein the mass ratio of triglyceride to active substance is higher than 1 to 1 and at most 10 to 1. 20
5. The pharmaceutical form according to at least one of the preceding claims, wherein the pharmaceutical form comprises at least one surfactant in an amount of at least 2 % by weight.
6. The pharmaceutical form according to at least one of the preceding claims, wherein the first active substance is cinnarizine or a salt of cinnarizine. 25
7. The pharmaceutical form according to at least one of the preceding claims, wherein the pharmaceutical form comprises two compartments.
8. The pharmaceutical form according to claim 7, wherein the compartments contain 30 different active substances.
9. The pharmaceutical form according to one of claims 7 or 8, wherein the pharmaceutical form in a first compartment contains the first active substance and the emulsifier and in a second compartment a second active substance. 35 32
10. The pharmaceutical form according to claim 9, wherein in the second compartment a retarding agent is contained.
11. The pharmaceutical form according to claim 9 or 10, wherein the first active substance 5 is cinnarizine or a salt of cinnarizine and the second active substance is dimenhydrinate.
12. The pharmaceutical form according to at least one of the preceding claims, wherein the first active substance in an aqueous solution at pH 7 has a solubility of lower than 0.5 mol/l. 10
13. The pharmaceutical form according to at least one of the preceding claims, wherein the pharmaceutical form is a layer tablet.
14. A method for the production of a pharmaceutical form according to at least one of the preceding claims with the steps: 15 a. mixing the constituents of the pharmaceutical form, b. granulating the mixture and c. preparing a monolithic pharmaceutical form from the granules.
15. The pharmaceutical form according to one of claims 1 to 13 for use in a therapy method.
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