DE10010509A1 - Oral pharmaceutical formulations with controllable release characteristics, e.g. rapid or delayed release, contain sucrose fatty acid ester as drug release controlling agent - Google Patents

Abstract

Oral pharmaceutical formulations with variable, controllable release characteristics contain, in addition to active agent(s) (A), one or more sucrose fatty acid ester(s) (I) as sole release controlling agent(s). An independent claim is included for the preparation of the formulations by melt-granulation or melt-pelleting.

Description

The present invention relates to novel oral pharmaceutical formulations with variably adjustable release behavior of the active ingredient in the form of Granules, pellets, tablets, film-coated tablets, microtablets, dragees, Capsules or therapeutic systems and process for their preparation by melt granulation or melt pelletization.

When using drugs, the reduced intake often plays Ideally, single-dose daily administration plays an important role.

One tablet in the morning or evening is taken more regularly than several tablets spread throughout the day. This increased patient compliance has a positive effect on the healing process. In addition, they often come along the reduced frequency of intake associated better compatibility of the active ingredient benefits the patient. The latter depends on the then required prolonged maintenance of the effective plasma concentration and mostly also more uniform plasma levels, where incompatible Peak values are largely avoided.

In exceptional cases can be already determined by the kinetic or dynamic Properties of an active substance such as for a long time Eliminationshalbwertszeit realize a single dose. In the vast majority Cases are, however, only by galenic-technological measures, such as for example, by a delayed release of the drug from the Dosage form, effective plasma levels over 12 to 24 hours allows.

In the literature there are a whole series of principle solutions that are available in Dependence on the chemical and physical properties of the  Active ingredients show advantages or disadvantages (review article: Recent trends and progress in sustained or controlled oral delivery of some water soluble drugs, drug development and industrial pharmacy 21 (9), 1037-1070 (1998)).

The state of the art, for example, in one of the newer textbooks of pharmaceutical technology reproduced (Voigt, R., Pharmaceutical Technology, Ullstein Mosby Verlag 1993, p 293 ff.). Thereafter, the effect of drugs can be prolonged by the following measures:
Molecular variations such as ester or salt formations, changes in drug modification, particle size, choice of appropriate excipients and methods. As an example, we will briefly discuss individual options:

Matrix sustained-release pharmaceutical

The are by an insoluble, possibly porous framework of indigestible Fats, waxes, polymers or inorganic matrix formers characterized. In this framework, the active ingredient is incorporated. The Drug release occurs through diffusion, erosion or matrix degradation.

Hydrocolloid sustained-release pharmaceutical

Here, the drug is embedded in hydrocolloid matrices, the consist for example of cellulose derivatives. After taking form through the digestive fluids, a gel through which the active ingredient in Dependence on surface and gel viscosity more or less fast diffused.

Coated (membrane-controlled) sustained-release medicament forms

Active substance particles or pharmaceutical forms are enveloped by a barrier. The diffusion through the diffusion barrier determines how fast the  Drug release takes place. To increase the diffusion rate Plasticizers or pore formers may be added.

Influence of the specific surface

In the case of poorly water-soluble active substances, there is generally a clear Dependence between dissolution rate and more specific Surface. By targeted crystallization of the drug, by sieving or Grinding can be a defined grain distribution and thus a specific specific surface can be adjusted. The bigger the particles, the better smaller is the specific surface and the slower it is Drug release.

Mixed forms of diffusion, erosion, dissolution processes

Furthermore, drug forms are known whose delayed Release of active ingredient on combination of diffusion, erosion and Release processes are based.

A particularly interesting and very effective in terms of drug release variable process represents the melt granulation. Among melt granulation or thermoplastic granulation is a process too understand in which the granule binding by the use of a low melting component and under the influence of thermal energy is carried out. (Lüdemann, J .; APV course 231 from 17.-18-06.1996)

There are two subtypes.

With the subtype wet granulation the process temperature is higher than the Melting point of the binding component. This is due to the granulation as liquid or semi-solid component. In place of drying occurs the melt granulation cooling.  

The subtype sintered granulation is used when the process temperature is not reaches the melting point of the binding component. Here is only one local melting takes place on the particle surface, so that the surfaces diffuse into each other (Voigt, R., Textbook of the Pharmaceutical Technology; Verlag Chemie, p. 159 (1984)).

The low melting point constituent may be an effective one Act ingredient or excipient. The melting points of the substances For stability reasons, they are generally above 35 ° C. Become the most frequent Substances with melting points in the range 50-90 ° C used.

Known active substances as meltable substances are phenylsalicylate, Ibuprofen, α-lipoic acid and meprobamate.

The meltable auxiliaries are water-soluble, swellable and lipophilic Substances used. As hydrophilic, for example, macrogol, polyvidone and Polymethacrylic acid derivatives.

Hydrocarbons (paraffin), waxes, fats and fatty acids are examples of lipophilic auxiliaries used.
(Flanders, P .; Dyer, GA; Jordan, D., Drug Dev. Ind., Pharm. 13 (&), 1001-1022 (1987); Schaefer, T., Holm, P., Kristensen, HG, Drug Dev Ind. Pharm. 16, 1249-1277 (1990); McTaggart, CM et al., Int J. Pharm 19, 139-148 (1984); Kinget, R .; Kemel, R .; Acta Pharm. Technol. 31, 57 (1985))

The melt granulation is usually in fluidized bed granulators, Centrifugal fluid bed equipment or high-speed intensive mixers carried out. Especially the use of the latter has procedural Advantages, as a costly air treatment can be omitted. Across from conventional granulation with organic solvents accounts Expenditure for explosion protection and solvent recovery. Also Residual solvents are omitted in the product. Opposite the aqueous granulation eliminates energy-intensive drying processes. Here is the Use of so-called one-pot systems favored.  

In general, the melt granulation process can be represented as follows:

The addition of the fusible binder may be solid or liquid, that is in the molten state.

On solid addition, the fusible material is used during the process Melting, therefore, this method is also melting method called.

In the latter method, either the solid components are presented, too where the liquid binder is added or according to the so-called fusion method, it is submitted to the liquid binder and stirred in the solids. For this purpose, the heating takes place before the Binder addition.

The energy supply can be done in intensive mixers in different ways:

• - mechanical energy through mixing tools and chopper
• - Contact heat over jacket
• - Radiation energy through IR or microwave
• - Warm air entry in product bed

From the patent literature are a variety of methods for the production such formulations known.

Controlled release formulations prepared by For example, melt granulation can be made described in DE 24 26 812, EP 351 580, EP 654 263, EP 672 416, EP 729 751 and WO 93/18753.

WO 93/18753 describes a process in which pellets to be produced at a later stage in the manufacture of water-insoluble, hydrophobic, waxy substances are added at a temperature at which these substances melt and lead to the coating of the pellets. this Process is called "hot melt coating".

Provided the thermostability of all involved in the process Starting materials under the prevailing process conditions is the Melt granulation is an interesting alternative to other granulations methods such as granulation with organic solvents or granulating with water.

The Schmelzpelletierung here represents a special form of process control, at the granule particles largely uniform size and rounded Be made in shape.

Despite the number of known fusible excipients are few Auxiliaries with graded HLB value (hydrophilic-lipophilic balance value) described for melt granulation or melt pelletization processes are particularly suitable.

Representatives of the few adjuvants with graded HLB value are hydrogenated Edible fats sold under the trade name Gelucire or  the sorbitol fatty acid esters, the z. B. are known as Span. These too do not cover the broad HLB range from 1 to 16.

With the classic fusible excipients can usually Release gradations only via the choice of the retarding agent or its quantity. Often one can Binders only in combination with another fusible binder, such as polyethylene glycol, because its granule forming capacity alone not enough. These binders also require the addition of slip or Mold release agents. Some have a waxy consistency.

In the known methods for melt granulation often have the resulting and solidified granules of a complex screening for Be subjected to comminution.

In the principle of retardation by means of a coating (coating) is due to the partially brittle, but also the relatively thin film covers at Pressing often observed a destruction of the film covers, unless with a relatively high external phase is counteracted. In destruction of the Film shell increases the drug release of the tablets. It means that the drug release of these tablets is usually press force dependent. often In this process, the drug release is sprayed over the Quantity set during production.

Depending on the film formation and the porosity, it may be during the Storage to changes in drug release come, for example wise by post-curing.  

An object of the present invention is therefore oral pharmaceutical formulations with variably adjustable Release behavior, that is releasing from fast to delayed release provide. In the modified or delayed release dosage forms both non-disintegrating dosage forms (so-called "single units"), but preferably rapidly disintegrating and modified or retarded from the Granulaten releasing drug forms (so-called "multiple units") produced can be.

Another object of the present invention is to provide methods for Production of such delayed-release formulations in particular by To provide melt granulation or melt pelletization.

According to the present invention, new oral pharmaceutical Formulations with variably adjustable release behavior provided, in addition to one or more active substances one or more Sucrose fatty acid ester as the sole release controlling agent contain.

The new pharmaceutical formulations are fast-release to sustained release drug forms.

The pharmaceutical formulations of the invention may be in the form of Granules, pellets, tablets, film-coated tablets, microtablets, dragees, Capsules and administered as therapeutic systems.

Surprisingly, sucrose fatty acid esters are capable of To control drug release in the desired way and beyond the technological properties in the production of the invention Formulations by melt granulation or melt pelleting to improve.  

Among other things, sucrose fatty acid esters are also suitable for the active ingredient granulate without the addition of other excipients. This is a gross mass Reduction compared to other methods where several fusible Retardierungs- or binders are used must, possible.

Sucrose fatty acid esters, especially low HLB stearates can be used simultaneously as lubricants and mold release agents.

Sucrose fatty acid esters are nonionic surfactants consisting of mono-, di-, tri- and polyesters of sucrose as hydrophilic ingredient and from saturated or unsaturated fatty acids as a lipophilic ingredient. By varying the degree of esterification and the type of fatty acids produce sucrose fatty acid esters with different HLB values, the influence on the biopharmaceutical properties, in particular the Drug release, the stability of the manufactured pharmaceutical Formulation as well as on technological behavior.

They are non-toxic, biodegradable, tasteless and odorless as well storage stable.

The sucrose fatty acid esters with a melting point of <30 ° C are included Room temperature in solid state and have an HLB value from 1-16.

Sucrose fatty acid esters are also known, for example, among the Designations sugar ester or sucrose ester among others from the companies Mitsubishi (brand name Ryoto), Gattefosse or Sisterna or others distributed.

Sucrose fatty acid esters are known in the literature, so they are according to US 4,844,067 for improving the surface of silk fibers and in WO 93/17667 as taste improver in pharmaceutical Preparations used.  

Its main application is in the food industry. So be Sucrose fatty acid esters e.g. B. to improve the mixture of Used chewing gum masses against segregation and denaturation of Ready-to-drink drinks, sugar refining, condensed milk and coffee whiteners used.

In the production of wheat flour products are Sucrose fatty acid esters, for example as stabilizers, for improvement the texture, used to prevent caking and sticking. at Dairy products for the stabilization of emulsions and avoidance of Protein degradation. Sucrose fatty acid esters improve that Crystallization behavior, are effective emulsifiers and lower the Viscosity in the production of fats and oils.

US 3 896 238, US 4 150 114 and US 4 046 886 disclose the use of Sucrose fatty acid esters in combination with alkyl sulfoxide or Phosphorus oxides in pharmaceutical compositions for improvement the penetration of the active substance through the skin.

Examples of special sucrose fatty acid esters are:
Sucrose monooctanate, monolaurate, monopalmitate, monostearate, as well as the di- and triesters of these compounds.

In JP 81 75 437, the use of sucrose fatty acid esters with an HLB value of 1 to 5 as a basis for suppositories disclosed.

In WO 88/06880 the use of sucrose fatty acid esters in topical Applications claimed, with mixtures of mono- and Dialkylsucrose esters with an HLB value of 8 to 16 for improving the Penetration through the skin can be used.

Preference is given to sucrose cocoate, sucrose eric oleate, sucrose laurate and sucrose stearate.  

Sucrose fatty acid esters are also particularly useful in cosmetic Products used (FR 2 421 605, JP 81 24 034, JP 81 55 306).

DE 40 03 844 describes pharmaceutical compositions, in addition to the active ingredient cyclosporin a Fettsäuresaccharidmonoester and a diluent or carrier.

These compositions allow for a reduction in achievement Ciclosporin dosage levels required for effective therapy and thus lead to the reduction of unwanted side effects.

As Fettsäuresaccharidmonoester here are particularly suitable:
C _6-14 fatty acid disaccharide monoesters and C _8-18 fatty acid trisaccharide monoesters.

In WO 93/00093 a new sustained release formulation for diltiazem in the form of Spheroids claimed, which is composed of the active ingredient, a Wetting agent and a polymer coating for control the release. Wetting agents are sucrose fatty acid esters used. The actual delay takes place by means of a polymer. there the wetting agent with the active ingredient by extrusion or by means Granulation processed with organic solvents. The coating of Extrusions are made with conventional polymers.

As wetting agents, for example, C ₁₂ -C ₂₀ fatty acid esters of sucrose or xylose be mentioned.

In DE 198 40 152 a sustained-release formulation is claimed, which Calcium valproate, at least one acrylic polymer and at least one sugar ester contains, by the acrylic polymer used, the desired Retardation is achieved. It is shown that the sugar ester alone no causes significant retardation.  

The suitability of sucrose fatty acid esters in the inventive pharmaceutical formulations as the sole release-controlling agent was all the more surprising because these sucrose fatty acid esters on the one hand have been known for some time and on the other hand oral pharmaceutical formulations with variably adjustable Release release behavior in a simple manner.

The sucrose fatty acid esters used in the present invention are esters of sucrose with saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable are C ₁₂ -C ₂₂ fatty acids.

Preference is given to sucrose stearates, sucrose palmitates, sucrose laurates, sucrose behenates and sucrose oleates having an HLB value of 1-16 used.

The melting point or melting range of the invention used Sucrose fatty acid ester is between 30-200 ° C.

Preference is given to sucrose fatty acid esters having a melting point or Melting range of 40-150 ° C used.

An essential advantage of the present invention is that the desired release behavior of the new pharmaceutical Formulations on the type and proportion of or the sucrose used fatty acid esters or via the process parameters of Manufacturing process can be controlled.

Low HLB sucrose fatty acid esters are preferred for the Obtaining a sustained release used. High-HLB sucrose fatty acid esters are preferably suitable for one fast or modified release behavior.  

The sucrose fatty acid esters can be used in the inventive pharmaceutical formulations in a proportion of 1 to 95 wt .-%, based on the portion to be granulated (inner phase) in the recipe to be available. A proportion of between 5 and 50% by weight is preferred. used. In addition to sucrose fatty acid esters can in the inner phase of Active substance alone or mixtures of the active substance with one or more present pharmaceutically acceptable excipients.

Another embodiment of the invention is that granules or Pellets containing either sucrose fatty acid esters in the granules or the no sucrose fatty acid ester coated with sucrose fatty acid ester could be.

The proportion of sucrose fatty acid ester in the casing is 1-60 wt .-%, preferably 3-20 wt .-% based on the coated dosage form.

The sucrose fatty acid esters can be used alone or optionally also in Combination with other fusible excipients can be used. In part, for the process, the addition of one or more excipients, such as plasticizers of advantage. About the embedding of so-called Pore formers, these are excipients with certain properties, such as Example of characteristic solubility or swellability, during the Schmelzgranulier- or Schmelzpelletierprozesses is another Modification of drug release possible.

The oral pharmaceutical formulations of the invention may be described as Active ingredients are both water-soluble and practically water-insoluble Contain connections.

Active substances of the following indication groups are suitable for this, although the enumeration is not conclusive:
Analeptics / antihypoxaemics (such as caffeine), analgesics / antirheumatics (such as diclofenac, morphine, tramadol, tilidine, flupirtine), antiallergic drugs (such as azelastine, pseudoephedrine), antiarrhythmics such as quinidine, disopyramide, diltiazem, verapamil), antidementia (nootropics) (such as Piracetam, nicergoline, xantinonicotinate, pentifylline, vincamine), antidiabetics (such as glibenclamide), antiemetics / antivertiginosa (such as betahistine dimesilate, dimenhydrinate), anticonvulsants (such as carbamazepine, valproic acid, calcium valproate dihydrate, retigabine), antihypertensives (such as talinolol, fosinopril, doxazosin, metoprolol, Nifedipine), antihypotonics (such as norfenefrine HCl, dihydroergotamine mesylate), broncholytics / antiasthmatics (such as salbutamol, terbutaline sulfate, theophylline), diuretics (such as furosemide, piretanide), circulation enhancers (such as buflomedil, naftidrofuryl, pentoxifylline), coronary agents (such as glycerol trinitrate, isosorbide mononitrate , Isosorbide dinitrate, molsidomine), lipid lowering agents (such as bezafibrate, fenofibrate, xant inol), migraine drugs (such as sumatriptan), muscle relaxants, Parkinson's drugs and others. other agents against extrapyramidal disorders (such as levodopa / benserazide, levodopa / carbidopa), psychotropic drugs (such as amitriptyline-HCl, venlafaxine-HCl, thioridazine-HCl, lithium carbonate, lithium acetate).

The pharmaceutical formulations according to the invention contain preferably flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine.

The pharmaceutical formulations according to the invention can according to the present invention by melt granulation or Schmelzpelletierung be prepared.

Here, for example, in a high-speed mixer, the mixture from the active substance and one or more sucrose fatty acid esters, optionally with the other excipients heated with stirring. The Heating can be done either by means of a heating jacket, with a microwave, Radiation energy or via the energy input of the stirrer done.  

When the melting temperature of the particular used Saccharosefettsäureesters achieved in the mixture or the surface thereof softened or melted, the granulation begins. Due to the incipient agglomeration and the associated increase in Friction increases the power consumption of the stirring motor.

The granulation termination usually takes place when the power consumption exponential begins to rise. Thereafter, the warm melt granules either discharged from the mixer and in thin layers at Room temperature cooled or with suitable cooling (eg cooling jacket) possibly cooled in the mixer with stirring.

According to the invention, there is also the possibility of adding the Sucrose fatty acid ester in the molten state.

Surprisingly, this results in a very narrow granule size distribution reached. The granules or pellet particles have depending on Process control a nearly rounded and smooth surface.

Likewise, the use of other heatable devices, such as Fluidized bed granulator, rotor granulator possible.

The granules thus produced may optionally be classified via a sieve be mixed, possibly with excipients of the outer phase and For example, compressed into tablets or filled into capsules.

As auxiliaries of the outer phase can pharmaceutically usual blasting or disintegrants, fillers, mold release agents or the like be used. In general, the use of mold release agents at Use of sucrose stearates of low HLB value omitted because low-HLB sucrose stearates themselves are also good Represent mold release agent.  

Depending on the pharmaceutical-technological goal, for example fast release or modified to sustained release formulations, (multiple units or single unit) are produced.

Furthermore, it was surprisingly found that the sucrose fatty acid esters are suitable as auxiliaries for "hot melt coating". This is done to an already prepared and solidified melt granules Again a lot of sucrose fatty acid same or different Type added and the mixture again above the melting point or the softening temperature of the added Warmed sucrose fatty acid ester. In this case, a coating of the melt takes place of the sucrose fatty acid ester over the melt granules. The coating can also be done in the presence of a plasticizer. Likewise, sucrose fatty acid ester-free granules or pure active ingredients be coated in the manner described.

The advantages of this method are that on the one hand by the coating sufficient release control, especially with already delayed release lower levels of sucrose fatty acid esters is achieved. On the other hand the surface of the granules or pellets thus produced is smoothed.

Another advantage is that with this method to simple As enteric coatings can be produced. This is the Possibility to strongly delay the release of active ingredient in the acidic pH range due to the practical insolubility of sucrose fatty acid esters in aqueous and acidic media.

The "powder coating" here represents a special form of "hot melt Here are, on the one hand, the free-flowing Sucrose fatty acid ester with the aid of a suitable powder feed, such as  powder feeder, and on the other hand, a plasticizer such as triethyl citrate to the added dosed starting materials.

This process is characterized by high cost and time savings, it are no compared to conventional aqueous coating process Drying processes required. In particular, pharmaceutical compositions prepared in this way are suitable Formulations for water-sensitive active ingredients, such as Na-valproate.

The following examples are intended to illustrate the subject matter of the invention in more detail explain without limiting it.

example 1 Tramadol hydrochloride with 50% sucrose stearate HLB value 1

• - recipe: substance weighing tramadol 400 g Sucrose stearate S-170 400 g
• - parameters: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 55.0 ° C

The starting materials are in a high-pressure mixer of the type GP1 Fa. Aeromatic-Fielder at the appropriate jacket temperature with stirring heated. Upon reaching a certain product temperature begins: the Granulation process. After reaching an increase in power consumption of the stirrer and a sudden increase in product temperature is the Granulation stopped and the product discharged through a sieve Mesh size 1.4 mm and cooled at room temperature.  

• - Evaluation: drug release

Release of active substance see Appendix 1

Example 2 Flupirtine maleate with 30% sucrose stearate HLB value 1

• - recipe: substance weighing flupirtine maleate 240.0 g Sucrose stearate S-170 102.9 g
• - parameters: batch quantity 342.9 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 61.2 ° C
• - Production is carried out according to Example 1.

Example 3 Nifedipine with 30% sucrose stearate HLB value 1

• - recipe: substance weighing nifedipine 560 g Sucrose stearate S-170 240 g
• - parameters: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 58 ° C
• - Production is carried out according to Example 1.
• - Evaluation: drug release

Release of active substance see Appendix 2

Example 4 Nifedipine with 30% sucrose palmitate HLB value 1

• - recipe: substance weighing nifedipine 560 g Sucrose palmitate P-170 240 g
• - parameters: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 52 ° C
• - Production is carried out according to Example 1.
• - Evaluation: drug release

Release of active substance see appendix 3  

Example 5 Melt granules of nifedipine with 30% sucrose stearate HLB value 5

• - recipe: substance weighing nifedipine 560 g Sucrose stearate S-570 240 g
• - parameters for granulation: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 70 ° C
• - Production is carried out according to Example 1.
• - parameters for tabletting:
  The pellets were then pressed with Tableting tool round, 6 mm diameter, medium vaulted into tablets with a gross mass of 71.4 mg.
• - Evaluation: drug release

Release of active ingredient see Appendix 4

Example 6 Granulated tablets of nifedipine with 50% sucrose stearate HLB- Value 9 and 2.5% sucrose stearate HLB value 1

• - recipe: substance weighing nifedipine 400 g Sucrose stearate S-970 380 g Sucrose stearate S-170 20 g
• - parameters for granulation: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 65 ° C
• - The preparation is carried out according to Example 1
• - parameters for tabletting:
  The pellets were compressed with tableting tool round, 6 mm diameter, medium-curved into tablets with a gross mass of 100 mg.
• - Evaluation of drug release:

Release of active substance see appendix 5

Example 7 Carbamazepine with 10% sucrose stearate HLB value 1

• - recipe: substance weighing carbamazepine 720g Sucrose stearate S-170 80 g
• - parameters: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 55 ° C
• - The preparation is carried out according to Example 1  
• - Evaluation: drug release

Release of active substance see appendix 6

Example 8 Carbamazepine with 30% sucrose stearate HLB value 9

• - recipe: substance weighing carbamazepine 560 g Sucrose stearate S-970 240 g
• - parameters: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 68 ° C
• - The preparation is carried out according to Example 1
• - Evaluation: drug release

Release of active substance see Appendix 7

Example 9 Carbamazepine with 50% sucrose behenate HLB value 3 and 2.5% triethylcitrate

• - recipe: substance weighing carbamazepine 400 g Sucrose behenate B-370 380 g triethylcitrate 20 g
• - parameters: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 50 ° C

In an intensive mixer type GP1 of the company Aeromatic Fielder the Starting materials carbamazepine and triethyl citrate mixed. After 1 min Mixing time Saccharosebehenat B-370 is added and the mixture at a jacket temperature of 50.0 ° C heated with stirring. After reaching a certain product temperature at which an increase in output is too observe, the granules through a sieve of mesh size 1.4 mm given and cooled to room temperature.

Example 10 Granular pellets of carbamazepine with 30% sucrose stearate HLB value 9

• - recipe: substance weighing carbamazepine 560 g Sucrose stearate S-970 240 g
• - parameters for granulation: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 68 ° C
• - The preparation is carried out according to Example 1  
• - parameters for tabletting:
  The pellets are pressed without further additions with tabletting tool round, 13 mm in diameter, flat to tablets with a gross mass of 571 mg with a compressive strength of 25 N pressed.
• - Evaluation: drug release
• - release of active substance see Annex 8

Example 11 Carbamazepine with 20% sucrose stearate HLB value 2

• - recipe: substance weighing carbamazepine 640 g Sucrose stearate S-270 160 g
• - parameters: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 54 ° C
• - The preparation is carried out according to Example 1

Example 12 Calcium valproate dihydrate with 35% calcium hydrogen phosphate and 30% Sucrose stearate HLB value 1

• - recipe: substance weighing calcium valproate dihydrate 280 g Calcium hydrogen phosphate 280 g Sucrose stearate S-170 240 g
• - parameters: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 53 ° C
• - The preparation is carried out according to Example 1, wherein the active ingredient Calcium valproate dihydrate be submitted with calcium hydrogen phosphate.
• - Evaluation: drug release
• - release of active substance see Annex 9

Example 13 Tablets of melted granules of calcium valproate dihydrate and 30% Sucrose stearate HLB value 1

• - recipe: substance weighing Calciumbvalproatdihydrat 560 g Sucrose stearate S-170 240 g
• - parameters for granulation: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 55 ° C
• - The preparation is carried out according to Example 1
• - parameters for tabletting:
  The granules are pressed oblong, 23 mm long, 9 mm wide, into oblong tablets with a gross mass of 951 mg and a compressive strength of 65 N using a tableting tool.
• - Evaluation: drug release
• - release of active substance see Appendix 10

Example 14 Tablets of melted granules of calcium valproate dihydrate and 30% Sucrose stearate HLB value 9

• - recipe: substance weighing Calciumvalproatdihpdrat 560 g Sucrose stearate S-970 240 g
• - parameters for granulation: batch quantity 800 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 65 ° C
• - The preparation is carried out according to Example 1
• - parameters for tabletting:
  The granules are pressed oblong, 23 mm long, 9 mm wide, into oblong tablets with a gross mass of 951 mg and a compressive strength of 50 N using a tableting tool.
• - Evaluation: drug release

Release of active substance see Appendix 11a

Comparison of the release of the calcium valproate formulations in pH 3.0 see Annex 11b  

Comparison of the release of the calcium valproate formulations in pH 6.8 see Annex 11c

Example 15 Retigabine with 20% sucrose stearate HLB value 1

• - recipe: substance weighing retigabine 800 g Sucrose stearate S-170 200 g
• - parameters: batch quantity 1000 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 52 ° C
• - The preparation is carried out according to Example 1
• - Evaluation: drug release

Release of active substance see Appendix 12

Example 16 Retigabine with 20% sucrose stearate HLB value 2

• - recipe: substance weighing retigabine 400 g Sucrose stearate S-270 100 g
• - parameters: batch quantity 500 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 55 ° C
• - The preparation is carried out according to Example 1
• - Evaluation: drug release
• - release of active substance see Appendix 13

Example 17 Retigabine with 20% sucrose stearate HLB value 1 and 10% sucrose stearate HLB value 9

• - recipe: substance weighing retigabine 210 g Sucrose stearate S-170 60 g Sucrose stearate S-970 30 g
• - parameters: batch quantity 300 g stirrer 500 rpm chopper speed 3000 rpm jacket temperature 65 ° C
• - The preparation is carried out according to Example 1
• - Evaluation of drug release

Release of active substance see Annexes 14a

Comparison of drug releases of retigabine formulations in 0.1 N HCl see Appendix 14b

Comparison of drug release of retigabine formulations in buffer pH 6.8 see Appendix 14c

Example 18 Pellets of melt granules with retigabine, 20% sucrose stearate HLB- Value 1 and 10% croscarmelose sodium

• - recipe: substance weighing retigabine 800 g Sucrose stearate S-170 200 g
• - parameters for granulation: batch quantity 1000 g stirrer 700 rpm chopper speed 3000 rpm jacket temperature 52 ° C
• - The preparation is carried out according to Example 1
• - parameters for tabletting: substance weighing Retigabine retard - granules (see above) 270 g Croscarmellose sodium 30 g

The tableting mixture is made with tablet tool round, diameter 9 mm, Chamfer 45 °, radius of curvature R13 pressed into tablets.

• - Evaluation: drug release

Release of active substance see Appendix 15

Example 19 Retigabine with 7% sucrose stearate HLB value 1

• - recipe: substance weighing retigabine 128g Sucrose stearate S-170 g 28 g
• - parameters: batch quantity 400 g stirrer 1300 rpm jacket temperature 50 ° C

In an intensive mixer type GP1 of the company Aeromatic Fielder the Starting materials in a special, provided with a PTFE liner Heated container at a jacket temperature of 50.0 ° C with stirring. To As the power consumption recovers, the pellets are removed and cooled to room temperature in thin layers.

• - Evaluation: drug release

Release of active ingredient see Appendix 16

Example 20 Retigabine with 20% sucrose stearate HLB value 11

• - recipe: substance weighing retigabine 320 g Sucrose stearate S-1170 80 g
• - parameters: batch quantity 400 g stirrer 1300-1100 rpm jacket temperature 50 ° C
• - Production is carried out according to Example 19
• - Evaluation: drug release

Release of active substance see Appendix 17

Example 21 Retigabine with 20% sucrose stearate HLB value 16

• - recipe: substance weighing retigabine 320 g Sucrose stearate S-1670 80 g
• - parameters: batch quantity 400 g stirrer 1300-1100 rpm jacket temperature 50-55 ° C
• - Production is carried out according to Example 19
• - Evaluation: drug release

Release of active substance see Appendix 18

Example 22 Retigabine with 16% sucrose stearate HLB value 15

• - recipe: substance weighing retigabine 336 g Sucrose stearate S-1570 64 g
• - parameters: batch quantity 400 g stirrer 1300 rpm jacket temperature 50-60 ° C
• - Production is carried out according to Example 19
• - Evaluation: drug release

Release of active ingredient see Appendix 19

Example 23 Retigabine tablets

• - Recipe melt granules: substance weighing retigabine 332 g Sucrose stearate S-1570 68 g
• - parameters: batch quantity 400 g stirrer 1300 rpm jacket temperature 50-60 ° C
• - Preparation according to Example 19
• - Formulation Coating: substance weighing Retigabine melt granules with 17% sucrose stearate HLB 15 1000 g Eudragit L 30 D-55 400 g (corresponds to 120 g of lacquer dry matter) talc 60 g triethylcitrate 12 g

The melt granules are combined from 5 batches and in a Rotor granulator with a supply air of 50 ° C at 300 rev / min with a suspension from Eudragit L 30 D-55, talc and triethyl citrate in 536 g of purified water sprayed. It is then allowed to reach a product temperature of 33 ° C dried.

The so-coated granules with 30 wt .-% microcrystalline cellulose and 5% by weight of croscarmellose sodium homogenized for 10 min in a Turbula.

The Tablettiermischung is curved into tablets oblong, 17 × 8 mm with a average compressive strength of 87 N pressed.

Release of active ingredient in 0.1 N HCl see Appendix 20a

Release of active ingredient in buffer pH 7.5, 1.7% Texapon see Appendix 20b

Example 24 "Hot melt coating" of retigabine melt granules with 10% sucrose stearate HLB value 1

• - Formulated coated granules: substance weighing Retigabine melt granules (90% by weight of retigabine and 10% by weight of sucrose stearate S-170) 500 g Sucrose stearate S-170 55.6 g
• - parameters: batch quantity 555.6 g stirrer 700 rpm jacket temperature 52 ° C

In an intensive mixer of the type GP1 of the company Aeromatic Fielder are the Retigabine melt granules at a jacket temperature of 52 ° C with stirring heated. At a product temperature of 30 ° C, sucrose stearate S-170 added and another 7 min with the chopper switched on (3000 rpm) granulated. The coated granules are removed and passed through a sieve of Mesh size 1.4 mm sieved.

• - Results of particle size distribution Grain class [μm] Proportion of [%] <1000 3.4 <800 4.0 <500 34.4 <315 40.9 <160 14.0 <50 3.4 <50 0

Release of active ingredient in 0.1 N HCl see Appendix 21a

Release of active ingredient in buffer pH 7.5, 2.5% Texapon see Appendix 21b

Claims (33)

1. oral pharmaceutical formulations with variably adjustable release behavior, characterized in that in addition to one or more active substances one or more sucrose fatty acid esters is contained as the sole release-controlling agent. 2. Pharmaceutical formulations according to claim 1 characterized characterized in that it is fast-release to retarded releasing dosage forms. 3. Pharmaceutical formulations according to claim 1 characterized characterized in that the release behavior is based on the type and proportion of the or the sucrose fatty acid ester and the process parameters of Manufacturing process can be controlled. 4. Pharmaceutical formulations according to claim 1 characterized characterized in that it is single unit as well as multiple unit Dosage forms is. 5. Pharmaceutical formulations according to claim 1 and 4 in the form of oral dosage forms such as granules, pellets, tablets, Film-coated tablets, microtablets, dragees, capsules or special ones therapeutic systems. 6. Pharmaceutical formulations according to claim 1 characterized characterized in that the active substance or substances in a matrix Embedded sucrose fatty acid esters and / or of Saccharosefettsäureester be wrapped.   7. Pharmaceutical formulations according to claim 6 characterized characterized in that granules or pellets containing an active ingredient or mixtures of active ingredients and sucrose fatty acid esters in addition to Saccharosefettsäureester can be enveloped. 8. Pharmaceutical formulations according to claim 6 characterized characterized in that sucrose fatty acid ester-free granules or Pellets are coated with sucrose fatty acid ester. 9. Pharmaceutical formulations according to claim 1 characterized characterized in that the sucrose fatty acid esters used from mono-, di-, tri- or polyesters of sucrose with medium to long-chain saturated and / or unsaturated fatty acids. 10. Pharmaceutical formulations according to claim 9, characterized in that are preferably used as sucrose fatty acid esters of sucrose with C ₁₂ -C ₂₂ fatty acids. 11. Pharmaceutical formulations according to claim 1 and 9 characterized characterized in that the HLB value of the sucrose fat used acid ester is 1 to 16. 12. Pharmaceutical formulations according to claim 1 and 9 characterized characterized in that the sucrose fatty acid esters used their Melting point or melting range in the temperature range from 30 to 200 ° C.   13. Pharmaceutical formulations according to claim 12 characterized characterized in that the sucrose fatty acid esters used preferably its melting point or melting range in Temperature range from 40 to 150 ° C have. 14. Pharmaceutical formulations according to claim 1 characterized characterized in that sucrose fatty acid ester in a proportion of 1 to 95 wt .-% are contained in the granules. 15. Pharmaceutical formulations according to claim 14 characterized characterized in that sucrose fatty acid ester preferably with a Part of 5 to 50 wt .-% contained in the granules. 16. Pharmaceutical formulations according to claim 1 and 8 characterized characterized in that sucrose fatty acid esters in a proportion of 1-60 wt .-% in the envelope based on the coated dosage form are included. 17. Pharmaceutical formulations according to claim 16 characterized characterized in that sucrose fatty acid ester preferably with a Proportion of 3-20 wt .-% in the envelope based on the coated Dosage form are included. 18. Pharmaceutical formulations according to claim 1 characterized characterized in that in addition to the sucrose fatty acid esters further In addition, adjuvants may be included. 19. Pharmaceutical formulations according to claim 18 characterized characterized in that as excipients fillers, fusible binders, Disintegrants, flow control agents, mold release agents, film formers and / or other commonly used adjuvants.   20. Pharmaceutical formulations according to claim 18 characterized characterized in that by the embedding of pore-forming agents during the Schmelzgranulier- or Schmelzpelletierprozesses a further modification of the drug release is possible. 21. Pharmaceutical formulations according to claim 1 characterized characterized in that as active ingredients well water-soluble to practical water-insoluble active ingredients can be used. 22. Pharmaceutical formulations according to claim 1 and 21 characterized characterized in that active substances especially from the indication areas Analeptics / antihypoxema, analgesics / anti-inflammatory drugs, antiallergic drugs, Antiarrhythmics, antidementia, antidiabetics, antiemetics / antivertiginosa, Antiepileptics, antihypertensives, antihypotonics, broncholytics, Antiasthmatics, diuretics, circulation-enhancing agents, Hypnotics / sedatives, coronary agents, lipid-lowering drugs, migraine remedies, Muscle relaxants, Parkinson's drugs and psychotropic drugs used can be. 23. Pharmaceutical formulations according to claim 1 and 21 containing Active ingredients, such as caffeine, diclofenac, morphine, tramadol, tilidine, flupirtine, Azelastine, pseudoephedrine, quinidine, disopyramide, diltiazem, verapamil, Piracetam, nicergoline, xantinonicotinate, pentifylline, vincamine Glibenclamide, betahistine dimesilate, dimenhydrinate, carbamazepine, Valproic acid, calcium valproate dihydrate, retigabine, talinolol, fosinopril, Doxazosin, Metoprolol, Nifedipine, Norfenefrin HCl, Dihydro ergotamine mesilate, salbutamol, terbutaline sulfate, theophylline, furosemide, Piretanide, buflomedil, naftidrofuryl, pentoxifylline, glycerol trinitrate, Isosorbide mononitrate, isosorbide dinitrate, molsidomine, bezafibrate, fenofibrate, Xantinol, sumatriptan, levodopa, benserazide, carbidopa, amitriptyline HCl, venlafaxine HCl, thioridazine HCl, lithium carbonate, lithium acetate.   24. Pharmaceutical formulations according to claim 1 and 21 containing preferably flupirtine, tramadol, nifedipine, carbamazepine, Calcium valproate or retigabine. 25. Pharmaceutical formulations according to claim 24 characterized characterized in that in addition to the active substance retigabine 1-95 wt .-% Sucrose fatty acid esters are contained in the granules. 26. Pharmaceutical formulations according to claim 25 characterized characterized in that in addition to the active ingredient retigabine preferably 5-50 wt .-% sucrose fatty acid ester contained in the granules. 27. Process for the preparation of pharmaceutical formulations according to Claim 1 by melt granulation or Schmelzpelletierung. 28. Process for the preparation of pharmaceutical formulations according to Claim 27, characterized in that in a suitable device the starting materials with stirring or in the fluidized bed to a Temperature at which the sucrose fatty acid ester (s) used soften, superficially melt or melt, warmed and be cooled after the formation of granules. 29. Process for the preparation of pharmaceutical formulations according to Claim 28, characterized in that in a suitable device the molten sucrose fatty acid ester (s) to be heated Be given active ingredient powder. 30. Process for the preparation of pharmaceutical formulations according to Claim 28 or 29, characterized in that as a suitable device preferably a high-speed mixer, a fluidized bed apparatus or a rotor granulator can be used.   31. A process for the preparation of pharmaceutical formulations according to Claim 1, 7 or 8 by coating the granules or pellets preferably by the "hot melt coating" process or "powder coating "process. 32. Process for the preparation of pharmaceutical formulations according to Claim 31, characterized in that the "hot melt coating" and in "powder coating" with the or the sucrose fatty acid ester alone or in combination with plasticizers. 33. Process for the preparation of pharmaceutical formulations according to Claim 32, characterized in that as a plasticizer Triethyl citrate, acetyl triethyl citrate, triacetin or dibutyl sebacate can be.