BG107064A - Pharmaceutical forms - Google Patents

Abstract

The invention relaters to novel oral pharmaceutical formulations having a variably adjustable release effect. Said formulations contain one or several sucrose fatty acid esters as exclusive release control agents, in addition to one or several active ingredients. The invention also relates to a method for the production of the formulations by fusion granulation of fusion pelletizing. The novel pharmaceutical formulations range from quick release to delayed release medicament forms. 33 claims

Description

The present invention relates to novel, oral, pharmaceutical formulations having variable adjustable release behavior of the active substance in the form of granules, pellets, tablets, film-tablets, micro-tablets, dragees, capsules or therapeutic systems, and a method for their preparation by granulation by melting or pelleting by melting.

Reduced frequency of administration, ideally once daily administration, plays a significant role in drug administration.

It is more common to take one tablet in the morning and evening than more tablets distributed throughout the day. This increased patient consent has a positive effect on the healing process. In addition, often concomitant tolerability with reduced frequency of administration of the active substance is beneficial to the patient. Tolerance depends on the need to maintain an effective plasma concentration for longer and often on more uniform plasma levels, thus largely avoiding intolerable peak values.

In exceptional cases, due to the kinetic or dynamic properties of an active substance, such as a long elimination half-life, a single administration can be achieved. However, in most cases effective plasma levels over a period of 12 to 24 hours are only possible with the application of galenic technological measures such as delayed release of the active substance from the corresponding formulation.

BACKGROUND OF THE INVENTION

On this subject, there are a number of fundamental solutions in the literature that, depending on the chemical and physical properties of the active substance, show advantages and disadvantages, respectively (review article: Recent Trends and Progress in Sustained or Controlled Oral Delivery of Some Water Soluble Drugs) and Industrial Pharmacy 21 (9), 1037-1070, 1998).

The state of the art is also indicated, for example, in one of the new textbooks in pharmaceutical technology (Voigt, R., Pharmazeutische Technologie, Ullstein Mosby Verlag, 1993, S 293 ff.). According to him, the effect of medicines can be prolonged by the following measures:

Modification of the molecule as the formation of an ester or salt, changes in the modification of the active substance, particle size, selection of appropriate excipients and methods. Some examples are briefly presented as examples:

Delayed matrix drugs

They are characterized by an insoluble, possibly porous, skeleton of indigestible fats, waxes, polymers or also inorganic matrix formers. The active substance is included in this skeleton. The release of the active substance is by diffusion, erosion or degradation of the matrix.

Delayed hydrocolloid drugs

In this case, the active substance is incorporated into the hydrocolloid matrix, which consists, for example, of cellulose derivatives. After digestion, a gel is formed through which the active substance diffuses faster or slower depending on the surface and viscosity of the gel. Delayed drug-coated drugs

The active substance particles or dosage forms are coated with a barrier. Diffusion through the barrier determines how fast the release of the active substance takes place. Softeners or vaporizers may be added to increase the rate of diffusion.

Impact of the specific surface

Typically, in water-soluble substances, there is a clear relationship between the dissolution rate and the specific surface area. By crystallization of the active substance, by sieving or grinding, a certain particle size distribution and thus a specific surface can be achieved. The larger the particles, the smaller the specific surface area and the slower the release of the active substance. Mixed Forms of diffusion, erosion, dissolution processes

Further known are dosage forms whose delayed release of the active substance is based on a combination of diffusion, erosion, and dissolution processes.

Particularly interesting, and in view of the release of the active substance, the method of application in many variations is melt granulation. Melting or thermoplastic granulation means a process whereby the formation of a granule is carried out by the use of a low-melting component, as well as by the influence of thermal energy (Luedemann, J., APV-Kurs 231, 17-18 June 1996). ).

In this case, there are two subtypes.

In the wet granulation subtype, the process temperature is higher than the melting point of the binder. During granulation, it is in the form of a liquid or semi-solid component. Instead of drying by pelletizing, we have cooling.

In the sintering granulation subtype, the process temperature does not reach the melting point of the binder. In this case, only the local melting of the particle surface is carried out so that the surfaces diffuse into each other (Voigt, R., Lehrbuch der pharmazeutischen Technologie, Verlag Chemie, S. 159, 1984).

The low-melting constituent may be an effective constituent or excipient. As a general rule, the melting points of substances for stability reasons are above 35 ° C. Most commonly, substances with a melting point in the range of 50-90 ° C are used.

Active substances known as soluble substances are phenylsalicylate, ibuprofen, α-lipoic acid and meprobamate.

Water soluble, swollen and lipophilic substances are used as soluble excipients. Hydrophilic are, for example, macrogol, polyvidone and polymethacrylic acid derivatives.

Hydrocarbons (paraffins), waxes, fats, and fatty acids are examples of lipophilic excipients used.

(Flanders, R., Dyer, G.A., Jordan, D., Drug Dev. Ind. Pharm.

(7), 1001-1022, 1987; Schaefer, T., Holm, P., Kristensen, H.G., Drug Dev. Ind. Pharm 16, 1249-1277, 1990; McTaggart, C.M. et al. Int. J. Pharm. 19, 139-148, 1984; Kinget, R., Kernel, R., Acta Pharm. Techno /. 31, 57, 1985).

Melting granulation is generally performed in fluidized bed granulators, fluidized bed centrifugal granules or high-speed intensive mixers. Particularly the use of the latter has methodological and technical advantages, as expensive primary air treatment may be eliminated. However, compared to conventional organic solvent granulation methods, the costs of environmental protection and solvent recovery are eliminated. The presence of solvent residues in the product is also avoided. Energy-intensive drying processes are eliminated compared to water granulation. It is preferable to use so-called mixed systems.

In principle, the process of granulation by melting can be represented as follows: mixing adding a binder (solid state) mixing heating g

addition of binder (solid state) granulation

Φ cooling in some cases size classification granulation cooling in some cases size classification

The addition of top and moto binders can be in solid or liquid, i. E. molten state.

w With a solid additive, the fusible substance melts during the process, so this method is also called the fusion method.

In the latter method, either the solid constituents are added to which the liquid binder is added, or in accordance with the so-called fusion method, the liquid binder is pre-fed and the solids are added with stirring. In this case, the heating is carried out before the binder is added.

With Intensive Mixer Power Supply, there are different ways of doing this:

- mechanical energy through mixing devices and shredders

- contact heat by means of a casing

- radiation energy via IR or microwaves

- Injection of warm air into the place of the product

Numerous methods for preparing such formulations are also known from the patent literature.

Controlled release formulations obtainable by melting granulation are described, for example, 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 by which, at a later point in time, pellets obtained are added water-insoluble, hydrophobic, wax-like substances at a temperature at which these substances melt and cause the pellets to wrap. This process is called hot melt coating.

With the premise of thermostability of all starting materials under the existing w process conditions, granulation by melting is an interesting alternative to other granulation methods, such as granulation with organic solvents or granulation with water.

Melting pellets are thus a special form of process that produces granular particles of largely uniform size and rounded shape.

Despite the number of known soluble excipients, only a few with a graduated HLB value ( _w value on hydrophilic-hydrophobic balance) have been described, which are particularly suitable for the process of granulation by melting or melting by melting.

Representatives of the few excipients with a graduated HLB value are hydrogenated edible fats, which are marketed under the trade name Gelucire, or sorbitol fatty acid esters, which are known for example as Span. They also do not cover the wide HLB range from 1 to 16.

With classical fusible excipients, release control can generally be carried out only by means of a delay agent or a quantity thereof. Often, one binder can only be treated in combination with another soluble binder such as polyethylene glycol, since its capacity to form granules alone is not sufficient. These binders also require the addition of a lubricant and a release agent. Some of them have a waxy texture.

In the known methods of melt granulation, the often obtained and solidified granules must be subjected to costly sieving.

With the principle of retarding by coating, due to the partially brittle but also relatively thin film coatings, the compression often causes destruction of the film coatings, even when counteracted by a relatively large outer phase. The destruction of the film coat increases the release of the active substance of the tablets. This means that the release of the active substance of the tablets is most often dependent on the compression force. Often in this method the release of the active substance is regulated by the amount injected.

Depending on the formation of the film and its porosity during storage, changes in the release of the active substance may occur, for example due to subsequent solidification.

SUMMARY OF THE INVENTION

Therefore, one object of the present invention is to provide oral pharmaceutical formulations with variable adjustable release behavior, i. from quick release to slow release. For modified or sustained release dosage forms, both non-disintegrating dosage forms (so-called single units) and preferably rapidly disintegrating and modified or delayed-release granular dosage forms (so-called multiple units) should be obtained.

Another object of the present invention is to provide a process for preparing such delayed formulations, in particular by melting or melting pellets.

According to the present invention, novel, oral, pharmaceutical formulations of variable adjustable behavior are prepared which, in addition to one or more active substances, contain one or more esters of sucrose with fatty acids as the sole controlling

With the release remedy.

New pharmaceutical formulations can range from rapid-release to delayed-release dosage forms.

The pharmaceutical formulations of the invention may be administered in the form of granules, pellets, tablets, film-coated tablets, micro-tablets, dragees, capsules as well as therapeutic systems.

It has surprisingly been shown that fatty acid sucrose esters are able to control the release of the active substance in the desired manner and further improve the technological properties of the formulations according to the invention by granulation or pellet melting.

In addition, sucrose esters of fatty acids are suitable for granulating the active substance without the addition of other excipients. This makes it possible to reduce the gross mass compared to other methods in which several soluble retardants, respectively, must be used.

Sucrose esters of fatty acids, especially stearates with low HLB value, can be used at the same time as a lubricant and a release aid.

Sucrose esters of fatty acids are nonionic surfactants consisting of mono-, di-, tri-, and polyesters of sucrose as a hydrophilic component and of saturated or unsaturated fatty acids as a lipophilic component. By varying the degree of esterification and the type of fatty acids, sucrose esters with Q fatty acids of different NLB values can be obtained that affect the biopharmaceutical properties, in particular the release of the active substance, the stability of the pharmaceutical formulation obtained, as well as technological behavior.

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

Sucrose esters of fatty acids having a melting point> 30 ° C are in solid state at room temperature and have an HLB value of 1 - 16.

Sucrose esters of fatty acids are also commercially available, for example under the names Sugar ester or Sucrose, from the Mitsubishi companies (brand name Ryoto), Gathefose or Sisterna or others.

Sucrose esters of fatty acids are known in the literature, for example, they are used in accordance with US 4 844 067 to improve the surface of silk fibers, and in accordance with WO 93/17667 are used as flavor enhancers in pharmaceutical formulations.

Their main application is in the food industry. For example, sucrose fatty acid esters are used to improve the chewing mixture, to prevent the breakdown of mixtures and to denature ready-made beverages, to refine sugar, to condensed milk, and to plant based coffee grounds.

Sucrose esters of fatty acids are used, for example, in the preparation of wheat flour products as stabilizers, to improve texture, to avoid caking and sticking. They are used in dairy products to stabilize emulsions and prevent protein breakdown. Sucrose esters of fatty acids improve crystallization ability and are effective emulsifiers and reduce the viscosity of the production of fats and oils.

US 3 896 238, US 4 150 114 and US 4 046 886 show the use of sucrose esters of fatty acids in combination with alkyl sulfoxide or phosphoroxides in pharmaceutical compositions to improve the penetration of the active substance through the skin.

Sucrose esters of fatty acids, for example, include sucrose mono-octanate, monolaurate, monopalmitate, monostearate, as well as two- and triesters of these compounds.

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

WO 88/06880 claims the use of fatty acid sucrose esters for topical applications, using mono- and dialkyl sucrose esters having an HLBw value of 8 to 16 to improve skin penetration.

Sucrose cocoa, ricinoleate, laurate and stearate are preferably used.

Sucrose esters of fatty acids are used especially in cosmetic products (FR 2 421 605, JP 81 24 034, JP 81 55 306).

DE 40 03 844 describes pharmaceutical compositions which, in addition to the active substance ciclosporin, contain a saccharide fatty acid monoester and a diluent or excipient. These formulations allow for a reduction in the dosage level of ciclosporin required to achieve effective therapy and lead to a reduction of undesirable side effects. As saccharide monoester of fatty acids are especially suitable: disaccharide monoester of C 14 fatty acid and a trisaccharide monoester of C ₈ -i8mastna acid.

WO 93/00093 claims a new saber-release saber release formulation consisting of an active substance, wetting agent, and a polymeric release control coat. Sucrose ester with fatty acid is used as a wetting agent. The real delay is via polymer. The active substance is then treated with the wetting agent by extrusion or by granulation with organic solvents. The extrudates are coated with conventional polymers. As a wetting agent included, for instance, and esters of sucrose or xylose with C1 ₂ -C ₂₀ -fatty acids.

DE 198 40 152 claims a sustained release formulation comprising calcium valproate, at least one acrylic polymer and at least one sugar ester, whereby the desired delay is achieved by the acrylic polymer used. Use of the sugar ester alone has not been shown to lead to a noticeable delayed release.

The suitability of fatty acid sucrose esters in the pharmaceutical formulations according to the invention as the only delayed release control agent has been particularly surprising, since these fatty acid sucrose esters have long been known and can be readily prepared by oral pharmaceutical formulations with variable adjustable release behavior.

The fatty acid sucrose esters used according to the invention are sucrose esters of saturated or unsaturated fatty acids or mixtures thereof. Cl ₂ -C ₂₂ fatty acids are particularly suitable.

Sucrose stearates, palmitates, laurates, bechenates and oleates with an HLB value of 1-16 are preferably used.

The melting point or melting range of the sucrose fatty acid esters used according to the invention is between 30-200 ° C.

Fatty acid sucrose esters with a melting point or melting range of 40 to 150 ° C are preferably used.

An important advantage of the present invention is that the desired release behavior of the new pharmaceutical formulations can be controlled by the type and portion (amount) of w or sucrose esters of fatty acids used, respectively, by the parameters of the production method .

Low-HLB fatty acid sucrose esters are preferably used to achieve sustained release.

Sucrose esters with high HLB fatty acids are suitable for rapid or modified release behavior.

Sucrose esters of fatty acids in the pharmaceutical formulations according to the invention _w may be included from 1 to 95 wt. % relative to the granulating portion (internal phase) in the formulation. Preferably between 5 and 50 wt. %. In addition to sucrose fatty acid esters, only the active substance or mixtures of the active substance with one or more pharmaceutically useful excipients may be present in the internal phase.

Another embodiment of the invention is that granules or pellets which either contain sucrose fatty acid esters or do not contain sucrose fatty acid esters may be coated with sucrose fatty acid esters.

The content of sucrose fatty acid esters in the shell is 1-60 wt. %, preferably 3-20 wt. % relative to the coated dosage form.

Sucrose esters of fatty acids can be used alone or in some cases also in combination with other soluble excipients. The addition of one or more excipients as softeners facilitates the process. By incorporating so-called w-formers, which are excipients with certain properties, such as specific solubility or swelling ability, during the melt granulation process or melt pelletization, another modification of the release of the active substance is possible.

The oral pharmaceutical formulations of the invention may contain as active substances both water-soluble and practically water-insoluble compounds.

_w Active substances from the following sample groups are suitable, in which case the list is not exhaustive:

Analgesics / antihypoxemic (such as caffeine), analgesics / antirheumatic (such as diclofenac, morphine, tramadol, tilidine, flupirtine), anti-allergic (such as azelastine, pseudoephedrine), antiarrhythmic (such as quinidine, disopyramide, diltiazemia) such as piracetam, nicergoline, xanthinonicotinate, pentifylline, vinkamine), anti-diabetic (such as glibenclamide), anti-vomiting / dizziness (such as betahistinedimezilate, dimenhydrinate), anti-epileptic (such as carbamazepine, valproic acid, valproic acid) in), antihypertensive (such as talinolol, fosinopril, doxacosin, metoprolol, nifedipine), antihypertensive (such as norphenephrine-HCI, dihydroergotamine mezylate), bronchodilator / anti-asthmatic (such as salbutamol, terbutalinsulphidate, pyrate) such as buflomedil, naphtydrofuryl, pentoxifylline), coronary vessels (such as glyceroltrinitrate, w isosorbid mononitrate, isosorbidinitrate, molsidomine), blood lipids (such as bezafibrate, fenofibrate, xanthine, xanthine sumatriptan), muscle relaxants, against Parkinson and other agents against extrapyramidal disorders (such as levodopa / benserazide, levodopa / carbidopa) psychopharma (such as amitriptyline-HC1, venlafaxine-HC1, thioridazine-HCI, lithium carbonate, lithium acetate); thioctic acid or R-thioctic acid and its salts as dexliptotam.

The pharmaceutical formulations of the invention C preferably comprise flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine.

The pharmaceutical formulations according to the invention can be prepared according to the present invention by granulation by melting or pelletizing by melting.

For example, in a high-speed mixer, the mixture of the active substance and one or more fatty acid sucrose esters, optionally with the other excipients, is heated with stirring. The heating can be done either through a heated casing, with microwaves, radiation energy, or through the energy loss of the stirrer.

Granulation begins when the melting point of the corresponding sucrose fatty acid ester in the mixture is reached or its surface is softened or melted. Due to the initial agglomeration and the associated increase in friction, the power consumption of the motor of the agitator increases.

The interruption of granulation generally occurs when the power consumption begins to increase exponentially.

w The warm granulate is then either removed from the mixer and cooled into thin layers at room temperature or cooled in the mixer with appropriate cooling (eg cooling jacket), possibly with stirring.

According to the invention, there is also the possibility of adding molten sucrose esters with fatty acids.

Surprisingly, this achieves a very narrow granule size distribution. The granulate particles or pellets have a nearly circular and smooth surface in accordance with the process of process ς.

It is also possible to use other heating apparatus such as a fluidized bed granulator, a rotor generator.

The granules thus obtained can in some cases be sieved, optionally mixed with excipients, for example, compressed into tablets or filled into capsules. Pharmaceutically acceptable disintegrants, excipients, form release agents or the like may be used as excipients of the external phase. As a rule, the use of form stripping agents in the application of low HLB-value sucrose stearates is discontinued because low-HLB sucrose stearates themselves are also good means of form stripping.

Depending on the pharmaceutical technology purpose, for example, quick release or slow release modified formulations (multiple units or single unit) may be obtained.

Further, it has surprisingly been found that sucrose fatty acid esters are suitable as excipients for hot melt coating.

To this end, a quantity of sucrose ester of fatty acid of the same or different type is added once more to the already obtained and solidified granulate, and the mixture is again heated above the melting point, respectively, at a soft temperature, of the added fatty acid sucrose ester. . This is done by wrapping the melt of sucrose with fatty acid on the granule.

The wrapping can also happen in the presence of

V softener.

Granulates containing sucrose ester with fatty acid or pure active substances may be coated as described.

The advantages of this method are that, on the one hand, the release is adequately controlled by the coating, in particular by delaying even small amounts of sucrose fatty acid esters. On the other hand, the surface of the granules or pellets thus obtained is smoothed.

Another advantage is that the gastric juice-resistant lining is easily obtained by this method. Thus, due to the practical insolubility of sucrose esters of fatty acids in aqueous and acidic media, the release of the active substance in the acidic pH region is greatly delayed.

A special form of hot melt coating is powder coating. In this case, to the starting materials available, on the one hand, is added the well-soluble fatty acid sucrose ester by means of a suitable powder feed as a powder feeder, on the other hand a softener such as triethyl citrate is added.

This method has great cost and time savings since no drying process is required compared to the conventional aqueous coating method.

The pharmaceutical formulations thus obtained are particularly suitable for water sensitive substances such as sodium valproate.

Examples of carrying out the invention

The following examples should illustrate the subject matter of the invention without limiting it.

Example 1:

Tramadol hydrochloride with 50% sucrose stearate having

H LB-value 1 -Repture:

Substance Source sample T ramadol hydrochloride 400 g Sucrose stearate S-170 400 g

-Parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 55 ° C

The starting materials were heated with stirring in an Aeromatic-Fielder type GP1 intensive mixer at the appropriate housing temperature. When the product reaches a certain temperature, the granulation process begins. After starting the increase in the engine power consumption and the sudden rise in the temperature of the product, the granulation is interrupted and the product is removed on a sieve with a hole size of 1.4 mm and cooled at room temperature.

-Calculation: release of the active substance

Time in min. 30 60 120 180 240 360 480 Release in% in 0.1 N HCl 74.03 89.40 95.75 95.57 97.61 98.58 97.87 To pH 6.8 buffer 78.99 89.29 93.99 93.37 94.26 96.5 96.88

Release of the active substance - see Annex 1

Example 2:

Flupirtine maleate with 30% sucrose stearate with HLB value 1

-Rescription:

Substance Output quantity Flupirtine maleate 240.0 g Sucrose stearate S-170 102.9 g

-Parameters:

Output quantity 342.9 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 61.2 ° C

The preparation is carried out according to example 1.

Example 3:

Nifedipine with 30% sucrose stearate with HLB value 1 - Formulation:

Substance Source sample Nifedipine 560 g Sucrose stearate S-170 240 g

-Parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 58 ° C

- Obtained according to Example 1.

-Calculation: release of active substance

Time in hours 1 2 4 6 8 24 Release in% in purified water / 1.25% SDS 2.14 3.76 5.84 8.42 10.72 25.91

- Release of the active substance - see Annex 2

Example 4:

Nifedipine with 30% sucrose palmitate with HLB value 1 - Formulation:

Substance Source sample Nifedipine 560 g Sucrose palmitate P-170 240 g

Options:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 52 ° C

- Obtained according to Example 1

-Calculation: except awakening is active (substance Time in hours 1 2 4 6 8 24 Release in% in purified water / 1.25% SDS 4.08 7.32 11.5 16.65 21.71 49.04

- Release of the active substance - see Annex 3

Example 5:

Tablets of nifedipine granulate with 30% sucrose stearate NLB value 5 - Formulation:

Substance Source sample Nifedipine 560 g Sucrose stearate S-570 240 g

-P granulation parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature 70 ° C

- Obtained according to Example 1.

-Pill parameters:

The granulate was pressed with a circular tablet device, 6 mm in diameter, with medium-sized tablets with a gross mass of 71.4 mg.

-Calculation: release from the active substance

Time in minutes 30 60 120 180 240 Release in% in purified water / 1.25% SDS 19.85 42.44 78.30 96.61 102.88

- Release of the active substance see Annex 4.

Example 6:

Nifedipine granulate tablets with 50% sucrose stearate with HLB value 9 and 2.5% sucrose stearate with HLB value 1

-Rescription:

Substance Source sample Nifedipine 400 g Sucrose stearate S-970 380 g Sucrose stearate S-170 20 g

-P granulation parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 65 ° C

- Obtained according to Example 1.

-Pill parameters:

The granulate was compressed with a 6 mm diameter circular tablet device, medium convex tablets with a gross weight of 100 mg.

-Calculation: release of active substance

Time in minutes 30 60 120 180 240 Release in% in purified water / 2.5% SDS 20.10 40.37 73.26 94.14 102.93

- Release of the active substance see Annex 5

Example 7:

Carbamazepine with 10% sucrose stearate with HLB value 1 - Formulation:

Substance Source sample Carbamazepine 720 g Sucrose stearate S-170 80 g

-Parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 55 ° C

-The preparation is carried out according to Example 1. -Calculation: release of the active substance

Time in min. 30 60 120 180 240 360 480 Releasing. in% in modification. stomach juice 10.68 20.06 38.08 51.45 62.47 73.89 81.58

- Release of the active substance see Annex 6

Example 8:

Carbamazepine with 30% sucrose stearate HLB-value 9 - Formulation:

Substance Source sample Carbamazepine 560 g Sucrose stearate S-970 240 g

-Parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 68 ° C

-The preparation is carried out according to Example 1. -Calculation: release of the active substance

Time in min. 30 60 120 180 240 360 480 Releasing. in% in modification. stomach juice 26.09 42.27 62.65 80.58 87.38 96.56 100.84

- Release of the active substance see Annex 7

Example 9:

Carbamazepine with 50% sucrose behenate with H LB-value 3 and 2.5% triethyl citrate

-Rescription:

Substance Source sample Carbamazepine 400 g Sucrose behenate B-370 380 g Triethyl citrate 20 g

-Parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 50 ° C

The starting materials are carbamazepine and triethyl citrate in an AeromaticFielder type GP1 intensive mixer. After 1 min, sucrose behenate B-370 was added and the mixture was heated with stirring at a jacket temperature of 50 ° C. After reaching a certain temperature of the product at which the increase in power is observed, the granulate is fed to a sieve with a hole size of 1.4 mm and cooled at room temperature.

Example 10:

Carbamazepine granulate tablets with 30% sucrose stearate with NLB value 9

-Rescription:

Substance Source sample Carbamazepine 560 g Sucrose stearate S-970 240 g

-P granulation parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 68 ° C

- Obtained according to Example 1.

-Pill parameters:

The granulate, without additional additives, is compressed into a round-shaped tablet device, 13 mm in diameter, flat tablets with a gross mass of 571 mg and a compressive strength of 25 N.

-Calculation: release of active substance

Time in min. 30 60 120 180 240 360 480 Releasing. in% in modification. stomach juice 5.36 8.04 13.78 17.89 21.01 27.31 32.08

- Release of the active substance - see Annex 8

Example 11:

Carbamazepine with 20% sucrose stearate with HLB value 2 - Formulation:

Substance Source sample Carbamazepine 640 g Sucrose stearate S-970 160-9

-Parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 54 ° C

- Obtained according to Example 1.

Example 12:

Calcium valproate dihydrate with 35% acidic calcium phosphate and 30% sucrose stearate with HLB value 1

-Rescription:

Substance Source sample Calcium valproate dihydrate 280 g Calcium phosphate acid 280 g Sucrose stearate S-170 l2405

-Parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 41 ° C

- The preparation is according to Example 1, wherein the active substance calcium valproate dihydrate and acidic calcium phosphate are pre-loaded.

-Calculation: release of active substance

Time in minutes 60 240 480 Release in% at pH 3.0 64.89 75.63 85.02 Release in% at pH 6.8 36.85 61.26 71.60

- Release of the active substance - see Annex 9

Example 13:

Tablets of calcium valproate dihydrate granulate and 30% sucrose stearate with H LB-value 1 -Rescription:

Substance Source sample Calcium valproate dihydrate 560 g Sucrose stearate S-170 Zhd

-P granulation parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 55 ° C

- Obtained according to Example 1.

-Pill parameters:

The granulate was compressed rectangular, 23 mm long, 9 mm wide, to rectangular tablets with a gross mass of 951 mg and a compressive strength of 65 N.

-Calculation: release of active substance

Time in minutes 60 240 480 Release in% at pH 3.0 4.96 9.14 13.66 Release in% at pH 6.8 92.93 98.57 99.43

- Release of the active substance - see Annex 10

Example 14:

Calcium valproate dihydrate tablets and tablets

30% sucrose stearate with HLB value of 9

-Rescription:

Substance Source sample Calcium valproate dihydrate 560 g Sucrose stearate S-970 240 ^

-P granulation parameters:

Output quantity 800 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 65 ° C

- Obtained according to Example 1.

-Pill parameters:

The granulate was pressed with a tablet device rectangular, 23 mm long, 9 mm wide, to rectangular tablets with a gross mass of 951 mg and a compressive strength of 50 N.

-Calculation: release of active substance

Time in minutes 60 240 480 Release in% at pH 3.0 16.89 ! 56.55 87.96 Release in% at pH 6.8 1.75 2.77 4.34

- Release of active substance - see Annex 11a - Comparison of release of active substance with calcium valproate formulations at pH 3.0 - see Annex lib

- Comparison of release of active substance with calcium valproate formulations at pH 6.8 - see annex lie

Example 15:

Retigabine with 20% sucrose stearate HLB-value 1 - Formulation:

Substance Source sample Retigabine 800 g Sucrose stearate S-170 2G9

-Parameters:

Output quantity 1000 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 52 ° C

- Obtained according to Example 1.

-Calculation: release of active substance

Time in minutes 30 60 120 180 240 360 480 % Release in 0.1N HCl 37.23 56.71 75.81 In buffer pH 6.8 / 1% Texapon 5.71 8.77 13.82 15.79 23.60 27.99 35.62

- Release of the active substance - see Annex 12

Example 16:

Retigabine with 20% sucrose stearate with HLB-value 2

Substance Source sample Retigabine 400 g Sucrose stearate S-270 lOOg

-Parameters:

Output quantity 500 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 55 ° C

- Obtained according to Example 1.

-Calculation: release of active substance

Time in minutes 15 30 60 120 240 360 480 Release in% in 0.1 N HCl 42.28 62.58 83.53 100.97 Release in% in buffer pH 7.5 11.82 20.77 34.41 61.63 66.37

- Release of the active substance - see Annex 13

Example 17:

Retigabine with 20% sucrose stearate with HLB value of 1 and

10% sucrose stearate with HLB value of 9

-Rescription:

Substance Source sample Retigabine 210 g Sucrose stearate S-170 60 g Sucrose stearate S-970 30 g

-Parameters:

Output quantity 300 g Mixer rpm 500 rpm Crusher RPM 3000 rpm Temperature of the casing 65 ° C

- Obtained according to Example 1.

-Calculation: release of active substance

Time in minutes 15 30 60 120 180 ί 240 360 480 Release in% in 0.1 N HCl 71.49 85.13 97.93 102.82 Release in% in buffer 6.8 31.02 36.93 51.97 61.25 Ϊ 70.63 j 79.01 78.77

- Release of active substance - see Annex 14a - Comparison of release of active substance with retigabine formulations in 0.1 N HCI - see Annex 14b - Comparison of release of active substance with retigabine formulations in buffer pH 6.8 - see Annex 14c

Example 18:

Retigabine granulate tablets, 20% sucrose stearate with HLB-value 1 and 10% croscarmellose-sodium

-Rescription:

Substance Source sample Retigabine 800 g Sucrose stearate S-170 200 g

-P granulation parameters:

Output quantity 1000 g Mixer rpm 700 rpm Crusher RPM 3000 rpm Temperature of the casing 52 ° C

- Obtained according to Example 1.

-Pill parameters:

Substance Source sample Funny retigabine granulate 270 g Croscarmellose-sodium 30 g

The tablet mixture was compressed to tablets in a circular, 9 mm diameter, 45 ° phase, convex radius R13.

-Calculation: release of active substance

Time in minutes 15 30 60 120 180 240 360 480 Release in% in 0.1 N HCl 40.76 81.59 96.13 100.76 Release in% in buffer 6.8 22.20 29.80 38.95 46.49 53.58 60.85 64.69

- Release of the active substance - see Annex 15

Example 19:

Retigabine with 7% sucrose stearate with HLB-value 1

-Rescription:

Substance Source sample Retigabine 372 g Sucrose stearate S-170 28 y

-Parameters:

Output quantity 400 g Mixer rpm 1300 rpm Temperature of the casing 50 ° C

In an AeromaticFielder type GP1 intensive mixer, the starting materials are heated under stirring in a special tank equipped with PTFE-Inliner at a jacket temperature of 50 ° C. After increasing the power consumption again, the pellets are removed and cooled into thin layers at room temperature.

-Calculation: release of active ve substance Time in minutes 30 60 120 180 240 360 480 Release in pH buffer 7.5 / 2.5% Texapon 16.62 29.85 50.39 67.14 69.35 83.20 90.96

- Release of the active substance - see Annex 16

Example 20:

Retigabine with 20% sucrose stearate with an HLB value of 11

-Rescription:

Substance Source sample Retigabine 320 g Sucrose stearate S-170 80 g

-Parameters:

Output quantity 400 g Mixer rpm 1300-1100 RPM Temperature of the casing 50 ° C

- Obtained according to Example 19

-Calculation: release of active substance

Time in minutes 30 60 120 180 240 Release in pH buffer 7.5 / 2.5% Texapon 49.91 79.95 100.81 106.03 104.36

- Release of the active substance - see Annex 17

Example 21:

Retigabine with 20% sucrose stearate with an HLB value of 16

-Rescription:

Substance Source sample Retigabine 320 g Sucrose stearate S-1670 80g

-Parameters:

Output quantity 400 g Mixer rpm 1300-1100 RPM Temperature of the casing 50-55 ° C

- Obtained according to Example 19.

-Calculation: release of active substance

Time in minutes 30 60 120 180 240 Release in pH buffer 7.5 / 2.5% Texapon 41.77 68.71 92.32 99.95 101.47

- Release of the active substance - see Annex 18

Example 22:

Retigabine with 16% sucrose stearate with an HLB value of 15

-Rescription:

Substance Source sample Retigabine 336 g Sucrose stearate S-1570 64 g

-Parameters:

Output quantity 400 g Mixer rpm 1300 rpm Temperature of the casing 50-60 ° C

- Obtained according to Example 19

-Calculation: release of active substance

Time in minutes 30 60 120 180 240 Release in pH buffer 7.5 / 2.5% Texapon 64.67 89.83 99.98 101.78 100.99

- Release of the active substance - see Annex 19

Example 23:

Retigabine Pills - Recipe for pellets

Substance Source sample Retigabine 332 g Sucrose stearate S-1570 68j

-Parameters:

Output quantity 400 g Mixer rpm 1300 rpm Temperature of the casing 50-60 ° C

-Preparation according to Example 19 -Coverage recipe:

Substance Source sample Retigabine granulate with 17% sucrose stearate with HLB 15 1000 g Eudragit L30 D-55 400 g (corresponds to 120 g dry lacquer substance) Talc 60 g Triethyl citrate Jig

The granules of the 5 starting mixtures were mixed and a rotor generator was sprayed at 50 ° C and a 300 U / min slurry of Eudragite L30 D-55, talc and triethyl citrate in 536 g of purified water. The product is then dried to a temperature of 33 ° C. The granulate thus coated is homogenized at 30% by weight. % microcrystalline cellulose and 5 wt. % croscarmellose sodium for 10 min in a Turbula mixer.

The tablet mixture was compressed to rectangular tablets, 17 x 8 mm, convex, with an average compressive strength of 87 N.

Time in minutes 15 30 60 120 180 240 Release in% in 0.1 N HCl 50.3 68.8 83 88.3 In buffer pH 7.5 / 1.7% Texapon 16.1 30.4 55.7 83.4 95.2 99.2

- Release of active substance in 0.1 N HCl - see Annex 20a

- Release of active substance in buffer pH 7.5 / 1.7% Texapone - see Annex 20b

Example 24:

Hot melt coating of retigabine granulate with 10% sucrose stearate with HLB value 1

-Recipe for coated granules:

Substance Source sample Retigabine granulate (90 wt.% Retigabine and 10 wt.% Sucrose stearate S-170 500 g Sucrose stearate S-170 55.6 g

-Parameters:

Output quantity 556.6 g Mixer rpm 700 rpm Temperature of the casing 52 ° C

In an AeromaticFielder type GP1 intensive mixer, retigabine granulate is heated at a jacket temperature of 52 ° C with stirring. At a product temperature of 30 ° C, sucrose stearate S-170 is added and granulated for a further 7 minutes with the shredder turned on (3000 U / min). The coated granulate is removed and sieved through a sieve with a hole size of 1.4 mm.

-Results: particle size distribution

Particle class [cm] Quantity [%] > 1000 3.4 > 800 4.0 > 500 34.4 > 315 40.9 > 160 14.0 > 50 3.4 <50 0

Time in minutes 15 30 60 120 180 240 360 480 Release in % in 0.1 N HCl 23.8 43.6 71.4 94.4 To the pH buffer 7.5 / 2.5% Texapon 7.2 13.2 19.8 25.4 31 40.2 47.4

- Release of active substance in 0.1 N HCl - see Annex 21a

- Release of active substance in buffer pH 7.5 / 2.5% Texapone - see Annex 21b

Example 25:

Dexliptam (trometamol salt of I ⁺ -thioctic acid) with 22.7% sucrose stearate HLB-value 15

-Rescription:

Substance Source sample Dexlipotam 255J Sucrose stearate S-170 Lzig

-Parameters:

Output quantity 330 g Mixer rpm 500 rpm Crusher RPM 3000 rpm Temperature of the casing 55.0-80.0 ° C

- Obtained according to Example 1.

-Calculation: release of active substance

Time in minutes 15 30 45 Release in% in pH buffer 4.5 93 95 101

Claims (33)

Claims Claims 1. Oral pharmaceutical formulations having variable adjustable release behavior, characterized in that, in addition to one or more active substances, they also contain one or more esters of sucrose with fatty acids as the sole release controlling agent. Pharmaceutical formulations according to claim 1, characterized in that the release of the drugs varies from fast to slow. Pharmaceutical formulations according to claim 1, characterized in that the release behavior is controlled by the type and amount of one or more sucrose fatty acid esters and by the parameters of the production method. Pharmaceutical formulations according to claim 1, characterized in that the medicaments are single unit and multiple units. P Pharmaceutical formulations according to claims 1 and 4 in the form of administration granules, pellets, tablets, film-coated tablets, micro-tablets, dragees, capsules or special therapeutic systems. Pharmaceutical formulations according to claim 1, characterized in that one or more active substances are enclosed in a matrix of sucrose fatty acid esters and / or coated with sucrose fatty acid esters. Pharmaceutical formulations according to claim 6, characterized in that the granules and pellets containing the active substance or mixtures of the active substance and the sucrose fatty acid esters may be further coated with the sucrose fatty acid esters. Pharmaceutical formulations according to claim 6, characterized in that the granules and pellets containing the sucrose fatty acid esters are coated with the sucrose fatty acid esters. 9. Pharmaceutical formulations according to claim 1, X * characterized in that the sucrose esters of fatty acids are 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 sucrose esters of CX-C2-fatty acids are preferably used as esters of sucrose with fatty acids. Pharmaceutical formulations according to claims 1 and 9, characterized in that the H LB-value of the sucrose fatty acid esters used is from 1 to 16. Pharmaceutical formulations according to claims 1 and 9, characterized in that the melting point or melting range of the sucrose fatty acid esters used is in the temperature range from 30 to 200 ° C. Pharmaceutical formulations according to claim 12, characterized in that the melting point or melting range of the sucrose fatty acid esters used is preferably in the temperature range from 40 to 150 ° C. Pharmaceutical formulations according to claim 1, characterized in that the sucrose fatty acid esters are contained in the granules in an amount of from 1 to 95% by weight. %. Pharmaceutical formulations according to claim 14, characterized in that the sucrose esters of fatty acids are contained in the granules, preferably in an amount of from 5 to 50% by weight. %. Pharmaceutical formulations according to claims 1 and 8, characterized in that the sucrose esters of fatty acids are contained in the coating in an amount of 1 60 wt. % relative to the coated dosage form. Pharmaceutical formulations according to claim 16, characterized in that the sucrose esters of fatty acids are contained in the coating preferably in an amount of 3-20 wt. % relative to the coated dosage form. Pharmaceutical formulations according to claim 1, characterized in that, in addition to the sucrose fatty acid esters, additional excipients may be present. 19. Pharmaceutical formulations according to claim 18, characterized in that excipients are used as excipients, soluble binders, disintegrating excipients, release agents, film-forming and / or other commonly used excipients. 20. Pharmaceutical formulations according to claim 18, characterized in that by incorporating the pore-forming agents during the granulation process or by the pelletizing process, it is possible to further modify the release of the active substance. 21. Pharmaceutical formulations according to claim 1, characterized in that well water-soluble to practically water-insoluble active substances can be used as active substances. Pharmaceutical formulations according to claim 1 V and 21, characterized in that active substances of the exemplary domains can be used: analeptics / antihypoxemic, analgesic / anti-rheumatic, anti-allergic, antiarrhythmic, anti-dementia, anti-diabetic, anti-vomiting / anti-vertigo, anti-epileptic, antihypertensive, bronchial, antihypertensive, bronchial , anti-asthmatic, circulatory-stimulating diuretics, hypnotic / sedative, lipid-lowering coronary vessels, migraines, muscle relaxants, Parkinson's and psychotropic. Pharmaceutical formulations according to claims 1 and 21, characterized in that they contain active substances such as caffeine, diclofenac, morphine, tramadol, tilidine, flupirtine, azelastine, pseudoephedrine, quinidine, disopyramide, diltiazem, verapamil, piracinetam, nicercin pentifylline, vincamine, glibenclamide, betahistinedimezilate, dimenhydrinate, carbamazepine, valproic acid, calcium valproate dihydrate, retigabine, talinolol, fosinopril, doxazosin, metoprolol, nifedipine, norfenefine, norfenefine, norfenefine, norfenefine, norfenefine rbutalinsulfat, theophylline, furosemide, piretanide, buflomedil, naftidrofuryl, pentoxifylline, nitroglycerin, izosorbidmononitrat, izosorbiddinitrot, molsidomine, bezafibrate, fenofibrate, xanthinol, sumatriptan, levodopa, benserazide, carbidopa, amitriptyline-HCI, venlafaxine-HC1, thioridazine-HCI, lithium carbonate , lithium acetate, thioctic acid or R-thioctic acid and their salts as dexliptotam. Pharmaceutical formulations according to claims 1 and 21, characterized in that they preferably contain V flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine. Pharmaceutical formulations according to claim 24, characterized in that in addition to the active substance retigabine, the granules contain 1-95 wt. % sucrose fatty acid esters. 26. Pharmaceutical formulations according to claim 25, characterized in that, in addition to the active substance, retigabine contains preferably 5-50 wt. % sucrose fatty acid esters. P A method for the preparation of pharmaceutical formulations according to claim 1 by melting or melting pellets. A method of producing pharmaceutical formulations according to claim 27, characterized in that in a suitable device, with stirring or in a fluid bed, the starting materials are heated to a temperature at which one or more sucrose esters of fatty acids are softened, superficially they melt or melt completely and, after granulation, cool. A method for the preparation of pharmaceutical formulations according to claim 28, characterized in that one or more molten sucrose esters of fatty acids are added to a warmed powder active substance in a suitable device. 30. A method for the preparation of pharmaceutical formulations according to claim 28 or 29, characterized in that, as a suitable device, a high-speed mixer, fluid bed device or a rotary granulator may be used. A method 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 method or by the powder coating method. A method for the preparation of pharmaceutical formulations according to claim 31, characterized in that hot melt coating and powder coating employ either one or more esters of sucrose with fatty acids or in combination with softeners. 33. A method for the preparation of pharmaceutical formulations according to claim 32, characterized in that triethyl citrate, acetyl triethyl citrate, triacetin or dibutyl zebacate can be used as softeners.