SK13252002A3 - Pharmaceutical preparations - Google Patents

Abstract

The invention relates 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 or fusion pelletizing . The novel pharmaceutical formulations range from quick release to delayed release medicament forms.

Description

PHARMACEUTICAL PREPARATIONS

Technical field

I ',

The present invention relates to novel oral variable-release oral pharmaceutical compositions in the form of granules, pellets, tablets, coated tablets, microtablets, dragees, capsules or treatment systems, as well as processes for their preparation by melt granulation or melt pelletizing.

BACKGROUND OF THE INVENTION

A limited role in the use of medicaments is of limited use, ideally a daily single use.

One tablet in the morning or in the evening is taken more regularly than several tablets per day. This increased patient compliance will have a positive effect on the treatment process. In addition, the patient benefits from the reduced frequency of use associated with improved tolerability of the active ingredient. Finally, it is associated with the consequently desirable longer maintenance of effective plasma concentrations, and in particular also with uniform plasma concentrations in which the unbearable peak values have been largely averted.

In exceptional cases, a single dose can already be determined by the kinetic or dynamic properties of the active substance, such as the long elimination half-life. In most cases, this is made possible by an effective plasma concentration of between 12 and 24 hours through galenical means, such as a delayed release of the active ingredient from the administered form.

In the literature there are a number of principal solutions which, depending on the chemical and physical properties of the active substance, show advantages or disadvantages (article with review: Drug Development and Drug Development) Industrial Pharmacy, 21 (9), 1037-1070 (1998)):

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For example, the prior art is also described in one of the newer textbooks of pharmaceutical technology (Voigt, R., Pharmazeutische Technologie, Ullstein Mosby Verlag, page 293 et seq. (1993)). Accordingly, the efficacy of the drug substance can be prolonged by the following means: molecular variation such as ester or salt formation, modification of the active substance modification, particle size, selection of the appropriate excipients and methods. Some examples need to be briefly mentioned.

Matrix retarded dosage forms

They are characterized by an insoluble, or porous, skeleton of indigestible fats, waxes, polymers or also inorganic matrix formers. The active substance is incorporated in this skeleton. The active ingredient is released by diffusion, erosion or matrix decomposition.

Hydrocolloid retarded dosage forms

Here, the drug substance is incorporated into hydrocolloid matrices consisting, for example, of cellulose derivatives. After use, a gel is formed by the digestive fluids through which the active substance diffuses more or less rapidly depending on the surface and the viscosity of the gel.

Coated (membrane controlled) retarded dosage forms

Here, the active agent particles or dosage forms are coated with a barrier. Diffusion through the diffusion barrier determines how quickly the release of the active agent follows. Plasticizers or pore formers can be added to increase the diffusion rate.

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Effect of specific surfaces

In the case of poorly water-soluble active substances, there is generally a clear relationship between the rate of dissolution and the specific surface area. By targeted crystallization of the active ingredient, sieving or milling, a defined particle size distribution and thus a specific surface area can be adjusted. The larger the particles, the smaller the specific surface area and the slower the release of the active ingredient.

Mixed forms from diffusion, erosion and dissolution

Further, dosage forms are known whose delayed release of the active ingredients consists of a combination of diffusion, erosion and dissolution.

One particularly interesting and very variable process for the release of the active substances is melt granulation. By melt granulation or thermoplastic granulation is meant a process in which granulate formation is carried out using low melting temperature components as well as under the influence of thermal energy (Ludemann, J., APV-Kurs, 231 from 17-18 June 1996).

There are two subtypes:

At the wet granulation subtype, the process temperature is higher than the melting point of the linking component. It is available in granulation as a liquid or semi-solid component. Cooling enters the drying site for melt granulation.

The sintered granulation subtype is referred to when the process temperature does not reach the melting point of the linking component. Here, only one local melting takes place on the surface of the particles so that the surfaces penetrate one another (Voight, R., Lehrbuch der pharmazeutischen Technologie, Verlag Chemie, page 159 (1984)).

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Low melting point components may be an important component or excipient. For stabilization reasons, the melting points of the substances are generally above 35 ° C. Substances with a melting point in the range of 50 to 90 ° C are most often used. Known active substances as fusible substances are phenyl salicylate, ibuprofen, α-lipoic acid and meprobamate. Water-soluble, swellable and lipophilic substances are used as fusible excipients. For example, macrogol, polyvidone and polymethylacrylic acid derivatives are hydrophilic. Hydrocarbons (paraffin), waxes, fats and fatty acids are examples of lipophilic excipients (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)):

Melting granulation is generally carried out in fluid bed granulators, fluid bed centrifuges or fast running intensive mixers. Especially the use of the latter has technical advantages for the process, where expensive air treatment may be omitted. In contrast to conventional organic solvent granulation methods, there is no need for environmental protection and solvent recovery costs. Also solvent residues in the product are omitted. Compared to aqueous granulation, energy-intensive drying processes are eliminated. The use of so-called " single pot system.

Generally, the granulation dissolution process can be illustrated as follows:

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mixing

Add binder (solid state) <=

Warm up <=

Granulation <=

Cooling <=

Possibly sorting

Mixing <=

Warm up <=

Addition of binder (liquid aggregate condition) <=

Granulation <=

chill

Possibly sorting

The addition of the meltable binder can be carried out in solid or liquid state, i.e. in the molten state.

When added in the solid state, the meltable material melts during the process, hence this process is also called the melt process.

In the latter process, either solid components are added to which a liquid binder is added or as corresponding to so-called &quot; in a fusion process, a liquid binder composition is presented and the solid admixed. This is followed by heating before adding the binder.

The energy supply can be followed in different ways with vigorous mixing:

- mechanical energy through mixing tools and chisel

- contact heat through the shell

radiant energy via infrared or microwaves, and

- supplying warm air to the product bed.

A large number of methods of making such compositions are also known from the patent literature. Controlled-release preparations which may be manufactured

985 / B by the melt granulation method 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 in which water-soluble, hydrophobic, wax-like substances are added to the formed pellets at a later stage of production at one temperature, in which they melt and result in coating of the pellets. This process is called "hot melt coating".

Assuming the thermal stability of all the starting materials involved in the process under the prevailing process conditions, melt granulation is an interesting alternative to other granulation methods, such as granulation with organic solvents or granulation with water.

Here, melt pelletizing is a special embodiment of the process in which the granulate particles are made in a far-reaching uniform size and rounded shape.

Despite the large number of known fusible excipients, only some of the excipients with graduated HLB (hydrophilic-lipophilic balance) values are described which are particularly suitable for the melt granulation method and the melt pelletization method.

Representatives of these few HLB graded excipients are hydrogenated edible fats under the trade name Gelucire or sorbitol fatty acid esters known as Span. However, neither do they cover a wide range of HLBs from 1 to 16.

With conventional fusible auxiliaries, the grading of the release can generally only be tested with respect to the choice of retardant or resp. in terms of quantity. More often, the binder composition is allowed to be processed only in combination with another meltable binder composition such as polyethylene glycol because its capacity to form granules alone is not sufficient. For this purpose, the binder means require the addition of a glidant to prevent sticking to the mold. Some have a waxy consistency. In known melt granulation processes, the resulting a

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Podrob subjected the solidified granules to costly screening and crushing.

Under the principle of coating retardation, due to the partial brittleness but also the relative thinness of the film wrap when compressed, destruction of the film wrap is often observed unless this is prevented by the relatively high outer phase. When the film coating is destroyed, the release of the active substance from the tablets is increased. This means that the release of the active ingredient from these tablets is most dependent on the compressive force. Often, in this process, the amount of active substance released is adjusted through the amount injected during manufacture.

Depending on the film formation and porosity, there may be changes in the release of the active ingredient during storage, for example due to subsequent curing.

SUMMARY OF THE INVENTION

It is therefore an object of the present invention to provide oral pharmaceutical formulations having a variable, adjustable release pattern, i.e., from fast to slow release. For modified or delayed release dosage forms, it should also be possible to produce non-disintegrating dosage forms (single units), preferably or rapidly disintegrating and modified or slow release dosage forms from granules (multiple units) ,,).

It is a further object of the present invention to provide methods of making such sustained release formulations, in particular melt granulation or melt pelletizing.

According to the present invention, novel orally adjustable pharmaceutical release formulations are provided which contain one or more sucrose fatty acid esters in addition to one or more active ingredients as the sole release controlling agent. The new pharmaceutical preparations are fast-release or slow-release dosage forms.

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The pharmaceutical compositions of this invention may be administered in the form of granules, pellets, tablets, coated tablets, microtablets, dragees, capsules, as well as treatment systems.

Surprisingly, fatty acid esters of sucrose are in a situation where they control the release of the active ingredient in a desirable manner, thereby improving the technological properties in the manufacture of the compositions produced by melt granulation or melt pelletizing.

The sucrose fatty acid esters are also suitable, inter alia, for the granulation of the active ingredient also without the addition of other excipients. This makes it possible to reduce the total mass compared to other methods in which a plurality of fusible retarding agents or binder means must be involved. Sucrose fatty acid esters, in particular a low HLB stearate, can be used simultaneously as a glidant and an anti-sticking agent.

Sucrose fatty acid esters are nonionic surfactants which consist of mono-, di-, tri- and polyesters of sucrose as hydrophilic components and saturated or unsaturated fatty acids as lipophilic components. By varying the degree of esterification and the type of fatty acids, sucrose fatty acid esters can be produced with different HLB values which have an effect on the biopharmaceutical properties, in particular on the release of the active substance, on the stability of the pharmaceutical preparations produced and on technological processes. They are nontoxic, biodegradable, stable in taste and smell as well as in storage. Sucrose fatty acid esters with a melting point of more than 30 ° C are in a solid aggregation state at room temperature and have an HLB value of 1 to 16.

Sucrose fatty acid esters are also marketed, for example, under the names Sugarester or Sucroseester, inter alia from Mitsubishi (trademark Ryoto), Gattefosse or Sisterna, or others.

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Fatty acid esters of sucrose are known in the literature, so U.S. Pat. No. 4,844,067 are used to improve the surface of silk yarns as well as in WO 93/17667 as a flavor enhancer in pharmaceutical formulations.

Their main use is in the food industry. Thus, sucrose fatty acid esters are used, for example, to improve the chewing gum mixture, to prevent blending and denaturation of finished beverages, in refining sugar, in condensed milk, and in bleaching coffee.

In the manufacture of wheat flour products, sucrose fatty acid esters are used, for example, as stabilizers, to improve texture, to prevent baking and sticking. For dairy products, to stabilize emulsions and prevent protein degradation. Fatty acid esters of sucrose improve crystallization, are effective emulsifiers and reduce viscosity in the production of fats and oils.

U.S. Pat. No. 3,896,238, 4,150,114 and 4,046,886, the use of sucrose fatty acid esters in combination with alkyl sulfoxide or phosphorus oxides in pharmaceutical compositions has been shown to improve penetration of the active substance through the skin. Special sucrose fatty acid esters are, for example, called sucrose monoctanoate, -monolaurate, -monopalmitate, -monostearate, and the di- and triesters of these compounds. JP 81 75 437 has shown the use of sucrose fatty acid esters with an HLB value of 1 to 5 as a basis for suppositories.

WO 88/06880 claims the use of sucrose fatty acid esters in a typical application, whereby mixtures of mono- and dialkyl sucrose esters having an HLB of from 8 to 16 are employed to improve penetration through the skin.

Preferably, sucrose cocoate, sucrose ricinoleate, sucrose laurate and sucrose stearate are used.

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

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DE 40 03 844 describes pharmaceutical compositions which, in addition to the active ingredient cyclosporine, comprise a sucrose fatty acid monoester and a diluent or carrier. These compositions make it possible to reduce the required dose level of cyclosporine to obtain effective therapy and thus to reduce unwanted side effects. Particularly suitable as the monoester of sucrose fatty acid are: a monoester of a fatty acid with two molecules of sucrose of 6 to 14 carbon atoms in the fatty acid moiety and a monoester of a fatty acid with three molecules of sucrose of 8 to 18 carbon atoms in the fatty acid moiety.

WO 93/00093 claims a novel retarding composition for diltiazem in the form of spheres, which consists of an active substance, a wetting agent and a polymerization sheath for controlling release. Fatty acid esters of sucrose are used as humectants. The actual deceleration occurs by means of a polymer. In this case, the humectant with the active substance is processed by extrusion or by granulation with an organic solvent. Coating of the extrudate occurs with conventional polymers. The humectant also includes, for example, a C12-C20 fatty acid ester in the fatty acid moiety or xylose.

In DE 198 40 152, a retarding agent comprising calcium valproate, at least one acrylic polymer and at least one sugar ester is used, the desired acrylic polymer to achieve the desired retardation. It has been shown that the sugar ester alone does not cause any slowdown worthy of mention.

The suitability of sucrose fatty acid esters in accordance with the pharmaceutical compositions of the present invention as the sole release of control agents has been so surprising, since sucrose fatty acid esters have been known for a long time, and for the next time they can be used with them. in a simple manner to produce oral pharmaceutical formulations with a variable adjustable release pattern.

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In accordance with the present invention, the sucrose fatty acid esters used are sucrose esters of saturated or unsaturated fatty acids or mixtures thereof. Particularly suitable are fatty acids having 12 to 22 carbon atoms. Preferably, sucrose stearate, sucrose palmitate, sucrose laurate, sucrose behenate, and sucrose oleate are used with an HLB of from 1 to 16.

The melting point or melting range of the sucrose fatty acid esters used according to the invention is from 30 to 200 ° C. Preferably, sucrose fatty acid esters with a melting point or melting range of 40 to 150 ° C are employed.

An essential advantage of the present invention is that the desired method of release of new pharmaceutical preparations can be controlled with respect to the type and proportion of the sucrose fatty acid esters employed or employed, optionally the method and process parameters of the production method.

Low HLB sucrose fatty acid esters are preferably employed to prolong the delayed release. High HLB sucrose fatty acid esters are preferably suitable for rapid or modified release.

Sucrose fatty acid esters may be available in the pharmaceutical compositions of the present invention with a proportion of from 1 to 95% by weight based on the granular fraction (internal phase) in the formulation. It is preferred to use a proportion of from 5 to 50% by weight. In addition to sucrose fatty acid esters, alone or mixtures of the active ingredient with one or more pharmaceutically acceptable excipients may be present in the internal phase of the active ingredient.

A further embodiment of the invention consists in that the granules or beads which either contain sucrose fatty acid esters in the granulate or contain no sucrose fatty acid ester and can be coated with sucrose fatty acid esters. Share of esters

The 985 / B sucrose fatty acids in the coating are 1 to 60% by weight, preferably 3 to 20% by weight, based on the coated dosage form.

The sucrose fatty acid esters may be used alone or optionally in combination with other fusible excipients. Partially preferred for this process is the addition of one or more excipients as plasticizers. Regarding the incorporation of the so-called. pore-forming substances, which are excipients with certain properties, such as characteristic solubility or swelling, during the melt granulation or melt pelletization process, further modification of the release of the active substance is possible.

According to the present invention, oral pharmaceutical preparations as active ingredients may well contain both water-soluble and practically water-insoluble compounds.

Active substances from the following indication groups are suitable for this purpose:

analeptics / antihypoxemics (such as caffeine), analgesics / anti-rheumatic drugs (such as diclofenac, morphine, tramadol, tilidine, flupirtine), antiallergics (such as acelastine, pseudoephedrine), antiarrhythmic agents (such as quinidine, disopyramine, disopyramine, disopyramide, dopyramol, disopyramide, dopyramol, , xanthinonicotinate, pentifylline, vincamine), antidiabetics (such as glibenclamide), antiemetics / antivertiginosis (such as betahistidine diaimesylate, dimenhydrinate), anti-epileptics (such as carbamazepine, valproic acid, metallvalproate dihydrate, fosinolpoline, retinaboline) , antihypotonic agents (such as norfenephrine hydrochloride, dihydroergotamine mesilate), broncholytics / antiasthmatics (such as salbutamol, terbutaline sulphate, theophylline), diuretics (such as furosemide, piretanide), blood flow enhancing agents (such as bufrofonedin, pentoxide, naphthidol, naphthidol) isosorbide dinitrate, molsidom hypolipidemics (such as bezafibrate, fenofibrate, xantinol), anti-migraine agents (such as sumatriptan), muscle relaxants, anti-parkinsonian drugs and other anti-extrapyramidal disorders (such as levodopa / benserazide, levodopa / carbidopa), psychopharmaceuticals (such as hydrochloride amide) , hydrochloride

985 / B thioridazine, lithium carbonate, lithium acetate); thioctic acid or Rthioctic acid and its salts, such as dexlipotam, but the calculation is not limited thereto.

According to the invention, the oral pharmaceutical preparations comprise in particular flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine.

According to the present invention, oral pharmaceutical preparations can be prepared according to the present invention by melt granulation or melt pelletizing. For example, a mixture of the active ingredient and one or more esters of fatty acids with sucrose or other excipients is heated in a high-speed mixer with stirring. The heating can follow either by means of a heating mantle, microwave, radiation energy, but also by supplying energy from the mixer.

When the melt temperature of the sucrose fatty acid esters just used in the mixture is reached or its surface softens or melts, granulation begins. Due to the set agglomeration and the associated increase in friction, the power input from the stirring motor increases. The end of the granulation usually follows when the power take-up starts to increase exponentially. Thereafter, the hot molten granulate is either removed from the mixer and cooled in thin layers at room temperature or cooled with a suitable cooling device (for example a cooling jacket) in the mixer, optionally with stirring. According to the invention, it is also possible to add the fatty acid esters of sucrose in the molten state.

Surprisingly, this results in a very narrow size distribution of the granulate. The granular or pellet particles have, depending on the process, almost spherical or flat surfaces.

It is likewise possible to use other heating devices, such as fluid bed granulators or rotor granulates.

The granules thus formed can optionally be screened, optionally mixed with external phase excipients and, for example, compressed into tablets or filled into capsules. External phase excipients may be used

985 / B conventional disintegrating agents, optionally disintegrating aids, fillers, anti-sticking agents or the like. As a rule, it can be resisted by a stick-inhibiting agent using low-HLB sucrose stearates, since low-HLB sucrose stearates are also stick-inhibiting agents.

Depending on the pharmaceutical technology objective, for example, rapid release or modified to slow release formulations ("multiple units" or "single units") can be produced.

It has further surprisingly been found that sucrose fatty acid esters are suitable as hot melt extrusion aids. To this end, a plurality of sucrose fatty acid esters of the same or a different type are added to the molten granules already prepared and irradiated, and the mixture is heated once more above the melting point or the softening temperature of the added sucrose fatty acid esters. This results in a coating of molten sucrose fatty acid esters on the molten granulate. The coating may also follow in the presence of a plasticizer. Likewise, sucrose-free fatty acid ester granules or pure active ingredients can be coated in the kind and method described.

The advantages of this method are that, firstly, the coating achieves a sufficient release control, in particular retardation, already with a small proportion of sucrose fatty acid esters. Next, the surface of the granulate or bead so produced is smoothed.

A further advantage is that gastric juice resistant coatings can be produced in a simple manner. There is thus the possibility of greatly retarding the release of the active ingredient in an acidic pH environment due to the practical insolubility of sucrose fatty acid esters in aqueous and acidic environments.

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Here, powder coating is a special form of hot melt coating process. Here, on the one hand, good free-flowing fatty acid esters of sucrose are metered in by means of a suitable powder feeder and, on the other hand, plasticizers, such as triethyl citrate, to the starting materials present. This method is characterized by high cost and time savings, for which no drying methods are required in comparison with the conventional aqueous coating method. Particularly suitable are pharmaceutical formulations prepared in this manner for water-sensitive active substances, such as sodium valproate.

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

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Tramadol hydrochloride with 50% sucrose stearate with an HLB value of 1

substance Infill Tramadol hydrochloride 400 g S-170 Sucrose Stearate 400 g

parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature 55.0 ° C

The starting materials are heated in an Aeromatic-Fielder GP1-type intensive mixer at the appropriate jacket temperature with stirring. When the specified product temperature is reached, the granulation process begins. After reaching ascension

985 / B receiving the power of the stirring motor and the sudden rise in temperature of the product, the granulation is interrupted and the product is removed, sieved through a 1.4 mm sieve and cooled at room temperature.

Evaluation: 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 in buffer pH 6.8 78.99 89,29 93,99 93.37 94.26 96.5 96.88

For release of the active substance see FIG. First

Example 2

Flupirtine maleate with 30% sucrose stearate with an HLB value of 1

substance Infill Flupirtine maleate 240.0 g S-170 Sucrose Stearate 102.9 g

parameters:

load 342.9 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature 61.2 ° C

Production takes place according to Example 1.

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Example 3

Nifedipine with 30% sucrose stearate with an HLB of 1

recipe:

substance Infill nifedipine 560 g S-170 Sucrose Stearate 240 g

parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature High: 55 ° C

Production takes place according to Example 1.

Evaluation: Release of the 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

For release of the active substance see FIG. Second

Example 4

Nifedipine with 30% sucrose palmitate with an HLB of 1

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recipe:

substance Infill nifedipine 560 g S-170 Sucrose Stearate 240 g

parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature Deň: 32 ° C

Production takes place according to Example 1.

Evaluation: Release of the 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

For release of the active substance see FIG. Third

Example 5

Nifedipine granulate melt tablets with 30% sucrose stearate having an HLB value of 5

recipe:

substance Infill nifedipine 560 g S-570 Sucrose Stearate 240 g

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Granulation parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature 70 ° C

Production takes place according to Example 1.

Tableting parameters:

The granulate, in conjunction with a tableting tool, is compressed into tablets having a gross weight of 71.4 mg and a diameter of 6 mm, which are round and in a central camber.

Evaluation: Release of the active substance

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

For release of the active substance see FIG. 4th

Example 6

Tablets of nifedipine granulate melt with 50% sucrose stearate value

HLB 9 and 2.5% sucrose stearate with an HLB of 1

recipe:

substance Infill nifedipine 400 g S-970 Sucrose Stearate 380 g S-170 Sucrose Stearate 20 g

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Granulation parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature 68 ° C

Production takes place according to Example 1.

Tableting parameters:

The granulate, in conjunction with a tableting tool, is compressed into tablets having a diameter of 6 mm and a 100 mg thick weight, which are round and in a central camber.

Evaluation: Release of the active substance

Time in min 30 60 120 180 240 Release in% in purified water / 2.5% SDS 20,10 40,37 73.26 94.14 102.93

For release of the active substance see FIG. 5th

Example 7

Carbamazepine with 10% sucrose stearate with an HLB value of 1

substance Infill carbamazepine 720 g S-170 Sucrose Stearate 80 g

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parameters;

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature High: 55 ° C

Production takes place according to Example 1.

Evaluation: Release of the active substance

Time in min 30 60 120 180 240 360 480 Release in% v modified intestinal juice 10.68 20,06 38.08 51,45 62,47 73.89 81.58

For release of the active substance see FIG. 6th

Example 8

Carbamazepine with 30% sucrose stearate with HLB 9 value.

substance Infill carbamazepine 560 g S-970 Sucrose Stearate 240 g

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parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature 68 ° C

Production takes place according to Example 1.

Evaluation: Release of the active substance

Time in min 30 60 120 180 240 360 480 Release in% v modified intestinal juice 26,09 42.27 62.65 80.58 87.38 96,56 100.84

For release of the active substance see FIG. 7th

Example 9

Carbamazepine with 50% sucrose behenate with HLB 3 value and 2.5% triethyl citrate

recipe:

substance Infill carbamazepine 400 g Sucrose behenate B-370 380 g Triethyl citrate 20 g

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parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature Deň: 32 ° C

In the Aeromatic-Fielder GP1 type intensive mixer, the starting materials carbamazepine and triethyl citrate are mixed. After stirring for 1 minute, sucrose behenate B-370 was added and the mixture was heated to a jacket temperature of 50.0 ° C with stirring. After reaching a certain product temperature at which an increase in performance can be observed, the granulate is sieved through a 1.4 mm sieve and cooled to room temperature.

Example 10

Tablets of carbamazepine granulate with 30% sucrose stearate having an HLB value of 9

recipe:

substance Infill carbamazepine 560 g S-970 Sucrose Stearate 240 g

Granulation parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature 68 ° C

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Production takes place according to Example 1.

Tableting parameters:

The granulate is compressed into tablets with a diameter of 13 mm, a gross weight of 571 mg and a compressive strength of 25 N, which are round, without further additives with a tableting tool.

Evaluation: Release of the active substance

Time in min 30 60 120 180 240 360 480 Release in% v modified intestinal juice 5.36 8.04 13.78 17.89 21.01 27.31 32.08

For release of the active substance see FIG. 8th

Example 11

Carbamazepine with 20% sucrose stearate with HLB 2 value

substance Infill carbamazepine 640 g Sucrose stearate S-270 160 g

parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature High: 34 ° C

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Production takes place according to Example 1.

Example 12

Calcium valproate dihydrate with 35% dibasic calcium phosphate and 30% sucrose stearate with an HLB of 1

recipe:

substance Infill Calcium valproate dihydrate 280 g Calcium hydrogen phosphate 280 g S-170 Sucrose Stearate 240 g

parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature High: 34 ° C

The preparation is carried out according to Example 1, wherein the active substance calcium valproate dihydrate and calcium hydrogen phosphate are provided.

Evaluation: Release of the active substance

Time in min 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

For release of the active substance see FIG. 9th

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Example 13

Melt granules of calcium valproate dihydrate and 30% sucrose stearate with an HLB of 1

recipe:

substance Infill Calcium valproate dihydrate 560 g S-170 Sucrose Stearate 240 g

Granulation parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature High: 55 ° C

Production takes place according to Example 1.

Tableting parameters:

The granulate is compressed into a longitudinal tablet with a tablet weight of 951 mg and a compressive strength of 65 N, a length of 23 mm and a width of 9 mm. Evaluation: Release of the active substance

Time in min 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

For release of the active substance see FIG. 10th

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Example 14

Melt granules of calcium valproate dihydrate and 30% sucrose stearate with an HLB of 9

recipe:

substance Infill Calcium valproate dihydrate 560 g S-970 Sucrose Stearate 240 g

Granulation parameters:

load 800 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature 68 ° C

Production takes place according to Example 1.

Tableting parameters:

The granulate is compressed into a longitudinal tablet with a tablet weight of 951 mg, a compressive strength of 50 N, a length of 23 mm and a width of 9 mm.

Evaluation: Release of the active substance

Time in min 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

For release of the active substance see FIG. 11a.

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Comparison of drug release from calcium valproate formulations in pH 3.0 environments see Fig. 11b.

Comparison of the release of the active substance from calcium valproate formulations in a pH 6.8 environment, see FIG. 11c.

Example 15

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

substance Infill retigabine 800 g S-170 Sucrose Stearate 200 g

parameters:

load 1000 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature Deň: 32 ° C

Production takes place according to Example 1.

Evaluation: Release of the active substance

Time in min 30 60 120 180 240 360 480 Release in% in 0,1 N 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

For release of the active substance see FIG. 12th

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Example 16

Retigabine with 20% sucrose stearate with HLB 2 value

substance Infill retigabine 400 g Sucrose stearate S-270 100 g

parameters:

load 500 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature High: 55 ° C

Production takes place according to Example 1. Evaluation: Release of the active substance

Time in min 15 30 60 120 180 360 480 Release in% at 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 4.74 61,63 66.37

For release of the active substance see FIG. 13th

Example 17

Retigabine with 20% sucrose stearate with HLB 1 and 10% sucrose stearate with HLB 9

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recipe:

substance Infill retigabine 210 grams S-170 Sucrose Stearate 60 g S-970 Sucrose Stearate 30 g

parameters:

load 300 g Mixer revolutions per minute 500 Chopper revolutions per minute 3000 Sheath temperature 68 ° C

Production takes place according to Example 1. Evaluation: Release of the active substance

Time in min 15 30 60 120 180 240 360 480 Release in% in 0.1 N HCl 71.49 85.13 97.93 102.82 Release in% in buffer pH 6.8 31.02 36.93 51.97 61,25 70.63 79.01 78,77

For release of the active substance see FIG. 14a.

For a comparison of drug release from recipes containing retigabine in 0.1 N HCl, see FIG. 14b.

For a comparison of the release of the active ingredient from the retigabine-containing formulations in a pH 6.8 buffer, see FIG. 14c.

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Example 18

Tablets of granulate with retigabine, 20% sucrose stearate with an HLB of 1 and 10% croscarmellose sodium

recipe:

substance Infill retigabine 800 g S-170 Sucrose Stearate 200 g

Granulation parameters:

load 1000 g Mixer revolutions per minute 700 Chopper revolutions per minute 3000 Sheath temperature Deň: 32 ° C

Production takes place according to example 1. Parameters for tabletting:

substance Infill Retigabine retarded granulate (see above) 270 g croscarmellose sodium 30 g

The tablet mixture is compressed with a tablet tool into round tablets, 9 mm diameter, 45 degree bevelled edge, radius of curvature R 13.

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Evaluation: Release of the active substance

Time in min 15 30 60 120 180 240 360 480 Release in% in 0.1 N HCl 40,76 81.59 96.13 100.76 In buffer pH 6.8 / 1% Texapon 22.20 29.80 38.95 46,49 53,58 60.85 64.69

For release of the active substance see FIG. 15th

Example 19

Retigabine with 7% sucrose stearate with an HLB value of 1

substance Infill retigabine 372 g S-170 Sucrose Stearate 28 g

parameters:

load 400 g Mixer revolutions per minute 1300 Sheath temperature Deň: 32 ° C

In an Aeromatic-Fielder GP1-type intensive mixer, the starting materials are heated with stirring in a special vessel equipped with a PTFE-Inliner at a jacket temperature of 50.0 ° C.

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Evaluation: Release of the active substance

Time in min 30 60 120 180 240 360 480 Release in buffer pH 7.5 / 2.5% Texapone 16.62 29.85 50.39 67.14 69.35 83.20 90.96

For release of the active substance see FIG. 16th

Example 20

Retigabine with 20% sucrose stearate with HLB 11 value

substance Infill retigabine 320 g S-1170 sucrose stearate 80 g

parameters:

load 400 g Mixer revolutions per minute 1300 to 1100 Sheath temperature Deň: 32 ° C

Production is carried out according to Example 19. Evaluation: Release of the active substance

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

For release of the active substance see FIG. 17th

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Example 21

Retigabine with 20% sucrose stearate with HLB 16 value

substance Infill retigabine 320 g S-1670 sucrose stearate 80 g

parameters:

load 400 g Mixer revolutions per minute 1300 to 1100 Sheath temperature Mp 50-55 ° C

Production takes place according to Example 19.

Evaluation: Release of the active substance

Time in min 30 60 120 180 240 Release in buffer pH 7.5 / 2.5% Texapon 41,77 68.71 92.32 99.95 101.47

For release of the active substance see FIG. 18th

Example 22

Retigabine with 16% sucrose stearate with HLB 15 value

substance Infill retigabine 336 g S-1570 sucrose stearate 64 g

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parameters:

load 400 g Mixer revolutions per minute 1300 Sheath temperature Mp 50-60 ° C

Production is carried out according to Example 19. Evaluation: Release of the active substance

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

For release of the active substance see FIG. 19th

Example 23

Retigabine tablets

Recipe of soluble granulate:

substance Infill retigabine 332 g S-1570 sucrose stearate 68 g

parameters:

load 400 g Mixer revolutions per minute 1300 Sheath temperature Mp 50-60 ° C

Production takes place according to Example 19.

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Cover recipe:

substance Infill Retigabine granulate melt with 17% sucrose stearate with an HLB value of 15 1000 g Eudragit L 30 D-55 400 g (equivalent to 120 g of paint dry matter) talc 60 g Triethyl citrate 12 grams

The 5-batch granulate melt was combined and sprayed with a slurry of Eudragit L 30 D-55, talc and triethyl citrate in 536 g purified water in a rotary granulator at an air inlet temperature of 50 ° C at 300 rpm. It is then dried up to a product temperature of 33 ° C.

The granulate thus coated is homogenized with 30% by weight of microcrystalline cellulose and 5% by weight of croscarmellose sodium for 10 minutes in a turbula.

The tablet mixture is compressed into longitudinal 17x8 mm domed tablets with an average compressive strength of 87 N.

in Time in min 15 30 60 120 180 240 Release in% in 0.1 N HCl 50.3 68.8 83.0 88.3 In pH 7.5 / 1.7% Texapon buffer 16.1 30.4 55.7 83.4 95.2 99.2

Release of the active ingredient in 0.1 N HCl see FIG. 20a.

Release of the active ingredient in a buffer of pH 7.5 / 1.7% Texapone, see FIG. 20b.

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Example 24

Hot melt coating of melt granulate with retigabine with 10% sucrose stearate with an HLB value of 1 Coated granulate granules:

substance Infill Retigabine granulate melt (90 wt. % retigabine and 10 wt. sucrose stearate S-170) 500 g S-170 Sucrose Stearate 55,6 g

parameters:

load 555.6 g Mixer revolutions per minute 700 Sheath temperature Deň: 32 ° C

In an Aeromatic-Fielder GP1 type intensive mixer, the retigabine granulate melt is heated to a jacket temperature of 52 ° C with stirring. S-170 sucrose stearate is added at a product temperature of 30 ° C and granulated for a further 7 minutes with the chisel on (3000 rpm). The coated granulate is removed and sieved through a 1.4 mm sieve.

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Results of grain size distribution

Grain class (pm) Percentage (%) > 1000 3.4 > 800 4.0 > 500 34.4 > 315 40.9 > 160 14.0 > 50 3.4 <50 0

Time in min 15 30 60 120 180 240 360 480 Release in% in 0,1 N HCl 23.8 43.6 71.4 94.4 In buffer pH 7.5 / 2.5% Texapon 7.2 13.2 19.8 25.4 31.0 40.2 47.4

Release of the active ingredient in 0.1 N HCl see FIG. 21a.

Release of the active ingredient in pH 7.5, 2.5% Texapone buffer see Fig. 21b.

Example 25

Dexlipotam (trometamol salt of R + thioctic acid) with 22.7% sucrose stearate with HLB 15

recipe:

substance Infill Dexlipotam 255 g S-170 Sucrose Stearate 75 g

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parameters:

load 330 g Mixer revolutions per minute 500 Chopper revolutions per minute 3000 Sheath temperature 55.0 to 80.0 ° C

Production takes place according to Example 1.

Evaluation: Release of the active substance

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

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Claims (33)

PATENT CLAIMS Oral pharmaceutical formulations with a variable adjustable release method, characterized in that, in addition to one or more active substances, they contain one or more sucrose fatty acid esters as the sole release control agent. Pharmaceutical preparations according to claim 1, characterized in that they are fast-to-slow-release dosage forms. Pharmaceutical preparations according to claim 1, characterized in that the release method can be controlled by the type and proportion of sucrose fatty acid esters and the process parameters of the production process. Pharmaceutical preparations according to claim 1, characterized in that they are unit or multiple dosage forms. Pharmaceutical preparations according to claims 1 and 4, characterized in that they are in the form of orally administered forms such as granules, pellets, tablets, coated tablets, micro-tablets, dragees, capsules or special therapeutic systems. Pharmaceutical preparations according to claim 1, characterized in that one or more active substances are incorporated into the matrix of sucrose fatty acid esters and / or are coated with sucrose fatty acid esters. 31,985 / B Pharmaceutical preparations according to claim 6, characterized in that the granules or pellets containing the active substance or mixtures of the active substance and sucrose fatty acid esters can additionally be coated with sucrose fatty acid esters. Pharmaceutical preparations according to claim 6, characterized in that the sucrose-free fatty acid ester granules or pellets are coated with sucrose fatty acid esters. Pharmaceutical preparations according to claim 1, characterized in that the sucrose fatty acid esters used consist of mono-, di-, trial or polyesters of saturated and / or unsaturated medium to long chain sucrose. Pharmaceutical preparations according to claim 9, characterized in that sucrose fatty acid esters of C 12 -C 22 are preferably used as sucrose fatty acid esters. Pharmaceutical preparations according to claims 1 and 9, characterized in that the HLB value of the sucrose fatty acid esters used is 1 to 16. Pharmaceutical preparations according to claims 1 and 9, characterized in that the sucrose fatty acid esters used have a melting point or a melting range in the range from 30 to 200 ° C. Pharmaceutical preparations according to claim 12, characterized in that the sucrose fatty acid esters used have a melting point or 31985 / B melting range preferably from 40 to 150 ° C. Pharmaceutical preparations according to claim 1, characterized in that the fatty acid esters of sucrose with a proportion of 1 to 95% by weight are contained in the granulate. Pharmaceutical preparations according to claim 14, characterized in that the fatty acid esters with sucrose are contained in the granulate preferably in a proportion of from 5 to 50% by weight. Pharmaceutical preparations according to claims 1 and 8, characterized in that the coating comprises sucrose fatty acid esters with a proportion of from 1 to 60% by weight, based on the coated dosage forms. Pharmaceutical preparations according to claim 16, characterized in that the coating comprises fatty acid esters of sucrose, preferably in a proportion of 1 to 60% by weight, based on the coated dosage forms. Pharmaceutical preparations according to claim 1, characterized in that, in addition to the sucrose fatty acid esters, additional excipients can additionally be included. Pharmaceutical preparations according to claim 18, characterized in that fillers, fusible binders, disintegrants, liquid-regulating agents, anti-sticking agents, film-forming and / or other commonly applied auxiliaries are used as auxiliaries. 31,985 / B Pharmaceutical preparations according to claim 18, characterized in that further modification of the release of the active substance is possible by incorporating the pore formers during the melt granulation or melt pelleting process. Pharmaceutical preparations according to claim 1, characterized in that active substances which are well water-soluble to practically water-insoluble can be used as active substances. Pharmaceutical preparations according to claims 1 and 21, characterized in that the active substances can be used, in particular from the indication areas analeptics / antihypoxemics, analgesics / anti-rheumatic drugs, antiallergics, antiarrhythmic agents, antidementics, antidiabetics, anti-emetics / antivertiginosis, anti-epileptics, anti-epileptics, anti-epileptics, broncholytics, anti-asthmatics, diuretics, blood-promoting agents, hypnotics / sedatives, coronary agents, hypolipidemics, anti-migraine agents, muscle relaxants, anti-Parkinson's agents, and psychopharmaceuticals. Pharmaceutical preparations 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, piracetam, nicergoline, pentanoline nicotinicotin. , vincamine, glibenclamide, betahistinedimesilate, dimenhydrinate, carbamazepine, valproic acid, calcium valproate dihydrate, retigabine, talinolol, fosinopril, doxazosin, metoprolol, nifedipine, norfenephrine hydrochloride, pirhydroisin tinate, dihydroergotamine sulphate, terhydroolbutinate , glycerol trinitrate, isosorbide mononitrate, isosorbide dinitrate, molsidomine, bezafibrate, fenofibrate, xantinol, sumatriptan, levodopa, benserazide, carbidopa, amitriptyline hydrochloride, venlafixine hydrochloride, thioridazine hydrochloride, 31 985 / B lithium carbonate, lithium acetate, thioctic acid or R-thioctic acid and its salts such as dexlipotam. Pharmaceutical preparations according to claims 1 and 21, characterized in that they contain preferably flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine. Pharmaceutical preparations according to claim 24, characterized in that, in addition to the active substance retigabine, the granulate contains from 1 to 95% by weight of sucrose fatty acid esters. Pharmaceutical preparations according to claim 25, characterized in that, in addition to the active substance retigabine, the sucrose fatty acid esters of fatty acids esters are preferably present in the granulate. 27. A process according to claim 1 which is melt granulation or melt pelletizing. 28. A method according to claim 27, wherein the starting materials are heated to a temperature at which the used or used fatty acid esters of sucrose soften, in a suitable apparatus, with stirring or in a fluidized bed, surface melted. or melted and cooled after subsequent granulate formation. A process for the production of pharmaceutical preparations according to claim 28, characterized in that, in a suitable apparatus, molten or molten fatty acid esters of sucrose are added to the heated powder of the active ingredient. 31 985 / B substances. A process for the production of pharmaceutical preparations according to claim 28 or 29, characterized in that a fast-running stirrer, a floating-layer apparatus or a rotor granulator can advantageously be used as a suitable apparatus. A process for the manufacture of pharmaceutical preparations according to claim 1, 7 or 8, characterized in that the coating of the granules or pellets is carried out preferably by a hot melt coating method or a powder coating method. A process for the production of pharmaceutical compositions according to claim 31, characterized in that the hot melt coating process and the powder coating process employ one or more sucrose fatty acid esters alone or in combination with a plasticizer. Process for the production of pharmaceutical preparations according to claim 32, characterized in that triethyl citrate, acetyl triethyl citrate, triacetin or dibutyl sebacate can be used as plasticizer. 31,985 / B Fig. 1