ZA200207050B

ZA200207050B - Pharmaceutical preparations.

Info

Publication number: ZA200207050B
Application number: ZA200207050A
Authority: ZA
Inventors: Hoffmann Torsten; Pieroth Michael; Zessin Gerhard; Landgraf Karl-Friedrich
Original assignee: Awd Pharma Gmbh & Co Kg
Priority date: 2000-03-08
Filing date: 2002-09-03
Publication date: 2002-11-20
Also published as: DE10010509A1

Description

LT Pharmaceutical formulations

The present invention relates to novel oral pharma- ceutical formulations with variably adjustable release characteristics of the active ingredient in the form of : granules, pellets, tablets, film-coated tablets, microtablets, sugar-coated tablets, capsules or thera- peutic systems, and to processes for the production thereof by melt granulation or melt pelletization.

A significant part is played in the use of medicaments by a reduction in the frequency of intake, ideally to - one dose a day.

One tablet in the morning or evening is taken more regularly than are several tablets distributed over the day. This increased patient compliance has beneficial effects on the curative process. In addition, the better tolerability, which is frequently associated with reduced frequency of intake, of the active ingredient is beneficial for the patient. The latter is connected with the longer maintenance, which is then necessary, of the effective plasma concentration and usually also more uniform plasma levels, with which there is substantial avoidance of peaks which are not tolerated.

In exceptional cases, one dose a day can be achieved merely through the kinetic or dynamic properties of an active ingredient, such as, for example, owing to a long elimination half-life. However, in most cases effective plasma levels lasting 12 to 24 hours are made possible only by pharmaceutical technology measures such as, for example, through sustained release of active ingredient from the dosage form.

A whole range of solutions in principle for this are given in the literature, and they show advantages or

LT - 2 - oo disadvantages depending on the chemical and physical ‘ properties of the active ingredient (review article:

Recent trends and progress in sustained or controlled oral delivery of some water soluble drugs, Drug

Development and Industrial Pharmacy 21 (9), 1037-1070 (1598)).

The state of the art is also represented for example in one of the more recent textbooks of pharmaceutical technology (Voigt, R., Pharmazeutische Technologie,

Ullstein Mosby Verlag 1993, pp. 293 ff.). According to this, the effect of medicinal substances can be extended by the following measures: ] molecular variations such as formation of esters or salts, changes in the active ingredient modification, the particle size, choice of appropriate excipients and processes. Individual possibilities will be dealt with briefly by way of example below:

Matrix slow release drug forms

They are characterized by an insoluble, possibly porous framework of indigestible fats, waxes, polymers or else inorganic matrix formers. The active ingredient is incorporated into this framework. The release of active ingredient takes place through diffusion, erosion or matrix degradation.

Hydrocolloid slow release drug forms

In this case, the medicinal substance 1s embedded in hydrocolloid matrices which consist, for example, of cellulose derivatives. After intake, a gel is formed by the digestive fluids, and the active ingredient diffuses through this more quickly or slowly depending on the surface area and viscosity of the gel.

Coated (membrane-controlled) slow release drug forms

In this case, active ingredient particles or drug forms are enveloped by a barrier. Diffusion through the diffusion barrier determines how quickly the active ingredient is released.

Wr - 3 - ‘ The rate of diffusion can be increased by adding plasticizers or pore formers.

Influence of the specific surface area

With active ingredients of low solubility in water there is generally a marked dependence between the rate of dissolution and the specific surface area. A defined particle size distribution, and thus a particular specific surface area, can be adjusted through inten- tional crystallization of the active ingredient, by sieving or grinding. Larger particles mean a smaller specific surface area and a slower release of active ingredient.

Forms combining diffusion, erosion, dissolving processes

Drug forms whose sustained release of active ingredient are based on combination of diffusion, erosion and dissolving processes are also known.

A process which 1s of particular interest and can be employed very variably in relation to release of active ingredient is represented by melt granulation. Melt granulation or thermoplastic granulation means a process in which the granules are bound through the use of a low-melting ingredient and under the influence of thermal energy (Lidemann, J.; APV Course 231 on

June 17-18, 1996).

Two subtypes are distinguished in this connection.

In the wet granulation subtype, the process temperature is higher than the melting point of the binding ingredient. The latter is in the form of a liquid or semisolid ingredient during the granulation. In melt granulation, drying is replaced by cooling.

The sinter granulation subtype is referred to when the process temperature does not reach the melting point of

. 7 - 4 - oo. the binding ingredient. In this case there is only ‘ local melting on the surface of the particles, so that the surfaces diffuse into one another (Voigt, R.;

Lehrbuch der pharmazeutischen Technologie; Verlag

Chemie, p. 159 (1984)).

The low-melting ingredient may be an active ingredient or an excipient. The melting points of the substances are, for stability reasons, usually above 35°C. Sub- stances with melting points in the range 50-90°C are used most frequently.

Active ingredients known as fusible substances are phenyl salicylate, ibuprofen, o-lipoic acid and meprobamate.

Water-soluble, swellable and lipophilic substances are employed as fusible excipients. Examples of hydrophilic ones are macrogol, polyvidone and polymethacrylic acid derivatives.

Hydrocarbons (paraffin), waxes, fats and fatty acids are examples of lipophilic excipients which are employed. (Flanders, P; Dyer, G.A.; Jordan, D.; Drug Dev. Ind.

Pharm. 13 (&), 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, 1359-148 (1984); Kinget, R.; Kemel, R.: Acta

Pharm. Technol. 31, 57 (1985)).

Melt granulation is usually carried out in fluidized bed granulators, centrifugal fluidized bed equipment or high-speed intensive mixers. The use of the latter in particular has technical advantages because costly air treatment can be dispensed with. Compared with conven- tional granulation methods using organic solvents, in this case expenditure on prevention of explosions and recovery of solvents is dispensed with. There are also no residual solvents in the product. Compared with aqueous granulation, energy-intensive drying processes are dispensed with. In this case, the use of so-called oo one-pot systems is favored.

The process of melt granulation can generally be depicted as follows:

Mixing Mixing

J {

Addition of binder Heating (solid state of aggregation)

J J

Heating Addition of binder (liquid state of aggregation) 4 l

Granulation Granulation : l l

Cooling Cooling

J J optional classification optional classification

The fusible binder can be added in solid or liquid form, that is to say in the molten state.

If added as solid, the fusible substance is melted during the process, which is why this method is also called a melting method.

In the latter method, either the liquid binder is added to the solid ingredients or, in accordance with the so-called fusion method, the solids are stirred into the liquid binder. For this purpose, the heating takes place before addition of the binder.

Input of energy is possible in various ways with intensive mixers: eo mechanical energy through mixers and choppers e jacket contact heat ® IR or microwave radiation energy ® introduction of hot air into the product bed

A large number of processes for producing such formula- tions are known from the patent literature.

<7 - 6 - oo Formulations with controlled release which can be pro- : duced by melt 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 in which water- insoluble, hydrophobic, wax-like substances are added to produced pellets at a later time during production, at a temperature at which these substances melt and lead to coating of the pellets. This process is called “hot melt coating”.

Provided that all the starting materials involved in the process are thermally stable under the prevailing process conditions, melt granulation is an interesting alternative to other granulation methods such as, for example, granulation using organic solvents or granulation using water.

Melt pelletization represents in this connection a special form of carrying out the process, in which granule particles of substantially uniform size and rounded shape are manufactured.

Despite the numerous known fusible excipients, only a few excipients with graded HLB (hydrophilic-lipophilic balance) particularly suitable for melt granulation or melt pelletization processes are described.

Representatives of the few excipients with graded HLB are hydrogenated edible fats, which carry the proprietary name Gelucire, or the sorbitol fatty acid esters which are known, for example, as Span. However, even these do not cover the wide HLB range from 1 to 16.

With conventional fusible excipients it is usually possible to graduate release only through the choice of the release-slowing agent or the amount thereof. It is often possible to process a binder only in combination

- 7 = with another fusible binder such as polyethylene glycol, because its granule-forming capacity is inade- quate on its own. These binders additionally require the addition of lubricants or mold release agents. Some of them have a waxy consistency.

It is often necessary in the known melt granulation ] processes to subject the resulting and solidified granules to elaborate sieving for size reduction.

In the principle of slowing release by means of a coating, because the film coatings are in some cases brittle, but also relatively thin, damage to the film coatings is often observed on compression, unless this is countered by a relatively high outer phase. If the film coating is damaged, the release of active ingredient from the tablets is increased. This means that the release of active ingredient from these tablets usually depends on the compressive force. In this process, the release of active ingredient is often adjusted via the amount sprayed during production.

Changes in the release of active ingredient may occur during storage, depending on the film formation and porosity, for example owing to subsequent hardening.

One object of the present invention is thus to provide oral pharmaceutical formulations with variably adjust- able release characteristics, that is to say from fast to slow release. In the case of drug forms with modified or slow release, it is intended to be able to produce both nondisintegrating drug forms (so-called “single units”), but preferably rapidly disintegrating drug forms with modified or slow release from the granules (so-called “multiple units”).

A further object of the present invention is to provide processes for producing such slow release formulations, in particular by melt granulation or melt pelletization.

oo The present invention provides novel oral pharma- : ceutical formulations which have variably adjustable release characteristics and which, besides one or more active ingredients, comprise one or more sucrose fatty acid esters as sole release-controlling agent.

The novel pharmaceutical formulations comprise drug forms with release ranging from rapid to slow release.

The pharmaceutical formulations of the invention can be administered in the form of granules, pellets, tablets, film-coated tablets, microtablets, sugar-coated tablets, capsules and as therapeutic systems.

Surprisingly, sucrose fatty acid esters are able to control the release of active ingredient in the desired manner and, in addition, to improve the technological properties in the production of the formulations of the invention by melt granulation or melt pelletization.

Sucrose fatty acid esters are also suitable inter alia for granulation of the active ingredient without the addition of other excipients. This makes it possible to reduce the gross weight compared with other processes, in which a plurality of fusible release-slowing agents or binders must be employed.

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

Sucrose fatty acid esters are nonionic surfactants which consist of mono-, di-, tri- and polyesters of sucrose as hydrophilic constituent and of saturated or unsaturated fatty acids as lipophilic constituent. It is possible by varying the degree of esterification and the nature of the fatty acids to produce sucrose fatty acid esters with different HLB values, which have an influence on the biopharmaceutical properties, in particular the release of active ingredient, the stability of the produced pharmaceutical formulation

LT - 9 - i and on the technological characteristics.

They are nontoxic, biodegradable, tasteless and odor- less, and stable on storage.

Sucrose fatty acid esters with a melting point of > 30°C are in the solid state of aggregation at room temperature and have an HLB of 1-16.

Sucrose fatty acid esters are also marketed for example under the names sugar esters or sucrose esters inter alia by the companies Mitsubishi (brandname Ryoto),

Gattefosse or Sisterna or others.

Sucrose fatty acid esters are known from the litera- ture; thus, they are employed according to US 4 844 067 for improving the surface of silk threads, and in

WO 93/17667 as taste improvers in pharmaceutical preparations.

Their main use is in the food industry sector. Thus, sucrose fatty acid esters are employed for example for improving the mixing of chewing gum compositions, to prevent inhomogeneity and denaturation of finished drinks, in sugar refining, in condensed milk and coffee whiteners.

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

US 3 896 238, US 4 150 114 and US 4 046 886 indicate the use of sucrose fatty acid esters in combination with alkyl sulfoxide or phosphorus oxides in pharma- ceutical compositions to improve the penetration of the active substance through the skin.

a - 10 - i Examples of specific sucrose fatty acid esters : mentioned are: sucrose monooctanoate, monolaurate, monopalmitate, monostearate, and the di- and triesters of these compounds.

JP 81 75 437 discloses the use of sucrose fatty acid esters with an HLB of from 1 to 5 as suppository base.

WO 88/06880 claims the use of sucrose fatty acid esters in topical applications, employing mixtures of mono-~ and dialkyl sucrose esters with an HLB of from 8 to 16 for improving the penetration through the skin. ] Sucrose cocoate, sucrose ricinoleate, sucrose laurate and sucrose stearate are preferably used.

Sucrose fatty acid esters are also used in particular in cosmetic products (FR 2 421 605, JP 81 24 034,

JP 81 55 306).

DE 40 03 844 describes pharmaceutical compositions which, besides the active ingredient cyclosporin, comprise a fatty acid saccharide monoester and a diluent or carrier.

These compositions make it possible to reduce the ciclosporin dosage level necessary to achieve an effective therapy, and thus lead to a reduction in unwanted side effects.

Particularly suitable fatty acid saccharide monoesters in this connection are:

Cs-14-fatty acid disaccharide monoesters and Cg.1g-fatty acid trisaccharide monoesters.

WO 93/00093 claims a novel slow release formulation for diltiazem in the form of spheroids which are composed of the active ingredient, a wetting agent and a polymer coating to control release. The wetting agents employed are sucrose fatty acid esters. The actual slowing of release is effected by means of a polymer. In this case, the wetting agent is processed with the active

. ingredient by means of extrusion or by means of granulation with organic solvents. The extrudates are coated with conventional polymers.

Examples of wetting agents mentioned are also

Ciz-20—fatty acid esters of sucrose or xylose.

DE 198 40 152 claims a slow release formulation which comprises calcium valproate, at least one acrylic polymer and at least one sugar ester, the desired control of release being achieved through the acrylic polymer employed. It is indicated that the sugar ester on its own brings about negligible slowing of release.

The suitability of sucrose fatty acid esters in the pharmaceutical formulations of the invention as sole release-controlling agent was all the more surprising since these sucrose fatty acid esters on the one hand have been known for a relatively long time, and on the other hand it is possible therewith to produce oral pharmaceutical formulations with variably adjustable release characteristics in a simple manner.

The sucrose fatty acid esters used according to the invention are esters of sucrose with saturated or unsaturated fatty acids or mixtures thereof.

C-.--C;:-fatty acids are particularly suitable.

Sucrose stearates, sucrose palmitates, sucrose laurates, sucrose behenates and sucrose oleates with an

HLB 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°cC.

Sucrose fatty acid esters with a melting point or melting range of 40-150°C are preferably employed.

An essential advantage of the present invention is that the desired release characteristics of the novel pharmaceutical formulations can be controlled via the type and proportion of the sucrose fatty acid ester(s)

a - 12 -

R employed, or via the process parameters of the : production process.

Sucrose fatty acid esters with a low HLB are preferably employed for achieving slow release.

Sucrose fatty acid esters with a high HLB are preferentially suitable for rapid or modified release characteristics.

The sucrose fatty acid esters may be present in the pharmaceutical formulations of the invention in a proportion of from 1 to 95% by weight based on the ] proportion to be granulated (inner phase) in the formula. A proportion between 5 and 50% by weight is preferably employed. Besides sucrose fatty acid esters, it is possible for the active ingredient alone or mixtures of the active ingredient with one or more pharmaceutically usable excipients to be present in the inner phase.

A further embodiment of the invention consists of the possibility of coating granules or pellets, which either contain sucrose fatty acid esters in the granules or which contain no sucrose fatty acid esters, with sucrose fatty acid esters.

The proportion of sucrose fatty acid ester in the coating is 1-60% by weight, preferably 3-20% by weight, based on the coated drug form.

The sucrose fatty acid esters can be used alone or, where appropriate, also in combination with other fusible excipients. In some cases, addition of one or more excipients such as plasticizers is advantageous for the process. Further modification of the release of active ingredient is possible via embedding so-called pore formers, which are excipients with particular pro- perties such as, for example, characteristic solubility or swellability, during the melt granulation or melt pelletization process.

Lo - 13 - : The oral pharmaceutical formulations of the invention may contain as active ingredients both readily water- soluble to virtually water-insoluble compounds.

Active ingredients of the following indication groups ) are suitable for this, the list not being definitive: analeptics/antihypoxemics (such as caffeine), anal- gesics/antirheumatics (such as diclofenac, morphine, tramadol, tilidine, flupirtine), antiallergics (such as azelastine, pseudoephedrine), antiarrhythmics, such as quinidine, disopyramide, diltiazem, verapamil), antidementia drugs (nootropics) (such as piracetam, nicergoline, xantinonicotinate, pentifylline, vincamine), antidiabetics (such as glibenclamide), antiemetics/antivertigo drugs (such as Dbetahistine dimesilate, dimenhydrinate), antiepileptics (such as carbamazepine, valproic acid, calcium valproate dihydrate, retigabine), antihypertensives (such as talinolol, fosinopril, doxazosin, metroprolol, nifedipine), antihypotensives (such as norfenefrine

HCI, dihydroergotamine mesilate), bronchospasmo- lytics/antiasthmatics (such as salbutamol, terbutaline sulfate, theophylline), diuretics (such as furosemide, piretanide), blood flow-stimulating agents (such as buflomedil, naftidrofuryl, pentoxifylline), coronary agents (such as glycerol trinitrate, isosorbide mononitrate, isosorbide nitrate, molsidomine), lipid- lowering agents (such as bezafibrate, fenofibrate, =xantinol), migraine remedies (such as sumatriptan), muscle relaxants, antiparkinson agents and other agents for extrapyramidal disorders (such as levodopa/ benserazide, levodopa/carbidopa), psychoactive drugs (such as amitriptyline HC1, venlaxafine HC1, thioridazine HCl, lithium carbonate, lithium acetate); thioctic acid or R-thioctic acid and its salts, such as dexlipotam.

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

The pharmaceutical formulations of the invention can be produced according to the present invention by melt granulation or melt pelletization.

This entails heating the mixture of the active ingredient and one or more sucrose fatty acid esters, where appropriate with the other excipients, with stirring for example in a high-speed mixer. The heating can be effected either by means of heating jackets, with microwave, radiation energy or else via the energy input of the stirrer.

The granulation starts when the melting point of the respectively used sucrose fatty acid ester in the mixture is reached or its surface softens or becomes partially molten. The onset of agglomeration and the increase, associated therewith, in the friction increases the power consumption by the stirring motor.

Granulation is usually stopped when the power consump- tion starts to rise expotentially. After this, the hot melt granules are either discharged from the mixer and cooled in thin layers at room temperature, or else cooled in the mixer with suitable cooling (for example cooling jacket), possibly while stirring.

There is also the possibility according to the inven- tion to add the sucrose fatty acid esters in the molten state.

Surprisingly, this results in a very narrow granule size distribution. The granule or pellet particles have, depending on the management of the process, a virtually rounded and smooth surface.

It is likewise possible to use other heatable equipment such as fluidized bed granulator, rotor granulator.

The granules produced in this way can, if desired, be

Co classified through a sieve, possibly mixed with ’ excipients of the outer phase and, for example, compressed to tablets or packed in capsules.

Excipients of the outer phase which can be used are pharmaceutically customary disintegrants or disintegra- tion aids, fillers, mold release agents or the like. It is usually possible to dispense with the use of mold release agents on use of sucrose stearates of low HLB because sucrose stearates with low HLB themselves also represent good mold release agents.

It is possible in this way to produce, for example, formulations with rapid release or modified to slow release (multiple units or single unit) depending on the pharmaceutical technology objective.

It has furthermore been found, surprisingly, that the sucrose fatty acid esters are suitable as excipients for hot melt coating.

For this purpose, a quantity of sucrose fatty acid ester of the same or different type is once again added to melt granules which have already been produced and solidified, and the mixture is heated once again above the melting point or the softening point of the added sucrose fatty acid ester. In this case the melt granules are coated with the melt of the sucrose fatty acid ester.

The coating can likewise take place in the presence of a plasticizer.

It is likewise possible to coat sucrose fatty acid ester-free granules or pure active ingredients in the manner described.

The advantages of this process are that, on the one hand, the coating achieves adequate control of release, in particular slowing of release, even with relatively small proportions of sucrose fatty acid esters. On the other hand, the surface of the granules or pellets produced in this way is smoothed.

: A further advantage is that enteric coatings can be produced in a simple way by this process. This means that it is possible to delay release of active ingredient in the acidic PH range greatly because of the virtual insolubility of the sucrose fatty acid esters in aqueous and acidic media.

The powder coating represents a particular type of hot melt coating in this connection. This entails, on the one hand, the free-flowing sucrose fatty acid esters being metered with the aid of a suitable powder ] delivery, such as powder feeder, and on the other hand a plasticizer such as triethyl citrate, into the starting materials.

This process is distinguished by great savings in costs and time; no drying processes are necessary compared with conventional aqueous coating processes.

Pharmaceutical formulations produced in this way are suitable in particular for water-sensitive active ingredients such as Na valproate.

The following examples are intended to illustrate the subject-matter of the invention without restricting it.

Example 1:

Tramadol hydrochloride with 50% sucrose stearate of

HIB 1 - Formula:

oo - Parameters: 700 rpm

Chopper speed 3 000 rpm 550°C

The starting materials are heated while stirring in an

Aeromatic-Fielder type GPl1 intensive mixer at the appropriate jacket temperature. When a particular pro- duct temperature is reached, the granulation process 1s started. After the power consumption by the stirring motor increases and there is a sudden rise in the - product temperature, the granulation is stopped and the product is discharged, passed through a sieve with a mesh width of 1.4 mm and cooled at room temperature. - Analysis: release of active ingredient

Time in min [30 [60 [120 [180 |ea0 560 ago

Release in % in 74.03 [89.40 [95.75 |95.57 |97.61 |98.58 |97.87 0.1N HC1

In buffer of 78.99 189.29 [93.99 193.37 194.26 {96.5 [96.88

PH 6.8

See Annex 1 for release of active ingredient

Example 2:

Flupirtine maleate with 30% sucrose stearate of HLB 1

Toby tLe Nd_eate willl SUS Sucrose stearate olf HLB 1 - Formula:

Flupirtine maleate 240.0 g

Sucrose stearate 5-170 102.9 ¢g

. - Parameters: 342.9 g 700 rpm

Chopper speed 3 000 rpm 61.20c - Production takes place as in example 1.

Example 3:

Nifedipine with 30% sucrose stearate of HLB 1 - Formula:

Nifedipine

Sucrose stearate S-170 - Parameters: 800 g 3 000 rpm - Production takes place as in example 1. - Analysis: release of active ingredient mmeinn | pi 2 Ja fe Js Jaa

Release in % in 2.14 (3.76 [5.84 (8.42 (10.72 (25.91 purified water/1.25% SDS

See Annex 2 for release of active ingredient

Example 4:

Nifedipine with 30% sucrose palmitate of HLB 1 ———TeopollC WALA JUD SUCXoOSe palmitate or HLB 1 - Formula:

Weight . Nifedipine 560 g

Sucrose palmitate P-170 240 g - Parameters: 800 g

Chopper speed 3 000 rpm ) Jacket temperature - Production takes place as in example 1. - Analysis: release of active ingredient

Fe SY PR PR

Release in % in 4.08 [7.32 {11.5 (16.65 (21.71 |49.04 purified water/1.25% SDS

See Annex 3 for release of active ingredient

Example 5:

Tablets made from melt granules of nifedipine with 30% —_ ee ee =e graliiles Ol N1lédipine with 50% sucrose stearate of HLB 5 - Formula:

Nifedipine 560 g

Sucrose stearate S-570 240 g

.a _ 20 _ } - Granulation parameters: 800 g 700 rpm

Chopper speed 3 000 rpm - Production takes place as in example 1. - Tableting parameters:

The granules were subsequently compressed with a round tabelting tool, of 6 mm diameter, middle-domed, to - tablets with a gross weight of 71.4 mg. - Analysis: release of active ingredient rime inmin [30 leo 120 [180 |2a0

Release in % in purified (19.85 [42.44]|78.30|96.61|102.88 water/1.25% SDS

See Annex 4 for release of active ingredient

Example 6:

Tablets made from melt granules of nifedipine with 50% sucrose stearate of HIB 9 and 2.5% sucrose stearate of

HLB 1 - Formula:

Substance Weight

Nifedipine 400 g

Sucrose stearate S-970 380 g

Sucrose stearate S-170 - Granulation parameters:

Stirrer speed 700 rpm

Chopper speed 3 000 rpm

Jacket temperature

) - Production takes place as in example 1. - Tableting parameters:

The granules were compressed with a round tableting tool, of 6 mm diameter, middle-domed, to tablets with a gross weight of 100 mg. - Analysis of release of active ingredient

Time in min [30 Jeo |i20 liso |ra0

Release in % in purified (20.10 {40.37 [73.26 [94.14 [102.93 - water/2.5% SDS

See Annex 5 for release of active ingredient

Example 7:

Carbamazepine with 10% sucrose stearate of HLB 1 - Formula: 720 g

Sucrose stearate S-170 - Parameters: 800 g 700 rpm

Chopper speed 3 000 rpm - Production takes place as in example 1. - Analysis: release of active ingredient rime inmin [30 lo [120 [180 [240 [360 [aso

Release in % in [10.68 (20.06 (38.08 |51.45 [62.47 [73.89 |81.58 modified intes- tinal fluid

: See Annex 6 for release of active ingredient

Example 8:

Carbamazepine with 30% sucrose stearate of HLB 9 - Formula: 560 g

Sucrose stearate S-970 240 g - Parameters: 800 g 700 rpm

Chopper speed 3 000 rpm - Production takes place as in example 1. - Analysis: release of active ingredient

Time in min [30 [60 [120 [180 |240 [360 |aso

Release in % in [26.09 {42.27 {62.65 {80.58 |87.38 |96.56 {100.84 modified intes- tinal fluid ! | ! i

See Annex 7 for release of active ingredient

Example 9:

Carbamazepine with 50% sucrose behenate of HLB 3 and 2.5% triethyl citrate - Formula: 400 g

Sucrose behenate B-370 380 g

Triethyl citrate

] - Parameters: 800 g stirrer speed

Chopper speed 3 000 rpm

The starting materials carbamazepine and triethyl citrate are mixed in an Aeromatic-Fielder type GP1 intensive mixer. After a mixing time of 1 min, sucrose behenate B-370 is added and the mixture is heated with stirring at a jacket temperature of 50.0°C. After a particular product temperature at which an increase in - power 1s to be observed is reached, the granules are passed through a sieve with a mesh width of 1.4 mm and cooled to room temperature.

Example 10:

Tablets made from melt granules of carbamazepine with 30% sucrose stearate of HLB 9 - Formula: - Granulation parameters:

The granules are compressed without other additions using a round tableting tool, of diameter 13 mm, flat,

] to tablets with a gross weight of 571 mg and a hardness of 25 N. - Analysis: release of active ingredient

Time in min [30 leo [120 [180 [240 [seo Jaso

Release in % in |5.36 [8.04 (13.78 (17.89 (21.01 |27.31 [32.08 modified intes- tinal fluid

See Annex 8 for release of active ingredient

Example 11: - Carbamazepine with 20% sucrose stearate of HLB 2 - Formula: 640 g

Sucrose stearate S-270 160 g - Parameters:

Chopper speed 3 000 rpm

Jacket temperature 1 54°C - Production takes place as in example 1.

Example 12:

Calcium valproate dihydrate with 35% calcium hydrogen phosphate and 30% sucrose stearate of HLB 1 - Formula:

Calcium valproate dihydrate | 280 g

Calcium hydrogen phosphate 280 g

Sucrose stearate S-170 240 g

] - Parameters:

Chopper speed 3 000 rpm - Production takes place as in example 1, initially introducing the active ingredient calcium valproate dihydrate with calcium hydrogen phosphate. - Analysis: release of active ingredient

Time in min leo [a0 lasso ) Release in % in pH 3.0 64.89 [75.63 [85.02

Release in % in pH 6.8 36.85 61.26 [71.60

See Annex 9 for release of active ingredient

Example 13:

Tablets made from melt granules of calcium valproate dihydrate and 30% sucrose stearate of HLB 1 - Formula:

Calciumb valproate dihydrate | 560 g

Sucrose stearate S$-170 | 240 g - Granulation parameters: 800 g 700 rpm

Chopper speed 3 000 rpm - Production takes place as in example 1 - Tableting parameters:

The granules are compressed with an oblong tableting i - 26 - i tool, 23 mm long, 9 mm wide, to oblong tablets with a ) gross weight of 951 mg and a hardness of 65 N. - Analysis: release of active ingredient

Time inmin leo so liso

Release in % in pH 3.0 4.96 lo.14 13.66

Release in % in pH 6.8 92.93 [98.57 (99.43

See Annex 10 for release of active ingredient

Example 14:

Tablets made from melt granules of calcium valproate

Semen et IO MeSt granules Of calcium valproate - 10 dihydrate and 30% sucrose stearate of HLB 9

Ze Yeoat aiid JUS SUCrosé stearate of HLB 3 - Formula:

Calcium valproate dihydrate 560 g

Sucrose stearate S-970 - Granulation parameters: 800 g 700 rpm 3 000 rpm

Jacket temperature | 65°C _— - Production takes place as in example 1 - Tableting parameters:

The granules are compressed with an oblong tableting tool, 23 mm long, 9 mm wide, to oblong tablets with a gross weight of 951 mg and a hardness of 50 N. - Analysis: release of active ingredient

Time inmin leo Jao laso

Release in % in pH 3.0 16.89 |56.55 [87.96

Release in % in pH 6.8 a - 27 -

See Annex lla for release of active ingredient

See Annex 1llb for comparison of the release of active ingredient from the «calcium valproate formulas in rH 3.0

See Annex llc for comparison of the release of active ingredient from the calcium valproate formulas in pH 6.8

Example 15: ] Retigabine with 20% sucrose stearate of HLB 1 - Formula:

Sucrose stearate S-170 200 ¢g - Granulation parameters: 1000 g

Chopper speed 3 000 rpm - Production takes place as in example 1 - Analysis: release of active ingredient rine nmin bo Jeo Joo Jeo eo Joe Jamo

Release in % in {37.23 [56.71 {75.81 0.1N HCl

In buffer of 5.71 [8.77 (13.82 15.79 [23.60 27.99 |35.62 pH 6.8/1%

Texapon

See Annex 12 for release of active ingredient

- - 28 ~ ) Example 16: : Retigabine with 20% sucrose stearate of HLB 2 - Formula: 400 g

Sucrose stearate S-270 100 g - Parameters: 500 g 700 rpm

Chopper speed 3 000 rpm - Production takes place as in example 1 - Analysis of release of active ingredient

Time in minis [30 leo [120 [180 ao [seo aso

Release in |42.28(62.58 {83.53 [100.97 % in 0.1N

HC1

Release in 11.82 |20.77 (34.41 (44.94 {52.74 [61.63 |66.37 % in buffer of pH 7.5 i | ! ; ! i ! : :

See Annex 13 for release of active ingredient

Example 17:

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

S=ELoga)ile Wolk <cVd SULIOSE Stearate of nLb 1 ana Vs sucrose stearate of HLB 9 - Formula:

Sucrose stearate S-170 60g

Sucrose stearate 5-970

- Parameters: 500 rpm 3 000 rpm - Production takes place as in example 1 - Analysis of release of active ingredient

Tine in minfis [30 Joo [120 [180 [a0 [seo aso

Release in |71.49|85.13 |97.93 [102.82 % in 0.1N ) HC1

Release in 31.02 [36.93 |51.97 161.25 |70.63 |79.01 {78.77 % in buffer 6.8

See Annexes l4a for release of active ingredient

See Annex 1l4b for comparison of the releases of active ingredient from retigabine formulas in 0.1N HCl

See Annex l4c for comparison of the releases of active ingredient from retigabine formulas in buffer of pH 6.8

Example 18:

Tablets made from melt granules with retigabine, 20% —ooo=es oT STUN et granu.esS will retigabine, Us sucrose stearate of HLB 1 and 10% croscarmelose sodium

So oUor stata OF HUB Lo did US croscarmeiose sodium - Formula:

Sucrose stearate S-170 200 g i - Granulation parameters: 1 000 g

Retigabine slow release 270 ¢g granules (see above)

Croscarmellose sodium

The tableting mixture is compressed to tablets with a round tableting tool of diameter 9 mm, bevel 450°, radius of curvature R13. - Analysis: release of active ingredient rine tn mins Poo Joo Jeo Jar Jeo fuer

Release in |40.76{81.59 |96.13 [100.76 % in 0.1N

HC1

In buffer 22.20 129.80 |38.95 [46.49 |53.58 |60.85 |64.69 ! | ! of pH 6.8/ | i | | i 1% Texapon

See Annex 15 for release of active ingredient

Example 19:

Retigabine with 7% sucrose stearate of HLB 1 - Formula:

Retigabine 372 g

Sucrose stearate S-170 i - Parameters: 1 300 rpm . The starting materials are heated with stirring in a special container provided with a PTFE inliner in an

Aeromatic-Fielder type GPl intensive mixer at a jacket temperature of 50.0°C. After the power consumption has risen again, the pellets are removed and cooled in thin layers to room temperature. - 10 - Analysis: release of active ingredient rime inmin [30 leo 120 [180 |aa0 [seo [aso |]

Release in buffer 16.62 {29.85 {50.39 [67.14 169.35 (83.20 190.96 of PH 7.5/2.5%

Texapon

See Annex 16 for release of active ingredient

Example 20:

Retigabine with 20% sucrose stearate of HLB 11 - Formula:

EE

Substance | Weight

Retigabine | 320 g

Sucrose stearate 5-1170 - Parameters: 400 g 1 300-1 100 rpm

Jacket temperature - Production takes place as in example 19

. - Analysis: release of active ingredient

Tine in min [o_ leo [120 so lao

Release in buffer of 49.91 (79.95 [100.81 [106.03 1104.36

PH 7.5/2.5% Texapon

See Annex 17 for release of active ingredient

Example 21:

Retigabine with 20% sucrose stearate of HLB 16 s=eogop ne WLI 2U% SUCrose stearate or HIB 16 - Formula: 320 g

Sucrose stearate S-1670 - Parameters: 1 300-1 100 rpm 50-55°C - Production takes place as in example 19 - Analysis: release of active ingredient

Time nmin [30 Jeo [120 iso pao

Release in buffer of 41.77 {68.71 192.32 199.95 (101.47

PH 7.5/2.5% Texapon

See Annex 18 for release of active ingredient

Example 22:

Retigabine with 16% sucrose stearate of HLB 15 - Formula:

Weight 336 g

Sucrose stearate S-1570 64g a - 33 - . - Parameters: 400 g 1 300 rpm 50-60°C - Production takes place as in example 19 - Analysis: release of active ingredient

Time inmin [50 Jeo 120 [so a0

Release in buffer of 64.67 [89.83 |99.98 [101.78 [100.99

PH 7.5/2.5% Texapon ) See Annex 19 for release of active ingredient

Example 23:

Retigabine tablets - Melt granules formula:

Sucrose stearate S-1570 - Parameters: - — —"™/T - —

Batch size 1 400 g 1 300 rpm 50-60°C - Production takes place as in example 19 hy - 34 - - Coating formula:

Retigabine melt granules 1 000 g with 17% sucrose stearate of HLB 15

Eudragit L 30 D-55 400 g (corresponds to 120 g of coating dry matter) tale leog

The melt granules from 5 batches are combined and - sprayed in a rotor granulator with inlet air at 50°C and at 300 rpm with a suspension of Eudragit L 30 D-55, talc and triethyl citrate in 536 g of purified water.

The product is then dried until its temperature is 33°C.

The granules coated in this way are homogenized with 30% by weight microcrystalline cellulose and 5% by weight croscarmellose sodium in a Turbula for 10 min.

The tableting mixture is compressed to oblong tablets, 17 Xx 8 mm, by convex with an average hardness of 87 N.

Time nmin 15 30 leo 120 lio Jaso

Fra al 0.1N HCl pH 7.5/1.7% Texapon

See Annex 20a for release of active ingredient in 0.1N

HC1

See Annex 20b for release of active ingredient in buffer of pH 7.5, 1.7% Texapon

A Example 24: : Hot melt coating of retigabine melt granules with 10%

Se mee voalllg Of retigabine melt granules with 10% sucrose stearate of HLB 1 - Formula for coated melt granules:

Retigabine melt granules 500 ¢ (90% by weight retigabine and 10% by weight sucrose stearate S-170)

Sucrose stearate S-170 - - Parameters: 555.6 g 700 rpm

The retigabine melt granules are heated with stirring in an Aeromatic-Fielder type GPl intensive mixer at a jacket temperature of 52°C. Sucrose stearate S-170 is added at a product temperature of 30°C, and granulation is continued for 7 min with the chopper (3 000 rpm) switched on. The coated granules are removed and sieved through a sieve with a mesh width of 1.4 mm. - Results of particle size distribution > 1 000 >s0 | a0 >m5 | a0 <so [7 e

S - 36 _ rime inmin pis [30 [eo [120 [iso [240 [360 Jago

Release in % in 0.1N|23.8 (43.6 (71.4 [94.4

HC1

In buffer of 7.2 13.2 [19.8 |25.4 31 40.2 147.4 pH 7.5/2.5% Texapon

See Annex 2la for release of active ingredient in 0.1N

HCl

See Annex 21b for release of active ingredient in buffer of pH 7.5, 2.5% Texapon

Example 25:

Dexlipotam (tromethamol salt of R'-thioctic acid) with 22.7% sucrose stearate of HLB 15 - Formula: - Parameters: 1

Stirrer speed 500 rpm

Chopper speed 3 000 rpm 55.0-80.0°C - Production takes place as in example 1 - Analysis: release of active ingredient

Release in % in 93 95 101 buffer of pH 4.5

Claims

Patent Claims:

1. An oral pharmaceutical formulation with variably adjustable release characteristics, characterized in that one or more sucrose fatty acid esters is

. Present as sole release-controlling agent, in addition to one or more active ingredients.

2. A pharmaceutical formulation as claimed in claim 1, characterized in that it is a drug form with release ranging from rapid to slow release.

-

3. A pharmaceutical formulation as claimed in claim 1, characterized in that the release characteristics can be controlled via the type and proportion of the sucrose fatty acid ester(s) and via the process parameters of the production process.

4. A pharmaceutical formulation as claimed in claim 1, characterized in that it comprises a single unit or multiple unit drug form.

5. A pharmaceutical formulation as claimed in claim 1 and 4 in the form of an oral dosage form such as granules, pellets, tablets, film-coated tablets, microtablets, sugar-coated tablets, capsules or special therapeutic systems.

6. A pharmaceutical formulation as claimed in claim 1, characterized in that the active ingredient (s) are embedded in a matrix composed of sucrose fatty acid ester and/or are coated by sucrose fatty acid ester.

7. A pharmaceutical formulation as claimed in claim 6, characterized in that granules or pellets comprising an active ingredient or active

. ingredient mixtures and sucrose fatty acid esters : may additionally be coated with sucrose fatty acid ester.

8. A pharmaceutical formulation as claimed in claim 6, characterized in that sucrose fatty acid ester-free granules or pellets are coated with sucrose fatty acid ester.

9. A pharmaceutical formulation as claimed in claim 1, characterized in that the sucrose fatty acid esters employed consist of mono-, di-, tri- or polyesters of sucrose with medium- to long- ) chain saturated and/or unsaturated fatty acids.

10. A pharmaceutical formulation as claimed in claim 9, characterized in that esters of sucrose with Ci;..2-fatty acids are preferably employed as sucrose fatty acid esters.

11. A pharmaceutical formulation as claimed in claim 1 and 9, characterized in that the HLB of the sucrose fatty acid esters employed is from 1 to

16.

12. A pharmaceutical formulation as claimed in claim 1 and 9, characterized in that the sucrose fatty acid esters employed have their melting point or melting range in the temperature range from 30 to 200°C.

13. A pharmaceutical formulation as claimed in claim 12, characterized in that the sucrose fatty acid esters employed preferably have their melting point or melting range in the temperature range from 40 to 150°C.

14. A pharmaceutical formulation as claimed in claim 1, characterized in that sucrose fatty acid esters are present in a proportion of from 1 to 95% by weight in the granules.

15. A pharmaceutical formulation as claimed in claim 14, characterized in that sucrose fatty acid esters are preferably present in a proportion of from 5 to 50% by weight in the granules.

16. A pharmaceutical formulation as claimed in claim 1 and 8, characterized in that sucrose fatty acid esters are present in a proportion of 1-60% by weight in the coating, based on the coated drug } form.

17. A pharmaceutical formulation as claimed in claim 16, characterized in that sucrose fatty acid esters are preferably present in a proportion of 3-20% in the coating, based on the coated drug form.

18. A pharmaceutical formulation as claimed in claim 1, characterized in that other excipients may additionally be present besides the sucrose fatty acid esters.

15. A pharmaceutical formilation as claimed in claim 18, characterized in that fillers, fusible binders, disintegration aids, flow regulators, mold release agents, film formers and/or other normally employed excipients are used as excipients.

20. A pharmaceutical formulation as claimed in claim 18, characterized in that further modifica- tion of the release of active ingredient is possible by embedding pore formers during the melt granulation or melt pelletization process.

21. A pharmaceutical formulation as claimed in

Nn claim 1, characterized in that readily water- soluble to virtually water-insoluble active ingredients can be employed as active ingredients.

22. A pharmaceutical formulation as claimed in claim 1 and 21, characterized in that active ingredients in particular from the indication areas analeptics/antihypoxemics, analgesics/antirheu- matics, antiallergics, antiarrhytmics, antidementia drugs, antidiabetics, antiemetics/antivertigo drugs, antiepileptics, antihypertensives, antihypotensives, } bronchospasmolytics, antiasthmatics, diuretics, blood flow-stimulating agents, hypnotics/ sedatives, coronary agents, lipid-lowering agents, migraine remedies, muscle relaxants, antiparkinson agents and psychoactive drugs can be employed.

22. A pharmaceutical formulation as claimed in claim 1 and 21, comprising active ingredients such as caffeine, diclofenac, morphine, tramadol, tili- dine, flupirtine, azelastine, pseudoephedrine, quinidine, disopyramide, diltiazem, verapamil, piracetam, nicergoline, xantinonicotinate, penti- fylline, vincamine, glibenclamide, betahistine dimesilate, dimenhydrinate, carbamazepine, valproic acid, calcium valproate dihydrate, retigabine, talinolol, fosinopril, doxazosin, metroprolol, nifedipine, norfenefrine HC1, dihydroergotamine mesilate, salbutamol, terbutaline sulfate, theophylline, furosemide, piretanide, buflomedil, naftidrofuryl, pentoxi- fylline, glycerol trinitrate, isosorbide mono- nitrate, isosorbide dinitrate, molsidomine, bezafibrate, fenofibrate, xantinol, sumatriptan, levodopa, benserazide, carbidopa, amitriptyline HCl, wvenlaxafine HCl, thioridazine HCl, lithium carbonate, lithium acetate, thioctic acid or R-thioctic acid and its salts, such as dexlipotam.

24. A pharmaceutical formulation as claimed in claim 1 and 21, preferably comprising flupirtine, tramadol, nifedipine, carbamazepine, calcium val- proate or retigabine.

25. A pharmaceutical formulation as claimed in claim 24, characterized in that 1-95% by weight sucrose fatty acid esters are present in the granules besides the active ingredient retigabine.

26. A pharmaceutical formulation as claimed in ] claim 25, characterized in that 5-50% by weight sucrose fatty acid esters are preferably present in the granules besides the active ingredient retigabine.

27. A process for producing a pharmaceutical formula- tion as claimed in claim 1 by melt granulation or melt pelletization.

28. A process for producing a pharmaceutical formula- tion as claimed in claim 27, characterized in that the starting materials are heated in a suitable apparatus with stirring or in a fluidized bed to a temperature at which there is softening, partial melting on the surface or melting of the sucrose fatty acid ester (s) used, and cooled after granules have formed.

29. A process for producing a pharmaceutical formula- tion as claimed in claim 28, characterized in that the molten sucrose fatty acid ester(s) are added to the heated active ingredient powder in a suitable apparatus.

30. A process for producing a pharmaceutical formula- tion as claimed in claim 28 or 29, characterized in that a high-speed mixer, a fluidized bed apparatus or a rotor granulator can preferably be used as suitable apparatus.

31. A process for producing a pharmaceutical formula- tion as claimed in claim 1, 7 or 8 by coating the granules or pellets preferably by the hot melt coating process or powder coating process.

32. A process for producing a pharmaceutical formula- tion as claimed in claim 31, characterized in that the sucrose fatty acid ester(s) is or are used alone or in combination with plasticizers in the ) hot melt coating and in the powder coating.

33. A process for producing a pharmaceutical formula- tion as claimed in claim 32, characterized in that triethyl citrate, acetyl triethyl citrate, triacetin or dibutyl sebacate can be used as plasticizers.