NZ521215A

NZ521215A - Pharmaceutical formulations

Info

Publication number: NZ521215A
Application number: NZ521215A
Authority: NZ
Inventors: Torsten Hoffmann; Michael Pieroth; Gerhard Zessin; Karl-Friedrich Landgraf
Original assignee: Awd
Priority date: 2000-03-08
Filing date: 2001-03-06
Publication date: 2005-04-29
Also published as: WO2001066081A2; WO2001066081A3; NO20024237D0; PL362547A1; AU2001250365A1; HRP20020804B1; HRP20020804A2; HUP0204513A2; HK1054697A1; EP1267828B1; SK13252002A3; EE200200504A; NO20024237L; PL202935B1; EP1267828A2; EA200200951A1; GEP20053455B; CZ20023009A3; CN1418091A; CN1212831C

Abstract

An oral pharmaceutical formulation with variably adjustable release characteristics, wherein one or more sucrose fatty acid esters is present as sole release-controlling agent, in addition to one or more active ingredients is disclosed. A method for the production of the formulations by melt granulation or melt palletizing is also described. The pharmaceutical formulations range from quick release to delayed release medicament forms.

Description

<div class="application article clearfix" id="description"> 521215 WO 01/66081 PCT/EP01/02500 Pharmaceutical formulations The present invention relates to novel oral pharmaceutical formulations with variably adjustable release 5 characteristics of the active ingredient in the form of granules, pellets, tablets, film-coated tablets, microtablets, sugar-coated tablets, capsules or therapeutic systems, and to processes for the production thereof by melt granulation or melt pelletization. 10 A significant part is played in the use of medicaments by a reduction in the frequency of intake, ideally to one dose a day. 15 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 20 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 25 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 30 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 35 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 - 2 - 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 5 Development and Industrial Pharmacy 21 (9) , 1037-1070 (1998)) . The state of the art is also represented for example in one of the more recent textbooks of pharmaceutical technology (Voigt, R., Pharmazeutische Technologie, 10 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, 15 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 20 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 25 matrix degradation. Hydrocolloid slow release drug forms In this case, the medicinal substance is embedded in hydrocolloid matrices which consist, for example, of 30 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. 35 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. - 3 - The rate of diffusion can be increased by adding plasticizers or pore formers. 5 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 10 specific surface area, can be adjusted through intentional crystallization of the active ingredient, by sieving or grinding. Larger particles mean a smaller specific surface area and a slower release of active ingredient. 15 Forms combining diffusion, erosion, dissolving processes Drug forms whose sustained release of active ingredient are based on combination of diffusion, erosion and 2 0 dissolving processes are also known. A process which is of particular interest and can be employed very variably in relation to release of active ingredient is represented by melt granulation. Melt 25 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 (Liidemann, J.; APV Course 231 on June 17-18, 1996). 30 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 35 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 - 4 - 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 5 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-10 stances with melting points in the range 50-90°C are used most frequently. Active ingredients known as fusible substances are phenyl salicylate, ibuprofen, a-lipoic acid and meprobamate. 15 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 20 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, 25 1249-1277 (1990); McTaggart, C.M. et al.; Int. J. Pharm. 19, 139-148 (1984); Kinget, R.; Kernel, R.; Acta Pharm. Technol. 31, 57 (1985)). Melt granulation is usually carried out in fluidized 30 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 conventional granulation methods using organic solvents, in 35 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 - 5 - one-pot systems is favored. The process of melt granulation can generally be depicted as follows: Mixing 4 Addition of binder (solid state of aggregation) 4 Heating 4 Granulation 4 Cooling 4 optional classification Mixing 4 Heating 4 Addition of binder (liquid state of aggregation) 4 Granulation 4 Cooling 4 optional classification 5 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 10 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 15 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: 20 • mechanical energy through mixers and choppers • jacket contact heat • IR or microwave radiation energy • introduction of hot air into the product bed 25 A large number of processes for producing such formulations are known from the patent literature. - 6 - Formulations with controlled release which can be produced 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. 5 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 10 "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 15 alternative to other granulation methods such as, for example, granulation using organic solvents or granulation using water. Melt pelletization represents in this connection a 20 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 25 few excipients with graded HLB (hydrophilie-lipophilic balance) particularly suitable for melt granulation or melt pelletization processes are described. Representatives of the few excipients with graded HLB 30 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. 35 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 «s - 7 - with another fusible binder such as polyethylene glycol, because its granule-forming capacity is inadequate 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 adjustable 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 non-disintegrating 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. The above objects of the invention are to be read disjunctively with the object of at least providing the public with a useful alternative. . ■"nf ' * FEB 2005 received - 8 - The present invention provides novel oral pharmaceutical formulations which have variably adjustable release characteristics and which, besides one or more active ingredients, comprise one or more sucrose fatty 5 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 10 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 15 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. 20 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 25 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. 30 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 35 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 and on the technological characteristics. They are nontoxic, biodegradable, tasteless and odorless, and stable on storage. Sucrose fatty acid esters with a melting point of 5 > 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 10 alia by the companies Mitsubishi (brandname Ryoto), Gattefosse or Sisterna or others. Sucrose fatty acid esters are known from the literature; thus, they are employed according to US 4 844 067 15 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, 2 0 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. 25 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 30 protein degradation. Sucrose fatty acid esters improve the crystallization characteristics, are effective emulsifiers and reduce the viscosity in the production of fats and oils. 35 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 pharmaceutical compositions to improve the penetration of the active substance through the skin. - 10 - Examples of specific sucrose fatty acid esters mentioned are: sucrose monooctanoate, monolaurate, monopalmitate, monostearate, and the di- and triesters of these compounds. 5 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-10 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. 15 Sucrose fatty acid esters are also used in particular in cosmetic products (FR 2 421 605, JP 81 24 034, JP 81 55 306) . 2 0 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 25 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: 30 C6-i4-fatty acid disaccharide monoesters and Cs-is-fatty acid trisaccharide monoesters. WO 93/00093 claims a novel slow release formulation for diltiazem in the form of spheroids which are composed 35 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 - 11 - 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 5 Ci2-2o~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 10 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 15 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 20 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 25 unsaturated fatty acids or mixtures thereof. Ci2~C22-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. 30 The melting point or melting range of the sucrose fatty acid esters used according to the invention is between 30-200°C. Sucrose fatty acid esters with a melting point or melting range of 40-150°C are preferably employed. 35 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) - 12 - employed, or via the process parameters of the production process. Sucrose fatty acid esters with a low HLB are preferably 5 employed for achieving slow release. Sucrose fatty acid esters with a high HLB are preferentially suitable for rapid or modified release characteristics. 10 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 15 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. 20 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, 25 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. 30 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 35 active ingredient is possible via embedding so-called pore formers, which are excipients with particular properties such as, for example, characteristic solubility or swellability, during the melt granulation or melt pelletization process. - 13 - The oral pharmaceutical formulations of the invention may contain as active ingredients both readily water-soluble to virtually water-insoluble compounds. 5 Active ingredients of the following indication groups are suitable for this, the list not being definitive: analeptics/antihypoxemics (such as caffeine), analgesics /antirheumatics (such as diclofenac, morphine, 10 tramadol, tilidine, flupirtine), antiallergics (such as azelastine, pseudoephedrine), antiarrhythmics, such as quinidine, disopyramide, diltiazem, verapamil), antidementia drugs (nootropics) (such as piracetam, nicergoline, xantinonicotinate, pentifylline, 15 vincamine), antidiabetics (such as glibenclamide), antiemetics/antivertigo drugs (such as betahistine dimesilate, dimenhydrinate), antiepileptics (such as carbamazepine, valproic acid, calcium valproate dihydrate, retigabine), antihypertensives (such as 20 talinolol, fosinopril, doxazosin, metroprolol, nifedipine), antihypotensives (such as norfenefrine HCl, dihydroergotamine mesilate), bronchospasmolytics /antiasthmatics (such as salbutamol, terbutaline sulfate, theophylline), diuretics (such as furosemide, 25 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, 30 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 HCl, venlaxafine HCl, 35 thioridazine HCl, lithium carbonate, lithium acetate); thioctic acid or R-thioctic acid and its salts, such as dexlipotam. The pharmaceutical formulations of the invention - 14 - preferably comprise flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine. The pharmaceutical formulations of the invention can be 5 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 10 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. 15 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 20 increases the power consumption by the stirring motor. Granulation is usually stopped when the power consumption 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 25 cooled in the mixer with suitable cooling (for example cooling jacket), possibly while stirring. There is also the possibility according to the invention to add the sucrose fatty acid esters in the molten state. 30 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. 35 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 - 15 - 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 5 pharmaceutically customary disintegrants or disintegration 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 10 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 15 the pharmaceutical technology objective. It has furthermore been found, surprisingly, that the sucrose fatty acid esters are suitable as excipients for hot melt coating. 20 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 25 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. 30 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 35 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. - 16 - 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 5 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 10 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 15 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 2 0 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. 25 Example 1: Tramadol hydrochloride with 50% sucrose stearate of HLB 1 30 - Formula: Substance Weight Tramadol hydrochloride 400 g Sucrose stearate S-170 400 g - 17 - - Parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 55.0°C The starting materials are heated while stirring in an Aeromatic-Fielder type GP1 intensive mixer at the 5 appropriate jacket temperature. When a particular product temperature is reached, the granulation process is 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 10 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 60 120 180 240 360 480 Release in % in 0.1N HCl 74.03 89.40 95.75 95.57 97.61 98.58 97.87 In buffer of pH 6.8 78.99 89.29 93 .99 93.37 94.26 96.5 96.88 15 See Annex 1 for release of active ingredient Example 2: Flupirtine maleate with 30% sucrose stearate of HLB 1 20 - Formula: Substance Weight Flupirtine maleate 240.0 g Sucrose stearate S-170 102.9 g - 18 - - Parameters: Batch size 342.9 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 61.2°C - Production takes place as in example 1. 5 Example 3: Nifedipine with 30% sucrose stearate of HLB 1 - Formula: Substance Weight Nifedipine 560 g Sucrose stearate S-170 240 g 10 - Parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 58°C - Production takes place as in example 1. - Analysis: release of active ingredient Time in h 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 15 See Annex 2 for release of active ingredient - 19 - Example 4: Nifedipine with 30% sucrose palmitate of HLB 1 - Formula: Substance Weight Nifedipine 560 g Sucrose palmitate P-170 240 g 5 - Parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 52°C - Production takes place as in example 1. 10 - Analysis: release of active ingredient Time in h 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 See Annex 3 for release of active ingredient Example 5: 15 Tablets made from melt granules of nifedipine with 30% sucrose stearate of HLB 5 - Formula: Substance Weight Nifedipine 560 g Sucrose stearate S-570 240 g - 20 - - Granulation parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature <1 o o O - Production takes place as in example 1. 5 - 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. 10 - Analysis: release of active ingredient Time in min 30 60 120 180 240 Release in % in purified water71.25% SDS 19.85 42.44 78.30 96.61 102.88 See Annex 4 for release of active ingredient 15 Example 6: Tablets made from melt granules of nifedipine with 50% sucrose stearate of HLB 9 and 2.5% sucrose stearate of HLB 1 20 - Formula: Substance Weight Nifedipine 400 g Sucrose stearate S-970 380 g Sucrose stearate S-170 20 g - Granulation parameters: Batch size 800 g Stirrer speed 7 00 rpm Chopper speed 3 000 rpm Jacket temperature 65°C - 21 - - Production takes place as in example 1. - Tableting parameters: 5 The granules were compressed with a round tableting tool, of 6 mm diameter, middle-domed, to tablets with a gross weight of 100 mg. 10 - Analysis of release of active ingredient 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 See Annex 5 for release of active ingredient Example 7: 15 Carbamazepine with 10% sucrose stearate of HLB 1 - Formula: Substance Weight Carbamazepine 720 g Sucrose stearate S-170 o CO - Parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 55°C 20 - Production takes place as in example 1. - Analysis: release of active ingredient Time in min 30 60 120 180 240 360 480 Release in % in modified intestinal fluid 10.68 20.06 38.08 51.45 62.47 73.89 81.58 - 22 - See Annex 6 for release of active ingredient Example 8: 5 Carbamazepine with 30% sucrose stearate of HLB 9 - Formula: Substance Weight Carbamazepine 560 g Sucrose stearate S-970 240 g - Parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 00 o O 10 - Production takes place as in example 1. - Analysis: release of active ingredient Time in min 30 60 120 180 240 360 480 Release in % in modified intestinal fluid 26.09 42.27 62.65 80.58 87.38 96.56 100.84 15 See Annex 7 for release of active ingredient Example 9: Carbamazepine with 50% sucrose behenate of HLB 3 and 2.5% triethyl citrate 20 - Formula: Substance Weight Carbamazepine 400 g Sucrose behenate B-370 380 g Triethyl citrate 20 g - 23 - - Parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 50°C The starting materials carbamazepine and triethyl citrate are mixed in an Aeromatic-Fielder type GP1 5 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 is to be observed is reached, the granules are 10 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 15 30% sucrose stearate of HLB 9 - Formula: Substance Weight Carbamazepine 560 g Sucrose stearate S-97 0 240 g - Granulation parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature (Ti 00 O O 20 - Production takes place as in example 1. - Tableting parameters: 25 The granules are compressed without other additions using a round tableting tool, of diameter 13 mm, flat, - 24 - to tablets with a gross weight of 571 mg and a hardness of 25 N. - Analysis: release of active ingredient Time in min 30 60 120 180 240 360 480 Release in % in modified intestinal fluid 5.36 8.04 13.78 17.89 21.01 27.31 32.08 5 See Annex 8 for release of active ingredient Example 11: Carbamazepine with 20% sucrose stearate of HLB 2 10 - Formula: Substance Weight Carbamazepine 640 g Sucrose stearate S-270 160 g - Parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 54°C 15 - Production takes place as in example 1. Example 12: Calcium valproate dihydrate with 35% calcium hydrogen phosphate and 30% sucrose stearate of HLB 1 20 - Formula: Substance Weight Calcium valproate dihydrate 280 g Calcium hydrogen phosphate 280 g Sucrose stearate S-170 240 g - 25 - - Parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 53°C Production takes place as in example 1, initially-introducing the active ingredient calcium valproate 5 dihydrate with calcium hydrogen phosphate. - Analysis: release of active ingredient Time in min 60 240 480 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 10 Example 13: Tablets made from melt granules of calcium valproate dihydrate and 30% sucrose stearate of HLB 1 15 - Formula: Substance Weight Calciumb valproate dihydrate 560 g Sucrose stearate S-170 240 g - Granulation parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 55°C Production takes place as in example 1 20 - Tableting parameters: The granules are compressed with an oblong tableting - 26 - 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 in min 60 240 480 Release in % in pH 3.0 4.96 9.14 13.66 Release in % in pH 6.8 92.93 98.57 99.43 5 See Annex 10 for release of active ingredient Example 14: Tablets made from melt granules of calcium valproate 10 dihydrate and 30% sucrose stearate of HLB 9 - Formula: Substance Weight Calcium valproate dihydrate 560 g Sucrose stearate S-970 240 g - Granulation parameters: Batch size 800 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 65°C 15 Production takes place as in example 1 - Tableting parameters: 20 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 in min 60 240 480 Release in % in pH 3.0 16.89 56.55 87.96 Release in % in pH 6.8 1.75 2.77 4.34 - 27 - See Annex 11a for release of active ingredient See Annex lib for comparison of the release of active 5 ingredient from the calcium valproate formulas in pH 3.0 See Annex 11c for comparison of the release of active ingredient from the calcium valproate formulas in 10 pH 6 . 8 Example 15: Retigabine with 20% sucrose stearate of HLB 1 15 - Formula: Substance Weight Retigabine 800 g Sucrose stearate S-170 200 g - Granulation parameters: Batch size 1000 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 52°C Production takes place as in example 1 20 - Analysis: release of active ingredient Time in min 30 60 120 180 240 360 480 Release in % in 0.IN HCl 37.23 56.71 75.81 In buffer of pH 6.8/1% Texapon 5.71 8.77 13.82 15.79 23.60 27.99 35.62 See Annex 12 for release of active ingredient - 28 - Example 16: Retigabine with 20% sucrose stearate of HLB 2 - Formula: Substance Weight Retigabine 400 g Sucrose stearate S-270 100 g - Parameters: Batch size 500 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature CJ1 (J1 o O Production takes place as in example 1 10 - Analysis of release of active ingredient Time in min 15 30 60 120 180 240 360 480 Release in % in 0.1N HCl 42.28 62.58 83 .53 100.97 Release in % in buffer of pH 7.5 11.82 20.77 34.41 44.94 52.74 61.63 66.37 See Annex 13 for release of active ingredient Example 17: 15 Retigabine with 20% sucrose stearate of HLB 1 and 10% sucrose stearate of HLB 9 - Formula: Substance Weight Retigabine 210 g Sucrose stearate S-170 60 g Sucrose stearate S-970 30 g - 29 - - Parameters: Batch size 300 g Stirrer speed 500 rpm Chopper speed 3 000 rpm Jacket temperature 65°C Production takes place as in example 1 5 - Analysis of release of active ingredient Time in min 15 30 60 120 180 240 360 480 Release in % in 0.IN HCl 71.49 85.13 97.93 102.82 Release in % in buffer 6.8 31.02 36.93 51.97 61.25 70.63 79.01 78.77 See Annexes 14a for release of active ingredient See Annex 14b for comparison of the releases of active 10 ingredient from retigabine formulas in 0.IN HCl See Annex 14c for comparison of the releases of active ingredient from retigabine formulas in buffer of pH 6.8 15 Example 18: Tablets made from melt granules with retigabine, 20% sucrose stearate of HLB 1 and 10% croscarmelose sodium - Formula: Substance Weight Retigabine 800 g Sucrose stearate S-170 200 g 20 - 30 - - Granulation parameters: Batch size 1 000 g Stirrer speed 700 rpm Chopper speed 3 000 rpm Jacket temperature 52°C Production takes place as in example 1 5 - Tableting parameters: Substance Weight Retigabine slow release granules (see above) 270 g Croscarmellose sodium 30 g The tableting mixture is compressed to tablets with a round tableting tool of diameter 9 mm, bevel 45°, radius of curvature R13. - Analysis: release of active ingredient Time in min 15 30 60 120 180 240 360 480 Release in % in 0.IN HCl 40.76 81.59 96.13 100.76 In buffer of pH 6.8/ 1% Texapon 22.20 29.80 38.95 46.49 53 .58 60.85 64.69 See Annex 15 for release of active ingredient 15 Example 19: Retigabine with 7% sucrose stearate of HLB 1 - Formula: Substance Weight Retigabine 372 g Sucrose stearate S-170 28 g - 31 - - Parameters: Batch size 400 g Stirrer speed 1 300 rpm Jacket temperature 50°C The starting materials are heated with stirring in a special container provided with a PTFE inliner in an 5 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 Time in min 30 60 120 180 240 360 480 Release in buffer of PH 7.5/2.5% Texapon 16.62 29.85 50.39 67.14 69.35 83.20 90.96 See Annex 16 for release of active ingredient Example 20: 15 Retigabine with 2 0% sucrose stearate of HLB 11 - Formula: Substance Weight Retigabine 320 g Sucrose stearate S-1170 80 g - Parameters: Batch size 400 g Stirrer speed 1 300-1 100 rpm Jacket temperature 50°C 20 - Production takes place as in example 19 - 32 - - Analysis: release of active ingredient Time in min 30 60 120 180 240 Release in buffer of PH 7.5/2.5% Texapon 49.91 79.95 100.81 106.03 104.36 See Annex 17 for release of active ingredient 5 Example 21: Retigabine with 20% sucrose stearate of HLB 16 - Formula: Substance Weight Retigabine 320 g Sucrose stearate S-1670 80 g 10 - Parameters: Batch size 400 g Stirrer speed 1 300-1 100 rpm Jacket temperature 50-55°C - Production takes place as in example 19 - Analysis: release of active ingredient Time in min 30 60 120 180 240 Release in buffer of PH 7.5/2.5% Texapon 41.77 68.71 92 .32 99.95 101.47 15 See Annex 18 for release of active ingredient Example 22: Retigabine with 16% sucrose stearate of HLB 15 20 - Formula: Substance Weight Retigabine 336 g Sucrose stearate S-1570 64 g - 33 - - Parameters: Batch size 400 g Stirrer speed 1 300 rpm Jacket temperature 50-60°C - Production takes place as in example 19 5 - Analysis: release of active ingredient Time in min 30 60 120 180 240 Release in buffer of PH 7.5/2.5% Texapon 64.67 89.83 99.98 101.78 100.99 See Annex 19 for release of active ingredient Example 23: 10 Retigabine tablets - Melt granules formula: Substance Weight Retigabine 332 g Sucrose stearate S-1570 68 g - Parameters: Batch size 400 g Stirrer speed 1 300 rpm Jacket temperature 50-60°C 15 - Production takes place as in example 19 - 34 - - Coating formula: Substance Weight Retigabine melt granules with 17% sucrose stearate of HLB 15 1 000 g Eudragit L 30 D-55 400 g (corresponds to 120 g of coating dry matter) Talc 60 g Triethyl citrate 12 g The melt granules from 5 batches are combined and sprayed in a rotor granulator with inlet air at 50°C 5 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. 10 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, 15 17 x 8 mm, by convex with an average hardness of 87 N. Time in min 15 30 60 120 180 240 Release in % in 0.1N HCl 50.3 68.8 83 88.3 In buffer of pH 7.5/1.7% Texapon 16.1 30.4 55.7 83.4 95.2 99.2 See Annex 20a for release of active ingredient in 0.IN HCl 20 See Annex 20b for release of active ingredient in buffer of pH 7.5, 1.7% Texapon - 35 - Example 24: Hot melt coating of retigabine melt granules with 10% sucrose stearate of HLB 1 5 - Formula for coated melt granules: Substance Weight Retigabine melt granules (90% by weight retigabine and 10% by weight sucrose stearate S-170) 500 g Sucrose stearate S-170 55.6 g - Parameters: Batch size 555.6 g Stirrer speed 700 rpm Jacket temperature 52°C The retigabine melt granules are heated with stirring 10 in an Aeromatic-Fielder type GP1 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 15 through a sieve with a mesh width of 1.4 mm. - Results of particle size distribution Particle class [pun] Proportion [%] > 1 000 3.4 > 800 4.0 > 500 34.4 > 315 40.9 > 160 14.0 o LO A 3.4 < 50 0 - 36 - Time in min 15 30 60 120 180 240 360 480 Release in % in 0.IN HCl 23.8 43 .6 71.4 94.4 In buffer of pH 7.5/2.5% Texapon 7.2 13.2 19.8 25.4 31 40.2 47.4 See Annex 21a for release of active ingredient in 0. IN HCl 5 See Annex 21b for release of active ingredient in buffer of pH 7.5, 2.5% Texapon Example 25: 10 Dexlipotam (tromethamol salt of R+-thioctic acid) with 22.7% sucrose stearate of HLB 15 - Formula: Substance Weight Dexlipotam 255 g Sucrose stearate S-170 75 g 15 - Parameters: Batch size 330 g Stirrer speed 500 rpm Chopper speed 3 000 rpm Jacket temperature en Ul o t 00 o o o o - Production takes place as in example 1 - Analysis: release of active ingredient Time in min 15 30 45 Release in % in buffer of pH 4.5 93 95 101 - 37 - </div>

Claims

<div class="application article clearfix printTableText" id="claims"> Claims:

1. An oral pharmaceutical formulation with variably adjustable release characteristics, wherein 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, wherein it is a drug form with release ranging from rapid to slow release.

3. A pharmaceutical formulation as claimed in claim 1 or claim 2, wherein 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 any one of claims 1 to 3, wherein it comprises a single unit or multiple unit drug form.

5. A pharmaceutical formulation as claimed in any one of claims 1 to 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 any one of claims 1 to 5, wherein 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, wherein 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. _ muti'DAL PROPERTY OFFICE* nt ' * FEB 2005 received - 38 -

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 any one of claims 1 to 8, wherein the sucrose fatty acid esters employed consist of mono-, di-, tri or polyesters of sucrose with medium- to longchain saturated and/or unsaturated fatty acids.

10. A pharmaceutical formulation as claimed in claim 9, wherin esters of sucrose with Ci2-22_fatty acids are employed as sucrose fatty acid esters.

11. A pharmaceutical formulation as claimed in any one of claims 1 to 10, wherein the HLB of the sucrose fatty acid esters employed is from 1 to 16.

12. A pharmaceutical formulation as claimed in any one of claims 1 to 11, wherein 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, wherein the sucrose fatty acid esters employed have their melting point or melting range in the temperature range from 40 to 150°C.

14. A pharmaceutical formulation as claimed in any one of claims 1 to 13, wherein 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, wherein sucrose fatty acid esters are present in a proportion of from 5 to 50% by ir i jlrL.J.ivo"17^"^' TTflTIV"100 ACTUAL PROPERTY OFRCET of n.z. 1 4 FEB 2005 received - 39 -

16. A pharmaceutical formulation as claimed in any one of claims 1 to 13, wherein 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, wherein sucrose fatty acid esters are present in a proportion of 3-20% in the coating, based on the coated drug form.

18. A pharmaceutical formulation as claimed in any one of claims 1 to 17, wherein other excipients may additionally be present besides the sucrose fatty acid esters.

19. A pharmaceutical formulation as claimed in claim 18, wherein 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 or claim 19, wherein further modification 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 any one of claims 1 to 20, wherein readily water-soluble to virtually water-insoluble active ingredients can be employed as active ingredients.

22. A pharmaceutical formulation as claimed in any one of claims 1 to 21, wherein active ingredients are from the indication areas analeptics/antihypoxemics, analgesics/antirheumatics, antiallergics, antiarrhytmics, antidementia drugs, antidiabetics, intellectual property office of n.z. 1 4 feb 2005 rftfiv/pn - 40 - antiemetics/antivertigo antihypertensives, drugs, antiepileptics, antihypotensives, bronchospasmolytics, antiasthmatics, diuretics, blood flow-stimulating agents, hypnotics/sedatives, coronary agents, lipid-lowering agents, migraine remedies, muscle relaxants, anti-parkinson agents and psychoactive drugs can be employed.

23. A pharmaceutical formulation as claimed in any one of claims 1 to 22, comprising active ingredients such as caffeine, diclofenac, morphine, tramadol, tilidine, flupirtine, azelastine, pseudoephedrine, quinidine, disopyramide, diltiazem, verapamil, piracetam, nicergoline, xantinonicotinate, pentifylline, vincamine, glibenclamide, betahistine dimesilate, dimenhydrinate, carbamazepine, valproic acid, calcium valproate dihydrate, retigabine, talinolol, fosinopril, doxazosin, metroprolol, nifedipine, norfenefrine HCl, dihydroergotamine mesilate, salbutamol, terbutaline sulfate, theophylline, furosemide, piretanide, buflomedil, naftidrofuryl, pentoxifylline, glycerol trinitrate, isosorbide mononitrate, isosorbide dinitrate, molsidomine, bezafibrate, fenofibrate, xantinol, sumatriptan, levodopa, benserazide, carbidopa, amitriptyline HCl, venlaxafine 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 any one of claims 1 to 22, comprising flupirtine, tramadol, nifedipine, carbamazepine, calcium valproate or retigabine.

25. A pharmaceutical formulation as claimed in claim 24, wherein 1-95% by weight sucrose fatty acid esters are present in the granules besides the active ingredient retigabine. intellectual property office o f N.z. 1 4 feb 2005 received - 41 -

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

27. A process for producing a pharmaceutical formulation as claimed in any one of claims 1 to 26 by melt granulation or melt pelletization.

28. A process for producing a pharmaceutical formulation as claimed in claim 27, wherein 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 formulation as claimed in claim 28, wherein 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 formulation as claimed in claim 28 or claim 2 9, wherein a high-speed mixer, a fluidized bed apparatus or a rotor granulator can be used as suitable apparatus.

31. A process for producing a pharmaceutical formulation as claimed in any one of claims 5, 7 or 8, by coating the granules or pellets by the hot melt coating process or powder coating process.

32. A process for producing a pharmaceutical formulation as claimed in claim 31, wherein 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. INTELLECTUAL property office ^ N.Z. 14 feb 2005 Received - 42 -

33. A process for producing a pharmaceutical formulation as claimed in claim 32, wherein triethyl citrate, acetyl triethyl citrate, triacetin or dibutyl sebacate can be used as plasticizers.

34. The formulation according to any one of claims 1 to 26, substantially as herein described with reference to examples 1-25 and annexes l-21b or part thereof.

35. The process according to any one of claims 27 to 30, substantially as herein described with reference to examples 1-25 and annexes l-21b or part thereof.

36. The process according to any one of claims 31 to 33, substantially as herein described with reference to examples 1-25 and annexes l-21b or part thereof. intellectual property office V M.Z 1 * feb 2005 received </div>