NZ260732A

NZ260732A - Ipsapirone delayed release compositions

Info

Publication number: NZ260732A
Application number: NZ260732A
Authority: NZ
Inventors: Peter Serno; Wolfgang Fischer; Roland Rupp; Mark Versavel; Ulrich Tenter; Gerhard Schmidt; Gunter Schollnhammer; Maria Ammen; Shinji Maegata
Original assignee: Bayer Ag
Priority date: 1993-06-15
Filing date: 1994-06-13
Publication date: 1996-02-27
Also published as: ZA944187B; FI942803A0; NO942228L; HU9401771D0; CA2125620A1; EP0629402A1; KR950000150A; AU6345794A; CN1099263A; DE4319760A1; HUT70759A; SK72494A3; FI942803A; IL109993A0; JPH06345649A; CZ146494A3; PL303822A1; NO942228D0

Description

<div class="application article clearfix" id="description"> 2 6 0 7 3 2 Patents Form 5 Priority Dc.te (s): .15".J .^3 Complete Specification Piled:.. Class: (6) .ft.feiJcsu|;a.Q:, .1 Ks2?t. \ So .T Publication Date: j??.®. P.O. Joumal ?-'o: L^r.Q.\ N.Z.No. NEW ZEALAND Patents Act 1953 COMPLETE SPECIFICATION IPSAPIRONE MEDICAMENT FORMULATION We, BAYER AKTIENGESELLSCHAFT, a company registered under the laws of the Federal Republic of Germany, of D 51368 Leverkusen, Federal Republic of Germany do hereby declare the invention, for which we pray that a patent may be granted to us, and the method by which it is to be performed, to be particularly described in and by the following statement: - -1 - (Followed by 1A) 260732 The invention relates to an ipsapirone medicament formu lation with delayed action and high storage stability, preparation process and the use thereof. Ipsapirone is a novel active substance which is employed 5 for the therapy of anxiety states and depressions. It has been found as the result of pharmacokinetic investigations that ipsapirone has a bioavailability of only 40% after oral administration. A considerable proportion of the active compound undergoes presystemic 10 metabolism and cannot become bioavailable. This is disadvantageous because this loss of substance must be compensated by an increased dose of active compound. This results in pharmaceutical forms which are large and difficult for the patient to swallow and in a con-15 siderable exposure of the patient to pharmacologically inactive ipsapirone metabolites. Furthermore/ as the bioavailability decreases there is an increase in the interindividual variations in the course of the plasma concentrations, and the therapy becomes unpredictable. 20 Another pharmacokinetic disadvantage of ipsapirone is the short elimination half-life. As a consequence, ipsapirone tablets must be taken at least three times a day. This has a number of inconvenient consequences for working patients, there is a high risk of forgetting to take the 25 tablets, and the readiness and ability of patients to 260 732 comply correctly with such a therapy over a long time are low. There is thus a considerable need for a pharmaceutical form of ipsapirone which compensates for the unfavourable 5 properties of the substance, that is to say increases the bioavailability of the active compound and simultaneously permits the frequency of intake to be reduced. Effective and therapeutically acceptable methods for reducing the presystemic metabolism of ipsapirone and 10 thus increasing the bioavailability have not been disclosed to date. Although absorption promoters such as those described, for example, in EP 0 206 947 for other active compounds are able to increase inadequate absorption, they cannot reduce extensive presystemic metabo-15 lism. The formulation in C12-C24 fatty acids described in WO 92/06680 for reducing the first-pass metabolism requires a sufficient solubility of the active compound in fatty acids, which ipsapirone does not have. Furthermore, there is a considerable exposure of the patient to 20 fatty acids. Methods for delaying the release of pharmacologically active compounds and thus reducing the frequency of intake are sufficiently well known to the skilled person. However, all conventional release delaying 25 methods are associated with a greater or lesser loss of bioavailability which in the case of ipsapirone is already critical. Release-delaying and increasing the 26 0 7 3 2 bioavailability are, according to the current state of the art, two contrary requirements and no methods are known for achieving them simultaneously. It has now been found that the bioavailability of ipsapi-5 rone can be increased, with simultaneous release-delaying, by converting the active compound into a pharmaceutical form which releases the active compound at an average release rate of 80% weight of the dose/5 hours to 80% weight of the dose/13 hours and whose initial release rate in 10 the first two hours of release is less than 35% weight. Surprisingly, the ipsapirone medicament forms according to the invention show em increase din bioavailability of, for example, 24% weight with, at the same time, a delay in the plasma concentration course so that the frequency of 15 intake can be reduced to once a day. This is all the more surprising since it is to be assumed according to current knowledge that the bioavailability of active compounds tends to decrease on controlled, slow release. Thus, SKELLY (Skelly, J., Regulatory Recommenda-20 tions in USA on Investigation and Evaluation of Oral Controlled Release Products, in: Gundert-Remy, Moller, Oral Controlled Release Products, Wiss. Verlagsgesellschaft Stuttgart 1990, page 180) summarizes: "many controlled release products are somewhat less 25 bioavailable than their immediate release counterparts." For the specific case of active compounds with high presystemic metabolism, WAGNER (Wagner, J.G., Oral Sustained Release and Prolonged-Action Medication, in: 26 0 7 3 Fundamentals of Clinical Pharmacokinetics, Hamilton Drug Intelligence Publ. 1975, page 149) describes the state of the art as follows: "if a drug is metabolized in the gastrointestinal barrier during absorption then it is 5 feasible that a greater percentage of the dose in a slow release form will be metabolized than when the same dose is administered in a fast release form.H Furthermore the formulations according to the invention overcome the previous prejudice "that release of the pharmaceutical 10 substance must be complete after about 7 hours. Otherwise, the extent of bioavailability must be expected to impaired" (Lippold, B.C., Biopharmazie. Wiss. Verlagsgesellschaft Stuttgart 1984, page 69). Various methods for delaying the release of active 15 compounds can be employed for preparing the ipsapirone medicament formulation according to the invention, but a release rate in the range according to the invention must be attained. To ascertain the initial and average release rate 20 required according to the invention, the pharmaceutical forms are tested in "apparatus 2" of USP XXII (The United States Pharmacopeia USP XXII 1990, page 1578). 900 ml of 0.1 molar hydrochloric acid are used as test medium. The speed of revolution of the stirrer is 75 revolutions per 25 minute. Samples are taken through an 8 |xm filter and the content of active compound therein is determined by HPLC. The dissolved amount of active compound determined in this way is converted into a percentage of the amount of 26 0 7 3 2 active compound employed. Preferred medicament formulations according to the invention cure diffusion-controlled pellets, erosion tablets or osmotic delivery systems of ipsapirone such as 5 tablets or pellets with membranes of controlled porosity or three-layer erosion tablets in which only the middle layer contains active compound. The diffusion-controlled pellets according to the invention generally consist of neutral pellets onto which a 10 mixture of the active compound with customary binders and thickeners, where appropriate together with additives, is applied and which are subsequently coated with a customary diffusion lacquer containing customary plasti-cizers. 15 Hydroxypropyljnethylcellulose is preferably used as binder and thickener. It is likewise also possible to employ other natural, synthetic or semisynthetic polymers such as, for example, methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose, polyacrylic acids or 20 gelatin. Suitable and preferred as diffusion lacquer is an aqueous dispersion ethyl cellulose, sold commercially as Aquacoat®, but also other materials such as acrylates, cellulose acetate, cellulose acetate butyrate, Surelease® or ethylcellulose in the form of other aqueous dispersions 25 or solutions. ^6 0 7 3 2 Triacetin is suitable and preferred as plasticizer, but it is also possible to employ dibutyl sebacate, medium-chain triglycerides, acetylated monoglycerides, triethyl citrate, tributyl acetylcitrate, diethyl phthalate or 5 dibutyl phthalate as plasticizer. Since the nature and the amount of the plasticizer influence the release rate, the amount of diffusion lacquer used for coating must be changed where appropriate in such a way that the resulting pellets have the release rate according to the 10 invention. In the case of the pellets according to the invention it is particularly important to use a particular ratio of pellets coated with active compound to the diffusion membrane and a particular ratio of lacquer dry matter to 15 plasticizer amount. On use of neutral pellets with a size of 0.85-1 mm, a ratio of neutral pellets to active compound (calculated as anhydrous ipsapirone hydrochloride) of 40:10, a ratio of binder, in particular EPMC, to active compound calcu-20 lated as anhydrous ipsapirone hydrochloride of 5:10 and a ratio of physiologically tolerated acid, especially potassium hydrogen tartrate, to active compound (calculated as anhydrous ipsapirone hydrochloride) of 10:10, it is preferable for the ratio of the mass of 25 pellets coated with active compound to the mass of diffusion lacquer (without plasticizer) to be 100:6 to 100:21 - 6 - 26 0 7 and for the ratio of the mass of diffusion lacquer to the employed mass of plasticizer to be 100:5 to 100:60, preferably 100:20 to 100:45. It must be taken into account that parts of the employed 5 plasticizer may evaporate during the coating and subsequent heat treatment. Thus, after application of 8.5% Aquae oat® dry matter, for example, only about 86% of the theoretical amount of triacetin are found, and after subsequent heat treatment at 70 °C for one hour in a 10 fluidized bed only about 15% of the theoretical amount of triacetin are found. When the stated boundary conditions are altered it i.3 necessary to change the amount of diffusion lacquer used for coating according to the invention. Thus, for 15 example, a larger amount is necessary for coating when the relative amount of neutral pellets is increased, the amount of hydroxypropylmethylcellulose is increased or the triacetin content is reduced. A smaller amount is necessary for coating when the relative amount of neutral 20 pellets is reduced, the amount of hydroxypropylmethylcellulose is reduced or the triacetin content is increased. The diffusion pellets according to the invention may be prepared, for example, by suspending or dissolving 25 microfine ipsapirone hydrochloride hydrate and, where appropriate, a physiologically tolerated acid in water and thickening with a concentrated methylhydroxypropyl- 26 0 7 cellulose solution. The suspension obtained in this way is applied to neutral pellets in a spray process in a fluidized bed system. The pellets are then coated with a diffusion membrane by spraying on, for example, an 5 aqueous ethylcellulose dispersion which contains a suitable, physiologically tolerated plasticizer. The pellets are subsequently heat-treated at temperatures of 50-125°C, preferably 60-110°C. In this connection higher temperatures for the heat-treatment lead to lower amounts 10 of applied lacquer tending to be sufficient to achieve the release rate according to the invention and the resulting pellets being more physically stable on storage. The thickness of the diffusion membrane, type of plasticizer, amount of plasticizer and pellet size are 15 chosen so that a release rate of 80% of ipsapirone in 5-13 hours results and less than 35% of the dose is released in the first two hours. The amount of pellets corresponding to a daily dose of, for example, 10 mg, 20 mg, 30 mg or 40 mg of ipsapirone is placed in a hard 20 gelatin capsule. Besides the described coating of neutral pellets, other methods for preparing pellets are also practicable, such as the extrusion/spheronizer process, rotor granulation or tabletting. 25 Additionally preferred are pharmaceutical formulations according to the invention in the form of erosion tablets. These tablets are characterized in that, besides customary auxiliaries and vehicles as well as tabletting 260 732 auxiliaries/ they contain a defined amount of water-soluble, hydrogel-forming polymers, it being necessary for these polymers to have a viscosity of at least 150 m?a* s (measured as 2% strength aqueous solution at 5 20°C). Examples of customary auxiliaries and vehicles sore lactose, microcrystalline cellulose, mannitol or calcium phosphates. Examples of customary tabletting aids are magnesium 10 stearate, talc or highly disperse silicon dioxide (Aerosil®). Preferably used as water-soluble, hydrogel-forming polymers are hydroxypropylcellulose/ but also hydroxy-propylmethylcelluloses/ methylcelluloses, carboxymethyl-15 cellulose, alginates, galactomannans, polyacrylic acid, polymethacrylic acids or copolymers of methacrylic acid and methyl methacrylate. The use of hydroxypropylcellulose is particularly preferred. 20 In this case, the erosion tablets according to the invention ought to contain at least 50 mg of a hydroxypropylcellulose type, based on the mass of one tablet/ whose viscosity (measured as 2% strength aqueous solution at 20°C) is at least 150 mPa-s. - 9 - 26 0 7 *>. o These data apply to hydroxypropylcelluloses with a hydroxypropoxy group content of 53-78% and a particle size of 99% < 150 pm, 20-35% 150-63 pm, 50-60% 63-38 |un and 15-25% < 38 |im. In the case of deviation therefrom, 5 adaptation to the amount according to the invention is necessary. The tablets according to the invention can be prepared, for example, by suspending ipsapirone hydrochloride hydrate in an hydroxypropylcellulose solution. The 10 suspension is used to granulate a mixture of powdered hydrophilic gel formers, for example hydroxypropylcelluloses of one or more viscosity levels, in a flui-dized bed granulator. In this connection, the amount and viscosity level of the hydroxypropylcellulose(s) is 15 chosen so that the resulting tablets have the average release rate and initial release rate according to the invention. The dry granules are screened, where appropriate mixed with a physiologically tolerated acid and then with a lubricant such as magnesium stearate, tablet-20 ted and, where appropriate, then coated. Another considerable problem in the formulation of ipsapirone comprises its instability. The active compound reacts to external influences such as temperature and moisture a& fellows: UL A 1J IW - 10 - 260 732 (CH2) 4— x HCl O + H 20 Ipsapirone hydrochloride .SOjNH—(CH2) A— x HCl 'COOH Bay t 8519 Breakdown product A The rate of this reaction is very considerable. Thus, it has beqn found that a solution of 6.7 mg of ipsapirone hydrochloride in 100 ml of phosphate buffer pB 6.8 is already 29% decomposed after 24 hours at 37°C. This 5 reaction may also take place in slow-release pharmaceutical forms so that portions of the active compound are broken down during passage through the stomach and intestines before they are absorbed. The consequence is a reduced bioavailability. 10 The same breakdown reaction also le?ds to instability on storage. Thus, the tablet of Comparative Example 1 shows 2.23% (based on content of active compound) of breakdown product A after storage at 40°C for 6 months. It has now been found that this breakdown reaction can be 15 avoided, without other disadvantages, when a physiologically tolerated acid or salts with an acidic reaction 2Q 0 U / v.; £ such as potassium hydrogen tartrate, adipic acid, ascorbic acid, aspartic acid, benzoic acid, citric acid, fumaric acid, glutamic acid, maleic acid, sodium • dihydrogen citrate, sodium dihydrogen phosphate, poly-5 acrylic acid, sorbic acid, stearic acid, succinic acid, tartaric acid or combinations thereof are added to the ipsapirone pharmaceutical form. Particularly preferred in this connection axe acids with a solubility in water of less than 10% (at 20°C) such as adipic acid, aspartic 10 acid, benzoic acid, fumaric acid, glutamic acid, potassium hydrogen tartrate, succinic acid and stearic acid. The results of the investigation of the bioavailability (Table 1) show that it was possible in this way to avoid considerable falls in the bioavailability compared with 15 the fast-release tablet (Example No. 1) in all cases (Examples Nos. 2-6). Furthermore, capsules with pellets of Example No. 6 were stored at 40°C for 6 months. In this case there was formation of only 0.22% of breakdown product A, which corresponds to a reduction to one tenth 20 of the value of the non-stabilized formulation of Comparative Example 1. To demonstrate the efficacy of the pharmaceutical form according to the invention, ipsapirone delayed-release pharmaceutical forms according to the invention and 25 others were in each case administered to 6-8 healthy volunteers, and the duration of the plasma level and the bioavailability were measured by comparison with a fast-release ipsapirone tablet (Figure 1). 08 IB! - 12 - /' n A 7 - 0 Sm W W B The formulation according to the invention, of Example No. 6, shows the surprising increase in the bioavailability of ipsapirone by 24.4% compared with a standard tablet without delayed release. As Fig. 1 shows, 5 for example, a plasma concentration of 2 |ig/l is maintained for 24 hours after intake of a single capsule. The delayed release formulations from Examples 2 and 3 do not meet the criteria according to the invention. Their bioavailability is, with values of 78 and 85%, correspon-10 ding to the state of the art described to date, below the bioavailability of the fast-release tablet. The formulations of Examples 4 and 5 have release properties in the marginal region of the criteria according to the invention. Accordingly, although their bioavaila-15 bility is increased, it is to a smaller extent. Comparing the delayed release formulation according to the invention, of Example 6, with a customary delayed release formulation corresponding to the state of the art known to date (Example 2), it was possible to increase 20 the bioavailability by almost 60%, which is extremely important for therapy. 260 732 Examples: Example 1 Fast-release tablets/state of the art Composition per tablet: 5 GRANULES: Ipsapirone hydrochloride 10.0 mg Lactose 107.6 mg Avicel 48.0 mg Maize starch 11.0 mg 10 Hydroxypropylmethylcellulose (HPMC) 2.8 mg SUBSEQUENT MIXING: Magnesium stearate 0.6 mg LACQUER COATING: HPMC 3.3 mg 15 Polyethylene glycol (PEG) 1.1 mg Titanium dioxide 1.1 mg Ipsapirone hydrochloride, lactose, Avicel and maize starch are mixed in powder form and granulated with aqueous HPMC solution. The granules are dried, screened 20 and mixed with magnesium stearate. This is followed by - 14 - 3 ~t ft «*"*. ^ A ^6 u / o 2 compression to tablets and coating with an aqueous dispersion of titanium dioxide, PEG and HPMC. Bvample 2 Delayed release tablet/not meeting the criteria of the 5 invention Composition per tablet: GRANULES: Ipsapirone hydrochloride hydrate 10.62 mg HPC 8 mPa*s 109.7 mg 10 HPC 300 mPa*s 45.0 mg Succinic acid 5.0 mg SUBSEQUENT MIXING: Magnesium stearate 0.3 mg LACQUER COATING: 15 HPMC 3.3 mg PEG 4000 1.1 mg Titanium dioxide 1.1 mg Ipsapirone hydrochloride hydrate is suspended in an aqueous solution of a portion of the HPC 300 mPa*s. The 20 remaining HPC 300 mPa* s and HPC 8 mPa- s are granulated 260732 with this suspension in a fluidized bed granulator. The granules are dried, screened, mixed with magnesium stearate, compressed to tablets of 8 mm diameter and coated. 5 The initial release rate of the pharmaceutical form is 40% in 2 hours, and the average release rate is 80% in 6 hours. Wvampli* 3 Delayed release pellet/not meeting the criteria of the 10 invention Composition per capsule: PELLET CORE: Neutral pellets 0.85-1.00 mm 40.0 mg Ipsapirone hydrochloride hydrate 10.62 mg 15 Potassium hydrogen tartrate 10.0 mg HPMC 5.0 mg DIFFUSION MEMBRANE: AQUACOAT® ECD30 dry matter 15.09 mg Triacetin, amount employed 5.03 mg 20 Hard gelatin capsule Capsule size 4 39.0 mg - 16 - 260 732 Ipsapirone hydrochloride hydrate and potassium hydrogen tartrate are suspended in aqueous HPMC solution and sprayed onto neutral pellets in a fluidized bed. An aqueous Aquacoat®/triacetin dispersion is sprayed on. The 5 mass of the diffusion membrane sprayed on is (calculated as Aquacoat® dry matter) 23% of the mass of the uncoated pellets. The spraying process is interrupted three times and the pellets are dried at 60°C for 1 hour each time. The coated pellets cure subsequently heat-treated at 60°C 10 for 1 hour and introduced into hard gelatin capsules. The initial release rate of the pharmaceutical form is 3% in 2 hours, and the average release rate is 80% in 14 hours. Brample 4 15 Delayed release tablets according to the invention Composition per tablet: GRANULES: Ipsapirone hydrochloride hydrate 10.62 mg HPC 300 mPa*s 154.1 mg 20 Succinic acid 5.0 mg SUBSEQUENT MIXING: Magnesium stearate 0.3 mg IB 101 - 17 - •% 260732 LACQUER COATING: HPMC 3.3 mg PEG 4000 1.1 mg Titanium dioxide 1.1 mg 5 The following are weighed out for one batch of tablets: 1. HPC 300 mPa-s 1.5 g 2. Water 348.8 g HPC 300 mPa-s is dissolved in water. 3. Ipsapirone hydrochloride 60.0 g 10 micronized Ipsapirone hydrochloride is suspended in the HPC-M solution. The granulation liquid is obtained. 4. HPC 300 mPa-s 923.1 g 5. Succinic acid 30.0 g 15 The mixture of HPC 300 mPa- s and succinic acid is granulated by spraying in the granulation liquid in a fluidized bed granulator. 6. Magnesium stearate 1.8 g The magnesium stearate is mixed with the dried and - 18 - 26 0 7 5 screened granules. The mixture is compressed in a tabletting machine to give tablets of 8 mm diameter (12 mm radius of curvature) and of weight 170 mg. 5 7. Water 85-95°C 1270.0 g 8. Polyethylene glycol 4000 30.0 g 9. HPMC 90.0 g PEG 4000 is dissolved in hot water. HPMC is then dissolved therein. 10 10. Water 635.0 g 11. Titanium dioxide 30.0 g Titanium dioxide is suspended in water. The suspension is combined with the HPMC/PEG 4000 solution and sprayed onto the tablets until the prescribed 15 application of lacquer is achieved. The initial release rate of the pharmaceutical form is 32% in the first 2 hours, and the average release rate is 80% in 10 hours. Bl IB L - 19 - 26 0 7 3 2 Example 5 Delayed release pellet according to the invention Composition per capsule: PELLET CORE: Neutral pellets 0.85-1.00 mm 40.00 mg Ipsapirone hydrochloride hydrate 10.62 mg Microfine potassium hydrogen tartrate 10.00 mg Hydroxypropylmethylcellulose 5.00 mg DIFFUSION MEMBRANE: 10 AQUACOAT® dry matter Triacetin, amount employed 5.577 mg 1.859 mg Hard gelatin capsule Capsule size 4 39.00 mg The following are weighed out for a batch of 62,500 15 delayed release capsules: 1. Neutral pellets 0.85-1.00 mm 2. Ipsapirone HCl hydrate 3. Potassium hydrogen tartrate 4. Methylhydroxypropylcellulose 20 5. Purified water for preparing the coating suspension, which is evaporated during the process. 2500.00 g 663.75 g 625.00 g 312.50 g 5300.00 g liu h BB IB* - 20 - 260732 Ipsapirone HCl and potassium hydrogen tartrate are suspended in a portion of the stated amount of water. Methylhydroxypropylcellulose is dissolved in the remaining water, and the two portions of the batch are 5 combined and mixed. This suspension is distributed homogeneously on the neutral pellets by a spraying process in a fluidized bed system. The following are also weighed out: 6. Ethylcellulose, 30% aqueous dispersion 1161.88 g 10 (Aquacoat*) 15 Aquacoat® ECD 30 and triacetin are suspended in the stated amount of water. This lacquer dispersion is used to coat the active compound pellets in a fluidized bed process. After the coating, the pellets are heat-treated in a drying oven at 60°C for 1 hour. 20 The content and the release are determined as in-process control, so that the release window according to the invention can be achieved where appropriate by subsequent coating. 7. Triacetin 8. Purified water for preparing the lacquer suspension, which is evaporated during the process. 116.19 g 1045.69 g The definitive amount to be introduced into the capsules 25 is determined from the determination of the content. The 26 0 7 o 2 amount of pellets corresponding to 10 mg of ipsapirone HCl is introduced into size 4 hard gelatin capsules. The initial release rate of the pharmaceutical form is 22% in the first 2 hours, and the average release rate is 5 80% in 5 hours. Exajnpl p fi Delayed release pellet according to the invention Composition per capsule: PELLET CORE: 10 Neutral pellets 0.85-1.00 mm 40.00 mg Ipsapirone hydrochloride hydrate 10.62 mg Microfine potassium hydrogen tartrate 10.00 mg Hydroxypropyljnethylcellulose 5.00 mg DIFFUSION MEMBRANE: 15 AQUACOAT® dry matter Triacetin, amount employed 12.47 mg 4.11 mg Bard gelatin capsule Capsule size 4 39.00 mg The initial release rate of the pharmaceutical form is 20 6.6% in the first 2 hours, and the average release rate 2 6 0 7 3 2 is 80% in 10 hours. The preparation is carried out as described in Example 5, but the spraying on of the Aquacoat/triacetin dispersion is interrupted twice and the pellets are dried at 60°C 5 for 1 hour each time. Pvampl 7 Delayed release pellet according to the invention Composition per capsule: PELLET CORE: 10 Neutral pellets 0.85-1.00 mm 120.00 mg Ipsapirone hydrochloride hydrate 31.86 mg Microfine potassium hydrogen tartrate 30.00 mg Hydroxypropylmethylcellulose 15.00 mg DIFFUSION MEMBRANE: 15 AQUACOAT® dry matter 17.72 mg Triacetin, amount employed 5.85 mg Hard gelatin capsule Preparation is carried out as described in Example 5 but, after the coating, the pellets are heat-treated at 65°C 20 for 4 hours. - 23 - 26 0 7 The initial release rate of the pharmaceutical form is 3.5% in the first 2 hours, and the average release rate is 80% in 9 hours. Bvample 8 Delayed release pellet according to the invention Composition per capsule: PELLET CORE: Neutral pellets 0.85-1.00 mm Ipsapirone hydrochloride hydrate Microfine potassium hydrogen tartrate Hydroxypropylmethylcellulose DIFFUSION MEMBRANE: AQUACOAT® dry matter Triacetin, amount employed Hard gelatin capsule The preparation is carried out as described in Example 5 but, after the coating, the pellets are heat-treated at 60°C for 1 hour. The initial release rate of the pharmaceutical form is 4.2% in the first 2 hours, and the average release rate 80.00 mg 21.24 mg 20.00 mg 10.00 mg 18.37 mg 6.06 mg 260732 is 80% in 9 hours. revamp! P Q Delayed release pellet according to the invention Composition per capsule: 5 PELLET CORE: Neutral pellets 0.5-0.6 mm 80.00 mg Ipsapirone hydrochloride hydrate 21.24 mg Potassium hydrogen tartrate 20.00 mg Hydroxypropylmethylcellulose 5.00 mg 10 DIFFUSION MEMBRANE: AQUACOAT® dry matter 12.62 mg Triacetin, amount employed 4.21 mg Hard gelatin capsule The preparation is carried out as described in Example 5. 15 The initial release rate of the pharmaceutical form is 8% in the first 2 hours, and the average release rate is 80% in 11 hours. 260732 •Rvample 10 Delayed release pellet according to the invention Composition per capsule: PELLET CORE: 5 Neutral pellets 0.85-1.00 mm Ipsapirone hydrochloride hydrate Potassium hydrogen tartrate Hydroxypropylmethylcellulose DIFFUSION MEMBRANE: 10 AQUACOAT® dry matter Triacetin, amount employed Hard gelatin capsule The preparation is carried out as described in Example 5 but, after the coating, the pellets are heat-treated in 15 a fluidized bed at 65°C for 1 hour. The initial release rate of the pharmaceutical form is 19% in the first 2 hours, and the average release rate is 80% in 7 hours. 160.00 mg 42.48 mg 40.00 mg 20.00 mg 21.00 mg 6.93 mg 260 732 Bvample 11 Delayed release tablet according to the invention Composition per tablet: UNCOATED TABLET: Ipsapirone hydrochloride hydrate 21. .24 mg HPC 8 mPa-s 49. .60 mg HPC 300 mPa- s 141, .10 mg Succinic acid 7. .50 mg Magnesium stearate 0.5 mg 10 LACQUER COATING: HPMC 3.60 mg PEG 4000 1.20 mg Titanium dioxide 1.20 mg Tablets of 226 mg with a diameter of 9 mm and a radius of 15 curvature of 15 mm are prepared as described in Example 4. The initial release rate of the pharmaceutical form is 29% in the first 2 hours and the average release rate is 80% in 12 hours. - 27 - 260 732 Example 12 Delayed release tablet according to the invention Composition per tablet: UNCOATED TABLET: 5 Ipsapirone hydrochloride hydrate 21.24 mg HPC 300 mPa-s 190.70 mg Succinic acid 7.50 mg Magnesium stearate 0.5 mg LACQUER COATING: 10 HPMC 3.60 mg PEG 4000 1.20 mg Titanium dioxide 1.20 mg Tablets of 226 mg with a diameter of 9 mm and a radius of curvature of 15 mm are prepared as described in Example 15 4. The initial release rate of the pharmaceutical form is 29% in the first 2 hours and the average release rate is 80% in 12 hours. - 28 - 2 6 0 7 3 2 revamp 1 e 13 Delayed release tablet according to the invention Composition per tablet: UNCOATED TABLET: 5 Ipsapirone hydrochloride hydrate 31.86 mg HPC 8 mPa-s 195.70 mg HPC 300 mPa-s 58.60 mg Succinic acid 12.50 mg Magnesium stearate 0.7 mg 10 LACQUER COATING: HPMC 4.20 mg PEG 4000 1.40 mg Titanium dioxide 1.40 mg Tablets of 307 mg with a diameter of 10 mm and a radius 15 of curvature of 15 mm are prepared as described in Example 4. The initial release rate of the pharmaceutical form is 35% in the first 2 hours and the average release rate is 80% in 7.5 hours. A li - 29 - 2 6 0 7 3 2 revamp!e 14 Delayed release tablet according to the invention Composition per tablet: UNCOATED TABLET: 5 Ipsapirone hydrochloride hydrate 31.86 mg HPC 300 mPa-s 254.90 mg Succinic acid 12.50 mg Magnesium stearate 0.7 mg LACQUER COATING: 10 HPMC 4.20 mg PEG 4000 1.40 mg Titanium dioxide 1.40 mg Tablets of 307 mg with a diameter of 10 mm and a radius of curvature of 15 mm are prepared as described in 15 Example 4. The initial releae rate of the pharmaceutical form is 28% in the first 2 hours and the average release rate is 80% in 13 hours. 26 0 7 "7 /•< * •Rvampl e 15 Delayed release pellet according to the invention Composition per capsule: PELLET CORE: 5 Neutral pellets 0.85-1.00 mm 80.00 mg Ipsapirone hydrochloride hydrate 21.24 mg Microfine potassium hydrogen tartrate 20.00 mg Hydroxypropylmethylcellulose 10.00 mg DIFFUSION MEMBRANE: 10 AQUACOAT® dry matter 18.36 mg Triacetin, amount employed 6.00 mg Hard gelatin capsule The preparation is carried out as described in Example 5 but, after the coating, the pellets are heat-treated at 15 65°C for 2 hours. The initial release rate of the pharmaceutical form is 5% in the first 2 hours, and the average release rate is 80% in 12 hours. • • ♦ Table X Exaaple Mo, 1 2 3 4 5 6 Method of delayed release None Erosion tablet Diffusion pellet Erosion tablet Diffusion pellet Diffusion pellet Pellets: Amount of diffusion lacquer used for coating - - 23% - 8.5% 19% Erosion tablet: Content of hydroxypropylcellulose 300 mPa-s - 46.2 mg - 154.1 mg - - Initial release rate* (after 2 hours) 40X/2 h 4X/72 h 32X/2 h 22X/2 h 7%/2 h Average release rate* - 80X/6 h 80%/14 h 80%/10 h 80%/5 h 80%/10 h Relative bioavailability 100% 78.3% 85.2% 107.3% 117.9% 124.4% *USP paddle method, 900 ml of 0.1 N hydrochloric acid, 75 revolutions per minute r*o </div>

Claims

<div class="application article clearfix printTableText" id="claims"> 260 7 3 2 WHAT WE CLAIM IS :

1. Ipsapirone pharmaceutical formulation with an average release rate of from 80% weight/5 hours to 80% weight/13 hours and an initial release rate of less than 35% weight of 5 ipsapirone in the first two hours of release.

2. Ipsapirone pharmaceutical formulation according to Claim 1 in the form of diffusion-controlled pellets or tablets.

3. Diffusion-controlled pellets according to Claim 2, 10 characterized in that they consist of neutral pellets coated with a mixture of active compound and binder, which mixture is coated with a diffusion layer.

4. Diffusion-controlled pellets according to any one of claims 2 to 15 3, characterized in that the diffusion layer con sists of a customary diffusion lacquer and of a customary plasticizer.

5. Diffusion-controlled pellets according to any one of claims 2 to 4, characterized in ^ that hydroxypropylmethyl-20 cellulose is used as binder, an aqueous dispersion of ethyl cellulose is used as diffusion lacquer and triacetin is used as plasticizer.

6. Process for the preparation of diffusion-controlled pellets according to any one of claims 2 to 5, characterized in 'El " - 33 - 26 0 7 3 2 that an active compound is suspended or dissolved, where appropriate with one or more additives, in water to form a suspension, which is thickened with a binder, this suspension is applied to neutral pellets, and these pellets are coated with a mixture of diffusion lacquer and one or more plasticizers. Tablets according to claim 2, containing one or more water-soluble, hydrogel-forming polymers as well as an active compound and one or more customary tabletting aids. 50 mg of hydroxypropylcellulose with a viscosity of at least 150 mPa*s. Ipsapirone pharmaceutical formulations according to Claim 1 or claim 2, characterized in that they additionally contain a physiologically tolerated acid. An ipsapirone pharmaceutical formulation according to claim 1 substantially as herein described or exemplified. A process according to claim 6 substantially as herein described or exemplified. A tablet according to claim 7, characterized in that, as well as an active cozupcund, it contains at least 34 </div>