Medicament formulation with a controlled release of an active agent

The invention relates to drug formulations which comprise 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3. 0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quino-lonecarboxylic acid and/or pharmaceutically tolerable salts thereof and/or hydrates thereof as active compound which release the active compound they contain at a defined release rate.

The invention relates to drug formulations which comprise
 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.
 0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quino-lonecarboxylic
 acid (hereinbelow referred to as compound I) and/or pharmaceutically
 tolerable salts thereof and/or hydrates thereof as active compound which
 release the active compound they contain at a defined release rate.
 The compound I has the INN (International Non-Proprietary Name)
 moxifloxacin.
 The compound I and/or its salts and/or hydrates is a novel
 8-methoxyquinolone having antibacterial action against gram-negative and
 gram-positive bacteria which is frequently significantly better than that
 of sparfloxacin and ciprofloxacin (Drugs of the Future 1997, 22 (2):
 109/113). EP-A-0 305 733 and also EP-A-0 550 903 describe the preparation
 of the compound I and also of its pharmaceutically tolerable salts. EP-A-0
 780 390 describes a specific crystal modification of the monohydrate
 hydrochloride of the compound I.
 Tablet formulations having delayed and/or controlled release of active
 compound which contain quinolonecarboxylic acid antibiotics are not well
 known. JP-A-06 024 959 does admittedly describe an oral drug which
 comprises ciprofloxacin-hydrochloride, but the preparation of
 administration forms which release the active compound throughout the
 entire gastrointestinal tract is virtually impossible for
 cyprofloxacin-hydrochloride. The reason for this is the absorption
 behaviour of ciprofloxacin in the colon (S. Harder, U. Fuhr, D. Beermann,
 A. H. Staib, "Ciprofloxacin absorption in different regions of the human
 gastrointestinal tract. Investigations with the hf-capsule", Br. J. clin.
 Pharmac. 30, (1990), 35-39). The data found by Staib and Fuhr for humans
 confirm the present data from animal experiments showing that
 cyprofloxacin-hydrochloride is only absorbed to a very small degree from
 the colon. Because of this, the great majority of the known ciprofloxacin
 formulations having delayed release of active compound are drug
 formulations which cannot be administered perorally. Thus, U.S. Pat. No.
 5,473,103 describes ciprofloxacin-comprising implants. Furthermore, U.S.
 Pat. No. 5,520,920 describes an eye drug formulation having delayed
 release of active compound. Likewise, only a parenteral formulation, which
 completely releases the active compound in approximately 3 hours (EP-A-0
 635 272), is described for the known quinolonecarboxylic acid antibiotic
 ofloxacin.
 EP-A-0 350 733 mentions the possibility of formulating the active compounds
 described in this document in compositions which release, optionally
 delayed, the active compound only or preferably in a certain part of the
 intestinal tract. However, concrete formulations having delayed release of
 active compound of the compounds disclosed therein are not described. The
 concrete tablet formulation which is described in EP-A-0 350 733 for the
 compound of example 1 mentioned therein is a rapid-release formulation
 which releases the active compound usually within approximately half an
 hour. The pharmaceutical formulations of the hydrochloride monohydrate of
 the compound I described in EP-A-0 780 390 are likewise formulations
 having rapid release of active compound which usually lead to the release
 of active compound within approximately half an hour.
 However, after administration of such a rapid-release tablet formulation,
 the concentrations of the active compound in the blood are subject to high
 fluctuations when the drug formulation is administered repeatedly, as is
 customary in therapies. After peroral administration, for example, of the
 above mentioned formulations having rapid release of active compound, the
 maximum concentrations of the active compound in the blood are reached
 within 4 hours. They then decrease considerably until the next
 administration. Thus, multiple administration of tablet formulations
 having rapid release of active compound result in high fluctuations of the
 concentration of the active compound in the blood. However, in some cases
 high concentrations of the active compound in the blood which occur after
 administration of a tablet formulation having rapid release of active
 compound are undesired, since, for example, side effects may also occur
 more frequently. Additionally, it is desirable in some cases to maintain
 the concentrations of the active compound in the blood at a higher level
 over a prolonged period.
 Such a drug formulation having delayed release moreover offers a number of
 fundamental advantages, such as less frequent administration, which
 improves patient compliance. Additionally, advantages may be achieved in
 the case of certain infections where even longer-lasting active compound
 levels than with a rapid-release tablet are important. Altogether, a drug
 formulation having delayed release offers greater possibilities to adjust
 the level of active compound to match the specific infection and the
 sensitivity of the patient.
 It was therefore the object of the present invention to develop a drug
 formulation of the compound I and pharmaceutically tolerable salts thereof
 and/or their hydrates which meets the requirements described above.
 Initially, therefore, the inventors intensively studied the absorption
 behaviour of the hydrochloride of the compound I (hereinbelow referred to
 as compound II) and found, very surprisingly, that, for example in
 contrast to the above mentioned ciprofloxacin, the compound II is also
 absorbed in the lower sections of the intestine (colon, rectum). Only this
 surprising absorption behaviour of moxifloxacin, which is different from
 known quinolonecarboxylic acid antibiotics, opens up any possibility of
 developing a retard formulation of moxifloxacin.
 During further intensive investigations, it was then also surprisingly
 possible to develop drug formulations which release the active compound
 over a prolonged period in the entire gastro-intestinal tract, and finally
 to develop drug formulations having certain release profiles which are
 suitable for solving the above-described problems of the prior art.
 The present invention, accordingly, provides a drug formulations having
 controlled release of active compound, which comprises
 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.
 0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolone-carboxylic
 acid or pharmaceutically tolerable salts and/or hydrates thereof and which
 has an average release between 80% in 2 hours and 80% in 16 hours and an
 initial release of less than 60% of the active compound in the first hour
 of release.
 To determine the initial and average release according to the definition of
 the invention, the drug formulations of the present invention are tested
 in "Apparatus 2" of USP XXIII (The United States Pharmacopeia USP XXIII
 1995, pages 1791-1792). The test medium used is 900 ml of 0.1 molar
 hydrochloric acid or a phosphate buffer with pH 7.4. The rotational speed
 of the stirrer is 50 revolutions per minute. Samples are passed through an
 8 .mu.m filter, and their active compound content is determined. The
 amount of active compound which is determined in this manner as being
 dissolved is converted into per cent by weight of the amount of active
 compound employed.
 The drug formulation having controlled release of active compound of the
 present invention preferably has an average release of 80% in the period
 between 4 and 14 hours (80% in 4 hours and 80% in 14 hours).
 In even more preferred embodiment of the drug formulation having controlled
 release of active compound of the present invention, the formulation has
 an average release of 80% in the period between 7 hours and 13 hours and
 an initial release of less than 50% of the active compound in the first
 hour of release.
 The drug formulation having controlled release of active compound of the
 present invention can be formulated in such a manner that a relatively
 high initial release in the first hour of 30 to 60% of the active compound
 or a relatively low initial release in the first hour of 0 to 30% of the
 active compound are obtained.
 In a preferred embodiment of the drug formulation having controlled release
 of active compound with a relatively high initial release between 45 and
 55% of the active compound in the first hour of release, the formulation
 has an average release of 80% in the period from 8 hours to 12 hours.
 In a preferred embodiment of the drug formulation having controlled release
 which has a relatively low initial release between 0 and 20% of the active
 compound in the first hour of release, this formulation is characterized
 by an average release of 80% in the period between 8 hours and 12 hours.
 The drug formulations described above having controlled release of active
 compound are present, for example, in the form of diffusion-controlled
 pellets. These diffusion-controlled pellets comprise, for example, neutral
 pellets onto which a mixture of the active compound with customary binders
 and thickeners, if appropriate together with customary auxiliaries and
 carriers, as defined, for example, below, is applied and which are
 subsequently coated with a diffusion coat comprising plasticizers, or they
 comprise an active-compound-containing core which is coated with a
 diffusion coat.
 Preferred binders and thickeners are hydroxypropylmethylcellulose or
 polyvinylpyrrolidone. It is also possible to employ other natural,
 synthetic or semi-synthetic polymers, such as, for example,
 methylcellulose, hydroxypropylcellulose, sodium carboxymethylcellulose,
 polyacrylic acids, polyvinyl alcohols or gelatin.
 A particularly suitable diffusion coat is ethylcellulose, commercially
 available, for example, as aqueous dispersion under the name Aquacoat.RTM.
 or Surelease.RTM.. However, other materials such as acrylates
 (Eudragit.RTM.), cellulose acetate and cellulose acetate butyrate can also
 be used.
 Suitable plasticizers are, for example, phthalic acid derivatives (for
 example dimethyl phthalate, diethyl phthalate, dibutyl phthalate), citric
 acid derivatives (for example triethyl citrate, tributyl citrate,
 acetyltriethyl citrate), other esters (for example diethyl sebacate,
 triacetin), fatty acids and derivatives (glycerol monostearate, acetylated
 fatty acid glycerides, castor oil and other native oils, miglyol), polyols
 (glycerol, 1,2-propanediol, polyethylene glycol of varying chain length).
 Furthermore, the nature and amount of plasticizer are adjusted such that
 the above-defined release according to the invention and the required
 stability of the pellets is obtained.
 The above-defined release is adjusted by controlling the pore size of the
 diffusion coat and its thickness. Pore formers which can be used to
 control the pore size are soluble polymers, such as, for example,
 polyethylene glycols, polyvinylpyrrolidones,
 hydroxypropylmethylcelluloses, carboxymethylcelluloses or salts thereof,
 methyl celluloses, dextrins, maltodextrins, cyclodextrins, dextrans or
 other soluble compounds, such as, for example, salts (common salt,
 potassium chloride, ammonium chloride, etc.), urea, sugars (glucose,
 sucrose, fructose, lactose, etc.), sugar alcohols (manitol, sorbitol,
 lactitol, etc.). The proportion of the pore former in the coating material
 is 0 to 50% (w/w), preferably 0 to 25%, or 5 to 25% (w/w) (w=weight).
 For the pellets, it is especially important to use a certain weight ratio
 of active-compound-coated pellets to the diffusion membrane and also a
 certain ratio of diffusion coat to the amount of plasticizer.
 During coating and subsequent thermal treatment, some of the plasticizer
 employed may evaporate. The amount of coat according to the invention of
 diffusion coat has to be modified when the marginal parameters are
 changed. Thus, for example, a large amount of coat is required when the
 desired release rate is reduced, the amount of pore former is increased or
 when, in the case of certain plasticizers, the proportion of plasticizer
 is reduced. A lower amount of coat is required when the desired release
 rate is increased, the amount of pore former is reduced or when, in the
 case of certain plasticizers, the proportion of plasticizer is increased.
 The diffusion pellets according to the invention can be prepared, for
 example, by suspending or dissolving the active compound in water, and
 thickening it with a concentrated hydroxypropylmethylcellulose solution.
 The resulting suspension is applied to the neutral pellets by spraying in
 a fluidized-bed unit. This is followed by coating of the pellets with a
 diffusion membrane by spraying on, for example, an aqueous ethylcellulose
 dispersion, preferably in a fluidized-bed unit, which contains a suitable,
 physiologically tolerable plasticizer. The pellets are subsequently
 subjected to thermal treatment at temperatures of from 50 to 125.degree.
 C., preferably from 60 to 110.degree. C. Higher temperatures during the
 thermal treatment result in lower amounts of coating being sufficient for
 obtaining the release according to the invention, and in the pellets
 formed being physically more stable on storage. The thickness of the
 diffusion membrane, the type and the amount of plasticizer and the pellet
 size are chosen so that a release rate of 80% of the compound I or II in 2
 to 16 hours results and less than 60% of the dose are released within the
 first hour. The amount of pellets corresponding to a daily dose of, for
 example, 400 mg of the compound I (Betaine form) is filled into a hard
 gelatin capsule.
 In addition to the described coating of neutral pellets, other methods of
 pellet preparation, such as the extrusion/spheronizer process, rotor
 granulation or fluidized-bed agglomeration, are also feasible.
 In the case of coated neutral pellets, a diffusion pellet thus comprises 10
 to 50% (w/w) (w=weight) of neutral pellets (for example sucrose and binder
 or citric acid), preferably 10 to 40% (w/w) of neutral pellets, onto which
 are applied 10 to 85% (w/w) of active compound layer, preferably 30 to 75%
 (w/w). For high doses of active compound (.gtoreq.400 mg of betaine per
 individual dose), particular preference is given to 10 to 30% (w/w) of
 neutral pellets onto which are applied 50 to 85% (w/w) of active compound
 layer. The active compound layer comprises 70 to 99.5% (w/w) of active
 compound and 0.5 to 30% (w/w) of binder, preferably 80 to 99.5% (w/w) of
 active compound and 0.5 to 20% (w/w) of binder. For high doses of the
 active compound, particular preference is given to 90 to 99.5% (w/w) of
 active compound and 0.5 to 10% (w/w) of binder.
 The pellets obtained in this manner are coated with the diffusion coat or
 the diffusion layer, preferably in an amount of 5 to 40% (w/w), which,
 based on the amount of coat, comprises 40 to 90% (w/w) of film former
 (film-forming polymer, for example ethylcellulose (Aquacoat.RTM. or
 Surelease.RTM.), acrylate (Eudragit.RTM.), cellulose acetate, cellulose
 acetatate butyrate), preferably 50 to 85% (w/w), particularly preferably
 60 to 85% (w/w), of pore former (soluble polymers, such as, for example,
 polyethylene glycols, polyvinylpyrrolidones,
 hydroxypropylmethylcelluloses, carboxymethyl-celluloses or salts thereof,
 methylcelluloses, dextrins, maltodextrins, cyclodextrins, dextrans or
 other soluble compounds, such as, for example, salts (common salt,
 potassium chloride, ammonium chloride, etc.), urea, sugar (glucose,
 sucrose, fructose, lactose, etc.), sugar alcohols (manitol, sorbitol,
 lactitol, etc.) in the range from 0 to 50% (w/w), preferably 0 to 35%
 (w/w), particularly preferably 0 to 25% (w/w) or 5 to 25% (w/w), and
 plasticizer in the range of 5 to 50% (w/w), preferably 5 to 35% (w/w),
 particularly preferably 10 to 35% (w/w).
 In the case of coated active compound pellets, a diffusion pellet comprises
 50 to 95% (w/w) of active compound pellets, preferably 60 to 95% (w/w).
 For high doses of the active compound (.gtoreq.400 mg of betaine per
 individual dose), particular preference is given to 70 to 95% (w/w) of
 active compound pellets. These active compound pellets comprise 70 to
 99.5% (w/w) of active compound and 0.5 to 30% (w/w) of binder,
 particularly preferably 80 to 99.5% (w/w) of active compound and 0.5 to
 20% (w/w) of binder. For high doses of the active compound, particular
 preference is given to 90 to 99.5% (w/w) of active compound and 0.5 to 10%
 (w/w) of binder, and also, if appropriate, further additives
 (microcrystalline cellulose, thermoplastic polymer, other pharmaceutically
 usual auxiliaries). The pellets obtained in this manner are coated with
 the diffusion coat or the diffusion layer in an amount of 5 to 50% (w/w),
 which, based on the amount of coat, comprises 40 to 90% (w/w) of film
 former (film-forming polymer, for example ethylcellulose (Aquacoat.RTM. or
 Surelease.RTM.), acrylate (Eudragit.RTM.), cellulose acetate, cellulose
 acetatate butyrate), preferably 50 to 85% (w/w), particularly preferably
 60 to 85% (w/w), of pore former (soluble polymers, such as, for example,
 polyethylene glycols, polyvinylpyrrolidones,
 hydroxypropylmethylcelluloses, carboxymethylcelluloses or salts thereof,
 methylcelluloses, dextrins, maltodextrins, cyclodextrins, dextrans or
 other soluble compounds, such as, for example, salts (common salt,
 potassium chloride, ammonium chloride, etc.), urea, sugar (glucose,
 sucrose, fructose, lactose, etc.), sugar alcohols (manitol, sorbitol,
 lactitol, etc.) in the range from 0 to 50% (w/w), preferably 0 to 35%
 (w/w), particularly preferably 0 to 25% (w/w) or 5 to 25% (w/w), and
 plasticizer in the range of 5 to 50% (w/w), preferably 5 to 35% (w/w),
 particularly preferably 10 to 35% (w/w).
 In a further embodiment of the drug formulation having controlled release
 of active compound of the present invention, formulations are used which
 comprise the active compound in a matrix of a water-swellable polymer.
 These formulations are preferably present in the form of a tablet.
 These so-called matrix formulations expediently comprise from 30 to 70% by
 weight, preferably 40 to 60% by weight, of the active compound.
 The proportion by weight of the matrix of the water-soluble polymer is
 expediently from 30 to 50% by weight, preferably 30 to 40% by weight.
 Preference is additionally given to drug preparations according to the
 invention in the form of erosion tablets. These tablets are characterized
 in that they contain, in addition to customary auxiliaries and carriers
 and tabletting auxiliaries, a certain amount of water-swellable
 hydrogel-forming polymers, where these polymers have to have a viscosity
 of at least 15, preferably at least 50 mPa.s (measured as a 2% strength
 aqueous solution at 20.degree. C.).
 Customary auxiliaries and carriers are, for example, lactose,
 microcrystalline cellulose, manitol or calcium phosphate. These are
 expediently present in an amount of 0 to 50% by weight, preferably 10 to
 40% by weight, particularly preferably 20 to 40% by weight.
 Customary tabletting auxiliaries are, for example, magnesium stearate, talc
 or finely divided silica (Aerosil.RTM.). In the case of magnesium
 stearate, these are expediently present in an amount of from 0.5 to 1.5%
 by weight, and in the case of finely divided silica expediently in an
 amount of from 0.1 to 0.5% by weight.
 Preferred water-soluble, hydrogel-forming polymers are
 hydroxypropylcelluloses, hydroxypropylmethylcelluloses (HPMC),
 methylcelluloses, carboxymethylcellulose, alginates, galactomannans,
 polyacrylic acids, polymethacrylic acids or copolymers of methacrylic acid
 and methyl methacrylate, guar gum, agar, pectin, tragacanth gum, gum
 arabic, xanthan gum, or mixtures of these substances.
 Particular preference is given to the use of HPMC.
 Here, the erosion tablets according to the invention should preferably
 contain at least 10% by weight, based on the weight of a tablet, of a
 hydroxypropylmethylcellulose type whose viscosity (measured as a 10%
 strength aqueous solution at 20.degree. C.) is at least 15, preferably at
 least 50, mPa.s.
 The drug formulation which comprises the active compound in a matrix of a
 water-swellable polymer is prepared by mixing and directly tabletting the
 active compound, the polymer and suitable auxiliaries and carriers (as
 described above) and also customary tabletting auxiliaries (as described
 above). Furthermore, it is possible to granulate the active compound, the
 water-swellable polymer and suitable carriers in a fluidized bed. The
 amount and the viscosity of the water-swellable polymer is chosen so that
 tablets having the average release rate and initial release described
 above result. The dry granules are sieved, mixed with a lubricant, such
 as, for example, magnesium stearate, and tabletted. The tablet is, if
 appropriate, additionally coated.
 In a further embodiment, the drug formulation having controlled release of
 active compound of the present invention is an osmotic drug release
 system. Such osmotic drug release systems are known in principle in the
 prior art and are discussed in detail, for example, in Richard W. Baker,
 "Osmotic Drug Delivery: A Review of the Patent Literature", Journal of
 Controlled Release 35 (1995) 1-21. The drug formulation as osmotic drug
 release system preferably comprises
 a) a core which contains the active compound, optionally a hydrophilic
 polymeric swelling agent and optionally a water-soluble substance for
 inducing osmosis, and
 b) a shell which is water-permeable and impermeable for the components of
 the active-compound-containing core,
 c) an opening through the shell b) for the transport of the components
 contained in the core into the surrounding aqueous body liquid.
 This specific osmotic drug release system is described in principle in the
 prior art, for example in DE-A-2 328 409 or U.S. Pat. No. 3,845,770. For
 the materials of the shell, reference is made to EP-A-0 277 092 and U.S.
 Pat. No. 3,916,899 and U.S. Pat. No. 3,977,404, which are mentioned in
 this document.
 For suitable hydrophilic polymeric swelling agents, reference is made, for
 example, to the polymeric swelling agents mentioned in EP-A-0 277 092 and
 WO 96/40080. It is possible to use, for example, ethylene oxide
 homopolymers (polyethylene glycol) having various degrees of
 polymerization, which are known under the name Polyox.RTM. having
 molecular weights between 100,000 and 8,000,000, and also to
 vinylpyrrolidone/vinyl acetate copolymers and other water-swellable
 polymers mentioned in U.S. Pat. No. 3,865,108, U.S. Pat. No. 4,002,173 and
 U.S. Pat. No. 4,207,893.
 Water-soluble substances for inducing osmosis are in principle all
 water-soluble substances whose use in pharmacy is conceivable, for example
 those mentioned as water-soluble auxiliaries in the pharmacopeias or in
 "Hager's Handbuch der Pharmazeutischen Praxis, 1990-1995, Springer
 Verlag", and also in Remington's Pharmaceutical Sciences. Since the
 compound I and/or its salts and/or hydrates have a relatively high water
 solubility (approximately 24 g/liter), the active compound itself is also
 osmotically active. This is taken into consideration in the formulation of
 the osmotic drug system. Further specific water-soluble substances are
 salts of inorganic or organic acids or non-ionic organic substances having
 high water solubility, such as, for example, carbohydrates such as sugars,
 etc. How to produce an opening in the shell of the tablet is known per se
 in the prior art and described, for example, in the U.S. Pat. Nos.
 3,845,770 and 3,916,899.
 The above-described average release and the initial release of the drug
 formulation having controlled release of active compound of the present
 invention are adjusted by the nature and the amount of the semi-permeable
 material which forms the shell, by the nature and the amount of the
 hydrophilic polymeric swelling agent which is optionally present, and by
 the optionally present water-soluble substance for inducing osmosis.
 The drug formulations of the invention expediently comprise, based on
 1-cyclopropyl-7-([S,S]-2,8-diazabicyclo[4.3.
 0]non-8-yl)-6-fluoro-1,4-dihydro-8-methoxy-4-oxo-3-quinolonecarboxylic
 acid, 200 to 800 mg, preferably 400 to 600 mg, of active compound.
 The drug formulation having controlled release of active compound of the
 present invention is preferably a formulation where, at the same dosage,
 the maximum blood level (c.sub.max) is lower than the value c.sub.max of a
 drug formulation with rapid release, as described in example 7 of EP-A-0
 780 390, and where the peak trough fluctuation PTF [%] is lower than the
 corresponding PTF value of the formulation of example 7 according to
 EP-A-0 780 390.
EQU PTF=c.sub.max -c.sub.min /c.sub.av,.tau.
 c.sub.min : minimum concentration of the active compound in blood, plasma
 or serum
 c.sub.av,.tau. : average steady state concentration calculated from the
 plasma concentration/time data after single administration or after the
 first dosage interval (.tau.) after multiple administration.
 The determination of PTF is described in H. Boxenbaum, "Pharmacokinetic
 determinants in the design and evaluation of sustained release dosage
 forms", Pharm. Res., 15, 82-88 (1984).
 The blood levels are determined as described in H. Stass, A. Dalhoff, D.
 Kubitza, "BAY 12-8039, A new 8-Methoxy-Quinolone: First pharmacokinetic
 results in healthy male volunteers", Proc. of 36th ICAAC, New Orleans,
 1996, F024, page 104.

EXAMPLES
 Comparative Example 1
 Rapid-release Tablet Corresponding to the Prior Art, According to Example 7
 of EP-A-0 780 390
 Composition:

Compound II (hydrochloride) 436.8 mg
 Microcrystalline cellulose 61.8 mg
 Maize starch 31.8 mg
 Croscarmellose sodium 3.6 mg
 Magnesium stearate 8.0 mg
 The tablet was prepared analogously to Example 7 of EP-A-0 780 390.
 Example 1
 Matrix Tablet
 A matrix tablet has the following composition:

Compound II (hydrochloride) 436.8 mg
 HPMC 90 SH 100 191.0 mg
 Magnesium stearate 8.0 mg
 Iron oxide 0.3 mg
 Titanium dioxide 2.7 mg
 Polyethylene glycol 4000 3.0 mg
 HPMC 15 cP 9.0 mg
 Compound II (hydrochloride), HPMC 90 SH 100 and magnesium stearate are
 mixed dry and compressed to tablets. The tablets are coated with an
 aqueous suspension containing the iron oxide, the titanium dioxide, the
 polyethylene glycol 4000 and the HPMC.
 Example 2
 Matrix Tablet
 A matrix tablet has the following composition:

Compound II (hydrochloride) 436.8 mg
 HPMC 15 cP 334.0 mg
 Calcium hydrogen phosphate 334.0 mg
 Magnesium stearate 8.2 mg
 Iron oxide 0.45 mg
 Titanium dioxide 4.05 mg
 Polyethylene glycol 4000 4.5 mg
 HPMC 15 cP 13.5 mg
 Compound II (hydrochloride), HPMC 15 cP and calcium hydrogen phosphate are
 granulated. The magnesium stearate is admixed and this mixture is
 compressed to tablets. The tablets are coated with an aqueous suspension
 containing the iron oxide, the titanium dioxide, the polyethylene glycol
 4000 and the HPMC.
 Example 4
 Matrix Tablet
 A matrix tablet has the following composition:

Compound II (hydrochloride) micronized 436.8 mg
 HPMC 50 cP 109.2 mg
 Magnesium stearate 4.0 mg
 Iron oxide 0.3 mg
 Titanium dioxide 2.7 mg
 Polyethylene glycol 4000 3.0 mg
 HPMC 15 cP 9.0 mg
 A comparison of the release of active compound (obtained in accordance with
 USP XXIII described above) of the formulations of Comparative Example 1
 and Examples 1-4 is shown in FIG. 1.
 Example 5
 Diffusion Pellets
 To prepare diffusion pellets, 436 g of the compound II, 17.5 g of
 polyvinylpyrrolidone 25, 110 g of hydroxypropylmethylcellulose, 18 g of
 polyethylene glycol 4000, 220 g of ethylcellulose and 21 g of triethyl
 citrate are employed for preparation and coating of the pellets in a
 fluidized-bed unit. The pellets are filled into capsules.
 Example 6
 Osmotic Release System
 724.6 g of compound II, 182.5 g of common salt and 82.9 g of
 microcrystalline cellulose are granulated, the granules are mixed with 10
 g of magnesium stearate and this mixture is compressed to tablets (format
 5.5 r 9). The tablets are coated with 49.8 g of a mixture of cellulose
 acetate, polyethylene glycol 3350 and glycerol in an acetone solution. The
 tablets are perforated in a suitable manner.