HK1178435A - Oral dosage form containing a pde 4 inhibitor as an active ingredient and polyvinylpyrrolidon as excipient - Google Patents

Description

Oral dosage form comprising a PDE4 inhibitor as active ingredient and polyvinylpyrrolidone as excipient

The present application is a divisional application of the invention patent application having application number 03804230.4 and application date of 2003, 2/19.

Technical Field

The present invention relates to the field of pharmaceutical technology and describes dosage forms for the oral administration of PDE4 inhibitors, the PDE4 inhibitors being used as active ingredient in tablet or pill dosage forms for the treatment of diseases such as asthma or airway obstruction. The invention further relates to a method for producing such a dosage form.

Background

There is currently particular interest in cyclic nucleotide Phosphodiesterase (PDE) inhibitors, particularly type 4, as new and improved forms of active ingredients for the treatment of inflammatory diseases, particularly airway inflammation such as asthma or airway obstruction (e.g. COPD ═ chronic obstructive pulmonary disease). Many PDE4 inhibitors are currently undergoing advanced clinical trials.

WO 00/50011 and WO 01/32165, which relate to controlled or sustained administration dosage forms of PDE4 inhibitors, indicate that a particular PDE4 inhibitor, e.g. a PDE4 inhibitor, is administered at higher doses(INN: cilomilast), undesirable CNS side effects become apparent. W000/50011 and WO 01/32165 regard this as a particular risk for immediate release dosage forms of the active ingredient and therefore suggest the administration of PDE4 inhibitors in controlled or sustained release dosage forms(INN：cilomilast)。

US 5,286,494 proposes controlled or sustained release dosage forms of the slightly soluble PDE4 inhibitor Rolipram. However, the production of controlled or sustained release dosage forms of sparingly soluble active ingredients is technically complicated, for example, by reference to US 5286494.

Probably depending on the chemical structure, active ingredients of the PDE4 inhibitor class have a low solubility in water and aqueous systems. Thus, the solubility of the PDE4 inhibitor N- (3, 5-dichloropyridin-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: roflumilast) in water was found to be described in WO 95/01338, and was only 0.53mg/l at 21 ℃. The bioavailability of a drug depends essentially on the release of the drug from the pharmaceutical dosage form. Faster release and dissolution of the drug from the formulation means faster absorption thereof. For drugs that are slightly soluble in water, bioavailability is therefore often limited by solubility or dissolution rate. This makes it difficult to produce a suitable dosage form.

Disclosure of Invention

It is an object of the present invention to provide a dosage form for the oral administration of a PDE4 inhibitor which is sparingly soluble, which dosage form does not require a high degree of technical complexity to produce, which takes into account the low solubility of the PDE4 inhibitor which is sparingly soluble, and which yields a rapid, acceptable bioavailability of the PDE4 inhibitor which is sparingly soluble, in order to achieve the required serum concentration in order to rapidly achieve the desired pharmacological effect without significant side effects.

It has now been found, surprisingly, that this object can be achieved by an oral administration form of a sparingly soluble PDE4 inhibitor using polyvinylpyrrolidone (PVP) as a binder for the form. The dosage forms of the invention show significantly improved pharmacokinetic properties compared to dosage forms not using PVP as a binder. Thus, especially concerning the bioavailability of the slightly soluble PDE4 inhibitors, a faster absorption and thus a faster onset of pharmacological action of the dosage form according to the invention is observed compared to dosage forms without PVP. The oral dosage form of the present invention is preferably a solid dosage form in the form of a tablet or pill. Solid oral dosage forms with immediate release of the active ingredient (immediate release solid oral dosage forms) are preferred.

The invention therefore relates to a dosage form for oral administration of a PDE4 inhibitor which is sparingly soluble, in the form of tablets or pills, comprising the PDE4 inhibitor which is sparingly soluble and polyvinylpyrrolidone as binder, together with one or more other suitable pharmaceutical excipients.

PDE4 inhibitors which are preferably sparingly soluble according to the invention are compounds selected from the group of compounds of the formula I

Wherein either

R1 is 3-7C cycloalkoxy, 3-7C cycloalkylmethoxy or benzyloxy and

r2 is 1-4C alkoxy which is completely or partially substituted by fluorine,

or

R1 is 1-4C alkoxy fully or partially substituted by fluorine and

r2 is 3-7C cycloalkylmethoxy or benzyloxy,

and

r3 is phenyl, pyridinyl, phenyl substituted by R31, R32 and R33, or pyridinyl substituted by R34, R35, R36 and R37, wherein

R31 is hydroxy, halogen, cyano, carboxy, trifluoromethyl, 1-4C alkyl, 1-4C alkoxy-carbonyl, 1-4C alkylcarbonyl, 1-4C alkylcarbonyloxy, amino, mono-or di-1-4C alkylamino or 1-4C alkylcarbonylamino,

r32 is hydrogen, hydroxy, halogen, amino, trifluoromethyl, 1-4C alkyl or 1-4C alkoxy,

r33 is hydrogen, halogen, 1-4C alkyl or 1-4C alkoxy,

r34 is hydroxy, halogen, cyano, carboxy, 1-4C alkyl, 1-4C alkoxy, 1-4C alkoxycarbonyl or amino,

r35 is hydrogen, halogen, amino or 1-4C alkyl,

r36 is hydrogen or halogen and

r37 is hydrogen or a halogen,

salts of these compounds and N-oxides of pyridines and salts thereof.

3-7C Cycloalkoxy is, for example, cyclopropyloxy, cyclobutyloxy, cyclopentyloxy, cyclohexyloxy and cycloheptyloxy, of which cyclopropyloxy, cyclobutyloxy and cyclopentyloxy are preferred.

3-7C Cyclocycloalkylmethoxy is, for example, cyclopropylmethoxy, cyclobutylmethoxy, cyclopentylmethoxy, cyclohexylmethoxy and cycloheptylmethoxy, of which cyclopropylmethoxy, cyclobutylmethoxy and cyclopentylmethoxy are preferred.

Examples which may be mentioned of 1-4C alkoxy which is completely or partially substituted by fluorine are the 1, 2, 2-trifluoroethoxy, 2, 2, 3, 3, 3-pentafluoropropoxy, the high fluoroethoxy and especially the 1, 1, 2, 2-tetrafluoroethoxy, trifluoromethoxy, 2, 2, 2-trifluoroethoxy and difluoromethoxy groups.

Halogen for the purposes of the present invention are bromine, chlorine and fluorine.

1-4C alkyl represents a straight-chain or branched alkyl group having 1-4 carbon atoms. Examples which may be mentioned are butyl, isobutyl, sec-butyl, tert-butyl, propyl, isopropyl, ethyl and methyl radicals.

1-4C alkoxy is a group which, outside the oxygen atom, contains one of the aforementioned 1-4C alkyl groups. Examples which may be mentioned are methoxy and ethoxy groups.

1-4C alkoxycarbonyl is a carbonyl group bound to one of the aforementioned 1-4C alkoxy groups, and an example which may be mentioned is methoxycarbonyl (CH)₃O-CO-) and ethoxycarbonyl (CH)₃CH₂An O-CO-) group.

1-4C alkylcarbonyl is carbonyl bound to one of the aforementioned 1-4C alkyl groups. Examples which may be mentioned are acetyl (CH)₃CO-)。

The 1-4C alkylcarbonyloxy group contains one of the aforementioned 1-4C alkylcarbonyl groups in addition to the oxygen atom. Examples which may be mentioned are acetoxy (CH)₃CO-O-)。

Examples of mono-or di-1-4C alkylamino groups which may be mentioned are methylamino, dimethylamino and diethylamino.

Examples of 1-4C alkylcarbonylamino which may be mentioned are acetylamino (-NH-CO-CH)₃)。

Examples of phenyl groups substituted by R31, R32 and R33 which may be mentioned are the groups: 2-acetylphenyl group, 2-aminophenyl group, 2-bromophenyl group, 2-chlorophenyl group, 2, 3-dichlorophenyl group, 2, 4-dichlorophenyl group, 4-diethylamino-2-methylphenyl group, 4-bromo-2-trifluoromethylphenyl group, 2-carboxy-5-chlorophenyl group, 3, 5-dichloro-2-hydroxyphenyl group, 2-bromo-4-carboxy-5-hydroxyphenyl group, 2, 6-dichlorophenyl group, 2, 5-dichlorophenyl group, 2, 4, 6-trichlorophenyl group, 2, 4, 6-trifluorophenyl group, 2, 6-dibromophenyl group, 2-cyanophenyl group, 4-cyano-2-fluorophenyl group, 2, 4-difluorophenyl group, 2-chlorophenyl group, 2, 6-difluorophenyl group, 2-chloro-6-fluorophenyl group, 2-hydroxyphenyl group, 2-hydroxy-4-methoxyphenyl group, 2, 4-dihydroxyphenyl group, 2-methoxyphenyl group, 2, 3-dimethoxy-phenyl group, 2, 4-dimethoxyphenyl group, 2, 6-dimethoxyphenyl group, 2-dimethylaminophenyl group, 2-methylphenyl group, 2-chloro-6-methylphenyl group, 2, 4-dimethylphenyl group, 2, 6-dimethylphenyl group, 2, 3-dimethylphenyl group, 2-methoxycarbonylphenyl group, 2-trifluoromethylphenyl group, 2, 6-dichloro-4-methoxyphenyl group, 2, 6-dichloro-4-cyanophenyl group, 2-chloro-6-fluorophenyl group, 2-hydroxyphenyl group, 2, 4-dimethoxyphenyl group, 2, 6-dimethylaminophenyl group, 2-dimethylaminop, 2, 6-dichloro-4-aminophenyl, 2, 6-dichloro-4-methoxycarbonylphenyl, 4-acetylamino-2, 6-dichlorophenyl and 2, 6-dichloro-4-ethoxycarbonylphenyl.

Examples of pyridyl groups which may be mentioned and which are substituted by R34, R35, R36 and R37 are the groups: 3, 5-dichloropyridin-4-yl, 2, 6-diaminopyridin-3-yl, 4-aminopyridin-3-yl, 3-methylpyridin-2-yl, 4-methylpyridin-2-yl, 5-hydroxypyridin-2-yl, 4-chloropyridin-3-yl, 3-chloropyridin-2-yl, 3-chloropyridin-4-yl, 2-chloropyridin-3-yl, 2, 3, 5, 6-tetrafluoropyridin-4-yl, 3, 5-dichloro-2, 6-difluoropyridin-4-yl, 3, 5-dibromopyridin-2-yl, 3, 5-dibromopyridin-4-yl, 3-chloropyridin-3-yl, 3, 3, 5-dichloropyridin-4-yl, 2, 6-dicyanopyridin-3-yl, 3, 5-dimethylpyridin-4-yl, 3-chloro-2, 5, 6-trifluoropyridin-4-yl and 2, 3, 5-trifluoropyridin-4-yl.

Suitable salts of the compounds of the formula I-depending on the substitution-are all acid addition salts, but especially all salts with bases. Mention may in particular be made of the pharmacologically acceptable salts formed from inorganic and organic acids and bases which are customarily used in pharmaceutical technology. Pharmacologically unacceptable salts, for example the initial products of a process which makes it possible to prepare the compounds of the invention on an industrial scale, are converted into pharmacologically acceptable salts by methods known to the person skilled in the art. Those suitable are on the one hand water-soluble and water-insoluble acid addition salts with acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid, sulfuric acid, acetic acid, citric acid, D-gluconic acid, benzoic acid, 2- (4-hydroxybenzoyl) benzoic acid, butyric acid, thiosalicylic acid, maleic acid, lauric acid, malic acid, fumaric acid, succinic acid, oxalic acid, tartaric acid, embonic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid or 3-hydroxy-2-naphthoic acid, the acids used to prepare the salts being in equimolar quantitative ratios or amounts differing therefrom-depending on whether the acid is monobasic or polybasic and depending on the salt to be obtained.

On the other hand, salts with bases are also particularly suitable. Examples of basic salts which may be mentioned are lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium salts, the bases which are again used to prepare the salts being in equimolar proportions or amounts differing therefrom.

Emphasized compounds of the formula I are those in which either

R1 is 3-5C cycloalkoxy, 3-5C cycloalkylmethoxy or benzyloxy and

r2 is 1-4C alkoxy which is completely or partially substituted by fluorine,

or

R1 is 1-4C alkoxy fully or partially substituted by fluorine and

r2 is 3-5C cycloalkylmethoxy or benzyloxy,

and

r3 is phenyl, pyridinyl, phenyl substituted by R31, R32 and R33, or pyridinyl substituted by R34, R35, R36 and R37, wherein

R31 is halogen, cyano, carboxy, 1-4C alkyl, 1-4C alkoxy or 1-4C alkoxycarbonyl,

r32 is hydrogen, halogen, 1-4C alkyl or 1-4C alkoxy,

r33 is hydrogen, halogen, 1-4C alkyl or 1-4C alkoxy,

r34 is halogen or 1-4C alkyl,

r35 is hydrogen or a halogen,

r36 is hydrogen or halogen and

r37 is hydrogen or a halogen,

salts of these compounds and N-oxides of pyridines and salts thereof.

Especially emphasized are the compounds of the formula I in which

R1 is 3-5C cycloalkoxy, 3-5C cycloalkylmethoxy or benzyloxy and

r2 is 1-4C alkoxy which is completely or partially substituted by fluorine,

or

R1 is 1-4C alkoxy fully or partially substituted by fluorine and

r2 is 3-5C cycloalkylmethoxy or benzyloxy, and

r3 is 2-bromophenyl, 2, 6-dichloro-4-ethoxycarbonylphenyl, 2, 6-dimethoxyphenyl, 4-cyano-2-fluoro-phenyl, 2, 4, 6-trifluorophenyl, 2-chloro-6-methylphenyl, 2, 6-dimethylphenyl, 2, 6-difluorophenyl, 2, 6-dichlorophenyl, 3, 5-dicyanopyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3, 5-dibromopyridin-2-yl, 2, 3, 5, 6-tetrafluoropyridin-4-yl, 3-chloro-2, 5, 6-trifluoropyridin-4-yl, 3, 5-dichloro-2, 6-difluoropyridin-4-yl or 2, 6-dichloropyridin-3-yl,

salts of these compounds and N-oxides of pyridines and salts thereof.

Preferred compounds of the formula I are those in which

R1 is a difluoromethoxy group,

r2 is cyclopropylmethoxy and

r3 is 2-bromophenyl, 2, 6-dichloro-4-ethoxycarbonylphenyl, 2, 6-dimethoxyphenyl, 4-cyano-2-fluorophenyl, 2, 4, 6-trifluorophenyl, 2-chloro-6-methylphenyl, 2, 6-dimethylphenyl, 2, 6-difluorophenyl, 2, 6-dichlorophenyl, 3, 5-dichloropyridin-4-yl, 3-methylpyridin-2-yl, 2-chloropyridin-3-yl, 3, 5-dibromopyridin-2-yl, 2, 3, 5, 6-tetrafluoropyridin-4-yl, 3-chloro-2, 5, 6-trifluoropyridin-4-yl, 3, 5-dichloro-2, 6-difluoropyridin-4-yl or 2, 6-dichloropyridin-3-yl,

salts of these compounds, and N-oxides of pyridine compounds and salts thereof.

A particularly preferred compound of the formula I is one in which

R1 is a difluoromethoxy group,

r2 is cyclopropylmethoxy and

r3 is 3, 5-dichloropyridin-4-yl,

salts of these compounds, and N-oxides of pyridine compounds and salts thereof.

The chemical name of this compound is N- (3, 5-dichloropyridin-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: roflumilast).

PDE4 inhibitors which are sparingly soluble are preferably PDE4 inhibitors which have a solubility in water of less than or equal to 100 mg/l, particularly preferably less than or equal to 1 mg/l, at temperatures of from 15 to 25 ℃, in particular at 21 ℃. This compound is particularly preferred as a compound of formula I.

The above-mentioned compounds of formula I and the use of these compounds as Phosphodiesterase (PDE)4 inhibitors are described in the international patent application WO 95/01338.

Further suitable pharmaceutical excipients which can be used in the dosage form of the present invention are pharmaceutical excipients such as fillers, additional binders, tablet disintegrants or other lubricants and release agents. Other suitable excipients which may be present in the dosage form of the invention are, for example, flavouring substances (e.g. flavouring agents and sweeteners), buffer substances, preservatives, colouring substances (e.g. iron yellow or iron red) or other emulsifiers. The flavoring agent is typically added in a proportion of 0.05% to 1% by weight. Other flavouring substances by way of example are acids such as citric acid, sweeteners such as saccharin, aspartame, sodium cyclamate or maltol, which are added as required to obtain the result.

The polyvinylpyrrolidones (PVP) used according to the invention are in particular water-soluble PVPs having an average molecular weight higher than 2000, preferably higher than 20000. Examples which may be mentioned are Kollidon 12PF (molecular weight 2000-3000), Kollidon 17 PF (molecular weight 7000-11000), Kollidon 25 (molecular weight 28000-34000), Kollidon 30 (molecular weight 44000-54000), Kollidon 90F (molecular weight 1000000-1500000). PVP with higher molecular weights, such as Kollidon 25, Kollidon 30 and Kollidon 90F, may be mentioned as preferred.

Other binders besides PVP may be used if desired, for example polyvinyl acetate (e.g. polyvinyl acetate)VA64), gelatin, corn starch mucilage, pre-swollen starch (starch 1500), Hydroxypropylmethylcellulose (HPMC), or hydroxypropylcellulose (L-HPC). Suitable fillers for the present invention are fillers such as calcium carbonate (e.g. calcium carbonate)CC or95) And sodium carbonate, sugar alcohols such as mannitol (e.g. sodium mannitol)OrM), sorbitol (e.g.) Xylitol or maltitol, starches such as corn starch, potato starch and wheat starch, microcrystalline cellulose, sugars such as glucose, lactose (e.g. lactose monohydrate), fructose, sucrose and dextrose. Mixtures thereof may also be used if desired. Corn starch, microcrystalline cellulose and lactose may be mentioned as preferred.

Examples of suitable lubricants and release agents which may be mentioned are sodium stearyl fumarate (sodium stearyl fumarate), magnesium stearate, calcium stearate, stearic acid, talc and colloidal anhydrous silicon dioxide (Aerosil).

Disintegrants suitable according to the invention are, in particular, insoluble polyvinylpyrrolidone (insoluble PVP, crospovidone), sodium starch glycolate [ ═ sodium starch glycolate ], sodium carboxymethylcellulose, alginic acid and starches which are capable of achieving a disintegrating function (e.g. starch 1500).

The proportion of the PDE4 inhibitor in the dosage form of the present invention, as a percentage based on the weight of the final dosage form, is generally 0.01 to 50% by weight, depending on the nature of the PDE4 inhibitor. The proportion of PDE4 inhibitors is preferably up to 20% by weight.

The proportion of binder (PVP and, if appropriate, further binders) according to the invention, as a percentage based on the weight of the final formulation, is preferably from 0.5 to 20% by weight. The proportion of PVP is preferably from 1 to 5% by weight, particularly preferably from 2 to 3% by weight.

The proportion of filler in the tablets of the invention (as a percentage based on the weight of the final dosage form) is preferably from 40 to 99% by weight. The proportion of fillers is preferably from 60 to 97% by weight.

The proportion of disintegrant (as a percentage based on the weight of the final dosage form) in rapidly disintegrating tablets will generally be up to 35% by weight. The proportion of disintegrant is preferably 2 to 20% by weight. The proportion of disintegrant is particularly preferably from 5 to 10% by weight.

The proportion of lubricant or release agent in the rapidly disintegrating tablets, as a percentage based on the weight of the final dosage form, is generally from 0.1 to 5% by weight. The proportion of lubricant or release agent is preferably from 0.3 to 3% by weight. The proportion of lubricant or release agent is particularly preferably from 0.5 to 2% by weight.

In a preferred embodiment of the invention, the dosage form is a tablet. Preferably, for tablets, at least one filler and at least one lubricant or release agent are included as further pharmaceutical excipients, in addition to the slightly soluble PDE4 inhibitor and PVP.

The pharmaceutical formulations of the present invention can be produced by methods known to those skilled in the art for the production of tablets and pills.

In a particular embodiment of the invention, the pharmaceutical form of the invention is produced by producing a solid solution of the PDE4 inhibitor which is sparingly soluble in the binder PVP as carrier. This can be carried out, for example, by a solvent process in which PVP, the PDE4 inhibitor and, if appropriate, further pharmaceutical excipients are dissolved in a suitable solvent and the solvent is subsequently removed again by spray drying, conventional drying, vacuum drying or freeze drying. It has surprisingly been found that solid solutions can also be produced by a mixing process in which the slightly soluble PDE4 inhibitor and, if appropriate, further pharmaceutical excipients are mixed vigorously together with PVP.

The invention also further relates to solid solutions of the slightly soluble PDE4 inhibitor in the binder PVP as a carrier. According to the invention, a solid solution of a PDE4 inhibitor in a binder PVP as carrier refers to a solid solution having an amorphous structure, wherein the PDE4 inhibitor is present in the carrier material in the form of a molecular dispersion.

In the case of further processing the solid solution into tablets or pills, the solid solution can be processed as an active ingredient together with filler, binder, disintegrant and lubricant ingredients to give the oral dosage form of the present invention by production methods familiar to those skilled in the art.

The invention therefore also relates to a process for the manufacture of a dosage form for oral administration of a PDE4 inhibitor in the form of a tablet or pill, comprising the steps of: (a) producing an active ingredient preparation in the form of a solid solution of a slightly soluble PDE4 inhibitor in PVP, (b) producing a mixture of the active ingredient preparation and pharmaceutical excipients, and (c) granulating the mixture obtained in (b) with an aqueous PVP solution.

In case the dosage form of the invention is in the form of a tablet, the granulate obtained in (c), after drying and mixing with a lubricant or a release agent, may be compressed in a tablet press. In case the dosage form of the invention is a pellet, the wet granulate obtained in (c) may be processed into suitable pellets by an extruder/spheronizer process. Alternatively, the dispersion/suspension of the active ingredient formulation may be applied in a pellet-like carrier (e.g. a pill or a HPMC-containing pill) in the form of a solid solution of the PDE4 inhibitor which is sparingly soluble in PVP, in a suitable solvent.

In another preferred embodiment of the invention, the dosage form of the invention is produced by granulating a mixture of the active ingredient and the pharmaceutical excipients with an aqueous PVP solution, drying the granules and, if desired, mixing with other pharmaceutical excipients. The wet formulation obtained after granulation may then be further processed into pellets, which may then be filled into capsules. The dried granules may be compressed in a tablet press after mixing with other pharmaceutical excipients, if desired, and after mixing with a release agent. The granulation is preferably carried out in a fluid bed granulator under suitable conditions. Furthermore, if desired, the active ingredient to be mixed with other pharmaceutical excipients may be mixed with pharmaceutical excipients (particularly fillers) in a developed form. This is especially preferred when the content of active ingredient in the dosage form is below 5% by weight. Such a trituration is generally obtained by grinding the active ingredient with pharmaceutical excipients (in particular fillers).

The invention therefore also relates to a process for the manufacture of a dosage form in the form of a tablet or pill for oral administration of a PDE4 inhibitor, comprising the steps of:

(a) producing a mixture of active ingredient and pharmaceutical excipient, and

(b) granulating the mixture obtained in (a) with an aqueous solution of PVP.

The dosage form of the invention is particularly preferably prepared by granulating the following mixture with an aqueous PVP solution

(a) A slightly soluble PDE4 inhibitor, or a development of a slightly soluble PDE4 inhibitor and corn starch,

(b) corn starch, and

(c) lactose monohydrate

Dry the granulate, mix the granulate with the release agent and compress the granulate in a tablet press. In this case, the sparingly soluble PDE4 inhibitors are particularly preferably roflumilast, salts thereof, N-oxides of pyridine and salts thereof.

Alternatively, the dosage form of the invention is particularly preferably prepared by granulating the following mixture with an aqueous PVP solution

(a) A slightly soluble PDE4 inhibitor, or a development of a slightly soluble PDE4 inhibitor and corn starch,

(b) corn starch

(c) Microcrystalline cellulose, and

(d) sodium carboxymethyl starch

Dry the granulate, mix the granulate with the release agent and compress the granulate in a tablet press. In this case, the sparingly soluble PDE4 inhibitor is particularly preferably roflumilast, its salts, the N-oxide of pyridine and its salts.

In a further preferred embodiment of the invention, the dosage form of the invention is produced by granulating a mixture of the pharmaceutical excipients with a suspension of the active ingredient in an aqueous PVP solution, drying the granules and, if desired, mixing with further pharmaceutical excipients. The preparation obtained in this way can then, after mixing with the release agent, be compressed in a tablet press. The granulation is preferably carried out in a fluid bed granulator under suitable conditions.

The invention therefore also relates to a process for the manufacture of a dosage form in the form of a tablet or pill for oral administration of a PDE4 inhibitor, comprising the steps of:

(a) producing a mixture of pharmaceutical excipients, and

(b) granulating a suspension of the active ingredient in an aqueous solution of PVP with the mixture obtained in (a).

The dosage form of the invention is particularly preferably produced by granulating a mixture of corn starch and lactose monohydrate with a suspension of the slightly soluble PDE4 inhibitor in an aqueous PVP solution, drying the granules, mixing the granules with the release agent and tabletting in a tabletting machine.

It has been unexpectedly found that dosage forms of the invention produced using a physical mixture or a development of the slightly soluble PDE4 inhibitor and a filler (e.g. by milling, intensive mixing or extrusion) followed by granulation with an aqueous PVP solution, or a suspension of the PDE4 inhibitor granulated in an aqueous PVP solution, have similar advantageous properties compared to the bioavailability of the slightly soluble PDE4 inhibitor, as compared to dosage forms produced by the first production of a solid solution of PVP and PDE4 inhibitor. This suggests that in the production of dosage forms of the invention based on physical mixtures or sparingly soluble PDE4 inhibitors and fillers, which are subsequently granulated with aqueous PVP solutions, or in their preparation using suspensions of granulated PDE4 inhibitors in aqueous PVP solutions, the interaction between PVP and the sparingly soluble PDE4 inhibitor is unexpectedly similar to that which occurs in solid solutions of PVP and PDE4 inhibitor. In the production of the dosage forms of the invention, it is therefore also possible to dispense with the technically more elaborate variant of solid solution production by solvent processes.

Drawings

Figure 1 shows the time course of the mean serum concentration of roflumilast after oral administration of 0.5mg (2 tablets each containing 0.25mg) of roflumilast from a dosage form according to the invention compared to a dosage form not containing PVP.

The production of the tablets and formulations of the invention is illustrated by the following examples. The following examples illustrate the invention in more detail without restricting it.

Detailed Description

Examples

Production of the tablets of the invention

Example A

Based on the weight of the tablet containing 0.1mg of roflumilast

Production of: mix (1) with part (3) and produce the triturate in a planetary mill. The triturate, together with (2) and the remaining amount of (3), is placed in the product container of a fluid bed granulation system and sprayed with a 5% granulation solution of (4) in pure water and dried under suitable conditions. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press into tablets having an average weight of 65.1 mg.

Example B

Based on the weight of the tablet containing 0.125mg of roflumilast

Production of: mix (1) with part (3) and produce the triturate in a planetary mill. The triturate, together with (2) and the remaining amount of (3), is placed in the product container of a fluid bed granulation system and sprayed with a 5% granulation solution of (4) in pure water and dried under suitable conditions. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press to tablets having an average weight of 65.125 mg.

Example C

Based on the weight of the tablet containing 0.25mg of roflumilast

Production of: mix (1) with part (3) and produce the triturate in a planetary mill. The triturated grind, together with (2), (5) and the remaining amount of (3), is placed in the product container of a fluid bed granulation system and sprayed with a 5% granulation solution of (4) in purified water and dried under suitable conditions. The granules were added to (6), and the mixture obtained after mixing was compressed in a tablet press to tablets having an average weight of 59.5 mg.

Example D

Based on the weight of the tablet containing 0.25mg of roflumilast

Production of: mix (1) with part (3) and produce the triturate in a planetary mill. The triturate, together with (2) and the remaining amount of (3), is placed in the product container of a fluid bed granulation system and sprayed with a 5% granulation solution of (4) in pure water and dried under suitable conditions. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press into tablets having an average weight of 65.25 mg.

Example E

Based on the weight of the tablet containing 0.5mg of roflumilast

Production of: mix (1) with part (3) and produce the triturate in a planetary mill. The ground material is put in a stream together with (2) and the rest of (3)The product container of the fluid bed granulation system is filled and sprayed with a 5% granulation solution of (4) in purified water and dried under suitable conditions. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press to tablets having an average weight of 65.500 mg.

Example F

Based on the weight of the tablet containing 0.5mg of roflumilast

Production of: mix (1) with part (3) and produce the triturate in a planetary mill. The triturate, together with (2) and the remaining amount of (3), is placed in the product container of a fluid bed granulation system and sprayed with a 5% granulation solution of (4) in pure water and dried under suitable conditions. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press into tablets having an average weight of 130.5 mg.

Example G

Based on the weight of the tablet containing 2.5mg of roflumilast

Production of: mix (1) with part (3) and produce the triturate in a planetary mill. The triturate is placed in the product container of a fluidized bed granulation system together with (2), (5) and the remaining amount of (3) and sprayed with a 5% granulation solution of (4) in purified water and under suitable conditionsAnd (5) drying. The granules of (6) were added, and the mixture obtained after mixing was compressed into tablets having an average weight of 61.75mg in a tablet press.

Example H

Production of tablets containing 0.1mg of roflumilast as active ingredient (weight for a batch of 70000 tablets)

Production of: mix (1) with 70g (3) and produce a triturate in a planetary mill. The triturate, together with (2) and the remaining amount of (3), was placed in the product container of a fluid bed granulation system and sprayed with a 5% granulation solution of (4) in purified water. (spraying pressure: 3 bar; production temperature: 28-33 ℃ C.; gas flow rate in the first third of the spraying process: 100 m)³H; the following air flow rate during spraying: 150m³H; inlet air temperature: 40-70 ℃; spraying speed: 30-40 g/min). After spraying was complete, drying was carried out until the product temperature reached 34 ℃. The granules were passed through a stainless steel sieve having a mesh width of 0.8mm, and the relative surface humidity was measured and adjusted to a value in the range of 20-50%. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press into tablets having an average weight of 65.1 mg.

Example I

Production of tablets containing 0.25mg of roflumilast as active ingredient (weighing 70000 tablets)

Production of: 19.25g of (1) was mixed with 192.5g of (3) and the triturate was produced in a planetary mill. The triturate, together with (2) and the remaining amount of (3), was placed in the product container of a fluid bed granulation system and sprayed with a 5% granulation solution of (4) in purified water. (spraying pressure: 3 bar; production temperature: 28-33 ℃ C.; gas flow rate in the first third of the spraying process: 100 m)³H; the following air flow rate during spraying: 150m³H; inlet air temperature: 40-70 ℃; spraying speed: 30-40 g/min). After spraying was complete, drying was carried out until the product temperature reached 34 ℃. The granules were passed through a stainless steel sieve having a mesh width of 0.8mm, and the relative surface humidity was measured and adjusted to a value in the range of 20-50%. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press into tablets having an average weight of 65.5 mg.

Example J

Production of tablets containing 0.1mg of roflumilast as active ingredient (a batch of 70000 tablets by weight)

Production of: uniformly suspending (1) in the granulation solution of (4) in purified water. Placing (2) and (3) in a product container of a suitable fluid bed granulation system and granulating with the granulation suspension, followed by drying. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press into tablets having an average weight of 65.1 mg.

Example K

Production of tablets containing 0.25mg of roflumilast as active ingredient (weighing 70000 tablets)

Production of: uniformly suspending (1) in the granulation solution of (4) in purified water. Placing (2) and (3) in a product container of a fluid bed granulation system, granulating with the above granulation suspension, and drying. The granules were added to (5), and the mixture obtained after mixing was compressed in a tablet press into tablets having an average weight of 65.25 mg.

Example L

Based on the weight of the tablet containing 0.25mg of roflumilast

Production of: producing a dispersion from (4) and water, and uniformly suspending (1) therein. (ii) dissolving (5) in water and adding to the dispersion. Granulating (2) and (3) with the dispersion in a suitable fluid bed granulation system under suitable conditions. To this mixture was added (6), and the mixture obtained after mixing was compressed into tablets having an average weight of 65.650mg in a tablet press.

Example M

Based on the weight of the tablet containing 0.25mg of roflumilast

Production of: mix (1) with part (3) and produce the triturate in a planetary mill. The triturate, together with (2) and the remaining amount of (3), is placed in the product container of a fluid bed granulation system and sprayed with 5% granulation solutions of (4) and (5) in pure water and dried under suitable conditions. The granules of (6) were added, and the mixture obtained after mixing was compressed into tablets having an average weight of 66.55mg in a tablet press.

Example M1

Pediatric preparation

Based on the weight of the tablet containing 0.125mg of roflumilast

The formulations were produced as described above.

Physical studies and comparative experiments with formulations without PVP as binder

Example N

The disintegration time and release of the active ingredient were determined for the dosage form of example D.

Disintegration time: the disintegration time was determined by the method described in the european pharmacopoeia using a disintegration tester.

As a result: 7.08 minutes.

Release of active ingredients: the release of the active ingredient is determined as described in the US pharmacopoeia (USP XXV; apparatus 2).

As a result: 78% of the active ingredient was released after 15 minutes and the quantitative release was observed after 60 minutes.

Example 0

Producing a dosage form comprising roflumilast, wherein PVP is not used:

based on the weight of the tablet containing 0.25mg of roflumilast

Production: producing a dispersion from (4) and water, and uniformly suspending (1) therein. Granulating (2) and (3) with the dispersion in a suitable fluid bed granulation system under suitable conditions. Add (5) to the dry granules and produce a homogeneous mixture. To this mixture was added (5), and the mixture obtained after mixing was compressed into tablets having an average weight of 96.438mg in a tablet press.

Comparative study

Designing: 24 patients, 3-cycle change, randomized; for each case, the dose was 0.5mg (2 tablets containing 0.25mg of roflumilast). After oral administration of 0.5mg (2 tablets containing 0.25mg per tablet) of roflumilast, the serum concentrations of roflumilast were investigated for the following dosage forms:

PVP as binder:

the tablet of example D, hereinafter referred to as "treatment a".

The tablet of example K, hereinafter referred to as "treatment B".

Without PVP as binder:

the tablet of example 0, hereinafter referred to as "treatment C".

The results are depicted in fig. 1. Higher serum levels were observed more rapidly and significantly after oral administration of formulations with PVP as a binder, compared to formulations without PVP. The rate of absorption of the dosage form of the present invention is therefore significantly increased.

Industrial applicability

The dosage forms of the invention can be used to treat and prevent all diseases which are considered to be treatable or preventable by the application of PDE4 inhibitors. Selective cyclic nucleotide Phosphodiesterase (PDE) inhibitors, in particular of type 4, are suitable on the one hand as bronchotherapeutic agents for the treatment of airway obstruction due to their vasodilatory action but also due to their increased respiratory rate and respiratory drive and for the elimination of erectile dysfunction due to vasodilatory action, but on the other hand, in particular for the treatment of diseases, in particular inflammatory properties, such as those of the airways (asthma prophylaxis), of the skin, of the central nervous system, of the intestine, of the eye and of the joints, which are promoted by mediators, such as histamine, PAF (platelet activating factor), arachidonic acid derivatives such as leukotrienes and prostaglandins, cytokines, interleukins, chemokines, alpha-, beta-and gamma interferons, Tumor Necrosis Factor (TNF) or oxygen radicals and proteases. The pharmaceutical preparations of the invention can therefore be used in human and veterinary medicine, for example for the treatment and prevention of the following diseases: acute and chronic (in particular inflammatory and allergen-induced) airway diseases of various etiology (bronchitis, allergic bronchitis and bronchial asthma, COPD); skin diseases (especially proliferative, inflammatory and allergic) such as psoriasis (recurrent), toxic and allergic contact eczema, disseminated neurodermatitis, seborrheic dermatitis, lichen simplex, sunburn, pruritus at the site of genineal, tufted alopecia, overgrowth scars, discoid lupus erythematosus, follicular and generalized pyoderma, endogenous and exogenous acne, rosacea and other proliferative, inflammatory and allergic skin diseases; diseases based on excessive release of TNF (a leukotriene), such as arthritic diseases (rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis and other arthritic conditions), immune system diseases (AIDS, multiple sclerosis), shock types [ septic shock, endotoxic shock, gram-negative sepsis, toxic shock syndrome and ARDS (adult respiratory distress syndrome) ] and systemic inflammation at the gastrointestinal site (Crohn's disease and ulcerative colitis); inflammatory and/or chronic abnormal immune response-based diseases in the upper respiratory tract (pharynx, nose) and adjacent areas (paranasal sinuses, eyes), such as allergic rhinitis/sinusitis, chronic rhinitis/sinusitis, allergic conjunctivitis and nasal polyps; but also cardiac diseases which can be treated by PDE inhibitors, such as heart failure, or diseases which can be treated as a result of the tissue-relaxant action of PDE inhibitors, such as erectile dysfunction or renal and ureteral colic associated with kidney stones; or other diseases of the CNS such as depression or arteriosclerotic dementia.

The invention further relates to a method of treating a mammal, including a human, suffering from one of the above mentioned diseases. The method is characterized by administering to a mammalian subject a therapeutically effective and pharmacologically suitable amount of a PDE4 inhibitor, the PDE4 inhibitor being present in the dosage form of the present invention. The disease is preferably asthma or airway obstruction, in particular COPD (chronic obstructive pulmonary disease).

The dosage forms of the invention comprise a PDE4 inhibitor at dosages typically used to treat a particular disease. The dosage of the active ingredient is of the order of magnitude of that normally used for PDE inhibitors, and daily dosages can be administered in one or more dosage units. The normal dose for systemic treatment (oral) is between 0.001mg-3mg per kilogram and per day. According to a preferred dosage form of the invention, each dosage unit contains 0.01mg to 5mg of roflumilast, preferably 0.05mg to 2.5mg, particularly preferably 0.1mg to 0.5mg of roflumilast. Examples of pharmaceutical formulations of the invention comprise 0.1mg, 0.125mg, 0.25mg and 0.5mg of roflumilast per dosage unit. Typically, one or more dosage units of the invention are administered once daily. If desired, one or more dosage units of the invention may be administered more than once per day.

Claims (15)

1. Dosage form in the form of a tablet or pill for oral administration of a PDE4 inhibitor which is sparingly soluble, comprising a PDE4 inhibitor which is sparingly soluble and polyvinylpyrrolidone, and one or more other suitable pharmaceutical excipients, wherein the PDE4 inhibitor is N- (3, 5-dichloropyridin-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (roflumilast), and wherein the dosage form is a solid oral dosage form with immediate release of the active ingredient (immediate release solid oral dosage form).

2. Dosage form according to claim 1, containing per dosage unit 0.01 to 5mg of roflumilast, 0.05 to 2.5mg of roflumilast or 0.1 to 0.5mg of roflumilast.

3. The dosage form according to claim 2, containing 0.5mg of roflumilast per dosage unit.

4. Dosage form in the form of a tablet or pill for oral administration of a PDE4 inhibitor which is sparingly soluble, comprising a PDE4 inhibitor which is sparingly soluble and polyvinylpyrrolidone, and one or more other suitable pharmaceutical excipients, wherein the PDE4 inhibitor is N- (3, 5-dichloropyridin-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (roflumilast), and wherein the dosage form contains 0.5mg of roflumilast per dosage unit.

5. A dosage form according to claim 1 or 4, which is a tablet.

6. The dosage form according to claim 1 or 4, wherein the proportion of polyvinylpyrrolidone is from 1 to 5% in percentage by weight based on the final dosage form.

7. The dosage form according to claim 1 or 4, wherein the pharmaceutical excipients are excipients from the group of fillers, additional binders, tablet disintegrating agents, lubricants or releasing agents, flavouring substances, buffering substances, preservatives, colouring substances and emulsifiers.

8. The dosage form according to claim 7, wherein the filler is selected from the group consisting of calcium carbonate, sodium carbonate, sugar alcohols such as mannitol, sorbitol, xylitol or maltitol, starches such as corn starch, potato starch and wheat starch, microcrystalline cellulose, sugars such as glucose, lactose monohydrate, fructose, sucrose, dextrose and mixtures thereof.

9. The dosage form according to claim 7, wherein the lubricant or release agent is selected from the group consisting of sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, talc and colloidal anhydrous silica.

10. The dosage form according to claim 7, wherein the pharmaceutical excipients are at least one filler and at least one lubricant or release agent.

11. A dosage form according to claim 1 or 4, which is obtainable by a process comprising the steps of: (a) producing a mixture of roflumilast and pharmaceutical excipients, and (b) granulating the mixture obtained in (a) with an aqueous solution of polyvinylpyrrolidone.

12. A dosage form according to claim 1 or 4, which is obtainable by a process comprising the steps of:

(a) producing a mixture of pharmaceutical excipients, and

(b) granulating a suspension of roflumilast in an aqueous PVP solution with the mixture obtained in (a).

13. The dosage form according to claim 1 or 4, which is obtained by a process comprising the step of producing a solid solution of polyvinylpyrrolidone and roflumilast.

14. Use of roflumilast for the preparation of a dosage form according to claim 1 or 4 for the treatment or prophylaxis of COPD (chronic obstructive pulmonary disease).

15. Use of roflumilast for the preparation of a dosage form according to claim 1 for the treatment or prophylaxis of COPD (chronic obstructive pulmonary disease), wherein the dosage form contains 0.5mg of roflumilast per dosage unit.