HK1079445B - Ophthalmological use of roflumilast for the treatment of diseases of the eye - Google Patents

Description

Ophthalmic use of roflumilast for treating ocular diseases

Technical Field

The present invention relates to a pharmaceutical preparation for the treatment of ophthalmic diseases comprising a PDE4 inhibitor, a process for the preparation of the pharmaceutical preparation, and a method for the treatment of ophthalmic diseases.

Background

Cyclic nucleotide Phosphodiesterase (PDE) inhibitors, in particular type 4, are today the most interesting new generation of active ingredients as new drugs for the treatment of inflammatory diseases, in particular for the treatment of respiratory diseases such as asthma or airway obstruction (such as, for example, COPD ═ chronic obstructive pulmonary disease). A number of PDE4 inhibitors are now undergoing further clinical trials, including a dosage form containing the active ingredient N- (3, 5-dichloro-pyridin-4-yl) -3-cyclopropylmethoxy-4-difluoromethoxybenzamide (INN: roflumilast) for oral administration. Such compounds with benzamide structure and other compounds and their use as cyclic nucleotide Phosphodiesterase (PDE) inhibitors for the treatment of disease are described in WO 95/01338.

DISCLOSURE OF THE INVENTION

Surprisingly, we have found that pharmaceutical formulations containing the PDE4 inhibitor roflumilast show very good efficacy in the treatment of ocular diseases, but also show other beneficial properties.

Accordingly, one aspect of the present invention relates to the use of a compound selected from roflumilast, salts of roflumilast, the N-oxide of the pyridine residue of roflumilast or salts thereof for the preparation of a pharmaceutical preparation for the prophylaxis or treatment of an ocular disease.

Roflumilast is a compound of formula I (INN):

wherein

R1 is a difluoromethoxy group,

r2 is cyclopropylmethoxy, and

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

The chemical name of the compound is N- (3, 5-dichloropyridin-4-yl) -3-cyclopropylmethoxy-4-difluoro-methoxybenzamide (INN: roflumilast). The chemical name of the N-oxide of roflumilast is 3-cyclopropylmethoxy-4-difluoromethoxy-N- (3, 5-dichloropyridin-4-yl 1-oxide) benzamide.

The compounds of formula I, their salts, N-oxides, their salts and the use of these compounds as inhibitors of Phosphodiesterase (PDE)4 are disclosed in international patent application WO 95/01338.

Suitable salts of the compounds of the formula I, depending on the substitution, are all acid addition salts, preferably, however, all salts bear bases. Particularly noteworthy are the pharmacologically acceptable salts of inorganic and organic acids and bases commonly used in pharmaceutical technology.

Pharmacologically unacceptable salts, for example, may be the initial products of the procedures used to prepare the compounds of the present invention on an industrial scale, and are converted to pharmaceutically acceptable salts by methods well known to those skilled in the art. Suitable salts are on the one hand water-soluble and water-insoluble acid addition salts with acids such as, for example, 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, pamoic acid, stearic acid, toluenesulfonic acid, methanesulfonic acid, or 3-hydroxy-2-naphthoic acid, which are used in equimolar quantitative ratios for the preparation of the salts, or in amounts differing therefrom-the different amounts of the acids being determined on the basis of whether the acids are mono-or polybasic and on the basis of the desired salt.

On the other hand, salts with bases are also particularly suitable. Examples of basic salts are salts of lithium, sodium, potassium, calcium, aluminum, magnesium, titanium, ammonium, meglumine or guanidinium, likewise the bases used for preparing the salts are prepared in equimolar amounts or amounts differing therefrom.

Pharmaceutical formulations containing roflumilast, salts of roflumilast, the N-oxide of the pyridine residue of roflumilast or salts thereof for the treatment of ocular diseases can be prepared by procedures well known in the art and well known to the person skilled in the art. As pharmaceutical preparations, the active ingredients of the invention can be applied, for example, in the form of, or preferably in combination with, suitable pharmaceutical adjuvants, for example in the form of tablets, coated tablets, capsules, suppositories, patches, emulsions, suspensions, gels or solutions, the active compound content preferably being between 0.1 and 95%. The person skilled in the art is familiar, on the basis of his expert knowledge, with the adjuvants which are suitable for the desired pharmaceutical preparations. Besides solvents, gel formers, ointment bases and other active compound excipients, for example antioxidants, dispersants, emulsifiers, preservatives, solubilizers or penetration enhancers, can be used. Further examples are suitable for the preparation of tablets, emulsions, suspensions, sprays, oils, ointments, salves, creams, pastes, gels, foams or solutions, and also carriers and/or excipients for transdermal therapeutic systems.

According to a preferred embodiment of the present invention, the pharmaceutical preparation for the treatment of ocular diseases is an ophthalmic pharmaceutical preparation suitable for administration in, on or near the eye.

In another embodiment, the pharmaceutical preparation for the treatment of ocular diseases according to the invention is administered in a systemic application.

A further subject of the invention is therefore an ophthalmological pharmaceutical preparation which simultaneously contains a therapeutically effective and pharmacologically suitable amount of an active pharmaceutical ingredient selected from the compounds roflumilast, salts of roflumilast, the N-oxide of roflumilast and salts thereof, and one or more pharmacologically acceptable carriers and/or excipients.

Examples associated with ophthalmic pharmaceutical preparations are ophthalmic baths, ophthalmic lotions, ophthalmic inserts, ophthalmic ointments, ophthalmic sprays, eye drops, preparations for intraocular use [ e.g. intravitreal application, intraocular injection ] and eyelid ointments.

In one embodiment of the invention, the ophthalmic pharmaceutical preparation is a topical pharmaceutical preparation suitable for administration on and near the eye, comprising a therapeutically effective and pharmacologically suitable amount of an active pharmaceutical ingredient selected from the group consisting of roflumilast, salts of roflumilast, roflumilast N-oxide and salts thereof and one or more pharmaceutically acceptable carriers and/or excipients.

In another embodiment of the invention, the ophthalmic pharmaceutical preparation is a pharmaceutical preparation suitable for intravitreal and/or intraocular use comprising a therapeutically effective and pharmacologically suitable amount of an active pharmaceutical ingredient selected from roflumilast, salts of roflumilast, roflumilast N-oxide and salts thereof, together with one or more pharmaceutically acceptable carriers and/or excipients.

In a preferred embodiment of the invention, the ophthalmic pharmaceutical preparation is suitable for conjunctival or eyelid administration.

In a preferred embodiment, the dosage form of the invention is an ophthalmic ointment or eye drops. According to the invention, the ophthalmic solution preferably contains an aqueous or oily suspension of the active ingredient. Preferably, 90% of the active ingredient used has a particle size of less than 10 μm.

In the case of aqueous suspensions, in addition to preservatives (e.g. chlorocresol, phenyl mercury compounds, phenethyl alcohol, benzalkonium chloride or mixtures of the individual components), preference is given to using suspension stabilizers such as, for example, substituted celluloses (e.g. methylcellulose, hydroxypropylmethylcellulose), polyvinyl alcohol, polyvinylpyrrolidone and, where appropriate, sodium chloride to adjust isotonicity. In the case of oily eye drops, castor oil, arachis oil or medium-chain triglycerides are preferably used. In the case of ophthalmic ointments, ointment bases having the following properties can be used according to the invention: sterile or low microbial content, non-irritating, excellent activity, excellent distribution of the active ingredient or its solution in the ointment, softness, rapid dispersion in a thin film on the eyeball, excellent adhesion to the eyeball, excellent stability, and less visual impairment. Thus, according to the present invention, a substrate containing a hydrocarbon or cholesterol is preferably used for an ophthalmic ointment. In the case of petrolatum ointment, liquid paraffin is preferably added to maintain consistency. In order to obtain a good spreading effect, it is preferred according to the invention to provide a composition of limited viscosity. The viscosity is preferably below 1000mpa.s and the yield point is preferably below 300mPa at 32 ℃. In the case of suspension ointments, it is preferred according to the invention that 90% of the active ingredient particles are below 10 μm and that no particles larger than 90 μm are present. In the case of water/oil emulsion ointments, it is preferred according to the invention to add preservatives such as benzalkonium chloride, thimerosal or phenylethyl alcohol.

The pharmaceutical preparation of the invention for systemic use may be a Transdermal Therapeutic System (TTS), for example, as described hereinafter: pharmazeutische technology: moderne Arzneiformen, Wissenschaftlichehelsholschaft Stuttgart 1997, pages 81 et sec. TTS(s) is mainly characterized in that: the skin is supplied with the drug in a given form, the total dose of drug in the TTS, the total administration area and other areas for releasing the drug, a drug-impermeable cover layer (backing layer), a drug reservoir, a control element for controlling the delivery of the drug to the skin, a (pressure-sensitive) adhesive layer and a detachable protective layer. In some cases, multiple functions may be performed by the same element, e.g., the reservoir, control, and adhesion functions may be performed by a suitable adhesion matrix. From the pharmaceutical technology point of view, tts(s) is classified according to the method obtained by the control function, i.e. how the supply of the drug to the skin is controlled. Examples mentioned here are tts(s) with membrane permeation-controlled release (membrane-controlled drug release), tts(s) with matrix diffusion-controlled release, and tts(s) with micro-depot solution-controlled release.

TTS(s) with membrane permeation-controlled release is characterized in that: PVA-VA copolymer (Chronomer) for controlling drug permeation from reservoir to skin) A polymer film of the composition. The drug is initially present in the reservoir as a solid particle, or as a dispersion or solution. The polymer film may be adhered to the reservoir in various ways (extrusion, encapsulation, microencapsulation). TTS(s) with matrix diffusion-controlled release has a comparatively simple structure. It does not contain a separate controlled release element. The release of the drug is controlled by the lipophilic or hydrophilic polymer matrix and/or the adhesion layer. Depending on the nature of the matrix, tts(s) in gel form can be distinguished from tts(s) with a solid polymer laminate. The drug reservoir is formed by dissolution of the drug in a matrix (monolithic system) or is a uniform dispersion of solid drug particles. The matrix TTS can be produced by mixing the drug particles with a viscous liquid or semisolid polymer at room temperature and then crosslinking the polymer chains. A further possible method is to mix the drug at elevated temperature with a softened polymer (hot melt technique) or, alternatively, to mix the two components together (dissolved in an organic solvent) and then remove the solvent under vacuum (evaporation of the solvent). The shaping can be carried out by casting into suitable moulds, spreading with special equipment (knives) or pressing. For TTS (tts) (microencapsulated drug release, MDD principle) with micro-depot solution-controlled release, a multitude of 10-200 μm minicells containing the active ingredient are implanted in a matrixSo that it represents both reservoir and transport-control elements. These ttss(s) are in fact designed as matrix systems due to the presence of a matrix. For manufacture, the drug is initially dispersed in isopropyl palmitate with water and 40% polyethylene glycol 400, the isopropyl palmitate being used as a penetration enhancer. The resulting dispersion is incorporated into a viscous silicone elastomer by high energy dispersion techniques while undergoing catalytic polymerization. The drug-containing matrix may be specially shaped by melt or extrusion techniques before it is combined with the carrier in the manner already described. Depending on the physicochemical properties of the drug and the desired release profile, the matrix may be coated with a biocompatible polymer to modify the device mechanism and the release rate.

In another embodiment of the invention, the pharmaceutical preparation for systemic administration is a dosage form for oral administration, preferably a tablet.

Suitable pharmaceutical excipients which can be used in the dosage forms for oral administration according to the invention are, for example, fillers, additional binders, tablet disintegrating agents or other lubricants and mold-release agents. Other suitable excipients which may be used are, for example, flavoring substances, such as flavorings and sweeteners, buffer substances, preservatives, coloring substances, such as yellow or red iron oxide, or emulsifiers. The flavoring agents are generally added in a proportion of 0.05 to 1% by weight. Other taste-modifying substances such as citric acid, and sweeteners such as saccharin, aspartame, sodium cyclamate or maltose are added according to the desired result.

In a preferred embodiment of the invention, tablets for oral administration use polyvinylpyrrolidone (PVP) as binder. In particular, the polyvinylpyrrolidone (PVP) used according to the invention is a water-soluble PVP having an average molecular weight higher than 2000, preferably higher than 20000. Examples which may be mentioned are Kollidon 12 PF (molecular weight 2000-3000), Kollidon 17 PF (molecular weight 7000-11000), Kollidon25 (molecular weight 28000-34000), Kollidon 30 (molecular weight 44000-54000), Kollidon 90F (molecular weight 1000000-1500000). Higher molecular weight PVP such as, for example, Kollidon25, Kollidon 30 and Kollidon 90F may be preferably used.

Binders other than PVP such as polyvinyl acetate may also be used if desired (e.g.,VA 64), gelatin, corn Starch gum, pre-swollen Starch (Starch1500), Hydroxypropylmethylcellulose (HPMC) or hydroxypropylcellulose (L-HPC).

Suitable fillers according to the present invention are, for example, calcium carbonate (e.g.,CC or95) And sodium carbonate, sugar alcohols such as mannitol (e.g.,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. As a preference, corn starch, microcrystalline cellulose and lactose may be mentioned.

Examples of suitable lubricants and mould release agents are sodium stearyl fumarate, magnesium stearate, calcium stearate, stearic acid, talc and anhydrous colloidal silica (Aerosil).

Suitable disintegrants according to the invention are, in particular, insoluble polyvinylpyrrolidone (insoluble PVP, crospovidone), sodium carboxymethyl Starch [ ═ sodium Starch glycolate ], sodium carboxymethyl cellulose, alginic acid, and starches which fulfil the function of a disintegrant (e.g. Starch 1500).

The proportion of the PDE4 inhibitor in the dosage form of the present invention (in percent by weight based on the final dosage form) is generally determined by the nature of the PDE4 inhibitor and is between 0.01 and 50% by weight. Preferably, the proportion of PDE4 inhibitor is up to 20% by weight.

According to the invention, the proportion of binder (PVP and, if appropriate, further binder) may preferably be between 0.5 and 20% by weight, based on the final dosage form. 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 according to the invention (in weight percent based on the final dosage form) is advantageously between 40 and 99% by weight. The proportion of fillers is preferably between 60 and 97% by weight.

The proportion of disintegrant in the rapidly disintegrating tablet (in weight percent based on the final dosage form) can be as high as 35% by weight. The proportion of disintegrant is preferably between 2 and 20% by weight. The proportion of disintegrant is particularly preferably between 5 and 10% by weight.

The proportion of lubricant or mould release agent in the rapidly disintegrating tablet (in weight percent based on the final dosage form, typically 0.1 to 5% by weight, the proportion of lubricant or mould release agent is preferably between 0.3 and 3% by weight, the proportion of lubricant or mould release agent is particularly preferably between 0.5 and 2% by weight.

In a preferred embodiment of the invention, the dosage form is a tablet. For tablets, it is preferred to contain, in addition to the active ingredient and PVP, at least one filler and at least one lubricant or mold release agent as further pharmaceutical excipients.

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

In one embodiment of the invention, the pharmaceutical preparation of the invention is prepared by producing a solid solution of the active ingredient in the binder PVP as carrier. This can be carried out illustratively by a solvent process in which the PVP, active ingredient, and, where appropriate, other pharmaceutical excipients are dissolved in a suitable solvent, followed by removal of the solvent by spray drying, normal drying, vacuum drying or freeze drying. We have surprisingly found that the production of solid solutions can also be carried out by a mixing process in which the active ingredient, if appropriate together with further pharmaceutical excipients, is stirred vigorously with PVP.

In the further processing of the solid solution into tablets or pills, the solid solution may be processed as an active ingredient component together with filler, binder, disintegrant and lubricant components using production operations well known to those skilled in the art to obtain the oral dosage form of the present invention. According to the invention, a solid solution of the active ingredient in the binder PVP as carrier means a solid solution having an amorphous structure, in which the active ingredient is present in the form of a molecular dispersion in the carrier material.

The pharmaceutical preparation can be prepared by a process for preparing a tablet or pill dosage form for oral administration of the active ingredient, comprising the steps of: (a) preparing an active ingredient preparation in the form of a PVP solid solution of the active ingredient, (b) preparing a mixture of the active ingredient preparation with pharmaceutical excipients, and (c) granulating the mixture obtained in step (b) with an aqueous PVP solution.

When the dosage form of the present invention is a tablet, the granules obtained in step (c) may be mixed with a lubricant or a mold release agent after drying, and then compressed in a tablet press. When the dosage form of the present invention is a pellet, the wet granules obtained in step (c) may be processed by an extruder/spheronizer to obtain a suitable pellet. Alternatively, the dispersion/suspension of the active ingredient preparation may be incorporated in a suitable solvent in the form of a solid solution of the PVP of the active ingredient to form a pelleted carrier (e.g. granules or pellets containing HPMC).

The dosage form of the present invention can also be prepared by the following method: the mixture of active ingredient and pharmaceutical excipients is granulated with aqueous PVP solution, the granules are dried and, if desired, other pharmaceutical excipients are mixed in. The wet preparation obtained after granulation can be further processed into pills or can be subsequently encapsulated. If desired, the dried granules, after mixing with other pharmaceutical excipients, can be compressed in a tablet press after mixing with a release agent. The granulation is preferably carried out in a fluid bed granulator under suitable conditions. It is furthermore possible, if desired, to admix the active ingredient with one of the pharmaceutical excipients, in particular the bulking agent, in the form of a trituration with the other excipient. This is particularly preferred when the content of active ingredient in the dosage form is less than 5% by weight. The abrasive product can be conventionally obtained by grinding the active ingredient with a pharmaceutical excipient (particularly a filler).

Thus, the pharmaceutical preparation can be prepared by an operation for preparing tablets or pills for oral administration of the active ingredient, which comprises:

(a) preparing a mixture of active ingredient and pharmaceutical excipients, and

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

The pharmaceutical preparation can also be prepared by mixing:

(a) active ingredient, or a ground product of active ingredient and corn starch,

(b) corn starch, and

(c) lactose monohydrate

Granulating with PVP aqueous solution, drying the granules, mixing the granules with a mold release agent, and tabletting in a tabletting machine.

In addition, the pharmaceutical preparation may be prepared by mixing:

(a) active ingredient, or a ground product of active ingredient and corn starch,

(b) the starch of the corn is prepared by the following steps of,

(c) microcrystalline cellulose, and

(d) sodium carboxymethyl starch

Aqueous granulation with PVP solution, drying the granules, mixing the granules with a release agent, and tableting in a tableting machine.

The pharmaceutical preparation can be prepared by the following method: the mixture of the pharmaceutical excipient and the suspension of the active ingredient in aqueous PVP solution is granulated, the granules are dried and, if necessary, further pharmaceutical excipients are added. The formulations obtained by this method are compressed in a tablet press after mixing with a mould release agent. The granulation is preferably carried out in a fluid bed granulator under suitable conditions.

The pharmaceutical preparation can also be prepared by the following steps:

(a) preparing a mixture of pharmaceutical excipients, and

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

The pharmaceutical formulation may be prepared in the following manner: the mixture of corn starch and lactose monohydrate is granulated with a suspension of the active ingredient in an aqueous PVP solution, the resulting granules are dried, the granules are mixed with a release agent and compressed in a tablet press.

The preparation of the pharmaceutical formulations of the present invention is illustrated by the following examples. The following examples illustrate the invention in more detail, but do not limit the invention.

Examples

Preparation of the pharmaceutical preparation of the invention

Example 1

Composition of ophthalmic ointment (1000 g amount)

Roflumilast 1g

Cetyl alcohol 4g

High viscosity Paraffin 200g

795g of white vaseline

Preparation: a clear melt of cetyl alcohol, high viscosity paraffin, and white petrolatum were prepared at about 70 ℃. Micro-granulated roflumilast (90% of the particles are below 10 μm) was stirred in and a homogeneous dispersion was prepared using an Ultra-Turrax. The suspension was cooled to room temperature with stirring for filling into suitable tubes.

Example 2

Composition of eye drops in emulsion form (amount of 1000 ml)

Roflumilast 1.5g

Medium chain length triglyceride 100.0g

Lecithin 12.0g

Glycerol 25.0g

Thimerosal 0.1g

Adding purified water to 1000ml

Preparation: first, roflumilast and then lecithin were dissolved in medium-chain long triglycerides and glycerol at 30-40 ℃. While stirring vigorously, purified water is added and homogenized until the droplet size of the dispersed phase is below 500 nm. The thimerosal was dissolved by stirring. The emulsion was filtered through a 0.45 μm filter and dispensed into a suitable container.

Example 3

Composition of eye drop solution in emulsion form (amount of 1000 ml)

Roflumilast 1.5g

Lecithin 1.5g

Thimerosal 0.1g

Povidone (C) 17) 10.0g

0.9% sodium chloride solution to 1000ml

Lecithin, thimerosal and povidone were dissolved in a 0.9% sodium chloride solution with vigorous stirring. Micronized roflumilast (90% of the particles below 10 μm) was added with stirring and distributed homogeneously.

Preparation of the tablets of the invention

Example A

Weight based on tablet containing 0.1mg of roflumilast

1. Roflumilast (micronized) 0.100mg

2. Lactose monohydrate 49.660mg

3. Corn starch 13.390mg

4. Povidone K901.300mg

5. Magnesium stearate (vegetable) 0.650mg

Total 65.100mg

Preparation of: (1) mixing with part of (3) and preparing the ground product in a planetary mill. Placing the ground product in a product container of a fluidized bed granulation system together with (2) and the rest of (3), (4) dissolving in waterA 5% granulation solution obtained with purified water was sprayed on and dried under appropriate conditions. To the granules was added (5), and the mixture obtained after mixing was compressed in a tablet press to tablets having an average weight of 65.1 mg.

Example B

Weight based on tablet containing 0.125mg roflumilast

1. Roflumilast 0.125mg

2. Lactose monohydrate 49.660mg

3. Corn starch 13.390mg

4. Povidone K901.300mg

5. Magnesium stearate (vegetable) 0.650mg

Total 65.125mg

Preparation of: (1) mixing with part of (3) and preparing the ground product in a planetary mill. The ground product is placed in the product container of a fluid bed granulation system together with (2) and the remainder of (3), (4) a 5% granulation solution in purified water is sprayed onto it and dried under suitable conditions. To the granules was added (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

Weight based on tablet containing 0.25mg of roflumilast

1. Roflumilast 0.250mg

2. Microcrystalline cellulose 33.990mg

3. Corn starch 2.500mg

4. Povidone K902.250mg

5. Sodium carboxymethyl starch (type A) 20.000mg

6. Magnesium stearate (vegetable) 0.600mg

Total 59.500mg

Preparation of: (1) mixing with part of (3) and preparing the ground product in a planetary mill. The ground product is placed in the product container of a fluid bed granulation system together with (2), (5) and the remainder of (3), (4) a 5% granulation solution in purified water is sprayed on and dried under suitable conditions. To the granules was added (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

Weight based on tablet containing 0.25mg of roflumilast

1. Roflumilast 0.250mg

2. Lactose monohydrate 49.660mg

3. Corn starch 13.390mg

4. Povidone K901.300mg

5. Magnesium stearate (vegetable) 0.650mg

Total 65.250mg

Preparation of: (1) mixing with part of (3) and preparing the ground product in a planetary mill. Placing the ground product in a product container of a fluidized bed granulation system together with (2) and the remainder of (3), (4) spraying a 5% granulation solution in purified waterDrying under suitable conditions after the above. To the granules was added (5), and the mixture obtained after mixing was compressed in a tablet press to tablets having an average weight of 65.25 mg.

Example E

Weight based on tablet containing 0.5mg of roflumilast

1. Roflumilast 0.500mg

2. Lactose monohydrate 49.660mg

3. Corn starch 13.390mg

4. Povidone K901.300mg

5. Magnesium stearate (vegetable) 0.650mg

Total 65.500mg

Preparation of: (1) mixing with part of (3) and preparing the ground product in a planetary mill. The ground product is placed in the product container of a fluid bed granulation system together with (2) and the remainder of (3), (4) a 5% granulation solution in purified water is sprayed onto it and dried under suitable conditions. To the granules was added (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

Weight based on tablet containing 0.5mg of roflumilast

1. Roflumilast 0.500mg

2. Lactose monohydrate 99.320mg

3. Corn starch 26.780mg

4. Povidone K902.600mg

5. Magnesium stearate (vegetable) 1.300mg

Total 130.500mg

Preparation of: (1) mixing with part of (3) and preparing the ground product in a planetary mill. The ground product is placed in the product container of a fluid bed granulation system together with (2) and the remainder of (3), (4) a 5% granulation solution in purified water is sprayed onto it and dried under suitable conditions. To the granules was added (5), and the mixture obtained after mixing was compressed in a tablet press to tablets having an average weight of 130.500 mg.

Example G

Weight based on tablet containing 2.5mg of roflumilast

1. Roflumilast 2.500mg

2. Microcrystalline cellulose 33.990mg

3. Corn starch 2.500mg

4. Povidone K902.250mg

5. Sodium carboxymethyl starch (type A) 20.000mg

6. Magnesium stearate (vegetable) 0.600mg

Total 61.750mg

Preparation of: (1) mixing with part of (3) and preparing the ground product in a planetary mill. Placing the ground product in a product container of a fluidized bed granulation system together with (2), (5) and the remainder of (3), (4) spraying a 5% granulation solution in purified water thereonAnd then dried under appropriate conditions. To the granules was added (6), and the mixture obtained after mixing was compressed into tablets having an average weight of 61.75mg in a tablet press.

Example H

Preparation of a tablet containing 0.1mg of roflumilast as active ingredient (weight of 70000 tablets in one batch)

1. Roflumilast (micronized) 7.000g

2. Lactose monohydrate 3476.200g

3. 937.300g of corn starch

4. Povidone K9091.000g

5. 45.500g of magnesium stearate (plant)

Total 4557.000g

Preparation of: (1) with 70g of (3), a ground product was prepared in a planetary mill. The ground product was placed in the product container of a fluidized bed system together with (2) and the remainder of (3), (4) a 5% granulating solution obtained in purified water was sprayed onto it (spray pressure: 3 bar; product temperature: 28-33 ℃; air flow rate for the first third of the spraying operation: 100m³H; the airflow rates in the subsequent spraying operation were: 150m³H; input air temperature: 40-70 ℃; spraying rate: 30-40 g/min). When 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, the relative surface humidity was measured and the value was adjusted to 20-50%. The compound (5) was added to the granules, and the mixture obtained after mixing was compressed in a tablet press to form tablets having an average weight of 65.1 mg.

Example I

Preparation of a tablet containing 0.25mg of roflumilast as active ingredient (weight of 70000 tablets in one batch)

1. Roflumilast (micronized) 35.000g

2. Lactose monohydrate 3476.200g

3. 937.300g of corn starch

4. Povidone K9091.000g

5. 45.500g of magnesium stearate (plant)

Total 4585.000g

Preparation of: 19.25g of (1) were mixed with 192.5g of (3) to prepare a ground product in a planetary mill. The ground product was placed in the product container of a fluidized bed system together with (2) and the remainder of (3), (4) a 5% granulating solution obtained in purified water was sprayed onto it (spray pressure: 3 bar; product temperature: 28-33 ℃; air flow rate for the first third of the spraying operation: 100m³H; the airflow rates in the subsequent spraying operation were: 150m³H; input air temperature: 40-70 ℃; spraying rate: 30-40 g/min). When 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, the relative surface humidity was measured and the value was adjusted to 20-50%. The compound (5) was added to the granules, and the mixture obtained after mixing was compressed in a tablet press to prepare tablets having an average weight of 65.5 mg.

Example J

Preparation of a tablet containing 0.1mg of roflumilast as active ingredient (weight of 70000 tablets in one batch)

1. Roflumilast (micronized) 7.000g

2. Lactose monohydrate 3476.200g

3. 937.300g of corn starch

4. Povidone K9091.000g

5. 45.500g of magnesium stearate (plant)

Total 4557.000g

Preparation of: (1) uniformly suspending the mixture in (4) a granulating solution obtained by dissolving the mixture in purified water. (2) And (3) placing in a product container of a suitable fluid bed granulation system and granulating with the granulation suspension described above, followed by drying. (5) Added to the granules and the mixture obtained after mixing was put in a tablet press to be pressed into tablets with an average weight of 65.1 mg.

Example K

Preparation of a tablet containing 0.25mg of roflumilast as active ingredient (weight of 70000 tablets in one batch)

1. Roflumilast (micronized) 35.000g

2. Lactose monohydrate 3476.200g

3. 937.300g of corn starch

4. Povidone K9091.000g

5. 45.500g of magnesium stearate (plant)

Total 4585.000g

Preparation of: (1) uniformly suspending the mixture in (4) a granulating solution obtained by dissolving the mixture in purified water. (2) And (3) placing in a product container of a suitable fluid bed granulation system and granulating with the granulation suspension described above, followed by drying. (5) Is added toAmong the granules, the mixture obtained after mixing was put in a tablet press to be pressed into tablets having an average weight of 65.25 mg.

Example L

Weight based on tablet containing 0.25mg of roflumilast

1. Roflumilast 0.250mg

2. Lactose monohydrate 49.660mg

3. Potato starch 10.000mg

4 corn starch 3.590mg

5PVP25 1.500mg

6. Magnesium stearate (plant) 0.650g

Total 65.650g

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

Example M

Weight based on tablet containing 0.25mg of roflumilast

1. Roflumilast 0.250mg

2. Lactose monohydrate 49.660mg

3. Corn starch 13.390mg

4 Povidone K901.300mg

5 gelatin 1.300mg

6. Magnesium stearate (plant) 0.650g

Total 66.550g

Preparation of: (1) mixing with part of (3) and preparing the ground product in a planetary mill. The ground product was placed in the product container of a fluidized bed granulation system together with (2) and the remaining amount of (3), and 5% granulation solutions obtained by dissolving (4) and (5) in purified water were sprayed on and dried under appropriate conditions. Adding the compound of (6) to the granules, and placing the mixture in a tablet press to press into tablets with an average weight of 66.55 mg.

Example M1

Pediatric preparation

Weight based on tablet containing 0.125mg roflumilast

1. Roflumilast 0.125mg

2. Lactose monohydrate 49.660mg

3. Corn starch 13.390mg

4 Povidone K901.300mg

5 mannitol 32.238mg

6 spice (Tutti Frutti) 0.329mg

7PVP (insoluble) 12.895mg

8. Magnesium stearate (plant) 1.649g

Total 111.586g

The formulation was prepared according to the methods disclosed above.

Industrial applicability

The pharmaceutical formulations of the present invention may be used for the treatment and prevention of all ocular diseases which are considered to be treatable or preventable by the use of PDE4 inhibitors. The pharmaceutical formulation of the invention is suitable for treating an ocular disorder selected from the group consisting of: blepharitis, conventional non-infectious eyelid dermatoses, conventional eyelid dermatoses (allergic, eczematous, contact), chronic disk of erythema (lupus-like chronic disks), chalazides, chronic blepharitis, watery eye, chronic punctitis, small vasculitis (canaliculitis), conjunctivitis (allergic, acute), keratoconjunctivitis, chronic conjunctivitis, blepharitis, conjunctival congestion, conjunctival edema, pseudonebula-like pterygium, ocular or conjunctival pemphigus, episcleritis, scleritis, scleral and episcleral inflammation, vitis, keratitis (reticular, chronic inflammatory, mummullar, posterior elastosis, star, stripe-shaped), photoakeratitis, solar-and keratoconjunctivitis, keratoconjunctivitis (neuroparalytic, bleb, exposure-induced keratitis), superficial inflammation with conjunctivitis, superficial inflammation of the cornea, Dry eye syndrome (dry cornea), ophthalmia, predatory corneal ulceration, scarring, corneal haze, interstitial and deep keratitis, corneal neovascularization (degeneration and erosion), iridocyclitis caused by sarcoidosis or alloheilodesic disease, acute and chronic iridocyclitis, iritis, anterior uveitis, iris atrophy, stratum corneum deposition, inflammation following intraocular lens implantation, retinal edema, (pre-operative) macular edema, granulomatous uveitis, pre-operative prevention, inflammatory complications, glaucoma, cataracts caused by chronic iridocyclitis, retinitis pigmentosa or ush syndrome, diabetic retinitis, macular degeneration, retrobulbar optic neuritis, neuromyelitis, vitreoretinopathy, inflammation following intraocular lens implantation, and retinal edema.

The invention further relates to a method of treating mammals, including humans, suffering from any of the above-mentioned diseases. The method is characterized in that a therapeutically effective and pharmacologically suitable amount of an active pharmaceutical ingredient selected from the group consisting of the compounds roflumilast, salts of roflumilast, roflumilast N-oxide and salts thereof is administered to a mammal suffering from the disease.

In another preferred embodiment, the invention relates to a method of treating a mammal, including a human, suffering from an ocular disease which is believed to be treatable or preventable by the use of a PDE4 inhibitor.

In one embodiment of the invention, the method is characterized in that "administering" is systemic or systemic administration of the pharmaceutical preparation. In this case, the ocular disease is preferably selected from the group consisting of blepharitis, conventional non-infective eyelid dermatoses, conventional eyelid dermatoses (allergic, eczematous, contact), chronic erythematous discs (lupus-like chronic discs), chalazides, chronic blepharitis, lacrimal overflow, chronic punctate inflammation, microangiolitis, conjunctivitis (allergic, acute), keratoconjunctivitis, chronic conjunctivitis, blepharitis, conjunctival congestion, conjunctival edema, pseudonebula pterygium, ocular or conjunctival pemphigus, episcleritis, scleritis, scleral and episcleral inflammation, vitis, keratitis (reticular, chronic inflammatory, mummular, posterior elastosis, star-shaped, stripe-shaped), keratophotinitis, solar-intense light and keratoconjunctivitis, keratoconjunctivitis (neuroparalysis, vesicular, exposure to light, and exposure to light) Superficial keratitis, dry eye syndrome (keratitis dryness), ophthalmia, predatory corneal ulceration, scarring, corneal opacities, interstitial and deep keratitis, corneal neovascularization (degeneration and erosion), iridocyclitis caused by sarcoidosis or alloheischiff's disease, acute and chronic iridocyclitis, iritis, anterior uveitis, iris atrophy, stratum corneum deposits, inflammatory conditions after intraocular lens implantation, retinal edema, with conjunctivitis.

In another embodiment of the invention, the method is characterized in that "administering" is systemic or intraocular and/or intravitreal administration of the pharmaceutical preparation. In this case, the ocular disease is preferably selected from (preoperative) macular edema, granulomatous uveitis, preoperative prophylaxis, inflammatory complications, glaucoma, cataracts due to chronic iridocyclitis, retinitis pigmentosa or Usher's syndrome, diabetic retinitis, macular degeneration, retrobulbar optic neuritis, neuromyelitis, vitreoretinopathy, inflammatory conditions after intraocular lens implantation, and retinal edema.

The pharmaceutical formulations of the present invention contain the active pharmaceutical ingredient in a dosage commonly used for the treatment of the particular disease. The dosage of the active ingredient is of the conventional order of magnitude for PDE inhibitors and may also be administered daily in one or more dosage units. Conventional dosages are disclosed, for example, in WO 95/01338. A typical dose for systemic therapy (oral) is in the range of 0.001-3mg per kg per day. Preferred pharmaceutical preparations according to the invention for topical administration contain 0.005mg-5mg of roflumilast, preferably 0.01mg-2.5mg, particularly preferably 0.1mg-0.5mg of roflumilast per dosage unit. Examples of pharmaceutical preparations of the invention contain 0.01mg, 0.1mg, 0.125mg, 0.25mg and 0.5mg of roflumilast per dosage unit.

Claims (8)

1. Use of a compound selected from roflumilast, salts of roflumilast, the N-oxide of the pyridine residue of roflumilast or salts thereof for the preparation of an ophthalmic pharmaceutical preparation for the prophylaxis or treatment of an ocular disease; wherein said ocular disease is selected from dry eye syndrome; wherein the ophthalmic pharmaceutical preparation comprises a therapeutically effective and pharmacologically suitable amount of the active compound and one or more pharmaceutically acceptable carriers and/or excipients.

2. The use as claimed in claim 1, wherein the roflumilast is a compound of formula I

Wherein the content of the first and second substances,

r1 is a difluoromethoxy group,

r2 is cyclopropylmethoxy, and

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

3. The use of claim 1, wherein the pharmaceutical formulation is an oily eye drop comprising a therapeutically effective amount of the active compound and an excipient selected from the group consisting of castor oil, peanut oil, and medium chain length triglycerides.

4. The use of claim 3 wherein the excipient in the oily eye drops is a medium chain length triglyceride.

5. Use according to claim 4, wherein said oily eye drops contain per 100 ml:

roflumilast 0.15g

Medium chain length triglycerides 10.0g

Lecithin 1.2g

Glycerol 2.5g

0.01g of thimerosal.

6. Use according to any one of claims 3 to 5, wherein 90% of the active compound has a particle size of less than 10 μm.

7. The use of claim 1, wherein the pharmaceutical formulation is selected from the group consisting of an ophthalmic bath, an ophthalmic lotion, an ophthalmic insert, an ophthalmic ointment, an ophthalmic spray, eye drops, a formulation for intraocular use and an eyelid ointment.

8. Ophthalmic pharmaceutical preparation comprising a therapeutically effective and pharmacologically suitable amount of an active pharmaceutical ingredient selected from the compounds roflumilast, salts of roflumilast, roflumilast N-oxide and salts thereof, together with one or more pharmaceutically acceptable carriers and/or excipients, which pharmaceutical preparation comprises medium-chain length triglycerides.