DE29980117U1 - Pharmaceutical agents as circulatory drugs - Google Patents

Description

WO 00/10542 PCT/DE99/02636

DRUG USE AND COMBINATION

Field of application of the invention

The present invention relates to the use of medicinally active substances. It can be used in the pharmaceutical industry. ·

Known technical background

The compound ip-iej-dihydro-i-methyl^-oxo-S-propyl-1H-pyrrazolo^.S-dlpyrimidin-S-ylH-ethoxyphenyljsulfonyl]-4-methylpiperazine, a phosphodiesterase-V inhibitor with the International Nonproprietary Name (INN) Sildenafil, as well as its production and use as an antianginal agent is known (EP-A1-0463756). It is also known that this compound is used to treat erectile dysfunction (Viagra®). Although it has only recently been officially approved as a medicinal product for this indication, its use has received widespread media coverage and is generally known. In a very short time, the opinion has become established that the simultaneous intake of sildenafil and vasodilators such as organic nitrates, namely glyceryl trinitrate (GTN), particularly pentaerythrityl tetranitrate (PETN ₁ Peritrate®), isosorbide-5-mononitrate (ISMN) ₁ isosorbide dinitrate (ISDN) and others, leads to severe interactions that often lead to the death of the patient. This prohibits the simultaneous administration of sildenafil and organic nitrates (Siegal, company publication Pfizer Inc., USA, May 1998). The official product information for Viagra®, approved and distributed by the US Food and Drug Administration (FDA), currently lists simultaneous treatment with organic nitrates as a contraindication. However, according to the FDA report on post-marketing surveillance (Summary of Death Reports in Viagra® Users Received from Marketing (late March), through June 1998), 77 deaths have been reported with Viagra®, in which at least 6 cases were associated with the simultaneous use of organic nitrates. Moreover, the simultaneous use of sildenafil and organic nitrates cannot be ruled out with certainty, as each of the two prescriptions may be made by different doctors and without knowledge of the other prescription. However, a not insignificant number of patients are dependent on the intake of anti-anginal drugs based on organic nitrates, as substitution of these drugs, for example with ACE inhibitors, beta-blockers or calcium antagonists, cannot replace all the advantages of nitrate therapy. Furthermore, it is known that at least the ACE inhibitors (VA Briner et al., Am. J. Physiol. 264: F322-F327 (1993); Keim et al., Biochem. Biophys. Res. Commun. 154:236-244 (1988)), calcium antagonists (Günther et al., Basic Res. Cardiol. 87: 452-460 (1992)) and highly cardioselective beta-blockers interfere with the nitric oxide metabolism in the same way as the organic nitrates, so that they too can cause severe drug interactions with sildenafil. Dosage, dosing interval, areas of application, side effects and interactions as well as contraindications of the active ingredients pentaerythrityl tetranitrate or sildenafil as well as their special galenic formulation in the products Pentalong® or Viagra®, in particular their dosage form and excipients contained in them, are available to the expert in detail from the instructions for use and scientific / technical publications associated with the respective product, as well as patent and

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Company documents, known.

Statement of the invention The object of the invention is;

(A) antianginal agents based on organic nitrates, in the case of simultaneous indication and/or systemic presence of phosphodiesterase inhibitors, and (B) products which safely ensure the treatment of the other indication in the case of simultaneous presence of heart/circulatory diseases and erectile dysfunction

The object (A) of the invention is achieved by the use of pentaerythrityltetra-, pentaerythrityltri-, peritaerythrityldi- or pentaerythritylmononitrate for the production of agents as cardiovascular therapeutics, in particular antianginal agents, for a given indication and/or systemic presence of phosphodiesterase inhibitors. The active ingredients pentaerythrityltetra-, pentaerythrityltri-, pentaerythrityldi- or pentaerythritylmononitrate are particularly suitable for use according to the invention when the phosphodiesterase inhibitor is a phosphodiesterase V inhibitor, in particular sildenafil. Phosphodiesterase inhibitors in the sense of the present invention also include their therapeutically applicable salts, such as the citrate in sildenafil. The agents obtained according to the invention are characterized in that they can contain the active ingredients in a broad dosage spectrum. They contain pentaerythrityl tetranitrate, pentaerythrityl trinitrate, pentaerythrityl dinitrate or pentaerythrityl mononitrate in addition to the usual galenic excipients in an amount of up to 600 mg, preferably in the ranges of 10 to 200 mg, 30 to 160 mg, 50 to 100 mg and 50 mg or 80 mg. The respective active ingredient can be contained in the corresponding agent in an amount of up to 50% by mass, preferably in an amount of 10 to 50% by mass. It is generally distributed homogeneously, but the active ingredient can be divided into an initial dose and a sustained-release dose, for example distributed in the shell and core. The agents are preferably available as solid oral administration in the form of powders, granules, pellets, tablets, film-coated tablets, capsules or dragees. These can contain the active ingredient in its entirety in unretarded or sustained-release form. The active ingredients pentaerythrityl trinitrate, pentaerythrityl dinitrate or pentaerythrityl mononitrate can be used in the amounts given above or in amounts that correspond to their therapeutic equivalent to pentaerythrityl tetranitrate, based on the number of nitric acid ester groups contained in the molecule. The solid dosage forms can also be provided with a coating or film, in particular one that is resistant to gastric juice. The agents obtained according to the invention are suitable for short-term therapy or long-term therapy. The selection of the respective active ingredient is based on general pharmacological principles and the therapeutic requirements that are familiar to the person skilled in the art. In addition to the desired pharmacological effect, the state of health, the stage of the disease, the physical condition, the known effects and side effects, contraindications, the frequency of treatment, the duration of use, drug interactions and parallel drug applications must also be taken into account. The dosage is in therapeutic doses that are based on those in which the active ingredients are already used for known indications.

WO 00/10542 PCT/DE99/02636

used. The total daily dose can be up to 600 mg, depending on the active ingredient. In general, daily doses of up to 350 mg will be sufficient. The dosage and dosage interval must be selected accordingly. The compounds used according to the invention can be used by themselves or as part of a galenic preparation. The galenic preparations are prepared according to the working methods and rules generally familiar to the pharmaceutical expert, with the selection of the technologies to be used and the galenic excipients used being based primarily on the active ingredient to be processed. Questions of its chemical and physical properties, the selected application form, the desired duration of action, the site of action and the avoidance of drug-excipient incompatibilities are of particular importance. It is therefore up to the expert to select the dosage form, excipients and production technology in a trivial manner based on known substance and process parameters. The pharmaceutical form in question should be designed in such a way that, in order to achieve therapeutic plasma levels, it contains the respective active ingredient in an amount which makes it possible to divide the daily dose into 1 to 2 individual doses in release-controlled systems and up to 10 individual doses in other pharmaceutical forms. Continuous application by means of long-term infusion is also suitable. According to the invention, the compounds mentioned can be administered primarily orally, intravenously, parenterally, sublingually or transdermally. The respective pharmaceutical preparation is preferably provided in liquid or solid form. Solutions, in particular for the preparation of drops, injections or aerosol sprays, as well as suspensions, emulsions, syrups, tablets, film-coated tablets, dragees, capsules, pellets, powders, lozenges, implants, suppositories, creams, gels, ointments, plasters or other transdermal systems are suitable for this purpose. The pharmaceutical preparations contain conventional galenically applicable, organic or inorganic carriers and excipients, which themselves are chemically indifferent to the respective active ingredients. Suitable for this purpose are, but are not limited to, water, salt solutions, alcohols, vegetable oils, polyethylene glycols, gelatin, lactose, amylose, magnesium stearate, talc, highly dispersed silicon dioxide, paraffin, fatty acid mono- and diglycerides, cellulose derivatives, polyvinylpyrrolidone and the like. The preparation can be sterilized and, if necessary, mixed with excipients such as fillers, binders, lubricants, mold release agents, lubricants, disintegrants, humectants, adsorbents or anti-disintegrants, preservatives, stabilizers, emulsifiers, solubilizers, salts to influence the osmotic pressure, buffer solutions, colorants, fragrances, flavors or sweeteners. The pharmaceutical expert will make a suitable selection based on known substance parameters to avoid drug-excipient incompatibilities. The selection of the therapeutic agent for the treatment of erectile dysfunction is based on general pharmacological principles and the therapeutic requirements that are familiar to the expert. In addition to the desired pharmacological effect, the state of health, the stage of the disease, the physical condition, the known effects and side effects, contraindications, the frequency of treatment, the duration of use, drug interactions and parallel drug applications must also be taken into account. The dosage is in therapeutic doses that are based on those in which the active ingredients, in particular sildenafil, are already used for this indication. The dosage and dosage interval are

3 -

WO 00/10542 PCT/DE99/02636

to choose accordingly.

The object (B) of the invention is achieved by products containing a heart / circulatory therapeutic, in particular a coronary therapeutic, based on

.5 Pentaerythrityl tetra-, pentaerythrityl tri-, pentaerythrityl di- or pentaerythrityl mononitrate and a phosphodiesterase inhibitor, in particular as described under (A), as a combination preparation for simultaneous, separate or staggered use in the treatment of erectile dysfunction and/or in the treatment of heart/circulatory diseases when the other indication is present at the same time. The therapeutic agents formulated as described above are prepackaged either individually or together and then combined to form the products according to the invention.

Surprisingly, it has been shown that the use of the medicinal substances pentaerythrityl tetra-, pentaerythrityl tri-, pentaerythrityl di- or pentaerythrityl mononitrate according to the invention leads to agents (A) which are suitable for reducing or preventing an interaction between phosphodiesterase inhibitors and organic nitrates to such an extent that, based on the state of medical science, such an extremely strong interaction should inevitably occur and should therefore be prohibited. The invention described also opens up a new therapeutic possibility, since the agents produced according to the invention allow the use of antianginal agents for the first time, which reliably guarantee that phosphodiesterase inhibitors, in particular sildenafil, and organic nitrates can be taken at the same time, even when prescribed by different doctors and without knowledge of the other prescription. This is therefore a new type of application which has not been described before and which would not have been expected in this form by the person skilled in the art.

Due to the products (B) according to the invention, it is possible to provide medicaments which for the first time enable the treatment of heart/circulatory diseases with organic nitrates or the treatment of erectile dysfunctions in the simultaneous presence of the other indication, without the therapist having to fear the most serious side effects to be expected according to the state of medical science, since by resorting to the products according to the invention he avoids the treatment of the two indications by separate prescription by himself or others.

The following examples are intended to illustrate the invention in more detail with regard to its nature and embodiment, without, however, limiting its scope.

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PCT/DE99/02636

Examples of implementation

example 1

The influence of the combination of PETN and sildenafil or ISDN and sildenafil on hemodynamics was investigated in dogs in an open, two-arm parallel study."

Group A (10 dogs) received PETN 10 mg kg' ¹ KG (body weight) for 2 days and then sildenafil in gradually increasing doses, totaling 5 mg'kg' ¹ KG; Group B (10 dogs) received ISDN 5 mg"kg' ¹ KG for 2 days, followed by sildenafil according to the same dosage regimen. The following were determined:

(a) mean arterial pressure (MAP) before administration of sildenafil and at each dosing step, with relevant decreases in MAP occurring more frequently and at lower sildenafil doses under ISDN than under PETN,

b) the left ventricular end-diastolic pressure,

c) heart rate, with the increase in heart rate being more moderate in the PETN group than in the ISDN group, and

d) the arteriovenous pO 2 difference in the coronary arteries at the above-mentioned measurement times, whereby the arteriovenous pO ₂ difference increased under ISDN, but not under PETN.

The administration of the entire sildenafil dose is therefore possible under PETN in contrast to ISDN.

20 Example 2

The acute interaction between GTN and sildenafil or between PETN and sildenafil was investigated in dogs. Group A (6 dogs) received GTN and sildenafil; group B (6 dogs) received PETN and sildenafil. The animals were permanently instrumented and the severity of the drop in blood pressure and the compensatory increase in heart rate were monitored while conscious during a 5-hour nitrate administration (infusion). The nitrates were administered in half-maximal doses (EC50) based on coronary artery vasodilation (GTN: 1.5 pgkg" ¹ min' ¹ , PETN: 0.75 μg kg" ¹ min' ¹ ). Sildenafil (4 mg kg" ¹ BW) was administered orally 4 hours after the start of the infusion. In group B, sildenafil under PETN caused a significantly (p < 0.01) lower mean blood pressure drop of 7 ± 1 mmHg with an increase in heart rate of 11 min" ¹ than in group A under GTN ₁ where a mean blood pressure drop of 28 ± 3 with an increase in heart rate of 23 min' ¹ was found. The use of sildenafil under the influence of nitrates therefore causes a significantly lower blood pressure drop under PETN compared to GTN at equieffective doses of nitrates.

35 Example 3

A typical tablet has the composition:

a) Pentaerythrityl tetranitrate 10 mg, or

b) . 20 mg, or

c) 50 mg, or d) 80 mg,

WO 00/10542 DAB10 137mg, PCT/DE99/02636 lactose DAB10 80mg, Potato starch DAB10 3mg, gelatin DAB10 22mg, talc DAB10 5mg, Magnesium stearate DAB10 6mg. Silicon dioxide, highly dispersed

Example 4

a) In a suitable mixer, 160 g of pentaerythrityl tetranitrate (PETN), _1,300 g of lactose, 80 g of microcrystalline cellulose, 76 g of corn starch, 20 g of talc, 20 g of silicon dioxide and 4 g of magnesium stearate are mixed homogeneously. The mixture is pressed at a pressure of 10 - 30 kN to form tablets with a nominal mass of 600 mg.

b) 350 g PETN, 1000 g lactose, 323 g microcrystalline cellulose and 273 g potato starch are mixed in a fluid bed granulator, granulated with 1050 ml of a 4% aqueous starch solution, then dried, sieved and homogeneously mixed with 60 g talc, 20 g magnesium stearate and 32 g silicon dioxide. The granules are pressed on a rotary tablet press at a pressing force of 10-30 kN to form tablets with a target mass of 1050 mg.

c) In a suitable mixer, 900 g lactose, 300 g corn starch, 30 g silicon dioxide and 300 g PETN are mixed until homogeneous. The mixture is filled into sachets with a filling weight of 1530 mg.

d) 450 g PETN, 1350 g lactose, 300 g microcrystalline cellulose and 400 g potato starch are mixed in a fluid bed granulator. 36 g gelatin and 18 g sorbitol, dissolved in 350 g water, are sprayed onto the mixture. The resulting granulate is dried and sieved. 80 g talc, 25 g magnesium stearate and 41 g silicon dioxide are added to the raw granulate and mixed until homogeneous. Tablets with a target mass of 900 mg are produced on a rotary tablet press with a pressing force of 10 - 30 kN.

e) PETN and gallic excipients are mixed homogeneously in defined quantities in a mixer. The mixture is processed into tablets in a tablet press (Table 1).

f) The substances PETN and defined amounts of gallic excipients are mixed in a mixer until homogeneous and then filled (A) into bags and (B) into capsules (Table 2).

g) PETN and a defined amount of galenic excipients are mixed in a mixer. This is followed by compaction. The compressed products are homogenized to a uniform particle size using a sieving machine. The sieved material is filled (A) into bags and (B) into capsules (Table 3).

h) PETN and defined amounts of galenic excipients are mixed in a fluid bed granulator and then granulated with an aqueous binder solution. The dried granules are sieved and mixed with galenic flow regulators, lubricants and glidants.

Tablets are produced on a tablet press (A). The tablets thus obtained

WO 00/10542 PCT/DE99/02636

are (B) coated in a coating system (Table 4).

Example 5

A typical tablet has the following composition: a) Sildenafil citrate (equivalent to mg Sildenafil) (25 mg),

b) or (50 mg),

c) or (100 mg),

microcrystalline cellulose, anhydrous dibasic calcium phosphate, sodium croscarmellose, magnesium stearate, hydroxypropyl methylcellulose, titanium dioxide, lactose, triacetin and FD & C Blue No. 2.

Example! 6

Tablets according to examples 3 a) and 5 a), for example, are packaged separately, provided with instructions for use and spatially separated in a packaging unit.

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Tabel!

PCT/DE99/02636

Fabrics PETN a) [mg] b) [mg] c) [mg] d) [mg] lactose 85 160 300 200 Cellulose 100 300 200 0 Strength 50 80 225 300 talc 100 76 150 100 Silicon dioxide 0 20 5 0 Magnesium stearate 40 20 15 20 Stearic acid 0 4 0 10 Target mass 5 0 5 0 380 660 900 630

Table 2:

Fabrics (A) - b) [mg] - ( ^B > 1 d) [mg] 0 PETN a) [mg] 500 c) [mg] 200 lactose 600 0 100 200 Cellulose 300 250 60 0 Strength 200 250 0 0 Silicon dioxide 250 5 60 5 Target mass 50 1005 5 405 Capsule size 1400 225

Table 3:

Fabrics (A) (B) PETN ■a) Image] b) [mg] lactose 150 180 Cellulose 300 0 Strength 300 500 Target mass 300 400 1050 1080

WO 00/10542

Table 4:

PCT/DE99/02636

Fabrics (Λ) a) [mg] b) [mg] c) [mg] d) [mg] (B) PETN 100 125 150 100 e) [mg] Cellulose 0 210 200 205 120 lactose 515 210 300 150 220 Strength 15 226 250 200 200 gelatin 0 10 0 0 200 Hydroxypropyl cellulose 0 0 0 15 15 Sorbit 0 5 0 ■ o 0 Poly(I-vinyl-2-pyrrolidone) 0 0 25 0 10 talc 15 21 5 10 0 Magnesium stearate 5 7 0 0 15 Silicon dioxide 10 11 15 &Iacgr;5 5 Stearic acid 0 0 5 5 15 Target mass 660 825 950 700 0 Methylhydroxypropylcellulose 0 0 0 0 800 Macrogol 4000 0 0 0 0 4 4

Claims (7)

1. Pharmaceutical agents, characterized in that they contain pentaerythrityl tetra-, pentaerythrityl tri-, pentaerythrityl di- or pentaerythrityl mononitrate in an amount of up to 600 mg, in particular a) from 10 to 200 mg, b) from 30 to 160 mg, c) from 50 to 100 mg, d) of 50 mg or 80 mg, and contain usual galenic excipients. 2. Pharmaceutical agents according to claim 1, characterized in that they contain pentaerythrityltetra-, pentaerythrityltri-, pentaerythrityldi- or pentaerythritylmononitrate in an amount of up to 50% by mass, in particular 10 to 50% by mass. 3. Pharmaceutical agents according to claims 1 to 2, characterized in that they contain pentaerythrityl tetra-, pentaerythrityl tri-, pentaerythrityl di- or pentaerythrityl mononitrate in homogeneous distribution. 4. Pharmaceutical agents according to claims 1 to 3, characterized in that they are present as solid oral administrations, in particular in the form of powders, granules, pellets, tablets, film-coated tablets, capsules or dragees. 5. Pharmaceutical agents according to claims 1 to 4, characterized in that they contain pentaerythrityl tetra-, pentaerythrityl tri-, pentaerythrityl di- or pentaerythrityl mononitrate in unretarded and/or retarded form. 6. Pharmaceutical agents according to claim 5, characterized in that they are provided with a coating or film, in particular one which is resistant to gastric juice. 7. Pharmaceutical agents according to claims 1 to 6, characterized in that they can be used for short-term therapy or for long-term therapy.