AU597718B2

AU597718B2 - Pharmaceutical composition comprising a phosphodiesterase inhibitor and a thromboxane a2 antagonist

Info

Publication number: AU597718B2
Application number: AU78296/87A
Authority: AU
Inventors: Walter Haarmann; Josef Nickl
Original assignee: Dr Karl Thomae GmbH
Current assignee: Boehringer Ingelheim Pharma GmbH and Co KG
Priority date: 1986-09-13
Filing date: 1987-09-11
Publication date: 1990-06-07
Anticipated expiration: 2007-09-11
Also published as: DK472487A; DK472487D0; KR880003624A; JPS6379838A; ES2033755T3; NZ221779A; EP0260527A3; ZA876806B; GR3004969T3; IL83872A0; EP0260527A2; DE3631294A1; AU7829687A; DE3777926D1; PH23553A; EP0260527B1

Description

Australia PATENTS ACT 1952 597718 Form COMPLETE SPECIFICATION

(ORIGINAL)

FOR OFFICE USE Short Title: Int. Cl: Application Number: Lodged: )lete Specification--Lodged: Accepted: Lapsed: Published: "I do-ument coiains ti amendm ents in)de un.urL Sertion and ij ci.rrecl o printirg, i ity: ited Art: ime of Applicant: ddress of Applicant: Actual Inventor: Address for Service: TO BE COMPLETED BY APPLICANT DR. KARL THOMAE GmbH D-7950 Biberach an der Riss, Federal Republic of Germany.

WALTER HAARMANN and JOSEF NICKL.

CALLINAN AND ASSOCIATES, Patent Attorneys, of 48-50 Bridge Road, Richmond, State of Victoria, Australia.

"PHARMACEUTICAL COMPOSITION COMPRISING A SPHOSPHODIESTERASE INHIBITOR AND A Complete Specification for the invention entitled: THROMBOXANE A ANTAGONIST" The following statement is a full description of this invention, including the best method of performing it known to me:-* SNote: The description is to be typed in double spacing, pica type face, in an area not exceeding 250 mm in depth and 160 m' width, on tough white paper of good quality and it is to be inserted inside this form. I la The present invention relates to a pharmaceutical composition comprising a phosphodiesterase inhibitor and a thromboxane A 2 antagonist.

Inventigations reported in J. Clin. Invest. 1591-1599 (1985) indicate that the combination of the phosphodiesterase (PDE) inhibitor dipyridamole with the thromboxane-synthesis inhibitor dazoxiben (4-[2-(1H-imidazol-1-yl)-ethoxy]benzoic acid) does not improve the antithrombotic activity of the PDE inhibitor.

We have now surprisingly found that a composition comprising a phosphodiesterase inhibitor and a thromboxane A 2 antagonist has a much more powerful A antithrombotic activity than do the individual substances. In other words, there is a strong unexpected synergistic effect.

According to one aspect of the present invention we therefore provide a pharmaceutical composition comprising a phosphodiesterase inhibitor and a thromboxane A 2 antagonist, optionally together with at least one carrier or excipient.

Numerous PDE inhibitors and thromboxane A 2 antagonists are described in the literature.

Examples of PDE inhibitors which are suitable for use in the present invention include those from the pyrimido[5,4-d]pyrimidine series (see, for example, US-A-3031450, US-A-3322755 and US-A-4518596), h

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-2those of the isoquinoline series (see, for example, US-A-3975524) those of the pyrido[3,2-dlpyrimidine series (see, for example, US-A-3843638) those from the indoline and carbostyril series (see, for example, US-A-4329347, GB-B-2098595 and US-A-444211l) and those of the benzoxazin-2-one series (see, for example, US-A-4513597).

The following compounds are examples of preferred PDE inhibitors for use in the present invention: papaverine, 2,6-bis(diethanolamino)-4,8-dipiperidino-pyrimidol5,4-d]pyrimidine (dipyridamole), 2,6-bis(diethanolamino)-4--piperidino-pyrimido[5,4-dlpyrimidine (mopidamole), 6,7-dichloro-1,5-dihydro-i.mic.-zo[2,1-b]quinazolin- 4. 2(3H)-one (Anagrelid), 7-bromo-1, 5-dihydro-3, 6-dimethyl-imidazo 1-bllquinazolin- 2 (3H) -one, (1-cyclohexyl-1H-5-tetrazolyl) butoxy]-2-oxotetrahydro-quinoline, 7-ethoxy-carbonyl-6, 8-dimethyl-4-hydroxymethyll(2H)-phthalazinone (phthalazinol), and 3, 4-dihydro-1-methyl-6- 6-tetrahydro-4-methyl- 6-oxo-3-pyridazinyl) -2 (lH) -quinolinone.

The daily dosage of the above compounds, for oral administration, is, conveniently: 3 1 to 2 mg/kg, preferably 1.5 mg/kg, for papaverine, to 7.5 mg/kg, preferably 5 mg/kg, for dipyridamole, 15 to 25 mg/kg, preferably 20 mg/kg, for mopidamole, 0.05 to 0.15 mg/kg, preferably 0.1 mg/kg, for Anagrelid, 0.075 to 0.15 mg/kg, preferably 0.1 mg/kg, for 7-bromo-l,5-dihydro-3,6-dimethyl-imidazo[2,l-b]quinazolin- 2(3H)-one, to 4.0 mg/kg, preferably 3 mg/kg, for 6-[4- (l-cyclohexyl-lH-5-tetrazolyl)-butoxy]-2-oxo-tetrahydroquinoline, to 7.0 mg/kg, preferably 4.0 mg/kg, for phthalazinol, and 0.05 to 0.15 mg/kg, preferably 0.1 mg/kg, for 3,4dihydro-l-methyl-6-(1,4,5,6-tetrahydro-4-methyl- 6-oxo-3-pyridazinyl)-2(1H)-quinolinone.

PDE inhibitors which have proved especially suitable for the present invention include those from the pyrimido[5,4-d]pyrimidine series, such as dipyridamole and mopidamole.

Examples of thromboxane A 2 antagonists which are suitable for use in the present invention include those from the benzenesulphonamidoethyl series (see, for example, DE-A-2809377, DE-A-3000377 and EP-A-194548) and from the heptenoic acid series (see, for example, NL-A-81/2116, EP-A-44711, Chemical Abstracts 98, 638n and 192,381t (1983), and Chemical Abstracts 99, 101 4 p (1983)). Md -4- The following compounds are examples of preferred thromboxane A 2 antagonists for use in the present invention: 4-[2-(benzeniesulphonamido)-ethyl]-phenoxy-acetic acid, the potassium salt of 3-[4-(2-benzenesulphonylaminoethyl)benzoyljpropionic acid, 1. 0 methyl 3-14-(2-(4-fluorobenzenesulphonylamino)ethyl)benzoyl] -propionate, (4-fluorobenzenesulphonylamino) ethyl) -benzoyllpropionic acid, methyl 3-[4-(2-(4-chlorobenzenesulphonylamino)ethyl)benzoyl] -propionate, 3-[4-(2-(4-chlorobenzenesulphonylamino)ethyl)-benzoylI- 2 propionic acid, methyl (p-toluenesulphonylamino) ethyl) benzoyl] prop ionate, (p-toluenesulphonylamino) ethyl) -ben2:oyllpropionic acid, methyl 3-[4-(2-(3-pyridinesulphonylamino)ethyl)benzoyllpropionate, (3-pyridinesulphonylamino) ethyl) -benzoylllpropionic acid, methyl 3-[4-(2-(2-thiophenesulphonylamino)ethyl)benzoyl3 -propionate, 4., 4 a 44 44 444 44 4 44, (2-thiophenesuiphonylamino) ethyl) -benzoyl]propionic acid, (2'-fluoro-4-biphenylyl-sulphonylamino) ethyl) benzoyll-propionic acid, 4-[4-(2-benzenesulphonylaninoethyl) -phenyll-4-hydroxybutyric acid, (2-benzenesulphonylaninoethyl) -benzoyllacrylic acid, ethyl (2-benzenesulphonylaminoethyl) -benzoyl]butyrate, 3- (2-benzenesulphonylaminoethyl) -benzoyl] butyric acid, 3- (p-chlorobenzenesulphonylamino) -ethyl) benzoyl]-butyric acid, ethyl (p-toluenesulphonylanino) -ethyl) benzoyl] butyrate, 3-[4-(2-(p-toluenesulphonylamino)-ethyl)-benzoyllbutyric acid, (3-pyridylsulphonylamino) ethyl) -benzoyllbutyric acid, ethyl (2-benzenesulphonylaininoethyl)-benzoyl]pentanoate, (2-benzenesulphonylaninoethyl) -benzoyllpentanoic acid, -6 methyl (l-naphthalenesulphonylanino) ethyl) benzoyl] -propionate, 3- (1-naphthalenesulphonylamino) ethyl) -benzoyl] propionic acid, 3-[4-(2-benzenesulphonylaminoethyl)-naphthoyl- (1)Ipropionic acid, ethyl (2-benzenesulphonylaminoethyl)-benzoyl]prop ionate, methyl (2-benzenesulphonylaminoethyl) -benzoyll- 4 propionate, a-methoxyethyl (2-benzenesulphonylaminoethyl) benzoyllpropionate, ethyl (2-benzenesulphonylaminoethyl) -benzoyllacetate, and 4-hydroxy-4-[4- (2-benzenesulphonylaminoethyl) -phenyllcrotonic acid.

Thromboxane A 2 antagonists which have proved particularly suitable for the present invention include those from the benzenesulphonamido series, such as, for example, 4- (benzenesulphonamido) -ethyl] -phenoxyacetic acid 4nd 3-[4-(2-(p-toluenesulphonamido)ethyl) -benzoylll-propionic acid.

The daily dosage of the above thromboxane A 2 antagonists, taken orally, is conveniently 5.0 to 20 mg/kg, preferably 7.5 to 12 mg/kg.

It is preferred that the pharmaceutical composition comprises a phosphodiesterase inhibitor selected rriX .009 0. a I ao t a Ia a a a 44 00 a a 7 from the pyrimido[5,4-d]pyrimidine series, the isoquinoline series, the pyrido[3,2-d]pyrimidine series, the indoline and carbostyril series or the benzoxazin-2-one series, and a thromboxane A 2 antagonist selected from the benzenesulphonamidoethyl series or the heptenoic acid series, more preferably dipyridamole and 4-[2-(benzenesulphonamido)ethyl]-phenoxy-acetic acid or 3-[4-(2-(p-toluenesulphonamido)ethyl)-benzoyl]-propionic acid.

The synergistic effect has been demonstrated, for example, using a pharmaceutical composition comprising dipyridamole (substance A) and the sodium salt of 3-[4-(2-(p-toluenesulphonamido)-ethyl)-benzoyl]propionic 15 acid (substance B) and, for comparison, the individual substances, and determining the inhibitory effect on clot formation in the rat. The following method (see Poliwoda et al., in Z. Ges. exp. Med. 145, 252 (1968)) was used: Male rats weighing 70 90 g, which had been given free access to food (Altromin) and water up till the start of the experiment, were anaesthetised with Nembutal by intraperitoneal route (50 to 60 mg/kg 25 of sodium pentobarbital). To prevent hypothermia the animals were kept on a heated bench (37°C).

After tranverse section of the abdomen, a loop of small intestine was taken out and fixed and a mesenterial-vein wi-h a diameter of 300 microns was placed under a binocular operating microscope with 40-fold magnification. A glass embedded monopolar V4A steel electrode with a diameter of 100 microns at the tip was placed on the vein as a stimulating cathode. The anode was placed opposite the cathode on the same vein. Stimulation was applied using a 150 Volt direct current for a period of 100 msec.

After the stimulation, the area under observation 1/ 6 4 04 o a 4 9 a 0 0 D 4 a a -8 was continuously bathed in warm (37'C) physiological saline solution.

The formation and growth of the clot were monitored under the microscope over a period of 20 minutes.

Throughout the observation period, the percentage narrowing of the diameter of the blood vessel caused by the clot was determined and recorded, initially at short intervals and later every minute.

The results were recorded graphically against time.

The area under the curve obtained constitutes a measurement of the clot size as a function of time.

Groups of 5 animals were given, by the oral route, either: i) 10 mg/kg of substance A,or ii) 2.5 mg/kg of substance B,or iii) 10 mg/kg of substance A and 2.5 mg/kg of substance B,or iv) the carrier (control) The experimental setup thus comprised 4 groups of animals.

The area under the curve for the animals treated with the substances was compared with that of the control animals. The reduction in clot size under the effect of the substances was expressed as a percentage reduction of the average "area under the curve" of the animals treated with the substances over the entire observation period compared with the average of the controls.

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0 0) 00 0 00l 00 0 00 9 The significance of the reduction was calculated using the t-test for independent random samples.

The following Table shows the results obtained: Clot formation Substance n inhibiting activity A 5 11 B 5 31 A+B 5 66 15 The composition tested on the rat comprising 10 mg/kg of substance A and 2.5 mg/kg of substance B is non-toxic since no toxic side effects could be detected on its administration.

In view of its pharmacological properties the new pharmaceutical composition is suitable for the treatment and prophylaxis of venous and arterial thrombosis, i.e. for the prevention or treatment of thrombo-embolic incidents associated with pathological thrombocyte behaviour, e.g. after heart valve or blood vessel operations, in deep leg vein thrombosis, in thrombotic-thrombocytopenic purpura, after coronary infarction, after cerebral infarction, in so-called transient ischaemic attacks, in Amaurosis fugax and for the prevention of arteriosclerosis.

According to another aspect of the present invention we provide the use of a combination of a phosphodiesterase inhibitor and a thromboxane A 2 antagonist for the manufacture of a medice-ment for combatting venous or arterial thrombosis.

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1 i 10 According to a further aspect of the present invention, we provide a method of treatment of the human or non-human animal body to combat venous or arterial thrombosis which method comprises coadministering to said body a phosphodiesterase inhibitor and a thromboxane A 2 antagonist hereinbefore described.

A single dose of the new composition conveniently comprises the single dose of the PDE inhibitor and the single dose of the thromboxane A 2 antagonist conventionally administered to humans. However, in view of the fact that it is well tolerated, the dosage of the thromboxane A 2 antagonist in particular may be varied within a wide dosage range, 15 e.g. between 10 and 1000 mg.

Taking the composition tested hereinbefore as-an example, a single dosage of this composition conveniently contains 50 100 mg (preferably 75 mg) of substance 20 A, plus 10-200 mg (preferably 10 to 100 mg) of substance B, and this dosage is conveniently administered 3 to 4 times a day.

0 40D 2o 0 C0U0 04 4 O O More generally, the new composition preferably is in dosage unit form comprising per dosage unit 1 to 500 mg (more preferably 2 to 75 mg) of a PDE inhibitor and 10 to 300 mg (more preferably to 200 mg) of aithromboxane A 2 antagonist. The inhibitor or antagonist may if desired be in the form of a physiologically acceptable addition salt and they will preferably be formulated with one or more carriers or excipients, such as inert conventional carriers and/or diluents corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethylene glycol, propylene glycol, cetyl 11 stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof), into conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions and suppositories.

In order to achieve the required effect in adults the single dose mentioned hereinbefore will conveniently be administered 2 to 4 times a day, preferably 3 or 4 times a day.

The following Examples illustrate the invention in a non-limiting manner (all percentages and ratios are by weight unless otherwise specified): 4

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Wt 12 Example 1 Film-coated tablets containing 75 mg of PDE inhibitor and 75 mg of thromboxane A 2 antagonist A powdered mixture consisting of Dipyridamole 4-[2-(Benzenesulphonamido)-ethyl]phenoxy acetic acid Fumaric acid Cellulose Corn starch 8% Polyvinylpyrrolidone 6% is moistened with water in a mixing apparatus and granulated by passing through a screen with a mesh size of 1.5 mm. After drying and passing through i the screen again, 1% of magnesium stearate is added and biconvex tablets measuring 10 mm and weighing 300 mg are prepared. These tablets are sprayed with hydroxypropylmethylcellulose lacquer until they weigh 312 mg.

Example 2 Hard gelatine capsules containing 50 mg of PDE inhibitor and 200 mg of thromboxane A 2 antagonist 10 kg of dipyridamole, 20 kg of fumaric acid, 11.5 kg of polyvinylpyrrolidone, 40 kg of 3-[4-(2-(p-toluenesulphonamido)-ethyl)-benzoyl]-propionic acid, 1.5 kg of silicon dioxide and 0.8 kg of magnesium stearate are mixed for 15 minutes in a cube mixer. This mixture is passed through a roller compactor having an adjoining dry granulating apparatus with a screen mechanism. The 0.25-1.0 mm fraction is used.

13- The capsule filling machine is set up so that each size 0 capsule receives the quantity of granulate corresponding to 50 mg of PDE inhibitor and 200 mg of thromboxane A 2 antagonist.

Example 3 Hard gelatine capsules containing 250 mg of PDE inhibitor and 100 mg of thromboxane A 2 antagonist a) Granulate 125 kg of mopidamole, 50 kg of fumaric acid and 13.5 kg of lactose are mixed together and moistened with a solution cf water/polyethylene glycol 6000.

15 After granulating through a screen with a mesh size of 1.0 mm and drying at 45 0 C, 1.4 kg of stearic acid are added.

b) Coated tablet 100 kg of the potassium salt of 3-[4-(2-benzenesulphonylaminoethyl)-benzoyl]propionic acid, 7.5 kg of hydroxypropylmethylcellulose, 2.5 kg of silicon dioxide and 15 kg of carboxymethylcellulose are moistened with ethanol and granulated by passage through a screen with a mesh size of 1.5 mm. After drying, 1 kg of magnesium stearate are added and the granulate is compressed to form biconvex tablet cores of mm diameter and weighing 126 mg.

These cores are coated in several stages with a coating suspension consisting of 5.6 kg of sucrose, kg of gum arabic and 3.8 kg of talc until the tablets weigh 135 mg.

c) Filling Using a capsule filling apparatus, the quantity of granulate corresponding to 250 mg of PDE inhibitor j .r 14 14 is packed into a hard gelatine capsule, size 0 long, and the coated tablet containing 100 mg of thromboxane A 2 antagonist is placed on top.

Example 4 Suspension containing 100 mg of dipyridamole and mg of thromboxane A 2 antagonist per 5 q The suspension has the following composition: Dipyridamole 3-[4-(2-(4-Fluorobenzenesulphonylamino)ethyl)-benzoyl]-propionic acid 0.2% Sorbitol 20.8% Cellulose Sodium carboxymethylcellulose Flavour correctors/preservatives 1.8% Water 65.2% Ingredients are stirred into hot water under high shearing forces. After cooling, ingredients and are incorporated in the viscous suspension.

g of this suspension contain 100 mg of PDE inhibitor (dipyridamole) and 10 mg of the thromboxane A 2 antagonist.

,2Z~ I I 15 Example Delayed release form containing 200 mg of dipyridamole and 50 mg of thromboxane A 2 antagonist a) Pellet I A mixture of 4-[2-(Benzenesulphonamido)-ethyl]-phenoxyacetic acid 50.0 kg Lysine 12.5 kg Highly polymeric hydroxypropylcellulose 52.5 kg Triacetine 4.0 kg Ethyl cellulose 2.5 kg Magnesium stearate 3.5 kg is kneaded with ethanol in an extruder and extruded in a spaghetti-like form (diameter 1 mm) which is rounded off to form pellets in a Spheronizer.

The pellets are then thoroughly dried.

b) Pellet II 300 kg of mixed tartaric acid starter pellets are sprayed in a pan with a suspension consisting of isopropanol, dipyridamole and polyvinylpyrrolidone until the active substance carrying pellets so produced contain about 45% dipyridamole.

These pellets are sprayed with a lacquer consisting of methacrylic acid/methyl methacrylate copolymer (Eudragit S available from Rohm) and hydroxypropylmethylcellulose phthalate (brand name HP 55) in a weight ratio of 85:15 to 50:50. The organic lacquer solutions still contain plasticiser and talc. Two batches of pellets are sprayed with 5 and 7% respectively =-11 16 of the coating substance and varying ratios of the lacquer components within the limits specified above. The two batches are mixed together so as to give the following release in vitro: Conditions (corresponding to USPXXI, Basket Method, 100 rpm, first hour: artificial gastric juices, pH 1.2, 2nd to 6th hours: artificial intestinal juices (phosphate buffer), pH Release of active substance per hour: 1st hour about 2nd hour about 3rd hour about 18% 4th hour about 12% after the 6th hour more than 90% of the dipyridamole has been released.

c) Filling In accordance with the content of active substance of pellet components I and II and the desired dosage the pellets are mixed together and packed into size 0 long capsules in a capsule machine. The capsule contains 200 mg of PDE inhibitor and 50 mg of thromboxane A 2 antagonist in a delayed released form.

L i, i, s~l V i;-r I- 17 Example 6 Ampoules containing 10 mg of PDE inhibitor and mg of thromboxane A 2 antagonist per 5 ml Composition: Dipyridamole 10 mg 4-[4-(2-Benzenesulphonylamino-ethyl)- 10 phenyl]-4-hydroxy-butyric acid 5 mg 0 00 Soao Propyleneglycol 50 mg o 0(4) Polyethyleneglycol 5 mg Ethanol 10 mg 0 Of o Water for injections, ad 5 ml 15 Dilute HC1, ad pH 3 0 0 Components and are dissolved, with heating, go in the solution consisting of ingredients o 0 After checking the pH and sterile filtration, the 0 0 20 solution is transferred into suitable ampoules 0o 0 and sterilised.

Example 7 Suppositories containing 100 mg of PDE inhibitor and 200 mg of thromboxane A 2 antagonist 1 suppository contains: Papaverine 100 mg Methyl 3-[4-(2-(p-toluenesulphonylamino)ethyl)-benzoyl]propionate 200 mg Fumaric acid 200 mg Suppository mass 1 500 mg At 50 0 C the micronised components free from any lumps, are suspended in the molten mass.

Suppositories weighing 2 g are moulded.

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q~Jg 18 Other PDE inhibitors and thromboxane A 2 antagonists may be incorporated in the dosages specified in the description into the pharmaceutical examples described hereinbefore.

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Claims

1. A pharmaceutical composition comprising a phosphodiesterase inhibitor and a thromboxane A 2 antagonist.

2. A pharmaceutical composition as claimed in claim 1, comprising a phosphodiesterase inhibitor selected from the pyrimido[5,4-d]pyrimidine series, the isoquinoline series, the pyrido[3,2-d]pyrimidine series, the indoline and carbostyril series or the benzoxazin-2-one series, and a thromboxane A 2 antagonist selected from the benzenesulphonamido- ethyl series or the heptenoic acid series.

3. A pharmaceutical composition as claimed in either one of claims 1 and 2, comprising dipyridamole and 4-[2-(benzenesulphonamido)-ethyl]-phenoxy-acetic o Sacid or 3-[4-(2-(p-toluenesulphonamido)-ethyl)- benzoyl]-propionic acid.

4. A pharmaceutical composition as claimed in any one of claims 1 to 3, comprising 1 to 500 mg ooo0 of said phosphodiesterase inhibitor and 10 to 300 mg o. of said thromboxane A 2 antagonist.

5. A pharmaceutical composition as claimed in any one of claims 1 to 4, comprising 2 to 75 mg of said phosphodiesterase inhibitor and 10 to 200 mg of said thromboxane A 2 antagonist.

6. A pharmaceutical composition as claimed in any one of claims 1 to 5, comprising said phosphodiesterase inhibitor and said thromboxane A 2 antagonist together with at least one carrier or excipient. IaT 20

7. A pharmaceutical composition as claimed in any one of claims 1 to 6 for use in a method of treatment of the human or non-human animal body to combat venous or arterial thrombosis.

8. A pharmaceutical composition substantially as herein described in any one of Examples 1 to 7.

9. A method of treatment of the human or non- human animal body to combat venous or arterial thrombosis which method comprises coadministering to said body a phosphodiesterase inhibitor and a thromboxane A 2 antagonist. D A T E D this 9th day of March, 1990. DR. KARL THOMAE G.M.B.H. By its Patent Attorneys: U o C o CALLINAN WRIE o oo