IE52176B1 - Pharmaceutical compositions containing a xanthine derivative - Google Patents

Description

The present invention relates to pharmaceutical compositions containing l,3-di-n-butyl-7-( 2-oxopropyl) xanthine.

British Patent Specification No. 1441562 referred 5 to the compounds of the formula (X): wherein and R2 which may be the same or different, each represents a straight-chain or branched-chain alkyl radical of 2 to 6 carbon atoms, or a cyclohexyl, alkoxy10 alkyl or hydroxyalkyl radical, and A represents a hydrocarbon radical having up to 4 carbon atoms which may be substituted by a methyl group. The compounds of the formula (I) were described as effective in increasing the blood flow through skeletal muscles while at the same time showing low toxicity. The compound of the formula (I) said to be preferred was that wherein is an n-butyl group, R2 is an n-butyl group and A is a CH2CH2 group.

That compound was shown to be highly effective. German Patent Application No. 2462367 indicates that the compounds of the formula (1) may in general be employed as unit doses of about 200-600 mgs so that they would be expected to be used at a similar dose to known agents such as pentoxyphylline. The published low oral toxicity of xanthines such as pentoxyphylline and the compound of the formula (I) where Rx and R2 are n-butyl groups and A is a CHjCHj group means that such high doses are acceptable.

It has now been discovered that l,3-di-n-butyl-7(2-oxopropyl)xanthine, which falls within formula (I) and is disclosed in British Patent Specification No. 441 562 (see Table VIII) and in DE-A-2 462 367 (See Table XI), is extremely potent in increasing oxygen tension and contractility in ischaemic and skeletal muscle. These properties reflect an improvement in the metabolic statue of the tissue which in turn makes the compound of great potential use as an agent for the treatment of peripheral vascular disease such as intermittent claudication.

Accordingly, in one aspect the present invention provides the use of l,3-di-n-butyl-7-(2-oxopropyl) xanthine for the manufacture of a medicamant for increasing oxygen tension and contractility in ischaemic skeletal muscle.

In another aspect, the present invention provides the use of 1,3-di-n-butyl-7-(2-oxopropyl)xanthine for the manufacture of a medicament for the treatment of peripheral vascular disease, such as intermittent claudication.

This compound has a low acute toxicity so that the conventional high doses would have been expected to be used in the clinic. However the extremely high potency of this compound allows its use in surprisingly low dose.

Thus in a preferred aspect, the invention provides 53176 the use of l,3-di-n-butyl-7-(2-oxopropyl)xanthine for the manufacture of a medicament as defined above, wherein the medicament is a pharmaceutical composition which comprises l to 30 mg of l,3-di-n-butyl-7-(2-oxopropyl) xanthine and a pharmaceutically acceptable carrier therefor.

The composition may contain from 2 to 25 mg of 1.3- di-n-butyl-7-(2-oxopropyl)xanthine, from 2.5 to 20 mg or from 5 to 15 mg.

Thus suitable compositions may contain about, for example, 2.5, 5, 7.5, 10, 12.5, 15, 17.5 or 20 mg of 1.3- di-n-butyl-7-(2-oxopropyl)xanthine.

The compositions may be administered one or more times a day so that the daily dose is in the region of 2.5-90 mg, and more usually 5-50 mg, for example about 10 - 40 mg.

In a further aspect the present invention provides a solid pharmaceutical dosage unit which consists of 1 to 10 mg of l,3-di-n-butyl-7-(2-oxopropyl)xanthine and a pharmaceutically acceptable carrier therefor in such a quantity that the dosage unit weighs 80 to 600 mg.

Thus suitable compositions of this invention may contain about, for example, 2.5, 5, 7.5 or 10 mgs of 1.3- di-n-butyl-7-(2-oxopropyl)xanthine.

The compositions of this invention may be administered one or more times a day so that the daily dose is in the region of 2.5 - 30 mgs. The composition, including the compositions according to the invention, is often administered twice or three times a day.

Generally the compositions, including the compositions of the invention, will be adapted for administration by injection or for oral administration.

Although l,3-di-n-butyl-7-(2-oxopropyl)xanthine is only sparingly soluble in aqueous media the enhanced potency of the compound renders it suitable for use in injectable solutions, for example in aqueous solution.

The injectable compositions of this invention may consist essentially of said sterile, pyrogen free 1,3-di-n-butyl7-(2-oxopropyl)xanthine, for example sealed into a vial or ampoule or the like. Other suitable injectable compositions, including the compositions of the invention may comprise said sterile material in admixture with, for example suspending agents or preserving agents. Such compositions may be made up for injection or admixture with sterile water or saline or the like. In general the volume to be injected will be from 0.5 to 2 mis, for example 1 ml.

Suitably the injectable composition in the use aspect of the invention will contain slightly less than the maximum orally administerable composition, for example from 1 to 25 mg of l,3-di-n-butyl-7-(2-oxopropyl) xanthine. More suitably the injectable composition will contain 2 to 20 mg and preferably 2.5 to 15 mg of 1,3-din-butyl-7-(2-oxopropyl)xanthine; for example about 5, 7.5, 10 or 12.5 mgs of said agent.

Particularly favoured compositions of this invention are those adapted for oral administration since they are more convenient for general use. Such dosage forms include, for example, tablets and capsules. The dosage units may contain such conventional agents as, for example, fillers (diluents), lubricants, binders, disintegrants, colourants, flavourings, surface active agents, preservatives and buffering agents.

Suitable fillers for use include cellulose, manitol, lactose and other similar agents. Suitable disintegrants include, for example, starch, polyvirylpolypyrrolidone and starch derivatives such as sodium starch glycollate. Suitable lubricants include, for example, stearic acid, magnesium stearate and magnesium lauryl sulphate.

Since l,3-di-n-butyl-7-(2-oxopropyl)xanthine is a medicament of high potency the solid orally administrable unit dosage form in the use aspects according to this invention may be small, for example under 80 mgs in weight, but for patient convenience it is usual to formulate the composition in such a manner that it weighs about 80 - 600 mgs, in total, for example about 100 - 400 mgs. This means that frequently relatively large proportions of a filler is employed. Thus formation of unit dosage forms will be simple since the skilled worker may select fillers or other agents of known physical properties to prepare the composition in conventional manner as the actual effect of the small quantity of l,3-di-n-butyl-7-(2-oxopropyl) xanthine is slight.

The oral compositions may be prepared by conventional methods of blending, filling, tabletting or the like. Repeated blending operations may be used to distribute the active agent throughout those compositions employing large quantities of fillers. Such operations are of course conventional in the art.

The following Examples illustrate the invention: Example 1 1.3- Di-n-butyl-7-(2-oxopropyl)xanthine, magnesium stearate and microcrystalline cellulose were blended together and passed through a 40 mesh sieve (UK). The mixture was tabletted on a conventional rotary machine to produce a batch of 5000 tablets of the following composition. 1.3- Di-n-butyl-7-(2-oxopropyl)xanthine: 10 mg magnesium stearate: 0.2 mg microcrystalline cellulose: 189.8 mg 53176 Example 2 1.3- Di-n-buty1-7-(2-oxopropyl)xanthine, sodium lauryl sulphate, lactose and sodium starch glycollate were blended together and passed through a 40 mesh sieve (UK).

The mixture was tabletted on a conventional rotary machine to produce a batch of 5000 tablets of the following composition: 1.3- Di-n-butyl-7-(2-oxopropyl)xanthine: 5 mg magnesium lauryl sulphate: lactose: sodium starch glycollate: 0.1 mg 103 mg 1,9 mg Example 3 a) 5.0 g of 1,3-di-n-buty1-7-(2-oxopropyl)xanthine were mixed with 51.04 g microcrystalline cellulose, passed through a 0.8 mm sieve with 91,35 g lactose and 2.61 g hydrogenated castor oil and mixed in a cubic mixer. The mixture was pressed into tablets of 150 mg with a single punch of diameter 7 mm, each tablet containing 5 mg of l,3-di-n-butyl-7-(2-oxopropyl)xanthine. b) The mixture prepared as above was filled into capsules size 3, so that each capsule contained 150 mg of the mixture.

Example 4 a) 10.0 g of 1,3-di-n-butyl-7-(2-oxopropyl)xanthine were mixed with 189.8 g microcrystalline cellulose, passed through a 0.8 mm sieve with 0.2 g magnesium stearate and mixed in a cubic mixer. The mixture was pressed into tablets of 200 mg with a single punch of diameter 8 mm, each tablet containing 10 mg of 1,3-di-n-buty1-7-(2-oxopropyl) xanthine. b) The mixture prepared as above was filled into capsules size 0, so that each capsule contained 200 mg of the mixture.

Illustration of Pharmacological Effectiveness of Xanthine Derivatives In the following illustrations l,3-di-n-butyl-7(2-oxopropyl)xanthine will be referred to as Compound A, pentoxyphylline will be referred to as Compound B and 1,3-di-n-buty1-7-(3-oxobutyl)xanthine will be referred to as Compound C. 53176 Investigation of the effects of Compounds A,B and C upon oxygen tension and contractility of ischaemic skeletal muscle of cats Methodology: Anaesthesia and administration of compounds: Cats of either sex were anaesthetized with urethane/ chloralose (120/60 mg/kg i.p.). In the course of the experiments, pentobarbital was injected intravenously (V. antebrachii ceph.) via a plastic tube. The intra10 duodenal (i.d.) application of compound was conducted by means of a plastic catheter, which was inserted into the duodenum. a) p02-measurements: PO2 was measured polarographically using Pt15 needle electrodes (modified according to BSumgartl and Ltibbers, 1973). The reference electrode, an Ag/AgCl system was sputtered on the glass mantle of the cathode, or it was a separate electrode. The cathode was coated with a polystyrol and a collodium membrane. A constant voltage supply provided a polarizing voltage between 600 and 800 mV. The reducing current was measured by a nano-ampere amplifying meter. The cathode was inserted in the tissue by means of a motor-driven micromanipulator.

Characteristics of pC^-elsctrodes characteristics p02 needle electrode for neasurement in tissues p02 catheter electrodes for measurement in blood vessels overall length 90 mm 15 mm tip length 5 - 8 nm - tip diameter diameter of the 2 - 4 pm 0.7 - 1.2 nm neasurement surface 0.5 pm 15 pm membrane collodium, polystyrol 12 pm teflcn, or collodium, polystyrol sensitivity -12 2 x 10 A/Torr 1 x 10-11 A/Torr drift 2 - 5 % 1 - 3 % response tine (Tgo) 0.8 - 1.2 sec 2-3 sec diffusion error 1 - 5 % 3 - 6 % Experimental procedure: A p02 - electrode was inserted in the muscle tissue (m. gastrocnemius) of both hindlegs of an anaesthetized cat. After recording the p02 of the normal perfused muscle, the blood flow to one measuring site was restricted by ligating the femoral artery. The p02 dropped steeply and the tissue became ischaemic. After a few minutes, the p02 increased and then decreased again. The values were constant after 30 to 60 min. After having reached a constant level of p02, the vehicle was given, followed by the test substance.

The recordings (Compound A i.v. vs. Compound B i.v.; Compound A i.d. vs. Compound B i.d.. Compound C i.d.) were evaluated, taking one value every 10 sec - at least 36 readings being taken. The mean value and the standard deviation were calculated, in order to check the significance of the effect. b) Skeletal muscle contractility: Cats of either sex were anaesthetized as for p02 measure20 ment. After dissection of the skin of the calf muscles, the sciatic nerve was cut about 3 cm proximal to the knee. The tendon of the calf muscles was cut and connected with an isometric force transducer (SWEMA, SG 3). In order to maintain constant differences and a resting tension of 100 p, the hind limb was fixed at the tibia by means of a clamp. Direct stimulation of the muscles consisted of square wave pulses of 4 msec duration at a frequency of 2 Hz and at a voltage of 50 V. In order to keep the muscles wet and at a normal temperature, the muscles were continuously superfused by means of a NaCl-solution (0.9%, 38°C). Femoral blood flow was restricted by a graded occlusion of the artery leading 5317b to a reduction of contractility by ca. 30%. After having reached a constant level of the contraction force, the vehicle (NaCl and Methocel, respectively) was injected, followed by the test substance.

Results; Table 1 demonstrates that Compound A leads to a distinct increase of the contractility and p02 of ischaemic skeletal muscle. Surprisingly, Compound A shows high activity in the pg-range (50 - 125 pg/kg). In contrast, the dose range of activity of Compounds B and C is 5 - 32 mg/kg, leading to changes which are less pronounced in comparison with Compound A (see tables 1-3) at 125 pg/kg. 53176 Table 1 ISCHAEMIC MUSCLE - CAT contractility (% initial value) p02 (mmHg) (increase) i.v. i.d. i.v. i.d. Compound A 36 32 10 4 (dose/kg) (50 pg) (125 pg) (125 pg) (50 pg) Compound B 9 23 2 3 (dose/kg) (5 mg) (32 mg) (5 mg) (12.5 mg) 10 Compound C (doseAg) NT 22 (12.5 rag) NT 6 (32 mg) NT not tested because of low water solubility Table 2 Cat COMPARISON COMPOUND B - COMPOUND A 1.8 - 2.6 kg PO2 in skeletal muscle n = 6 pO2 prior to ligaticn (Torr + SEM)* pO2 after ligation (Torr + SEM)* hind linto art. ligaticn control 20.1 + 0.04 11.0 + 0.66 15.6 + 0.19 hind lint) art. ligation control 26.7 + 0.08 12.0 + 0.02 20.6 + 0.52 hind lint) art. ligation control 37.4+0.1 24.7 + 0.64 hind linto art. ligation control 27.9 + 0.99 20.1 + 0.12 16.4 + 1.14 hind lint) art. ligation control 30.5 + 0 2.0 + 0 12.5 +0.12 hind limb art. ligation control 8.2 + 0.23 13.71 + 0.11 4.9 + 0.23 Table 2 cont Table 2 cont.. effect of Caipcund B 5mg/kg i.v. ApOjtTorr) effect of Catpound A 125 pg/kg i.v. Δ pO2(Tarr) effect of Caipound B in relation to Conpound A (%) hind limb art.lig. 1.6(pi0.01) 6.2(ps£O.Ol) 26.6 control O.3(n.s.) 13.2(p£O.Ol) 0 hind limb art. lig. -0.16(n.s.) 7.3(pSO.Ol) 0 control 1.02(p«0.01) 3.8(ρέΟ.Ο1) 27 hind limb art.lig. -1.5(n.s.) 5.2(p40.01) 0 control - - - hind limb art. lig. 4.9(ρζΟ.Ο1) 27.1(p£O.Ol) 17.9 control -2.4(p£O.Ol) 3.5(pSO.Ol) 0 hind limb art. lig. 7.3(p60.0l) U.2(p$0.01) 65.6 control 14.3(pSO.Ol) 19.3(piO.Ol 74.3 hind limb art. lig. 1.3{p£0.Ol) 5.6{pS0.01) 22.9 control -O.9(piO.Ol) 3.4(p£O.Ol) 0 Mean effect of Compound B at 5 mg/kg compared to Compound A at 125 pg/kg= 21.3% * n = between 36 and 120 531 76 Table 3 SUBSTANCE: Ccnpound A Formulation: aqueous solution Species: Cat Wfelgbt: 1.8 - 2.0 kg n: 4 d) j Suppliers: Stock/Ehillips NaCl-sol. t (min) dosage 50 pgAg i.v. t (min) & muscle + X contract. — g ± 0 * + 36.0 + 21.0 > 60 Δ initial phase BP + decrease S + 0 * - 14.0 + 8.0 2 Δ second phase BP + increase S + 0 * + 17.0 + 9.0 33 Table 3 cont ......

Table 3 cont dosage 125 pg/kg i.v. t · (min) dosage 313 pg/kg i-v. t (min) muscle X contract. + S * + 19.0 + 12.0 > 60 + 25.0 n = 1 > 60 Δ initial phase BP + decrease S * - 23.1 + 3.3 3 - 25.0 n = 1 2 Δ second phase BP + increase S + 10.8 + 8.3 32 + 15.0 n = 1 6 (percentage of initial values) p < 0.05 (t = tine interval to reach initial values) The average decrease of muscle ccntractility induced by the arterial occlusion was 26 %.

Die ID5o in mice of l,3-di-n-butyl-7-(2-oxcprcpyl) xanthine has been found to be greater than 1 g/kg per Oral.

Claims (16)

1. A solid pharmaceutical dosage unit which consists of 1 to 10 mg of l,3-di-n-butyl-7-(2-oxopropyl)xanthine and a pharmaceutically acceptable carrier therefor 5 in such a guantity that the dosage unit weighs 80 to 600 mg.

2. A solid pharmaceutical dosage unit as claimed in Claim 1 adapted for oral administration.

3. A solid pharmaceutical dosage unit as claimed in 10 Claim 2 in the form of a capsule or tablet.

4. A solid pharmaceutical dosage unit as claimed in Claim 2 or 3 which weighs 100 to 400 mg.

5. A solid pharmaceutical dosage unit according to Claim 1, substantially as hereinbefore described 15 with particular reference to the accompanying Examples.

6. A pharmaceutical composition adapted for administration by injection which consists of 1 to 10 mg of l,3-di-n-butyl-7-(2-oxopropyl)xanthine and 20 a pharmaceutically acceptable carrier therefor.

7. The use of l,3-di-n-butyl-7-(2-oxopropyl) xanthine for the manufacture of a medicament for increasing oxygen tension and contractility in ischaemic skeletal muscle. 5

8. The use of 1,3-di-n-buty1-7-(2-oxopropyl) xanthine for the manufacture of a medicament for the treatment of peripheral vascular disease

9. The use as claimed in Claim 8, wherein the medicament is for the treatment of intermittent 10. Claudication.

10. The use as claimed in any of Claims 7 to 9, wherein the medicament comprises 1 to 30 mg of 1,3-di-n-butyl-7-(2-oxopropyl,xanthine and a pharmaceutically acceptable carrier 15 therefor.

11. . The use as claimed in any of Claims 7 to 10, wherein the medicament is adapted for administration by injection. 53176

12. The use as claimed in Claim 11,wherein the medicament comprises an aqueous solution.

13. The use as claimed in any of Claims 7 to 10, wherein the medicament is adapted for oral 5 administration.

14. The use as claimed in Claim 13, wherein the medicament is in the form of a capsule or tablet.

15. The use as claimed in Claim 13 or 14, 10 wherein the medicament weighs 80 to 600 mg.

16. The use as claimed in Claim 15, wherein the medicament weighs 100 to 400 mg.