IE65420B1 - Nitroglycerin spray - Google Patents

Abstract

The invention relates to a hydrophilic propellant gas spray with the claimed composition, whose container sealing material absorbs less than 10 mg of nitroglycerin per 1 g of sealing material. The spray according to the invention produces a quicker rise in the nitroglycerin level, while the pharmaceutical product is of good quality.

Description

Description The invention relates to a nitroglycerin spray on a hydrophilic basis having a defined composition and in continuous contact with the spray composition sealing material, whose absorption value for nitroglycerin is less than 10 mg/1 g of sealing material.

Nitroglycerin, also known as GTN, is an active compound for the treatment of angina pectoris attacks. Among other things, it is employed in emergency situa10 tions in which the medicament form is intended to make possible a rapid onset of action.

The medicament forms employed in this special indication, such as sublingual tablets or bite-through capsules, have disadvantages. It is disadvantageous, among other things, that in these medicament forms the active compound once taken must first be released and distributed before it is available for absorption in dissolved form. Furthermore, an unnecessary loss of time occurs in the treatment of acute attack if the medicament form first has to be removed from package and blister.

GTN-containing sprays were developed to avoid the disadvantages of these medicament forms. By spraying the active compound-containing dose into the mouth, a direct and rapid application of a solution of the active com25 pound to as large as possible a part of the oral mucosa readily absorbing the active compound GTN is ensured. By means of this, a large surface area should be reached, which accelerates the diffusion of the active compound.

However, the properties of GTN such as high vapour pressure, solubility behaviour and explosiveness hitherto set limits to this aim. For reasons of safety, therefore, desensitised active compound/auxiliary mixtures have to be employed in the formulation of the medicament form spray.

Owing to its lipophilicity, GTN is highly soluble in solvents such as ether, acetone, ethyl acetate, benzene, chloroform and triglycerides. However, the solubility in hydrophilic solvents such as water is limited. The solubility in water is only about 1.1 mg/ml of GTN.

The solvents used in conventional spray formulations are accordingly lipophilic. Oils or triglycerides are customary.

However, lipophilic solvents prevent the active compound GTN from being distributed in the hydrophilic mucosa with the rapidity desired in the case of acute attacks of angina pectoris.

In the past, a starting point for increasing the availability of active compound was to reduce the amount of the lipophilic solvent employed. However, the inflow period, measurable by means of the maximum plasma concentration (Caax) and time of the maximum concentration (tmax), was only slightly affected.

P.M. Dewland et al. [in Herz & GefaBe, 7, 536-544 (1987)] indeed obtained higher values (Tab. 1) for three GTN sprays prepared using lipophilic solutions with a decreasing amount of the lipophilic recipe components, but t„„ is not significantly different.

Another starting point for increasing the availability of the active compound is described in DE-A 3,246,081.

This is achieved by increasing the content of 5 propellant gas to 60-95% of the recipe constituents.

The increased content of propellant gas in this case causes a higher concentration of the active compound in the non-volatile, oily solvent. The medicament must furthermore first diffuse from the oily active compound solution into the mucosa. The inflow of the active compound which is important in cases of attack, however, cannot be significantly shortened. An increased content of propellant gas is also disadvantageous from standpoints of increased environmental awareness and is therefore to be avoided.

A qualitatively distinct improvement of the spray in cases of attack is not possible with the retention of lipophilic solvents.

Another starting point for distributing the active compound rapidly in the hydrophilic mucosa is the use of a solvent whose dissolving properties for the active compound GTN are as low as possible. The spray formulation must in this case take into account that this solvent or solvent mixture sufficiently desensitises the active compound GTN and is also safe to handle industrially under production conditions.

US Patent Specification 3,155,574 describes a nitroglycerin spray formulation for inhalation based on hydrophilic solvent, containing the active compound GTN, 1,2-propanediol and anhydrous ethanol; practical exemplary embodiments of the primary packing agents are absent. Inhalation, however, is rather a disadvantage in cases of attack, as it is more difficult to carry out. GTN sprays are desirable in which the active compound is sufficiently absorbed via the oral mucosa and inhalation of the active compound is accordingly unnecessary.

Investigations by H. Laufen et al. in Therapiewoche 34, 963-970 (1984) gave the result that in the case of the hydrophilic recipe in comparison to GTN sprays on a lipophilic basis, both the appearance of the active compound in the blood and the amount of the absorbed substance is more rapid and greater respectively. The authors use a pump spray for metering the solution. According to general experience, pump sprays to date do not fulfil the requirements placed on medicaments, so that the formulation having the therapeutically favourable effect cannot be converted into a medicament.

EP-A 0,310,910 describes a nitroglycerin spray formulation which apart from the active compound only contains ethanol and water as solvents and is adjusted to a pH range from 2.4 to 6.7. However, in this formulation, on evaporation of the ethanol the active compound undergoes a phase separation from the water and is thus not desensitised, whereas desensitisation would be desirable particularly for reasons of safety.

The prior art of sprays on a hydrophilic basis in comparison to those on a lipophilic basis shows deficiencies such as an absorption of nitroglycerin in valve components and a reduction of the dose amount of active compound GTN with each new burst of spray.

Surprisingly, it has now been found that a nitroglycerin spray on a hydrophilic basis in a special composition which, in combination with container sealing material whose absorption value for glycerol trinitrate is less than 10 mg/1 g of sealing material, has a constant active compound content per individual dosage.

The invention accordingly relates to a nitroglycerin spray which consists of the constituents glycerol trinitrate, ethanol, 1,2-propylene glycol, dichlorodif luoromethane and dichlorotetrafluoromethane, which are in a certain weight ratio to one another and are in continuous contact with container sealing material made of synthetic material, whose absorption value for GTN is less than 10 mg/1 g of sealing material. A nitroglycerin spray according to the invention is a nitroglycerin metered aerosol which is composed of 0.73% by weight of nitroglycerin in a hydrophilic solution of 13.83% by weight of ethanol and 7.28% by weight of 1,2-propylene glycol having a content of propellant gas of 78.16% by weight, and this composition is in continuous contact with the container sealing material whose absorption value for GTN is less than 10 mg/1 g of sealing material.

Apart from the principle constituents previously mentioned, the nitroglycerin spray according to the invention can contain customary additives such as, for example, flavourings, which are well-known to the person skilled in the art.

A nitroglycerin spray according to the invention is prepared by filling a homogeneous, single-phase solution of glycerol trinitrate, ethanol and 1,2-propylene glycol, such as in the % by weight indicated in Table 1, into aerosol cans or bottles, crimping on a suitable metering valve whose absorption value for glycerol trinitrate is less than 10 mg/1 g of sealing material, and pressurising with a made-up mixture of dichlorodifluoromethane and dichlorotetrafluoroethane, as in the % by weight indicated in Table 1.

Table 2 gives a comparative summary of the recipe composition of the prior art and of a spray according to the invention.

The composition of a spray according to the invention reads: Serial No. Name in 100 1 glycerol trinitrate 0.73 2 ethanol 13.83 3 1,2-propylene glycol 7.28 4 dichlorodi fluoromethane 31.26 5 dichlorotetrafluoroethane 46.90 6 sealing material having an absorption value for GTN of less than 10 mg/1 g of sealing material The hydrophilic spray composition in the made-up product is in contact with the container material and the Ί • metering valve materials. Stability investigations on sprays having identical contents according to the invention, identical containers, but qualitatively different valves showed . 5 that the pharmaceutical quality of the product is only ensured when using valves prepared using special materials. Only in the case of these special materials does no absorption or a tolerable absorption of the active compound glycerol trinitrate take place in the valve 10 components. The interaction of the critical valve components, i.e. seals, with the spray according to the invention is represented in Tab. 3. The active compound absorption in the seals was determined by quantification of the gly- 15 cerol trinitrate after extraction from valve seals after incubation in the spray for 2 or 4 weeks. The WE number is an identity number of the valve from which the respective sealing material was removed. During the preparation of spray according to the inven- 20 tion, a defined mass of sealing material was additionally added to the active compound solution in the spray container, a valve was crimped on, the container was pressurised and the spray was stored upright under the appropriate conditions. At the end of the investigation 25 period, the spray bottle was depressurised in the cooled state, the seals were removed and washed, and the GTN content was determined after extraction. Testing gave the values listed in Tab. 3 as results.

The glycerol trinitrate absorption at 20 °C is mg of GTN/1 g of seal No. 400, 45 mg of GTN/1 g of Buna BA 170 T, 3.4 mg of GTN/1 g of Neoprene beige and < 1 mg of GTN/1 g of Butyl FA 7500.

Valves with sealing materials of an absorption value of > 10 mg/1 g of sealing material lead to reduction of active compound in the package during storage of the spray, so that the active compound content per individual dosage falls below the pharmaceutically legally accepted limits. In addition, valves having these strongly absorbing sealing materials which, in the area of the metering chamber have contact with the next dose to be administered, likewise lead in these to reduced contents which are no longer permissible.

Tabs. 4 and 5 show this phenomenon in four batches of sprays which have been prepared with valves containing different sealing materials. The amount of active compound found is shown as a percentage of the intended dose in the 1st, 2nd and 3rd individual burst of spray after different, utilisation-free time intervals. Only valves which contain Butyl FA 7500 and Neoprene ensure a sufficient pharmaceutical quality.

The embodiment of the medicament in practice thus requires the use of metering valves containing special sealing materials.

The different distribution coefficient (Pu) of GTN between the constituents of the recipe (R) and the hydrophilic oral mucosa (M) is determining for this: Pu = M is greater in the case of the hydrophilic R recipe than in the case of the lipophilic recipe, as a result of which the rapid inflow in vivo is achieved. The distribution Pk - D (seal = D), i.e. in identical seals is R However, then also greater in the case of the hydrophilic 5 spray and makes the use of new, special sealing materials necessary which have a low solubility for GTN or a lower absorption.

The desired more rapid inflow of the active compound in comparison to slower lipophilic sprays was verified and the rapid action was shown in a bioavailability study and in a clinical study using the glycerol trinitrate metering spray according to the invention.

Of importance therapeutically is a rapid inflow (tmaz) to give high active compound concentrations. This leads to a rapid onset of action and to an effective action. Connected with this is an earlier curtailment of the angina pectoris attack and rapid aid for the patient in this life-threatening situation which is marked by fear of death.

Two pharmaceutically different GTN sprays were compared with one another in an identical manner of administration.

The test spray (T) is the spray according to the 25 invention containing the particular sealing material and contains the active compound in a hydrophilic solvent. The reference spray (R) contains the active compound in a lipophilic solvent.

Table 6 shows the result of the test.

Table 6 Parameter T R T/R P [pg/ml] 1774 + 1272 884 ± 693 2.16 0.006 t^ [min] 4.4 ± 1.4 7.9 + 2.8 < 0.05 AUC [pg min/ml] 9488 ± 5303 6990 i 5168 1.52 n.s.

The test shows that the active compound is absorbed significantly more rapidly from the test preparation than from the reference spray; CL., was higher by the factor 2.2 and t„., was reduced from 7.9 to 4.4 min.

The spray according to the invention causes the more rapid inflow of the active compound together with good quality of the pharmaceutical product. For the angina pectoris patient in cases of attack, this means a more rapid action and a more rapid elimination of the states of anxiety occurring in cases of attack.

Tab. 1 Literature data of pharmacokinetic parameters for GTN spray on sublingual administration Preparation Source No. Subjects (Number) Dose (-max (pg/ml) t-oiex (min) AUC (min .pg/ml-1) rel. AUC (%) Lipophilic 1 3 0.4 1. 400 4-5 — spray A 2. 860 3 3. 590 5 Lipophilic 1 3 0.4 1. 2260 3.2 ·. spray B 2. 1620 6.5 3. 1444 10.0 Lipophilic 2 12 0.8 670 ± 500 10.0 5740 1 4590 56.26 spray C Lipophilic 2 12 0.8 760 1 450 8.0 6360 1 3970 58.9 spray D Lipophilic 2 12 0.8 1150 1 770 8.0 9990 1 8080 100 spray B p < 0.05 p > 0.05 p < 0.05 Lipophilic 3 8 0.8 780 1 850 7 1369 1 16040 36.5 spray A Hydrophilic 3 8 0.8 3810 12810 4 37460 1 14640 100 spray A p < 0.05 Continuation of Tab. 1 Preparation Source No.

Subjects Dose (Number) Lipophilic spray B Hydrophilic spray B 12 0.8 12 0.8 Lipophilic 5 24 spray B Spray according 5 24 to the invention 0.4 0.4 C(nax (pg/ml) ^Ίηβχ (min) AUC (min .pg/ml-1) rel. AUC (%) 340 ± 234 8.3 ± 2.0 3516 36.9 1387 ± 630 4.3 1 1.6 9534 100 p < 0.001 p < 0.05 p < 0.001 884 ± 693 7.9 + 2.8 6990 ± 5158 73 1774 ± 1272 p = 0.006 4.4 ± 1.4 p < 0.05 9488 ± 5303 n. s. 100 Tab, 2 Recipe composition of the sprays Preparation Lipophilic Lipophilic Hydrophilic Hydrophilic Spray according to spray A spray B spray A spray B the invention Source No. 1 1 3 Vidale dictionary Composition • 1987 Contents in 100 g in 100 g in 100 ml in 100 g GTN dis- 0.9 0.7 Hydrophilic GTN 4% m/m GTN 5% m/m solved in water- in ethanol 34.0 ml in ethanol 14.56 neutral 27 15.0 miscible oil pump spray Ethanol 1,2-propylene Paraffin 95% v/v 14.0 ml glycol 7.28 sub. 12.4 - Diethylene — Ether 2.2 1.8 glycol Flavouring 0.5 0.4 monoethyl 1.0 ml Propellant 57.0 82.1 ether gas Flavouring 1.0 ml — Dichloro- Dichlorodi- difluoro- fluoromethane 31.26 methane 50.0 ml Dichlorotetra- fluoroethane 46.90 to I Table 3 Interaction of valve sealing materials in the spray according to the invention Absorption of glycerol trinitrate (GTN) in sealing material [mg of GTN/1 g of seal] Sealing material Storage conditions 20eC/ 2 weeks 40eC/ 2 weeks 20°C/ 4 weeks 40°C/ 4 weeks Buna BA 170T (from valve WE 947) 45.0 51.0 44.5 49.0 Seal No. 400 (from valve WE 999) 53.2 61.1 - - 1 B 470 PA (from valve WE 1010) 56.3 53.6 - - 1 RP 3-49-16 (from valve WE 1008) 44.0 49.0 - - Neoprene, black (from valve WE 1007/1008) 11.4 14.3 14.6 15.2 Neoprene, beige (from valve WE 1031) 1.5-7.5 6.9-7.5 3.4 13.0 Butyl FA 7500 (from valve WE 1123, 1124, - - 0.05-0.07 - 1125) Table 4 Glycerol trinitrate/burst of spray Product Spray according to the invention Spray according to the invention Batch no. 1 2 Sealing material Butyl FA 7500 Neoprene, carbon- free Storage period Storage period Content of GTN [%]/ Content of GTN [%]/ [months] after prepara- 1st -3rd burst of 1st -3rd burst of tion and priming spray spray [weeks] 1st 2nd 3rd 1st 2nd 3rd A 74.5 83.2 89.1 A 76.0 93.3 99.5 2,5 B 75.7 87.8 91.6 B 78.2 92.0 97.5 Storage period C 71.8 91.3 96.4 between 2 dates [weeks] 0.8 1 A 86.4 94.8 99.0 A 86.9 96.8 100.0 B 83.8 92.2 98.9 B 86.9 98.9 100.0 C 82.6 94.3 99.8 1.5 3 A 85.2 92.0 100.7 A 76.9 93.4 96.7 B 83.1 96.7 98.0 B 79.4 92.0 96.3 C 80.9 90.2 99.2 3.9 10 A 83.8 98.7 102.5 A 62.2 85.2 99.2 B 98.9 98.0 97.2 B 58.9 81.4 93.8 C 64.4 91.6 99.6 Storage condition 20 - 25°C/40-60% relative humidity Content data GTN [%]/burst of spray based on the glycerol trinitrate content/burst of spray which was determined as a constant value after several valve deliveries (see Tab. 5) A, B, C = designation of the spray container ι H* I Table 5 Glycerol trinitrate/burst of spray Spray according to the invention Spray according to the invention Product Batch no. 1 2 Sealing material Buna BA 170T Seal No. 400 Storage period Storage period Content of GTN [%]/ Content of GTN [%]/ [months] after prepara- lst-3rd burst of lst-3rd burst of tion and priming spray spray [weeks] 1st 2nd 3rd 1st 2nd 3rd 4 A 56.3 85.0 92.1 A 69.7 77.4 81.2 1 B 55.6 80.9 94.1 B 72.0 82.0 86.2 Storage period between 2 C 69.3 86.8 dates [weeks] 1.25 1 A 54.0 83.5 94.2 A 65.0 75.2 85.3 B 59.5 82.5 98.5 B 51.1 69.1 82.3 2 3 A 48.8 81.8 94.1 B 48.8 87.7 104.9 Seal No. 400: 4.5 10 A 63.5 87.7 92.7 A GTN content of 100%/ B 51.8 - 95.3 burst of spray is only achieved from the " 15th burst of spray. ι I-* O' Storage condition 20 - 25°C/40-60% relative humidity Content data GTN [%]/burst of spray based on the glycerol trinitrate content/burst of spray which was determined as a constant value after several valve deliveries A, B, C = designation of the spray container

Claims (9)

1. Nitroglycerin spray comprising nitroglycerin, ethanol, l,2-propyleneglycol and propellant gas characterized in that the composition consisting of 0.73% by weight of nitroglycerin, 13.83% by weight of ethanol, 7.28% by weight of 1,2-propyleneglycol, 31.26% by weight of dichlorodif luoromethane and 46 .90% by weight of dichlorotetrafluoroethane is in continuous contact with container sealing material which has a nitroglycerin absorption value less than 10 mg/1 g of sealing material.

2. Nitroglycerin spray according to claim 1 characterized in that the container sealing material is Butyl FA 7500.

3. Nitroglycerin spray according to claim 1 characterized in that the container sealing material is neoprene free of carbon.

4. The use of container sealing material which has nitroglycerin absorption values less than 10 mg/l g of sealing material in aerosol spray propellant gas containers containing nitroglycerin.

5. A nitroglycerin spray according to claim 1, substantially as hereinbefore described. F.R. KELLY & CO., AGENTS FOR THE APPLICANTS. -18containing the customary additives.

6. ) Nitroglycerin spray according to Claims 1-5, characterised in that the container sealing material is Butyl FA 7500. 5

7. ) Nitroglycerin spray according to Claims 1-5, characterised in that the container sealing material is Neoprene.

8. ) Nitroglycerin spray according to Claims 1-5, characterised in that the container sealing material is 10 carbon-free Neoprene. ,

9. ) Nitroglycerin spray according to Claims 1-8, characterised in that the constituent causing the desensitisation of the active compound is a polyhydric, slightly volatile, water-soluble alcohol, glycerol, 15 diethylene glycol or propylene glycol.