HK1116431A - Intravenous formulations of pde-5 inhibitors - Google Patents

Description

Intravenous formulations of PDE-5 inhibitors

The invention relates to a novel use of a PDE inhibitor in the form of an intravenous administration and to novel pharmaceutical preparations therefor.

PDE, and PDE 5 inhibitors in particular, are known to be potent active pharmaceutical ingredients and may be useful in the treatment of diseases. Thus, for example, the compound vardenafil and its physiologically acceptable salts, which have the systematic name { 2-ethoxy-5- [ 4-ethyl-1-piperazinyl) sulfonyl ] phenyl } -5-methyl-7-propylimidazo [5, 1-f ] triazin-4 (3H) one, are described, for example, in WO 99/24433. Other PDE 5 inhibitors are:

sildenafil, tadalafil,

DA 8159: enantiomers of 5- [ 2-propoxy-5- (1-methyl-2-pyrrolidinylethylamino-sulfonyl) phenyl ] -1-methyl-3-propyl-1, 6-dihydro-7H-pyrazolo (4, 3-d) pyrimidin-7-one, as described in WO2001098304,

TA 1790: avanafil, (S) -2- (2-hydroxymethyl-1-pyrrolidinyl) -4- (3-chloro-4-methoxy-benzylamino) -5- [ (2-pyrimidinylmethyl) carbamoyl ] pyrimidine

EMD-221829: 4- {4- [ (3-chloro-4-methoxybenzyl) amino ] [1] benzothieno [2, 3-d ] pyrimidin-2-yl } cyclohexanecarboxylic acid ethanolamine salt

QAD-171A, as described in WO00177110,

PT131 and

ABT 724: 2- [ (4-pyridin-2-ylpiperazin-1-yl) methyl ] -1H-benzimidazole.

Like sildenafil and tadalafil, vardenafil inhibits the intracellular degradation of cGMP by inhibiting PDE 5. As a result, NO activation leads to increased intracellular cGMP levels. The following mechanism has been described so far: for the treatment of erectile dysfunction and for the treatment and prophylaxis of other disorders such as hypertension, neuronal hypertension, stable and unstable angina, peripheral and cardiovascular disorders, arrhythmias, for the treatment of thromboembolic disorders and ischaemias such as myocardial infarction, stroke, transient ischaemic attacks, angina, reduced peripheral blood flow capacity, for the prevention of restenosis following thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA) and Bypass surgery (Bypass).

In addition to these known uses, PDE 5 inhibitors have now been found to be useful in the treatment of a number of other disorders, and to date the possibility of treating these disorders by PDE 5 inhibitors has not been suspected, especially when the various compounds are provided intravenously.

Especially when PDE inhibitors are provided intravenously, the different expression of phosphodiesterases in different cells, tissues and organs, and the different subcellular localization of these enzymes enable the selective localization of various cGMP-regulated processes (adresierung). Therefore, the formulations of the present invention are suitable for the prevention and/or treatment of disorders in which an increase in the concentration of cGMP is beneficial, i.e., disorders associated with the process of cGMP regulation (often referred to simply as cGMP-related diseases). Moreover, PDE 5 inhibitors enhance the effect of substances such as, for example, EDRF (endothelial derived relaxin), ANP (atrial natriuretic peptide), nitrovasodilators and all other substances which increase the cpcmp concentration in a different manner than phosphodiesterase inhibitors.

In particular, cardiovascular disorders can now also be treated after administration of PDE 5 inhibitors in the form of infusion formulations according to the invention. Examples are: hypertension, heart failure, pulmonary hypertension, nitrate-induced tolerance, neuronal hypertension, stable and unstable angina, peripheral and cardiovascular disorders, achieving or improving pretreatment effects, cardiac ischemia, acute myocardial infarction, reperfusion injury (particularly after myocardial infarction), arrhythmia, thromboembolic disorders and ischemia such as myocardial infarction, coronary heart disease, stroke, transient and ischemic attacks, angina pectoris, reduced peripheral blood flow capacity, Raynaud's syndrome and intermittent claudication. They are further suitable for the prevention of restenosis following thrombolytic therapy, Percutaneous Transluminal Angioplasty (PTA), Percutaneous Transluminal Coronary Angioplasty (PTCA) and the like.

Infusion formulations of the invention comprising a PEDE 5 inhibitor may further be used for the treatment of genitourinary disorders such as prostate hypertrophy, incontinence, bladder disorders, erectile dysfunction, priapism, Peyronie's disease, premature birth, premature ejaculation, male infertility, asthenospermia, dysmenorrhea, polycystic ovary syndrome, incontinence (e.g. urge incontinence), acute and chronic renal failure, renal syndrome, glomerulopathy, nephritis, tubuloinestinal disorders, glomultopathy, female infertility, female sexual dysfunction and female sexual arousal impairment. Applications in reproductive medicine are also possible, for example, for promoting the growth and improving the survival of egg cells, fertilized eggs, embryos or fetuses, for increasing the weight of premature infants, for increasing milk production in mammals, particularly in humans, for preterm birth and preeclampsia.

Other fields of application are the treatment and/or prevention of impairments of perception, concentration, learning and/or memory, especially if said impairments are caused by dementia. The formulations used according to the invention are particularly suitable for improving perception, concentration, learning or memory after cognitive impairment, such as those which are particularly present in disorders/diseases/syndromes, such as "mild cognitive impairment", age-related learning and memory impairment, age-related memory loss, vascular dementia, craniocerebral trauma, stroke, dementia occurring after stroke ("post-stroke dementia") and post-traumatic craniocerebral trauma. Said use is also useful for the treatment of impairments of childhood attention concentration related to learning and memory problems, alzheimer's disease, vascular dementia, dementia with lewy bodies, dementia with frontal lobe degeneration, including Pick's syndrome, parkinson's disease, progressive nuclear palsy, dementia with corticobasal degeneration, amyoplalatilsklelose (als), Huntingtonscher disease, multiple sclerosis, thalamic degenerative diseases (thalamic degeneration), Creutzfeld-Jacob dementia, HIV dementia, schizophrenia or Korsakoff-psychosis with dementia, treatment of depression, amnesia, disturbance of consciousness, autism, speech disorders, Lennox syndrome and epilepsy.

The intravenous formulations of the present invention comprising a PDFE 5 inhibitor may also be used for the treatment or prevention of ocular disorders such as glaucoma, in particular acute glaucoma, central retinal or posterior ciliary body (zilliar) artery occlusion, central retinal vein occlusion, optic neuropathy such as anterior ischemic optic neuropathy and glaucomatous optic neuropathy, and macular degeneration.

Further fields of application are diabetes, insulin resistance, hyperglycemia, diabetic gastroparesis, diabetic nephropathy, diabetic neuropathy, diabetic retinopathy, diabetic gangrene, nodular glomerulosclerosis, diabetic skin diseases, diabetic arthropathies, diabetic dermatosis and diabetic cataracts.

The intravenous formulations of the invention of PDE 5 inhibitors are also suitable for the treatment of the following disorders: impairment of gastric and esophageal motility, liver disorders such as, for example, cirrhosis, portal hypertension, pancreatitis, inflammatory bowel disease (e.g., Crohn's disease and ulcerative colitis), impairment of gastric motility, and also for supporting and promoting liver regeneration or liver cancer following hepatic surgical resection, and for inhibiting contraction of esophageal muscles (e.g., nutcracker esophagus, spastic esophageal disorder).

The formulations of the invention may also be used to prevent and/or treat: osteoporosis, psoriasis, cancer, cystic fibrosis, hair loss, pain, tinnitus, sudden hearing loss, COPD, asthma, bronchitis, and allergic rhinitis, fibrotic disorders, arteriosclerosis, leukemia (e.g., chronic lymphocytic leukemia), platelet adhesion and aggregation associated with renal ischemia, achalasia, hypertensive LES, lupus, scleroderma, hair loss or loss, multiple sclerosis and rheumatoid arthritis, allergy, osteoporosis, autoimmune diseases, cachexia, hyperlipidemia, and dyslipidemia, and migraine.

Another aspect of the invention provides formulations for intravenous administration of PDE 5 inhibitors, particularly vardenafil.

Solutions of vardenafil and its physiologically acceptable salts are described in WO 99/24433. For their preparation, the therapeutically active compounds are said to be present in concentrations of from 0.5 to 90% by weight of the final mixture. However, problems have arisen in that the low moderate solubility and instability of vardenafil in various organic solvents have prevented the conventional formulation vardenafil from being available for intravenous injection. Moreover, said concentration of the active ingredient in the formulation only allows a rapid intravenous administration of the active ingredient, such as for example a rapid bolus or infusion at a very low infusion rate.

According to the present invention, when 0.0004 to 0.1% (m/v) of a PDE inhibitor is dissolved in an aqueous solvent as a free base or as a salt, a formulation of an intravenously administrable PDE 5 inhibitor, such as vardenafil, can be obtained which is easy to handle and well tolerated. Particularly preferred solutions here are solutions which, in addition to the PDE inhibitor, also contain an acid. Among them, a molar ratio of from 1: 0.9 to 1: 2.0(PDE inhibitor: acid) is particularly preferred. When the PDE inhibitor is applied in the form of a salt, the amount of acid added is reduced, a smaller amount being the amount used for the formation of the salt. In the case of polyprotic acids, the specified amount of acid can be divided, if desired, by the number of protons released per molecule of acid, depending on the acid strength of the corresponding dissociation stage.

Compared to the formulations disclosed hitherto, for example, vardenafil, the infusion solutions of the invention have the following advantages: good tolerability after parenteral administration, effective plasma concentrations that accumulate virtually immediately, good controllability of the drug supply, since the infusion rate can be reduced if unwanted side effects occur. A particular advantage is represented by the very high bioavailability after administration of the formulation of the invention, which is surprisingly 6 to 7 times higher than that of the orally administered tablets.

In particular, for the preparation of the solutions of the invention, the PDE 5 inhibitor is dissolved in an aqueous solvent in amorphous, crystalline or solvent-containing form. This may be achieved by adding one or more acids thereto. Examples of suitable acids are: acetic acid, adipic acid, ascorbic acid, aspartic acid, benzenesulfonic acid, benzoic acid, citric acid, ethanesulfonic acid, 2-hydroxyethanesulfonic acid, fumaric acid, glucoheptonic acid, gluconic acid, glucuronic acid, glutamic acid, hydrochloric acid, lactic acid, lactobionic acid, maleic acid, malic acid, malonic acid, methanesulfonic acid, naphthalenesulfonic acid, naphthalenedisulfonic acid, nitric acid, phosphoric acid, succinic acid, sulfuric acid, tartaric acid, toluenesulfonic acid, mono-or diesters of orthophosphoric acid, for example phosphoglycerides. In the case of polyacids, it is also possible to use their acid salts, such as, for example, sodium hydrogen sulfate or sodium dihydrogen phosphate.

In addition, isotonic agents, for example sodium chloride, glucose, fructose, mannitol, sorbitol, glycerol, acetate buffers, citrate buffers, phosphate buffers or lactate buffers or amino acids, may also be added to the formulations of the invention.

The pH of the formulation can be adjusted with one of the acids, or if the pH is already acidic, with a base such as sodium hydroxide, tromethamine, arginine or lysine. For the formulations of the present invention, the preferred pH range is from 3 to 7.

To improve solubility, organic solvents which can be administered parenterally, such as ethanol, propylene glycol or polyethylene glycol, surfactants or polymers such as polyvinylpyrrolidone, polysorbate, poloxamer, cremophor, Solutol HS 15, phospholipids and natural or substituted cyclodextrins may also be added.

The formulations of the invention can be filled into known containers for parenteral administration, for example into injection vials or infusion bottles made of glass with stoppers, Flexibags or other large-volume or small-volume containers made of plastic, prefilled syringes or carpules. It can also be filled into plastic containers by the blow-fill-seal method.

To prepare the formulations of the invention, for example, by dissolving vardenafil or a vardenafil salt with an acid, an isotonicity agent, and, if desired, other adjuvants in a solvent (usually water). The pH was adjusted after making up the total amount with water, sterilized by filtration through a 0.2 μm filter and filled. Although an entirely sterile manufacturing process or freeze-drying of the formulations of the invention is possible, in general, sterilization of the filling solution in the final container is preferred, for example 15 minutes at 121 ℃. However, if packaging materials are used which cannot withstand this temperature without any damage, sterile preparation can be used, with no or only a subsequent heat treatment which may be at a temperature below 121 ℃.

A particular embodiment of the invention is a concentrate. To avoid expensive shipping and storage in large volume containers, a concentrated solution of vardenafil is first prepared and shipped. The infusion solution of the invention is then prepared by the user, for example by adding a concentrated solution to a standard infusion solution or by serially diluting the concentrate through a Y-tube.

The infusion solutions of the present invention may be administered intravenously in different ways depending on the dosage of the active ingredient, the concentration of the active ingredient and the site of application. Administration as a bolus, as a gravity intravenous drip, or via an infusion tubing pump or an infusion syringe driven pump is possible. Infusion is usually administered into peripheral veins, but may also be administered into central veins in the case of intensive care patients, or into arteries in special cases.

The following comparative examples 1-2, which represent formulations not according to the invention, are described in detail to illustrate the advantages obtained with the formulations of the invention.

Example 1 (comparative example)

Formulations not according to the invention, active ingredient concentrations of 0.005mg/ml

Vardenafil dihydrate 0.005g

Sodium chloride 9.00g

991g of water for injection

The solution contains considerable amounts of insoluble active ingredient and is not suitable for intravenous infusion.

Example 2 (comparative example)

Formulations not according to the invention, containing 70% polyethylene glycol 400

Vardenafil dihydrate 0.50g

Polyethylene glycol 400700 g

299.5g of water for injection

The solution is unstable. 6.5% vardenafil N-oxide had formed when the solution was prepared. After heat sterilization of the solution, its content increased to 11%.

Example 3

Stable watermelon agricultural and biological evidence of good tolerability and excellent bioavailability of the formulations of the invention

Vardenafil hydrochloride trihydrate 0.119g

Sodium chloride 9.00g

20% lactic acid solution 5.00g

2M sodium hydroxide solution, pH adjusted to 4.00 to 10g

Water for injection was used to a total amount of 1005.1g

20ml of this solution (corresponding to 2mg of vardenafil free base) were administered to each of 12 subjects in a crossover test, in comparison with a tablet containing 11.85mg of vardenafil HCl trihydrate (corresponding to 10mg of vardenafil free base). For this purpose, the solution was continuously infused for about 1 hour. The infusion is well tolerated. All observed side effects were generally mild to moderate and were reversible upon completion of the study. Only mild reactions were observed at the injection site in one subject. Bioavailability AUC determined from plasma concentration: the infusion solution of the invention was 35.4. mu.g.h/l (geometric mean) and the tablet was 25.7. mu.g.h/l (geometric mean). This shows that the bioavailability of the infusion solution is 689% of the tablet, taking into account the administered dose.

The stability of the solution at 6 ℃, 25 ℃ and 40 ℃ over 13 weeks was also investigated. Under all conditions, the vardenafil content at the end of storage was initially 0.100mg/ml and finally 0.099 mg/ml. The total amount of all degradation products was initially undetectable (< 0.02%); and is also undetectable (< 0.02%) after 13 weeks at 6 ℃, < 0.1% after 13 weeks at 25 ℃ and 0.1% after 13 weeks at 40 ℃. These values show the excellent stability of the formulations of the invention.

Example 4

0.268kg of vardenafil dihydrate, 61.5g of methanesulfonic acid and 25.9kg of mannitol were dissolved in 174.7kg of water for injection under sterile conditions. The solution was sterilized by filtration and filled in injection vials at 1.6g portions. The solution was lyophilized, stoppered and crimped in the injection vial. Transporting the formulation in this form. The user then reconstitutes the lyophilizate and delivers it to 2100ml of a 5% strength glucose solution, which at the time of use has the following composition:

vardenafil dihydrate (equivalent to 2.00mg of vardenafil) 2.15mg

Methanesulfonic acid 0.492mg

Mannitol 200mg

Glucose 5.00g

Water for injection 96.6g

Example 5

107.4mg of vardenafil dihydrate, 27.7mg of tartaric acid and 9g of sodium chloride were dissolved in one liter of water for injection. The solution was sterile filtered, filled into finished syringes in 2ml quantities, and sterilized. Each finished syringe contained 0.2mg of vardenafil.

Example 6

859mg of vardenafil dihydrate and 452mg of citric acid are dissolved in 900ml of water for injection. Then, the volume was made up to 1 liter with water for injection. The solution was sterile filtered through a 0.2 μm filter, filled into a vial in an amount of 5.0ml, and heat-sterilized at 121 ℃ for 15 minutes. Before use, 500ml of 5% glucose was added and slowly infused.

Example 7

5.72mg of vardenafil dimesylate monohydrate was added to 1000ml of a physiological saline solution. The solution was filter sterilized and filled into an infusion bottle in an amount of 250ml under aseptic conditions. Each infusion bottle contained 1mg of vardenafil.

Example 8

Sildenafil 10g, 0.1M hydrochloric acid 500g and glucose 5kg were dissolved in water for injection 96.1kg, sterilized by filtration, and filled in an infusion bottle in an amount of 100ml under aseptic conditions.

Example 9

0.005kg of tadalafil was dissolved in 30kg of polyethylene glycol 400 and 30kg of 96% ethanol. Then, the volume was made up to 200 liters with water for injection. The solution was filter sterilized and aseptically filled into infusion bottles in an amount of 100 ml.

Claims (8)

1. An intravenous formulation comprising at least one PDE 5 inhibitor or a salt thereof.

2. The intravenous formulation of claim 1, comprising vardenafil, tadalafil and/or sildenafil and/or salts thereof as PDE 5 inhibitors.

3. The intravenous formulation of claim 1, comprising vardenafil and/or a salt of vardenafil as a PDE 5 inhibitor.

4. Use of an intravenous formulation comprising at least one PDE 5 inhibitor for the treatment of portal hypertension, stroke, craniocerebral trauma, premature labor, acute renal failure, acute glaucoma, pancreatitis, sudden hearing loss, tinnitus, achalasia and spasmodic esophageal disorders.

5. Use of an intravenous formulation comprising vardenafil, sildenafil or tadalafil for the treatment of portal hypertension, stroke, craniocerebral trauma, premature labor, acute renal failure, acute glaucoma, pancreatitis, sudden hearing loss, tinnitus, achalasia and spasmodic oesophageal disorders.

6. An intravenous formulation as claimed in any one of claims 1 to 3 comprising vardenafil at a concentration of 0.005 to 0.1% by weight.

7. The intravenous formulation of any one of claims 1 to 4, comprising vardenafil and acid in a molar ratio of 1: 0.9-2.0.

8. Use of an intravenous formulation comprising at least one PDE 5 inhibitor for the differential treatment and selective treatment of various cGMP-regulated processes.