SE427083B - Antihypertensive preparation in unit dose form, comprising, inter alia, 2-[1-(2,6-dichlorophenoxy)ethyl]- 4,5-dihydro-1H-imidazole - Google Patents

Abstract

A therapeutic antihypertensive composition which comprises 2-[1-(2,6-dichlorophenoxy)ethyl]-4,5-dihydro-1H- imidazole and N-(2-chloroethyl)-N-(1-methyl-2- phenoxyethyl)benzenemethaneamine or their nontoxic, pharmaceutically acceptable salts.

Description

7806470-6 10 15 20 25 30 _ 2 _ with hypertension. Its low effectiveness and concomitant side effects, such as mood-dependent hypotension, palpitations and problems with sexual function, have prevented its use.

The compound 2- [1- (2,6-dichlorophenoxy) ethyl] -4,5-dihydro-1H-imidazole, hereinafter referred to by its generic name lofexidine, is an effective antihypertensive agent. Evidence suggests that lofexidine acts at the α-adrenergic receptor points in the brain to reduce blood pressure. In contrast to phenoxybenzamine, lofexidine acts by mimicking rather than blocking the neurotransmitter-norepinephrine at the α-adrenergic receptors. Lofexidine acts both as an α-adrenergic receptor in the blood vessels to raise blood pressure as well as on the α-adrenergic receptors on certain neurons in the brain to lower blood pressure. At clinical doses, the latter type of action, which results in a reduction in sympathetic activity, usually results in cardiac output through blood pressure.

It has now been found that the concomitant administration of certain combinations of phenoxybenzamine and lofexidine actually improves the antihypertensive effect obtained with lofexidine alone, thereby enabling a total administration of a reduced amount of lofexidine to the patient. The ability to administer decreasing amounts of lofexidine is extremely desirable from a therapeutic point of view in that it reduces the risk of undesirable side effects associated with each drug and reduces the risk of drug tolerance that may occur in some patients, whereby hypertensive patients may have an increased benefit. of this useful drug which has not previously been possible.

Thus, the present invention relates to novel therapeutic compositions of lofexidine and phenoxybenzamine. In particular, the invention relates to antihypertensive compositions consisting of unit doses administered daily and consisting of 0.1 to 1.0 mg of lofexidine and of im., - phage> zwfssw ~ wu nu »10 15 20 30 35 7sos47o ~ 6 _ 3 _ 0.5 to 15 mg N- (2-chloroethyl) -N- (1-methyl-2-phenoxyethyl) -benzenesethanamine (phenoxybenzamine) or any of their pharmacologically acceptable salts in combination with an inert pharmaceutical carrier.

The invention enables a process for lowering the blood pressure of hypertensive mammals consisting of daily administration of from 0.002 to 0.08 mg / kg of lofexidine in combination with 0.01 to 5 mg / kg of phenoxybenzamine.

Lofexidine is a centrally acting antihypertensive agent. It acts on α-adrenergic receptors in the brain to lower blood pressure. The administration of a u-adrenergic receptor blocking agent, such as phenoxybenzamine, with a centrally acting antihypertensive agent is contraindicated according to the prior art. Thus, the antihypertensive action of the compound N- (2,6-dichlorophenyl) -4,5-dihydro-1H-imidazol-2-amine, generically known as clonidine, is thus antagonized by an α-adrenergic receptor blocking agent piperoxane [ šchmitt and co-workers, Eur.J.Pharmacol, 14, 98-100 (1971 [7 and phenoxybenzamine [Éolme and Fuxe, Eur.J.Pharmacol. 13, 168-174 (1971 [7. The fact that phenoxybenzamine antagonizes or blocks it) The antihypertensive action of a centrally acting antihypertensive agent, such as clonidine, clearly indicates that phenoxybenzamine should not be co-administered with lofexidine.

However, it has surprisingly been found that the antihypertensive effects of lofexidine can actually be enhanced or potentiated rather than antagonized or blocked by a concomitant administration of amounts of phenoxybenzamine less than those required to block the central u-adrenergic receptors. Thus, when lofexidine and phenoxybenzamine are administered in combination with each other to humans, the antihypertensive effect of lofexidine will obviously not be antagonized, which was to be expected from what was previously known. ..-__ _ _. __..__.___.._..__. _. _...._., .. _ 78Û6h70'6 10 15 20 25 30 _4_ Due to many contributing factors resulting in essential hypertension in humans, such as stress, mental and emotional factors and due to large variations in blood pressure obtained. read also in the same patient, hypertensive rats can be best utilized to demonstrate the improvement in antihypertensive efficacy of phenoxybenzamine and lofexidine. Thus, Example 5 illustrates that the administration of phenoxybenzamine and lofexidine to spontaneously hypertensive rats results in a significant improvement or potentiation of the antihypertensive effect of lofexidine to a greater extent than can be obtained with either lofexidine I or phenoxybenzamine alone. Although the effect of this particular combination of drugs is not clear in detail, it is believed, inter alia, that the amounts of phenoxybenzamine used herein may serve to selectively inhibit the known pressor effect of lofexidine due to its effect on the peripheral α-adrenergic receptor points, enabling that lafexidine can exert a more dramatic antihypertensive effect due to its uninhibited effect on the brain.

Accordingly, the present invention relates to unit dosage form antihypertensive compositions containing lofexidine in combination with phenoxybenzamine. Lofexidine is described and can be prepared in accordance with U.S. Pat. No. 3,966,757. Phenoxybenzamine can be obtained and prepared in accordance with U.S. Pat. No. 2,599,000.

The term "pharmaceutically acceptable salts" includes acid addition salts of either lofexidine and / or phenoxybenzamine and includes both non-toxic inorganic and organic acid addition salts with the basic compounds. Examples of inorganic acids which form suitable salts include hydrochloric acid, hydrobromic acid, sulfuric acid, and phosphoric acid and acidic metal salts such as sodium mono-hydrogen orthophosphate and potassium hydrogen sulphate. Examples of organic acids which form suitable salts include mono, di and tricarboxylic acids, for example acetic acid, fumaric acid, malic acid, tartaric acid, citric acid, ascorbic acid, maleic acid, hydroxymaleic acid, benzoic acid, p-hydroxybenzoic acid, phenylacetic acid, cinnamic acid, salicylic acid 2 'phenoxybenzoic acid and sulfonic acids, such as methanesulfonic acid and 2-hydroxyethanesulfonic acid. Preferably, the hydrochloride salt of lofexidine and phenoxybenzamine is utilized due to their pharmaceutical stability and pharmacological miscibility.

The new compositions containing lofexidine and phenoxybenzamine can be administered in different ways and in different, different unit dosage forms, e.g. oral compositions such as tablets, capsules, lozenges, elixirs and emulsions, clear readings and suspensions and parenteral compositions such as intramuscular, intravenous and intradermal preparations. The amount of active ingredients in each unit dosage form will, of course, vary widely depending upon the particular unit dosage form employed, the treatment period, the age and sex of the treated patient and the nature of the particular type of hypertension being treated. Thus, a particular unit dose may contain from as little as 1 mg to just over 16 mg of the combined active ingredients in addition to the pharmaceutical diluents which may be included. Preferably, the total amount of active ingredient is from about 1 to about 15 mg per unit dose.

The combination of lofexidine and phenoxybenzamine is suitably administered as a pharmaceutical composition in combination with or in admixture with superficial organic and inorganic pharmaceutical diluents. Suitable solid diluents include inert diluents, for example calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate, granulating and disintegrating agents, for example corn starch or alginic acid; Binders such as various starches, gelatin, lactose and acacia mucus and lubricants such as magnesium stearate, stearic acid or talc. Suitable liquid diluents include water and alcohols, such as ethanol, benzyl alcohol and polyethylene alcohols, either with or without the addition of a surfactant. In general, the preferred liquid diluents, especially for injectable preparations, include water, brine, dextrose and glycol solutions, such as aqueous propylene glycol or aqueous solutions of polyethylene glycol. Liquid preparations for use as sterile injectable solutions normally contain from about 0.1% to about 25% by weight and preferably from about 0.1% to 10% by weight of active ingredients in the solution.

A preferred method of administering the composition described herein is an oral administration, either in a solid dosage form, such as tablets or capsules, or in a liquid dosage form such as an elixir, a suspension or an emulsion or syrup. Typically, the active ingredients comprise from about 0.5 to about 10% by weight in an oral composition. In such pocket positions, the pharmaceutical carrier is usually of the aqueous type, for example aromatic water, sugar-based syrup or a pharmaceutical mucus. Suspension agents are added as well as viscosity control agents, for example magnesium aluminum silicate or carboxymethylcellulose. Buffers, preservatives, emulsifiers and other diluents may also be added.

Formulations for oral use may be prepared as hard or soft gelatin capsules containing only the active ingredient or the active ingredient in admixture with a solid diluent such as lactose, sorbitol, calcium carbonate, potassium phosphate or kaolin. Tablets containing lofexidine and phenoxybenzamine can be prepared on conventional sweeteners by granulation methods, which consist in wetting the dry powder with or without the addition of a binder, until the whole is converted into a crumbly mass. - sa. Well-known wetting agents, such as water and other solvents, can be used. In general, it is common to add a substance, such as gelatin, starch or acacia gum, to facilitate granulation of these materials. The granules prepared on this sweet can be lubricated by powdering or dry mixing with a lubricant, such as talc or zinc stearate, and pressed onto ordinary sweet.

Alternatively, a dry granulation process can be used consisting of a pre-pressing of the active ingredient and / or diluents as a dry powder into large tablets or vials.

These large tablets or pre-pieces are broken into granules, sieved, lubricated and beaten into tablets on a tablet machine to form tablets of the desired size and shape. Such tablets may remain uncoated or may be coated by any known method to delay the disintegration in the gastrointestinal tract, thereby obtaining a delayed action over a longer period of time.

Tablets can be prepared where lofexidine is separately formulated into a sustained release form and then mixed with phenoxybenzamine in the tablet. Thus, lofexidine may be formulated as a coated pellet and mixed with uncoated phenoxybenzamine pellets as a capsule or the sustained release formulation may be introduced into a tablet as a separate core or layer. Such unit doses with delayed release can be readily prepared for administration only once a day, thereby reducing the inconvenience to patients.

For parenteral administration, such as intramuscular, intravenous or subcutaneous administration, the amount of active material ranges from about 0.05 to about 20% by weight, preferably from about 0.1 to about 10% by weight of the liquid composition. To reduce or eliminate irritation at the injection site, such compositions may contain a nonionic surfactant having a hydrophilic-lipophilic balance (HLB) of from about 12 to about 17. The amount of surfactant in such formulations ranges from about 1 to about 15% by weight. The surfactant may be a single component with the above HLB or a mixture of two or more components with the desired HLB value. Examples of surfactants for parenteral preparation are the type of polyoxyethylene sorbitan fatty acid esters as well as, for example, sorbitan monooleate and high molecular weight adducts of ethylene oxide with a hydrophobic base, formed by condensation of propylene oxide with propylene glycol. The concentration of active ingredient in these various parenteral unit dosage forms varies over a wide range and in any case consists from about 0.05 to about 20% by weight of the total formulation, the remaining components being liquid pharmacological diluents of the aforementioned type.

With the present invention it is possible to lower the blood pressure in case of hypertension in mammals, consisting of concomitant administration of an effective amount of lofexidine with phenoxybenzamine, preferably as one of the compositions in unit dosage forms described above. In addition to humans, the term "mammal" refers to humans, mice, rats, guinea pigs, rabbits, weasels, dogs, cats, cows, horses and primates. The use of the term "concomitant administration" implies that the active ingredient is either administered simultaneously, in the same or different route of administration or that they are administered at appropriate time intervals so that the patient enjoys maximum benefit from the combination therapy.

The pharmaceutical compositions are administered to animals at a daily dose of from about 0.002 to 0.08 mg / kg lofexidine and from about 0.01 toll 5 mg / kg phenoxybenzamine per kg body weight.

Preferably, a dose of from about 0.002 to about 0.02 mg / kg of lofexidine and from about 0.01 to about 1.0 mg / kg of phenoxybenzamine is administered, thereby providing an antihypertensive effect in people with severe hypertension. Weak or moderate types of hypertension can be treated with smaller doses or at larger intervals. People are much more sensitive to the α-adrenergic blocking action of phenoxybenzamine. Thus, an adequate blockade of α-adrenergic receptors in humans can be obtained with a daily dose of phenoxybenzamine of from about 0.01 to 1.0 mg / kg.

Preferably, the active ingredients are administered orally as tablets or capsules one to four times daily. Even more preferably, the active ingredients are proportionally increased in these unit dosage forms so that they can be administered two or three times or only once a day.

The invention is illustrated by the following examples.

EXAMPLE 1 Preparation of a Tablet Preparation 1000 tablets suitable for oral use are prepared according to the following preparation. Gram (a) 2- [1- (2,6-dichlorophenoxy) ethyl] -4,5-dihydro-1H-imidazole 0.4 hydrochloride .................... ............................ (b) N- (2-chloroethyl) -N- (1-methyl-2-phenoxyethyl) benzenemethanamine hydrochloride .............................................. 5.0 (c) Dicalcium phosphate. . . . . ..................................... 150.0 (d) Netylcellulose, USP- '(15 eps) 6.6 (e) Talk ............................................. ......... 20.0 2.5 (f) Calcium stearate ................................... ......... '7806470-6 10 15 20 25 30 -10- 2- [1- (2,6-dichlorophenoxy) ethyl] -4,5-dihydro-1H-imidazole hydrochloride, N- (2-chloroethyl) -N- (1-methyl-2-phenoxyethyl) benzenemethonamine hydrochloride and dicolcium phosphate are mixed well as a dry powder. The resulting powder can be granulated using a 7.5% mitten solution of methylcellulose, passed through a No. 8 sieve and carefully dried. The dried granules prepared in this way were passed through a No. 12 sieve, lubricated with residual talc and calcium stearate and beaten into tablets. Each tablet contained 0.4 mg lofexidine and 5 mg phenoxybenzamine and was suitable for administration twice, to four times daily.

EXAMPLE 2 Preparation of a capsule preparation rig 1000 hard capsules in two pieces suitable for oral use were prepared from the following ingredients. - Gram (a) 2- [1- (2,6-dichlorophenoxy) ethyl] -4,5-dihydro-1H-imidazole hydrochloride ................... ...................... 0.4 (b) N- (2-chloroethyl) -N- (1-methyl-2-phenoxyethyl) benzenemethanamine hydrochloride ................................... 5.0 (c) Lactose, USP ..................................... 100.0 (d) Starch, USP ...... ............................. 10.0 (e) Talk, USP ....................................... 5.0 1.0 (f) Calcium stearate ..... ................................

All the finely powdered materials were dry blended until evenly distributed and then filled into hard gelatin capsules of suitable size.

Similarly, one-piece soft gelatin capsules could be prepared with the above formulation which were granulated and beaten or pressed directly onto a rotary nozzle or planar mold, forming capsules. Alternatively, the above diluent could be omitted and the active ingredients introduced as a powder directly into the capsule.

Each capsule contained 0.1 mg lofexidine and 5 mg phenoxybenzamine and was suitable for oral administration two to four ~ 9å 99fi I Öa91i9e fi EXAMPLE 3 Preparation of a parenteral solution A sterile solution was prepared on the following sweet. (o) 2- [1- (216-dichlorophenoxy) ethyl] -4,5-dihydro-1H-ene; benSen- methanamine hydrochloride ........................ {{.. 8.0 (0) Sodium chloride ............ ........................ 0.9 (d) Methylparaben ..................... ................ 0.18 .............. 0.02 (e) Propyl paraben ....

(F) Water for injection into 1000 ml of non-nasal nasal nasus The above ingredients were dissolved in water and sterilized by filtration. Each ml of solution contained 0.6 mg lofexidine and 8 mg phenoxybenzamine and was suitable for intravenous injection two 9ån9eP daily.

EXAMPLE 4 Preparation of a slow release tablet. 1000 layered tablets containing one layer for the slow release of lofexidine and one layer for the rapid release of phenoxybenzamine were prepared on the following sweet. 10 15 20 25 30 78061170-'6 _12 ..

The slow release layer -Q (a) 2- [1- (2,6-dichlorophenoxy) ethyl] -4,5-dihydro-1H-imidazole hydrochloride ............... ... 0.8 (b) Hydroxypropyl methylcellulose (4000 eps) .............................. 100.0 (c) Mannitol ... . . . . ......................... 200.0 (d) Maize starch .................... ....... 6.0 (e) Zinc stearate .................} ........... 3.6 The layer for rapid release§_ (f) N- (2-chloroethyl) -N- (1-methyl-2-phenoxyethyl) -benzenemethanamine hydrochloride ............. 10.0 (g) Microcrystalline cellulose ..... ........... 150.0 (h) Starch ................................ 150.0 Med using a suitable mixer, 2- [1- (2,6-dichlorophenoxy) ethyl] -4,5-dihydro-1H-imidazole hydrochloride, mannitol and hydroxypropyl methylcellulose were mixed thoroughly by geometric dilution. Fitàmill equipped with a No. 000 sieve and was granulated using 5% starch paste prepared by adding corn starch to about 115 ml of water. Additional water was added as needed to prepare a suitable granulate. The resulting granulate was wet sieved using Sieve No. 2 and dried at 40-50 ° C for 8 to 12 hours. The dried granules were ground and passed through a No. 10 sieve. Zinc stearate, which had passed through a No. 20 sieve, was added to the granules and mixed well, and the resulting granules were stored after slow release for tablet preparation.

N- (2-chloroethyl) -N- (1-methyl-2-phenoxyethyl) -benzenethamine hydrochloride was ground, if necessary to obtain a powder, the majority of the particles having a size of about 10-150 microns. . The ground powder, microcrystalline cellulose and starch are mixed well in a Fitzmill equipped with No. 000 sieve and the resulting rapid release mixture is stored for tablet beating.

Using a suitable layer press, such as a Manesty Layer press, the slow release granules were added to the adjusted nozzle cavity to obtain a layer weighing 310 mg. The granulate was lightly pressed by subjecting it to pressure pressure and then the rapid release layer was added to give a layer weighing 310 mg. The final compression pressure was adjusted to obtain suitable tablets with a total weight of 620 g. Each tablet contained 0.8 mg lofexidine and 10 mg phenoxybenzamine and can be administered once daily for maximum patient convenience.

EXAMPLE 5 The following examples illustrate the enhanced antihypertensive effect of lofexidine in combination with an insufficient amount of phenoxybenzamine to act as a central α-adrenergic agent.

Two distinct groups of male rats with spontaneous hypertension (7 months of age, 12 rats per group) were placed in plexiglass cages equipped with a pressure cuff and photocell transducer connected to a Sphygmomancmeter via a photopulse amplifier suitable for measuring blood pressure. Male rats were preferred due to their larger size, which facilitated the blood pressure measurements and made them more reliable.

One group of animals was administered propylene glycol at a dose of 1 ml / kg, after which the remaining two groups of animals were administered with phenoxybenzamine hydrochloride at a dose of 2.5 mg / kg.

Two hours later, half of the animals received propylene glycol and half of the animals received phenoxybenzamine and were administered with lofexidine hydrochloride (intraperitoneally) at a dose of 0.06 mg / kg. At the same time, the remaining group of the phenoxybenzamine pretreated animals received an equivalent volume of saline. All administrations were performed by intraperitoneal administration. The following blood pressure values were recorded one hour later. Blood pressure was expressed in mm Hg.

Animals 155 I ”2 Phenoxybenzamine (2.5 mg / kg 138 1 3 Lofexidine (0.06 mg / kg) 1s4'i 7 Phenoxybenzamine (2.5 mg / kg) in combination with hfexicun (cos mg / kg) no ï 1o The above data clearly show that while the amount of phenoxybenzamine administered alone is insufficient to produce a marker antihypertensive effect, the same amount of phenoxybenzamine in combination with lofexidine provides a further 20% reduction in blood pressure over that obtained with phenoxybenzamine alone, and a a further 30% reduction in blood pressure compared to lofexidine alone.

Claims (2)

10 7806470-6 15 Patent claims Antihypertensive preparation in unit dosage form with improved antihypertensive effect, characterized in that it consists of from 0.1 to 1.0 mg of 2- [ imidazole and from 0.5 to 15 mg of N- (2-chloroethyl) -N- (1-methyl-2-phenoxyethyl) -benzenemethanamine or pharmaceutically acceptable salts of each and a pharmaceutical carrier. A composition according to claim 1, characterized in that said unit dosage form is a tablet. SUMMARY Therapeutic antihypertensive composition containing 2- [2- (2,6-dichlorophenoxy) ethyl] -4-4,5-dihydro-1H-imidazole and N- (2-chloroethyl) -N- (1-methyl -2-phenoxyethyl) benzene-methanamine or their non-toxic, pharmaceutically acceptable salts. .___ now... _ _-, _... . ._. .