KR20030069693A - Pharmaceutical combination of angiotensin II antagonists and angiotensin I converting enzyme inhibitors - Google Patents

Abstract

The present invention provides a method for the treatment of dementia and / or cognitive degeneration, characterized by co-administration of an effective amount of angiotensin II antagonist and angiotensin I converting enzyme, a pharmaceutical composition containing an angiotensin II antagonist with an ACE inhibitor, and a corresponding To an angiotensin II antagonist and an ACE inhibitor in the manufacture of a pharmaceutical composition.

Description

Pharmaceutical combinations of angiotensin II antagonists and angiotensin I converting enzyme inhibitors

The present invention is characterized by co-administration of an effective amount of an ANG II antagonist and an ACE inhibitor, the latter of which increases the bradykinin mediated effect, to a person in need of treatment of dementia and / or cognitive degeneration. And / or to a method of treating cognitive degeneration and to the use of angiotensin II antagonists (ANG II) in the manufacture of pharmaceutical compositions for the treatment of the symptoms when used in combination with angiotensin converting enzyme (ACE inhibitor).

The beneficial efficacy according to the invention is based on the organoprotective, tissue-protective and vascular-protective effects on the peak of blood pressure, which lowers the effectiveness of the combination treatment.

ANG II plays a major role in pathophysiology, especially as the most effective human blood pressure increasing agent. Thus, ANG II antagonists are suitable for treating hypertension and congestive heart failure in mammals. Examples of ANG II antagonists are described in EP-A-0 502 314, EP-A-0 253310, EP-A-0 323 841, EP-A-0 324 377, US-A-4,355,040 and US-A-4,880,804 It is. Specific ANG II antagonists are sartans such as candesartan, eprosartan, irbesartan, losartan, telmisartan or valsartan, olmesartan and tasosartan.

In addition, a series of ACE inhibitors such as benazepril, captopril, sernapril, enalapril, posinopril, imidapril, risinopril, moexipril, quinapril, ramipril, trandolapril and Perindopril is known as a treatment for hypertension and congestive heart failure. Examples are described in EP-A-0 079 022, US-A-4,046,889 and 4,374,829.

In addition to its blood pressure increasing effect, ANG II is known to further have a growth promoting effect which is the cause of left ventricular hypertrophy, vascular thickening, atherosclerosis, renal failure and stroke. Bradykinin, on the other hand, acts as a vasodilator and tissue protective agent, as described in the literature published below:

It has also been shown that the anti-proteinuria effect of enalapril is enhanced by losartan in normal pressure patients with diabetic nephropathy [15th Sci Mtg of the American Society of Hypertension, 16-20 May 2000]. Am J Hypertens 13 (4, Part 2), 117A Abstr A017 (2000)].

According to the results of the Heart Outcomes Prevention Evaluation (HOPE) study (New Engl J Med 432/3, January 20, 2000, p 145-153), treatment with AMI inhibitor ramipril Significantly reduces the risk to combined primary cardiovascular by 22% and consistently reduces the risk for the end of the secondary ending, including total mortality. The cardiovascular benefit has been found to be nearly independent of the blood pressure lowering effect, suggesting that ramipril independently exhibits vasoprotective and organprotective efficacy.

However, long-term treatment with ACE inhibitors may lead to adverse effects due to the persistent AT ₁ receptor mediated action of ANG II, in particular other ANG II producing enzymes (e.g. human kinase, cathepsin G) that may lead to ongoing end organ damage. There is evidence that due to the compensatory activity of), it does not effectively inhibit ANG II levels (see mechanism (Willenheimer, Eur. Heart J. 1999; 20, 997-1008)).

ANG II antagonist and AT ₂ receptors leaving selectively blocking the AT ₁ receptor, anti-growth and tissue regeneration in action, and plays a part not being opposed. Clinical trials completed with ANG II antagonists appear to exhibit similar blood pressure reducing and tissue protective effects as with ACE inhibitors. This is described in the literature:

Most recently, the benefits of ACE inhibition and bradykinin potency benefit from the more efficient inhibition of the Lenin-Angiotensin-Aldosterone system through AT ₁ receptor blockade and transfer of the remaining ANG II action from the AT ₁ receptor to the AT ₂ receptor. There is a growing interest in combining the two drug principles in the treatment of congestive heart failure on the basis of the merging together (M Burnier, IDrugs 3 (3): 304-309, (2000)). Pharmacologically, this is a very attractive attempt, and many studies are currently underway on congestive heart failure to substantiate this hypothesis [VAL-HeFT, Cardiology 1999, 91 (Supp I), 19-22; CHARM, J Cardiac Failure 1999, 5: 276-282.

The combination therapy and the corresponding composition comprising at least two therapeutic agents selected from the group consisting of renin inhibitors, ACE inhibitors and ANG II antagonists in an amount sufficient to reduce blood pressure and cause a synergistic therapeutic effect in the treatment of congestive heart failure in mammals. EP-A-0 527 879. Preferred ACE inhibitors are captopril, enalapril, ricinopril and ramipril. Losartan has been found as a preferred ANG II antagonist. Dosage ranges for ACE inhibitors have been found to be, for example, 40 mg to 450 mg per day for oral administration and 20 mg per day for parenteral administration. Dosage ranges for ANG II antagonists have been found to be, for example, 0.5 to 500 mg / kg, preferably 2 to 80 mg / kg for oral administration and 3 mg / kg for intravenous administration.

EP-A-1 013 273 describes AT ₁ receptor antagonists or ATs for the treatment of diseases caused by an increase in AT ₁ receptors in the subepithelial region and an increase in AT ₂ receptors in the epithelium, in particular for the treatment of some lung diseases. The use of _two receptor modulators is described.

Co-administration of ANG II antagonists and ACE inhibitors provides unexpected advantages in treating dementia and degeneration of cognitive function over administration of ANG II antagonists or ACE inhibitors alone.

According to a first aspect, the present invention is characterized by co-administering an effective amount of an ANG II antagonist and an ACE inhibitor in the body of a mammal other than a person or human in need of treatment of dementia and cognitive degeneration. And a method for treating the degeneration of cognitive function.

In a particularly preferred aspect of the treatment method of the invention, the ANG II antagonist is telmisartan and the ACE inhibitor is ramipril.

In consideration of another aspect, the present invention provides an ANG II antagonist (particularly preferably telme) in the preparation of a pharmaceutical composition for the treatment of dementia and cognitive degeneration when used with an ACE inhibitor (particularly ramipril). Satan).

With respect to aspects of the present invention, unless otherwise stated, all ANG II antagonists are suitable, examples being candesartan, eprosartan, irbesartan, losartan, telmisartan, which are previously listed herein. And sartans such as valsartan, olmesartan and tasosartan, of which losartan or telmisartan are preferred, and telmisartan {4 '-[2-n-propyl-4-methyl-6- (1-methylbenzimidazol-2-yl) benzimidazol-1-ylmethyl] biphenyl-2-carboxylic acid} and pharmaceutically acceptable salts thereof are most preferred.

In addition, with respect to aspects of the present invention, unless stated otherwise, all ACE inhibitors listed above may be used, for example benazepril, captopril, sernaapril, enalapril, fosinopril, already Dapril, ricinopril, moexipril, quinapril, ramipril, trandolapril and perindopril, of which double captopril, enalapril, ricinophril and ramipril are preferred, and ramipril is most preferred. .

In a preferred aspect of the method of treatment, ramipril is co-administered with an ANG II antagonist.

In a second preferred aspect of the method of treatment, the ACE inhibitor is co-administered with telmisartan.

In a third preferred aspect of the method of treatment, ramipril is co-administered with telmisartan.

Co-administration of an ANG II antagonist with an ACE inhibitor is meant to include continuous or simultaneous administration in time, with simultaneous administration being preferred. In the case of continuous administration, the ANG II antagonist may be administered before or after administration of the ACE inhibitor.

The active substance can be administered orally, orally, parenterally, inhalationally, rectally or topically, with oral administration being preferred. Parenteral administration can include subcutaneous, intravenous, intramuscular and intrasternal injection and infusion techniques.

The active substances can be administered orally in a wide variety of different dosage forms, ie they are tablets, capsules, lozenges, oral tablets, hard candy, powders, sprays, aqueous suspensions with various pharmaceutically acceptable inert carriers. It may be formulated in the form of preparations, elixirs, syrups, and the like. Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, and the like. In addition, such pharmaceutical formulations may be appropriately flavored and / or flavored using various agents commonly used for the purpose of flavoring or flavoring. In general, the compounds of the present invention are present in oral dosage forms at concentration levels ranging from about 0.5% to about 90% by weight of the total composition, which amount is sufficient to provide the desired unit dosage. Other suitable dosage forms of the compounds of the present invention include controlled release formulations and devices well known to those skilled in the art.

For oral administration, tablets containing various excipients (e.g. sodium citrate, calcium carbonate and calcium phosphate) may be used for various disintegrants (e.g. starch, preferably potato or tapioca starch, alginic acid and certain complex silicates). ) And a binder (eg, polyvinylpolydone, sucrose, gelatin and gum arabic). In addition, lubricants such as magnesium stearate, sodium lauryl sulfate and talc or similar types of compositions can also be used as fillers in soft and hard-filled gelatin capsules; Lactose or lactose and high molecular weight polyethylene glycols. If aqueous suspensions and / or elixirs are to be used for oral administration, the essential active ingredients of this genus may be combined with various sweetening or fragrances, colorants or dyes, optionally emulsifiers and / or water, ethanol, propylene It may be combined with glycols, glycerin and various similar combinations thereof.

For parenteral administration, not only liquid solutions of compounds in sesame or peanut oil or compounds in aqueous propylene glycol can be used, but also sterile aqueous solutions of the corresponding pharmaceutically acceptable salts can also be used. Such aqueous solutions should be properly buffered if necessary, and the liquid diluent is to be isotonic with sufficient saline or glucose. These particular aqueous solutions are particularly suitable for intravenous, intramuscular and subcutaneous injection purposes. In this regard, the sterile aqueous medium used is readily obtained by standard techniques well known to those skilled in the art. For example, distilled water is commonly used as a liquid diluent and the final formulation is passed through a suitable bacterial filter, such as a sintered glass filter, or a diatomaceous earth or matt ceramic filter. Preferred filters of this type include Berkefeld filters, Chamberland filters, and Asbestos Disk-Metal Seitz filters, which draw fluid into sterile vessels through suction pumps. Necessary steps should be taken throughout the preparation of these injectable solutions to ensure that the final product is obtained sterile. When intended for transdermal administration, the dosage form of the particular compound (s) includes, for example, solutions, lotions, ointments, creams, gels, suppositories, rate-limiting sustained release formulations and devices therefor. Such dosage forms include specific compound (s) and may include ethanol, water, penetration enhancers, and inert carriers such as gel-generating materials, mineral oils, emulsifiers, benzyl alcohols, and the like.

Several ANG II antagonists are already commercially available and can be used for administration, examples of which include Micardis ^R , Lorzaar ^R , Cozaar ^R , Lortaan ^R , Losaprex ^R , Neo-Lotan ^R or Oscaar ^R , Approvel ^R , Karvea ^R , Diovan ^R , Atacand ^R , Blopress ^R and Teveten ^R.

In addition, several ACE inhibitors are already commercially available and can be used for administration, examples of which include Briem ^R , Cibacen ^R , Cibacne ^R , Lotensin ^R , Dynacil ^R , Elidiur ^R , Fosinorm ^R , Fositen ^R , Fozitec ^R , Monopril ^R , Staril ^R , Tensozide ^R , Novaloc ^R , Tanapril ^R , Fempress ^R , Perdix ^R , Univasc ^R , Accupril ^R , Accuprin ^R , Accupro ^R , Acequin ^R , Acuitel ^R , Korec ^R , Quinazil ^R , Xanef ^R , Pres ^R , Acerbon ^R , Lopirin ^R , Tensoben ^R , Delix ^R or Vesdil ^R.

ACE inhibitors can be administered in a daily dosage of 1.25 mg (or 0.018 mg / kg based on a 70 kg body weight) to 450 mg (6.429 mg / kg) orally or about 20 mg (0.286 mg / kg) for parenteral administration. kg), and preferably orally, in a daily dose of 5 mg (0.071 mg / kg) to 100 mg (1.429 mg / kg). Particularly preferably, it is administered orally in a daily dose of 2.5 mg (0.036 mg / kg) to 10 mg (0.143 mg / kg).

ANG II antagonists are administered at a daily dosage of 10 mg (or 0.143 mg / kg based on a 70 kg body weight) to 500 mg (7.143 mg / kg) orally or about 20 mg (0.286 mg / kg) for parenteral administration. kg), and preferably orally, in a daily dosage of 20 mg (0.286 mg / kg) to 100 mg (1.429 mg / kg). Particularly preferably, it is administered orally in a daily dosage of 40 mg (0.571 mg / kg) to 80 mg (1.143 mg / kg).

For all the modes of administration and doses mentioned herein above, the preferred ACE inhibitor is ramipril and the preferred ANG II antagonist is telmisartan. In the most preferred embodiment, about 10 mg of the daily dose of ramipril is administered orally simultaneously with about 80 mg of the daily dose of telmisartan.

A pharmaceutical composition comprising one ACE inhibitor 1.25 mg to 450 mg and one ANG II antagonist 10 mg to 500 mg, optionally together with one or more pharmaceutically acceptable diluents and / or carriers, in a single dosage unit It can be used as an aspect of.

For example, a group consisting of benazepril, captopril, sernaapril, enalapril, posinopril, imidapril, ricinopril, moexipril, quinapril, ramipril, trandolapril and perindopril One ACE inhibitor selected from 1.25 mg to 100 mg, and one ANG selected from the group consisting of candesartan, eprosartan, irbesartan, losartan, telmisartan, valsartan, olmesartan and tasosartan Pharmaceutical compositions comprising from 20 mg to 100 mg of II antagonist, optionally in a single dosage unit with one or more pharmaceutically acceptable diluents and / or carriers, will be suitable for the treatment methods according to the invention.

Most preferred pharmaceutical compositions comprise 1.25 mg to 100 mg of ramipril as an ACE inhibitor and 20 mg to 100 mg of telmisartan as an ANG II antagonist, optionally together with one or more pharmaceutically acceptable diluents and / or carriers, in a single dosage unit.

Particularly preferred pharmaceutical compositions comprise about 10 mg ramipril as an ACE inhibitor and 80 mg telmisartan as an ANG II antagonist, optionally in a single dosage unit, with one or more pharmaceutically acceptable diluents and / or carriers.

As already mentioned above, the present invention also relates to ANG II antagonists in the manufacture of pharmaceutical compositions for the treatment of humans and non-human mammals for the treatment of the aforementioned symptoms when used in combination with ACE inhibitors. Serves the purpose of. This use aspect is intended to include the preparation of all of the antimicrobial compositions mentioned herein above.

Co-administration of an ANG II antagonist with an ACE inhibitor, according to the present invention, provides an unexpected advantage in treating dementia and degeneration of cognitive function over administration of an ANG II antagonist or ACE inhibitor alone.

Claims (10)

A method of treating dementia and / or cognitive degeneration, characterized by co-administration of an effective amount of an ANG II antagonist and an ACE inhibitor to a person in need of treatment of dementia and / or cognitive degeneration. The ACE inhibitor of claim 1, wherein the ACE inhibitor is benazepril, captopril, sernaphril, enalapril, posinopril, imidapril, risinopril, moexipril, quinapril, ramipril, trandolapril and perrin. The method is characterized in that it is selected from dopryl. The method of claim 1 or 2, wherein the ANG II antagonist is selected from sartans. The ACE inhibitor of claim 1, wherein the ACE inhibitor is administered at a daily dosage of 0.018 mg / kg to 6.429 mg / kg orally or about 0.286 mg / kg daily. ANG II antagonist is administered in a daily dosage of 0.143 mg / kg to 7.143 mg / kg orally or at a daily dosage of about 0.286 mg / kg for parenteral administration. Way. The method of claim 1, wherein the ACE inhibitor is administered orally at a daily dosage of 0.071 mg / kg to 1.429 mg / kg, and the ANG II antagonist is 0.286 mg / kg to 1.429 mg / kg. A method characterized by being administered in a daily dose. The method of claim 1, wherein the ACE inhibitor is administered orally at a daily dosage of 0.036 mg / kg to 0.143 mg / kg, and the ANG II antagonist is 0.571 mg / kg to 1.143 mg / kg. A method characterized by being administered in a daily dose. The method of claim 1, wherein the ACE inhibitor is ramipril and the ANG II antagonist is telmisartan. 40 mg to 80 mg of telmisartan as an ANG II antagonist and 2.5 mg to 10 mg of ramipril as an ACE inhibitor, in combination with one or more pharmaceutically acceptable diluents and / or carriers, simultaneously to treat dementia and / or cognitive degeneration A pharmaceutical composition for treating dementia and / or cognitive degeneration in humans or mammals other than humans, comprising in a single dosage unit for separate or continuous use. Use of an ANG II antagonist in the manufacture of a pharmaceutical composition according to claim 8 for the treatment of dementia and / or cognitive degeneration in humans or mammals other than humans when used with an ACE inhibitor. Use of an ANG II antagonist in the manufacture of a pharmaceutical composition according to claim 8 for the treatment of dementia and / or cognitive degeneration in humans or mammals other than humans, when used in combination with the ACE inhibitor ramipril.