WO2012041258A1 - Compositions et méthodes de traitement de l'hypertension au moyen de l'éprosartane et de l'amlodipine - Google Patents

Compositions et méthodes de traitement de l'hypertension au moyen de l'éprosartane et de l'amlodipine Download PDF

Info

Publication number
WO2012041258A1
WO2012041258A1 PCT/CN2011/080486 CN2011080486W WO2012041258A1 WO 2012041258 A1 WO2012041258 A1 WO 2012041258A1 CN 2011080486 W CN2011080486 W CN 2011080486W WO 2012041258 A1 WO2012041258 A1 WO 2012041258A1
Authority
WO
WIPO (PCT)
Prior art keywords
amlodipine
eprosartan
effective amount
pharmaceutical composition
subject
Prior art date
Application number
PCT/CN2011/080486
Other languages
English (en)
Inventor
Jung-Chin Lin
Hsi-Chieh Wang
Shiu-Ren Hwang
Shin-Yi Juang
Original Assignee
Tsh Biopharm Corporation Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Tsh Biopharm Corporation Limited filed Critical Tsh Biopharm Corporation Limited
Publication of WO2012041258A1 publication Critical patent/WO2012041258A1/fr

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/4164—1,3-Diazoles
    • A61K31/4178—1,3-Diazoles not condensed 1,3-diazoles and containing further heterocyclic rings, e.g. pilocarpine, nitrofurantoin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/4422—1,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives

Definitions

  • the present invention relates to compositions and methods for treating hypertension, particularly, to compositions and methods for treating hypertension using eprosartan and amlodipine.
  • Hypertension is a public health problem that affects more than 25% of the adult population worldwide [1 ' 2 Hypertension has been identified as the leading risk factor for mortality and as the third ranked factor for disability-adjusted life years [1 ' 3] .
  • CCBs Calcium channel blockers
  • Ca 2+ calcium channel blockers
  • Their benefits and the possible risks have been explored in several clinical trials [9"14] .
  • Use of high-dose CCBs has been associated with a high incidence of adverse events, such as peripheral edema and constipation [8 ' u ' 12] .
  • Amlodipine is a CCB with antihypertensive properties prescribed as monotherapy. It has been found to be well tolerated even in high-risk patients, such as those with coronary disease, heart failure, or multiple risk factors for cardiovascular events [12"16] .
  • Amlodipine has a generally slower onset and longer duration of action than, for example, nifedipine [18] .
  • the metabolites of amlodipine apparently do not possess significant calcium channel blocking activity, while the parent drug offers a biological half-life of some 35-40 hours, prompting a once-daily dosage regimen [19 ' 20] .
  • the ability of amlodipine to block calcium channels in smooth muscle produces peripheral vasodilation, which results in decreases in both systolic and diastolic blood pressure.
  • the racemic mixture of amlodipine is presently used primarily as an antihypertensive agent, which produces peripheral vasodilation, resulting in decreases in both systolic and diastolic blood pressure when used as an antihypertensive agent.
  • This antihypertensive effect occurs in the relative absence of significant or sustained effects on cardiac rate.
  • the administration of the racemic mixture of amlodipine to a human has been found to cause adverse effects, such as increased heart rate, edema of the extremities, peripheral edema, headache, flushing/hot flashes, fatigue, vertigo, muscle cramps and dizziness.
  • Angiotensin II receptor antagonists also known as angiotensin receptor blockers (ARB), ATi-receptor antagonists or saltans, have been primarily used for the treatment of hypertension where the patient is intolerant of angiotensin-converting enzyme (ACE) inhibitor therapy. They have also been used in treating diabetic nephropathy (kidney damage due to diabetes) and congestive heart failure. This class of drugs is usually well- tolerated. The question of whether or not angiotensin II receptor antagonists slightly increase the risk of heart attack (myocardial infarction) is currently being investigated.
  • ARB angiotensin receptor blockers
  • ACE angiotensin-converting enzyme
  • U.S. Pat. No. 5,656,650 disclosed use of eprosartan, an angiotensin II receptor antagonist, and hydrocholothiazide (HCTZ), a first line diuretic drug of the thiazide class that acts by inhibiting the kidneys' ability to retain water, in a pharmaceutical composition for regulating hypertension, and treating congestive heart failure, renal failure, and glaucoma.
  • a pharmaceutical composition having a combination of eprosartan, amlodipine and HCTZ is also disclosed in CN101690725 for treating cardiovascular diseases such as hypertension, corona heart disease and angina pectoris.
  • diuretics or thiazide therapy [17] .
  • eprosartan and amlodipine act synergistically in lowering the blood pressure in a subject suffering from hypertension, without causing significant or unacceptable adverse effects.
  • the synergy between eprosartan and amlodipine is observed in the absence of HCTZ or any other diuretic drug of the thiazide class.
  • embodiments of the present invention relate to a method of treating hypertension or a symptom associated therewith in a subject.
  • the method comprises administering to the subject an effective amount of amlodipine and an effective amount of eprosartan, provided that the method does not further comprise administering to the subject an effective amount of a diuretic drug of the thiazide class, such as hydrochlorothiazide.
  • the method comprises administering to the subject a pharmaceutical composition consisting essentially of an effective amount of amlodipine and an effective amount of eprosartan as the therapeutically active ingredients.
  • embodiments of the present invention relate to a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject.
  • the pharmaceutical composition comprises an effective amount of amlodipine and an effective amount of eprosartan, and a pharmaceutically acceptable carrier, provided that the pharmaceutical composition does not further comprise an effective amount of a diuretic drug of the thiazide class, such as hydrochlorothiazide.
  • the pharmaceutical composition consists essentially of an effective amount of amlodipine and an effective amount of eprosartan as the therapeutically active ingredients.
  • Another general aspect of the present invention relates to a method of preparing a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject.
  • the method comprises mixing an effective amount of amlodipine, an effective amount of eprosartan, and a pharmaceutically acceptable carrier in the pharmaceutical composition, provided that the method does not further comprise including an effective amount of a diuretic drug of the thiazide class in the pharmaceutical composition.
  • Embodiments of the present invention relate to the use of an effective amount of amlodipine and an effective amount of eprosartan for the manufacture of a medicament for treating hypertension or a symptom associated therewith in a subject, provided that the medicament does not further comprise an effective amount of a diuretic drug of the thiazide class.
  • administration of a pharmaceutical composition or a medicament according to the present invention results in a synergistic effect in treating hypertension or the symptom in the subject.
  • compositions as used herein, means those salts of a compound of interest that are safe and effective for pharmaceutical use in mammals and that possess the desired biological activity.
  • Pharmaceutically acceptable salts include salts of acidic or basic groups present in the specified compounds.
  • the acidic or basic groups can be organic or inorganic.
  • Pharmaceutically acceptable acid addition salts include, but are not limited to, hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, isonicotinate, acetate, lactate, salicylate, citrate, tartrate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzensulfonate, p-toluenesulfonate and pamoate (i.e., ⁇ , ⁇ -methylene-bis- (2-hydroxy-3-naphthoate)) salts.
  • Suitable base salts include, but are not limited to, aluminum, calcium, lithium, magnesium, potassium, sodium, zinc, and diethanolamine salts.
  • Certain compounds used in the present invention can form pharmaceutically acceptable salts with various amino acids, e.g., lysine, ⁇ , ⁇ '-dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, meglumine (N-methylglucamine), procaine, and tris, and other salts which are currently in widespread pharmaceutical use and are listed in sources well known to those of skill in the art, such as The Merck Index.
  • Any suitable constituent can be selected to make a salt of an active drug discussed herein, provided that it is non-toxic and does not substantially interfere with the desired activity.
  • pharmaceutically acceptable salts see [23], which is incorporated herein by reference.
  • eprosartan or “E” refers to a compound having formula (I):
  • eprosartan includes eprosartan mesylate, a salt of methanesulfonic acid (CH3SO3H).
  • Eprosartan has been marketed for the treatment of high blood pressure, for example as Teveten® or Eprozar®, which contains eprosartan mesylate as the therapeutic agent.
  • Teveten® or Eprozar® which contains eprosartan mesylate as the therapeutic agent.
  • ACE inhibitors such as enalapril
  • amlodipine As used herein, "amlodipine”, “AM” or “A” refers to a compound having formula (II):
  • amlodipine includes amlodipine in a
  • amlodipine also includes a pharmaceutically acceptable ester of amlodipine, particularly lower alkyl esters.
  • Amlodipine has been marketed, for example, as NORVASC®, which contains amlodipine besylate, for the treatment of high blood pressure (hypertension), chest pain (angina) and other conditions caused by coronary artery disease.
  • Amlodipine is a chiral compound.
  • a pharmaceutical composition according to embodiments of the present invention can comprise a racemate, i.e., 1 : 1 mixture of (R)-(+)- and (,S)-(-)-amlodipine or a racemic mixture of the (R)-(+)- and (,S)-(-)-amlodipine at different ratios.
  • the pharmaceutical composition can also comprise isolated (R)-(+)- amlodipine or (S)-(-)-amlodipine that is substantially free of the other stereoisomer.
  • a pharmaceutical composition according to embodiments of the present invention comprises substantially optically pure (S)-(-)-amlodipine or is substantially free of (R)-(+)-amlodipine.
  • substantially free of (R)-(+)- amlodipine means that the pharmaceutical composition contains a greater proportion or percentage of (S)-(-)-amlodipine in relation to (R)-(+)- amlodipine.
  • the pharmaceutical composition preferably contains about 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% or 100%, by weight, of (S)-(-)- amlodipine, wherein the percentage is based on the total amount of (R)-(+)-amlodipine and (S)-(-)-amlodipine in the pharmaceutical composition.
  • the chemical synthesis of the racemic mixture of amlodipine can be performed using methods known in the art, e.g., as described in Arrowsmith, J. E. et al, [22 It is also available from various commercial sources. Separation of the amlodipine optical isomers from the racemic mixture can be performed by methods known in the art, such as those illustrated in U. S. Patent No. 6,448,275 or U. S. Patent No. 7,482,464. The contents of the references are hereby incorporated by reference.
  • the term "pharmaceutical composition” is intended to encompass a product or composition comprising the specified ingredient in the specified amount, as well as any product which results, directly or indirectly, from combinations with the specified ingredient in the specified amount.
  • the term "subject” means any animal, preferably a mammal, most preferably a human, to whom will be or has been administered compounds or pharmaceutical compositions according to embodiments of the invention.
  • the term "mammal” as used herein, encompasses any mammal. Examples of mammals include, but are not limited to, cows, horses, sheep, pigs, cats, dogs, mice, rats, rabbits, guinea pigs, monkeys, humans etc., more preferably, a human.
  • a subject is in need of, or has been the object of observation or experiment of, treatment or prevention of hypertension and symptoms associated therewith.
  • treating hypertension or a symptom associated therewith means to elicit an antihypertensive effect, such as by providing a normalization to otherwise elevated systolic and/or diastolic blood pressure, and by so doing providing relief from one or more possible symptoms or other hemodynamic effects caused by the elevated blood pressure.
  • treating refers to an amelioration, prophylaxis, or reversal of a disease or disorder or at least one discernible symptom thereof, for example, treating hypertension or a symptom associated therewith by lowering the elevated systolic and/or diastolic blood pressure.
  • treating refers to an amelioration, prophylaxis, or reversal of at least one measurable physical parameter related to the disease or disorder being treated, not necessarily the discernible symptom in or by the mammal, for example, treating hypertension or a symptom associated therewith by blocking voltage-gated calcium channels in cardiac muscle and/or by blocking the activation of angiotensin II ATi receptors.
  • treating refers to inhibiting or slowing the progression of a disease or disorder, either physically, e.g., stabilization of a discernible symptom, or physiologically, e.g., stabilization of a physical parameter, or both.
  • treating refers to delaying the onset of a disease or disorder or reducing the risk of acquiring a disease or disorder, such as hypertension or a symptom associated therewith.
  • the specified pharmaceutical compositions are administered as a preventative measure to a subject having a predisposition to hypertension, even though symptoms of hypertension are absent or minimal.
  • the term "effective amount" of a compound refers to the amount of the compound to be used in a treatment, a pharmaceutical composition or a medicament that elicits the biological or medicinal response in a tissue system, animal or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes alleviation of the symptoms of the disease or disorder being treated.
  • the effective amount of a compound is sufficient to treat, improve the treatment of, or prophylactically prevent, hypertension or a symptom associated therewith, but is insufficient to cause significant adverse effects associated with
  • a therapeutically active ingredient according to embodiments of the present invention.
  • the dosage level will depend on the particular active ingredient used, e.g., its chemical and physical properties, mechanism of action, etc.
  • specific dose levels for any particular subject will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, any additional therapeutic agents administered in combination therewith and the severity of the disease or condition being treated.
  • the prophylactic or therapeutic treatment of the above identified conditions is expected to be achieved via administration of dosage levels of the active ingredients in amounts from about 0.01 mg/kg to about 100 mg/kg body weight per day, such as about 0.03 mg/kg to about 75 mg/kg body weight per day, about 0.05 mg/kg to about 50 mg/kg body weight per day, or about 0.1 mg/kg to about 10 mg/kg body weight per day.
  • the dosage levels of eprosartan, particularly eprosartan mesylate can be about 0.5 mg/kg to 50 mg/kg body weight per day; and the dosage levels of amlodipine, particularly amlodipine besylate, can be about 0.01 mg/kg to 1 mg/kg body weight per day.
  • the desired or appropriate dosage level may be administered in a single daily dose, or the total daily dosage can be administered in divided doses of two, three or four times daily.
  • the dosage can be formulated to be delivered in a substantially continuous fashion, as may be provided by sustained and/or controlled release dosage forms, or by a transdermal patch.
  • the appropriate dosage level is administered in a single daily dose.
  • the term "adverse effect” includes, but is not limited to, any adverse or side effect associated with the use of eprosartan or amlodipine in a subject in need of the treatment, such as cardiovascular side effects (including tachycardia and diminished contractility of the heart), edema of the extremities, headache, dizziness, flushing, fatigue, vertigo, muscle cramps, hallucination, diarrhea, fever, urinary retention, vomiting, body rash/itching, etc.
  • cardiovascular side effects including tachycardia and diminished contractility of the heart
  • edema of the extremities headache, dizziness, flushing, fatigue, vertigo, muscle cramps, hallucination, diarrhea, fever, urinary retention, vomiting, body rash/itching, etc.
  • eprosartan and amlodipine act synergistically in lowering the blood pressure in a subject suffering from hypertension, without causing significant or unacceptable adverse effects.
  • the anti-hypertensive effect observed upon combined administration of eprosartan and amlodipine is greater than the sum of the individual anti-hypertensive effects observed upon the separate administration of eprosartan and amlodipine.
  • This synergistic effect is obtained in the absence of HCTZ or any other diuretic drug of the thiazide class.
  • Novel and improved pharmaceutical compositions and methods for treating hypertension or a symptom associated therewith are thus developed based on the combination of eprosartan and amlodipine in the absence of a diuretic drug of the thiazide class, such as HCTZ.
  • embodiments of the present invention relate to a method of treating hypertension or a symptom associated therewith in a subject, comprising administering to the subject an effective amount of eprosartan and an effective amount of amlodipine, provided that the method does not further comprise administering to the subject an effective amount of a diuretic drug of the thiazide class, such as HCTZ.
  • a diuretic drug of the thiazide class such as HCTZ.
  • any of the pharmaceutically acceptable salts or pharmaceutically acceptable esters of eprosartan such as eprosartan mesylate, can be used in the present invention.
  • any of the optical isomer, enantiomer, diastereomer, racemate or racemic mixture, pharmaceutically acceptable salts, or pharmaceutically acceptable esters, of amlodipine, such as amlodipine besylate, can be used in the present invention.
  • a racemic mixture of amlodipine or (R,S)-amlodipine is used in the present invention.
  • a substantially optically pure (S)-(-)-amlodipine such as a substantially optically pure (S)-(-)-amlodipine besylate, (S)-(-)-amlodipine mesylate or S)-(-)-amlodipine maleate, is used in the present invention.
  • eprosartan and amlodipine can be administered together in the same pharmaceutical composition, or separately in different pharmaceutical compositions in any order, so long as the dosing schedules of eprosartan and amlodipine overlap in time.
  • amlodipine and eprosartan are administered to the subject at a ratio of, for example, 1 :2000 to 1 : 1, such as 1 : 1000 to 1 : 10, by weight.
  • Examples of such combinations include those wherein the ratio of amlodipine to eprosartan is 1 : 1, 1 :5; 1 :6.67; 1 : 10; 1 : 13.33; 1 :20; 1 :50; 1 : 100; 1 : 120; 1 :200; 1 : 1000 or 1 :2000, by weight.
  • amlodipine besylate and eprosartan mesylate are administered to the subject at a ratio of about 1 : 120 to about 1 : 1, by weight, such as about 1 : 120, 1 : 100, 1 :75, 1 :50, 1 :25, 1 : 10, 1 :5, 1 : 1, etc., by weight.
  • each of amlodipine and eprosartan is employed at an amount at or below which it exhibits an antihypertensive effect when used alone.
  • the administration of the effective amount of amlodipine and the effective amount of eprosartan to a subject in need of the treatment results in a synergistic effect in treating hypertension or the symptom in the subject.
  • a suitable dose of amlodipine besylate for administration to a human for the treatment of hypertension can be in the range of 0.1 to 20 mg per day, such as 0.1 to 10 mg per day, 1 to 10 mg per day, etc.
  • Amlodipine is preferably administered by an oral route once a day.
  • a suitable dose of eprosartan mesylate for administration to a human for the treatment of hypertension can be in the range of 10 to 2000 mg per day, such as 10 to 800 mg per day, 100 to 800 mg or 100 to 500 mg per day, etc.
  • Eprosartan is preferably administered by oral route once a day.
  • the method comprises orally administering to the subject about 1 to 10 mg/day amlodipine besylate and about 10 to 800 mg/day eprosartan mesylate.
  • the method comprises administering to the subject a pharmaceutical composition consisting essentially of an effective amount of eprosartan and an effective amount of amlodipine as the therapeutically active ingredients.
  • the method comprises administering to the subject an oral dosage form once daily, and the oral dosage form consists essentially of about 10 to 800 mg eprosartan mesylate and about 1 to 10 mg amlodipine besylate as the therapeutically active ingredients per dosage form.
  • the methods according to embodiments of the present invention comprise administering to the subject one or more additional therapeutically active ingredients, such as an additional antihypertensive agent, provided that the additional therapeutically active ingredient is not a diuretic drug of the thiazide class, such as HCTZ.
  • additional antihypertensive agent can be selected from the group consisting of ⁇ -adrenoceptor antagonists ( ⁇ -blockers), ACE inhibitors, renin inhibitors, central sympatholytics, CCBs other than amlodipine and ARBs other than eprosartan.
  • one or more other CCBs or ARBs that are effective in lowering blood pressure in patients suffering from Coronary Artery Disease (CAD) can be used in combination with eprosartan and amlodipine.
  • Eprosartan can reduce the increases in heart rates caused by amlodipine and the other CCBs.
  • Another general aspect of the present invention relates to a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject, which comprises an effective amount of eprosartan, an effective amount of amlodipine, and a pharmaceutically acceptable carrier, provided that the pharmaceutical composition does not comprise a diuretic drug of the thiazide class, such as HCTZ.
  • a pharmaceutical composition for treating hypertension or a symptom associated therewith in a subject which comprises an effective amount of eprosartan, an effective amount of amlodipine, and a pharmaceutically acceptable carrier, provided that the pharmaceutical composition does not comprise a diuretic drug of the thiazide class, such as HCTZ.
  • the pharmaceutical composition comprises amlodipine and eprosartan at a ratio of 1 :2000 to 1 : 1, preferably 1 : 120 to 1 : 1, by weight.
  • ratio of amlodipine to eprosartan is 1 : 1; 1 :5; 1 :6.67; 1 : 10; 1 : 13.33; 1 :20; 1 :50; 1 : 100; 1 : 120; 1 :200; 1 : 1000 or 1 :2000, by weight.
  • the pharmaceutical composition comprises an oral dosage form for once daily administration to the subject.
  • the oral dosage form comprises amlodipine besylate in the range of about 0.1 to 20 mg, preferably about 1 to 10 mg or about 1 to 5 mg, and eprosartan mesylate in the range of about 10 to 2000 mg, preferably about 10 to 800 mg, 100 to 800 mg, or about 100 to 500 mg, per dosage form.
  • the pharmaceutical composition consists essentially of an effective amount of eprosartan and an effective amount of amlodipine as the therapeutically active ingredients.
  • the pharmaceutical composition is an oral dosage form for once daily administration to the subject, which consists essentially of about 10 to 800 mg eprosartan mesylate and about 1 to 10 mg amlodipine besylate as the active ingredients per dosage form.
  • compositions according to embodiments of the present invention comprise one or more additional therapeutically active ingredients, such as an additional antihypertensive agent, provided that the additional therapeutically active ingredient is not a diuretic drug of the thiazide class, such as HCTZ.
  • additional therapeutically active ingredients such as an additional antihypertensive agent
  • embodiments of the present invention can be administered by any known route of administration, including, orally, topically, parenterally (including subcutaneous, intravenous, intramuscular, and intrasternal injection or infusion administration techniques), by inhalation spray or rectally in dosage units or pharmaceutical compositions containing conventional pharmaceutically acceptable carriers and any such dosage units or
  • compositions are within the scope of the present invention.
  • compositions adapted for oral administration include solid forms such as pills, tablets, caplets, and hard or soft capsules (each including immediate release, timed release, and sustained release formulations) as well as lozenges and dispersible powders or granules.
  • Liquid forms of pharmaceutical compositions adapted for oral administration include solutions, syrups, elixirs, emulsions, and aqueous or oily suspensions. In view of the present disclosure, any of these dosage forms may be prepared according to any method or compounding technique known in the art for the manufacture of pharmaceutical compositions.
  • compositions according to the invention can be prepared in a manner known per se and include those suitable for enteral, such as oral or rectal, and parenteral administration to mammals (warm-blooded animals), including human.
  • enteral such as oral or rectal
  • parenteral administration to mammals (warm-blooded animals), including human.
  • the pharmaceutical compositions comprise an effective amount of the pharmacologically active compound, alone or in combination with one or more
  • pharmaceutically acceptable carriers especially suitable for enteral or parenteral applications.
  • Pharmaceutically acceptable carriers that can be desirably utilized in the manufacture of solid oral dosage forms include inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating or disintegrating agents, such as corn starch or alginic acid; binding agents, such as starch, gelatin, or acacia; and lubricating agents such as magnesium stearate, stearic acid or talc.
  • solid pharmaceutical compositions adapted for oral administration can further include one or more sweetening agents, flavoring agents, coloring agents, or preserving agents in order to provide attractive or palatable preparations.
  • the dosage form is a tablet or pill
  • it can either be uncoated or coated, and if coated, can be coated by any known technique.
  • the coating if desirably provided, can be formulated or applied by known techniques so that the coating can delay disintegration of the tablet or pill, and thus, absorption of the active ingredient, thereby providing a controlled and/or sustained release dosage form capable of providing sustained therapeutic or prophylactic effect over a longer period.
  • the tablet or pill can comprise an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former.
  • An enteric layer that serves to resist disintegration in the stomach and permits the inner component to pass substantially intact into the duodenum or to be delayed in release can separate the two components.
  • enteric layers or coatings including a number of polymeric acids, shellac, cetyl alcohol and cellulose acetate.
  • enteric layers or coatings including a number of polymeric acids, shellac, cetyl alcohol and cellulose acetate.
  • tablets, pills or capsules may be formulated as osmotic pump dosage forms by any known method.
  • compositions adapted for oral administration can also be prepared as hard or soft gelatin capsules, wherein the active ingredient can be mixed with an inert solid diluent, such as calcium carbonate, calcium phosphate or kaolin in the case of the former or with water or miscible solvents such as propylene glycol, PEG's and ethanol, or an oil medium such as peanut oil, liquid paraffin, or olive oil in the case of the latter.
  • an inert solid diluent such as calcium carbonate, calcium phosphate or kaolin in the case of the former or with water or miscible solvents such as propylene glycol, PEG's and ethanol, or an oil medium such as peanut oil, liquid paraffin, or olive oil in the case of the latter.
  • Aqueous suspensions can be prepared that contain the active ingredient(s) in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients include suspending agents, such as sodium carboxymethylcellulose,
  • dispersing or wetting agents such as lecithin, polyoxy ethylene stearate, heptadecaethyleneoxycetanol, polyoxyethylene sorbitol monooleate, and polyethylene sorbitan monooleate.
  • Aqueous suspensions can also contain one or more preservatives, such as ethyl or n-propyl, p- hydroxybenzoate; one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharine or aspartame.
  • preservatives such as ethyl or n-propyl, p- hydroxybenzoate
  • coloring agents such as a coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharine or aspartame.
  • sweetening agents such as sucrose, saccharine or aspartame.
  • Oily suspensions can be formulated by suspending the active ingredient(s) in a vegetable oil, such as cottonseed, olive, sesame or coconut oil, or in a mineral oil, such as liquid paraffin.
  • the oily suspensions can contain a thickening agent, such as beeswax, hard paraffin, or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents can be added to provide a palatable oral preparation.
  • Such oily suspensions can be preserved by the inclusion of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for the preparation of an aqueous suspension suitable for oral administration can provide the active ingredient(s) in admixture with a dispersing or wetting agent, suspending agent, and one or more preservatives, all of which have been discussed above.
  • a dispersing or wetting agent e.g., glycerol, glycerol, glycerol, glycerol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbitol, sorbito
  • compositions suitable for oral administration can also be presented in the form of an oil-in- water emulsion.
  • the oily phase can be a vegetable or mineral oil, such as those described above, or mixtures of these.
  • Suitable emulsifying agents can be naturally-occurring phosphatides, such as soy bean, lecithin, sorbitan monooleate, or polyoxyethylene sorbitan monooleate.
  • the emulsions can also contain sweetening or flavoring agents.
  • Syrups and elixirs can be formulated with sweetening agents, for example, glycerol, propylene glycol, sorbitol or sucrose. Such formulations can also contain a demulcent, a preservative and flavoring or coloring agents.
  • sweetening agents for example, glycerol, propylene glycol, sorbitol or sucrose.
  • Such formulations can also contain a demulcent, a preservative and flavoring or coloring agents.
  • compositions can be further provided in a form adapted for parenteral administration, i.e., by injection or infusion.
  • Injectable aqueous or oleaginous suspensions are desirably sterile and can be formulated according to known methods using suitable dispersing, wetting and suspending agents as described herein.
  • a parenterally- acceptable diluent or solvent can also be utilized, such as 1,3-butanediol, water, Ringer's solution, and isotonic sodium chloride.
  • Cosolvents such as ethanol, propylene glycol or polyethylene glycols can also be used.
  • sterile, fixed oils are conventionally employed as solvents or suspending mediums in injectable or infusible solutions, and these may include any bland fixed oil, such as any of the synthetic mono- or diglycerides.
  • Fatty acids such as oleic acid also can be utilized in the preparation of injectable or infusible solutions.
  • the pharmaceutical composition can also be presented in the form of a suppository.
  • Suppositories can be formulated by mixing the active ingredient(s) and any additional desired therapeutic agent(s) with a suitable non-irritating excipient that is solid at room temperature but molten at body temperature, thereby releasing the active ingredient(s).
  • suitable materials include cocoa butter and polyethylene glycols.
  • Topical use creams, ointments, gels, solutions or suspensions containing the active ingredient(s) may be prepared.
  • topical use includes mouth washes and gargles.
  • Topical formulations can include cosolvents, emulsifiers, penetration enhancers, preservatives, emollients, and the like.
  • the therapeutically active ingredients according to embodiments of the present invention can also be provided in a pharmaceutical composition in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles, and multilamellar vesicles.
  • Liposomes can be formed from a variety of lipids, including but not limited to amphipathic lipids such as phosphatidylcholines, sphingomyelins,
  • phosphatidylethanolamines phophatidylcholines, cardiolipins, phosphatidylserines, phosphatidylglycerols, phosphatidic acids, phosphatidylinositols, diacyl
  • trimethylammonium propanes diacyl dimethylammonium propanes, and stearylamine, neutral lipids such as triglycerides, and combinations thereof. They can either contain cholesterol or can be cholesterol-free.
  • compositions according to embodiments of the present invention are formulated for oral administration.
  • the pharmaceutical compositions can be conveniently presented in dosage form, and prepared by any of the methods known in the art of pharmacy in view of the present disclosure.
  • the pharmaceutical compositions are prepared by uniformly and intimately admixing the active ingredient with liquid carriers or finely divided solid carriers or both, and then, if necessary, shaping the product into the desired presentation.
  • the corresponding therapeutically active ingredient or pharmaceutically acceptable salt thereof can also be used in form of a hydrate or include other solvents used for crystallization.
  • the amount of therapeutically active ingredients to be included in a dosage form will depend upon the patient being treated, the mode of administration and the desired delivered dose.
  • each dosage form for oral administration such as a pill, a tablet, a caplet, a hard or soft capsule, comprises a ratio of AM to eprosartan of 1 : 1 to 1 :2000, such as 1 : 1 to 1 : 120, by weight.
  • each dosage form for oral administration comprises AM and eprosartan at a ratio of, e.g., 1 : 1; 1 :5; 1:6.67; 1 : 10;
  • a suitable dosage range of eprosartan for use in the present invention is from about 10 mg to about 2000 mg total daily dose, and a suitable dosage range of AM for use in the present invention is from about 0.1 mg to about 20 mg total daily dose, given as a once daily administration in the morning or in divided doses if required.
  • a dose range of about 10 mg to about 1200 mg is given as a once daily administration or in divided doses if required, and preferably a dose range of about 10 mg to about 800 mg, about 100 mg to about 800 mg or about 100 mg to about 500 mg is given as a once daily administration or in divided doses if required.
  • a dose range of about 0.1 mg to about 20.0 mg is given as a once daily administration or in divided doses if required, and preferably a dose range of about 1 mg to about 10.0 mg or about 1 mg to about 5.0 mg is given as a once daily administration or in divided doses if required.
  • Patients can be upward titrated from below to within this dose range to a satisfactory control of symptoms or blood pressure as appropriate.
  • the pharmaceutical composition is a once daily oral dosage form that comprises about 10 to about 800 mg eprosartan mesylate and about 1 mg to about 10.0 mg amlodipine besylate per dosage form.
  • Amlodipine besylate (A) and eprosartan mesylate (E) were formulated in 1% methylcellulose and were administered orally at a dose level of 1 or 20 mg/kg alone or in combination.
  • the dosing volume was 5 mL/kg.
  • Test compounds amlodipine besylate and eprosartan mesylate, were given orally to SHR rats (18 weeks of age) weighing 400 ⁇ 100 g with an average systolic blood pressures of 200 ⁇ 20 mmHg and heart rates of 400 ⁇ 50 beats/min for confirmation of the efficacy of a treatment.
  • One-way ANOVA followed by Dunnett's test was applied for the comparison between vehicle control and test compound treated groups. P ⁇ 0.05 is considered significant.
  • Total cholesterol, LDL-cholesterol, alanine aminotransferase (ALT), aspartate aminotransferase (AST) and Creatinine are measured by using automatic biochemical analyzers (Spotchem TM SP 4410 Kyoto Daiichi Kagaku Co. Ltd.).
  • Table 3 shows the mean results measured from four animals.
  • the decrease in systolic blood pressure (SBP) is expressed as the percentage of decrease in SBP compared to the pre-treatment SBP.
  • results shown in Table 3 illustrated that amlodipine besylate (A) administered alone at 1 mg/kg by oral gavage (p.o.) for consecutive 28 days did not result in a significant attenuation of the systolic blood pressure in SHR rats, when measured on days 1, 14 and 28.
  • the combination of A (1 mg/kg) and E-low (1 mg/kg) resulted in a hypotensive effect that was more than the additive effects of the two treatments
  • results shown in Table 4 illustrated that amlodipine besylate (A) administered alone at 1 mg/kg by oral gavage (p.o.) for consecutive 28 days resulted in a slight increase in heart rate in SHR rats, when measured on days 1, 14 and 28.
  • the increase in heart rate was generally not observed when A (1 mg/kg) was combined with E-low (1 mg/kg) or E- high (20 mg/kg), indicating that eprosartan can reduce the undesirable increase in heart rate caused by amlodipine.
  • ESH European Society of Hypertension
  • ESC European Society of Cardiology
  • Amlodipine Survival Evaluation Study Group Effect of amlodipine on morbidity and mortality in severe chronic heart failure. N. Engl. J. Med. 1996;335: 1107-1114.

Landscapes

  • Health & Medical Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne une composition pharmaceutique pour traiter l'hypertension ou un symptôme associé chez un sujet, son procédé de préparation et son utilisation. La composition pharmaceutique comprend une quantité efficace d'amlodipine, une quantité efficace d'éprosartane et un excipient pharmaceutiquement acceptable, à condition que la composition pharmaceutique ne comprenne pas également une quantité efficace de médicament diurétique de la classe des thiazides.
PCT/CN2011/080486 2010-09-30 2011-09-30 Compositions et méthodes de traitement de l'hypertension au moyen de l'éprosartane et de l'amlodipine WO2012041258A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US38809210P 2010-09-30 2010-09-30
US61/388,092 2010-09-30

Publications (1)

Publication Number Publication Date
WO2012041258A1 true WO2012041258A1 (fr) 2012-04-05

Family

ID=45891981

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2011/080486 WO2012041258A1 (fr) 2010-09-30 2011-09-30 Compositions et méthodes de traitement de l'hypertension au moyen de l'éprosartane et de l'amlodipine

Country Status (2)

Country Link
TW (1) TW201304775A (fr)
WO (1) WO2012041258A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1883478A (zh) * 2006-05-30 2006-12-27 石家庄制药集团欧意药业有限公司 治疗高血压心血管疾病的药物组合物
CN101564536A (zh) * 2008-04-21 2009-10-28 鲁南制药集团股份有限公司 一种治疗高血压的药物组合物缓控释制剂
CN101711747A (zh) * 2008-10-08 2010-05-26 鲁南制药集团股份有限公司 一种治疗高血压的药物应用制剂
CN101766610A (zh) * 2009-01-05 2010-07-07 青岛科技大学 氨氯地平、甲磺酸依普罗沙坦复方制剂

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1883478A (zh) * 2006-05-30 2006-12-27 石家庄制药集团欧意药业有限公司 治疗高血压心血管疾病的药物组合物
CN101564536A (zh) * 2008-04-21 2009-10-28 鲁南制药集团股份有限公司 一种治疗高血压的药物组合物缓控释制剂
CN101711747A (zh) * 2008-10-08 2010-05-26 鲁南制药集团股份有限公司 一种治疗高血压的药物应用制剂
CN101766610A (zh) * 2009-01-05 2010-07-07 青岛科技大学 氨氯地平、甲磺酸依普罗沙坦复方制剂

Also Published As

Publication number Publication date
TW201304775A (zh) 2013-02-01

Similar Documents

Publication Publication Date Title
RU2324482C2 (ru) Комбинация органических соединений
US9592231B2 (en) Therapy for complications of diabetes
AU2001225816B2 (en) Therapeutic combination of amlodipine and benazepril
JP6151123B2 (ja) ネコの全身性疾患の予防又は治療の為のアンジオテンシンｉｉ受容体アンタゴニスト
JP2005526130A (ja) Ａｃｅインヒビター、カルシウムチャネルブロッカーおよび利尿剤の組合せ
BR112013025222B1 (pt) Composição farmacêutica anti-hipertensiva e uso da mesma
US9597302B1 (en) Combination of dofetilide and mexiletine for the prevention and treatment of atrial fibrillation
CN106456637B (zh) (s)-吡吲哚及其药学上可接受的盐的药学用途
CN113230411B (zh) 一种阿利沙坦酯或其盐与钙离子通道拮抗剂的复方药物组合物
AU2004283047B2 (en) Pharmaceutical composition comprising a selective I1 imidazoline receptor agonist and an angiotensin II receptor blocker
US20230277523A1 (en) Methods for inhibiting phosphate transport
JP6227535B2 (ja) 脂質異常症の予防又は治療薬
WO2012041258A1 (fr) Compositions et méthodes de traitement de l'hypertension au moyen de l'éprosartane et de l'amlodipine
WO2012048045A1 (fr) Compositions, dosages, et procédés d'utilisation de dérivés de tétrahydrocannabinol
DK2852386T3 (en) PHARMACEUTICAL COMPOSITION, COVERING (1R, 4R) -6'-FLUOR-N, N-DIMETHYL-4-PHENYL-4 ', 9'-DIHYDRO-3'H-SPIRO [CYCLOHEXAN-1,1'-PYRANO- [ 3,4, B] INDOL] -4-AMINE AND ACETYLSALICYLIC ACID
CN113876768B (zh) 一种阿利沙坦酯氨氯地平复方药物组合物的新应用
RU2756320C2 (ru) Фармацевтическая композиция, содержащая бета-блокатор, ингибитор превращающего фермента и гипотензивное средство или нпвс
WO2006002983A1 (fr) Combinaison de composes organiques
CN1708308A (zh) 福辛普利降低透析患者心血管事件的用途
JP2023052054A (ja) トリアザスピロ［４．５］デカノンによる胃不全麻痺の処置
Malacco Nebivolol/Hydrochlorothiazide.
ZA200304330B (en) Therapeutic combination of amlodipine and benazepril.
NZ526385A (en) High dose therapeutic combination of amlodipine and benazepril

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 11828154

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 11828154

Country of ref document: EP

Kind code of ref document: A1