EP1284719A2 - The use of a calcium channel blocker for treating renal disorders - Google Patents
The use of a calcium channel blocker for treating renal disordersInfo
- Publication number
- EP1284719A2 EP1284719A2 EP01914134A EP01914134A EP1284719A2 EP 1284719 A2 EP1284719 A2 EP 1284719A2 EP 01914134 A EP01914134 A EP 01914134A EP 01914134 A EP01914134 A EP 01914134A EP 1284719 A2 EP1284719 A2 EP 1284719A2
- Authority
- EP
- European Patent Office
- Prior art keywords
- calcium channel
- amlodipine
- channel blocker
- treatment
- agent
- Prior art date
- Legal status (The legal status 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 status listed.)
- Withdrawn
Links
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- A61K9/2068—Compounds of unknown constitution, e.g. material from plants or animals
Definitions
- This invention relates to the treatment of renal disease in animals, especially chronic renal failure.
- Renal disease including renal failure (acute and chronic) is a common clinical problem which tends to increase with the age of animals (including humans). Conditions are described in "The Merck Manual", 16th edition, ch.149, pp.1661, 1665 (Merck Research Laboratories (1992), and are commonly, but not always, associated with abnormally high blood pressure (hypertension). Renal disease often results in long suffering periods where the patient endures uncomfortable and painful symptoms, often involving injury to eyes, heart and brain. Dialysis and kidney transplantation can be used as treatments if circumstances allow, but these procedures can have serious complications, including, for transplantation, organ rejection.
- Amlodipine disclosed in EP 0 089 167, etc., is a dihydropyridine calcium channel blocker which is licensed for use as an antihypertensive and antianginal agent. It is sold as the besylate salt (disclosed in EP 0 244 944, etc.) in 2.5mg, 5mg and 10mg dosages under the trade names Norvasc, Norvas, Istin, Amlor, etc. by Pfizer Inc. and related companies. Both of these publications are herein incorporated by reference.
- calcium channel blockers such as amlodipine (e.g. as the besylate salt) can be used to treat renal disease in animals which are not hypertensive, i.e. animals which are "normotensive".
- Normal means having systemic arterial blood pressure values within normal or reference ranges established for the animal species of interest, using acceptable methods for measuring such blood pressure under appropriate circumstances, and below generally accepted “hypertensive” ranges for such animals.
- reference range values may be established for representative subclasses, races, breeds, etc. (e.g. humans, lab. animals, specific subpopulations, etc.).
- renal disease in normotensive patients especially normotensive companion animals such as cats
- a calcium channel blocker such as amlodipine
- An aspect of the current invention is the treatment of renal disease in normotensive animals with a calcium channel blocker.
- the animal is a mammal.
- a preferred mammal is a human.
- Another preferred group of mammals are companion animals such as horses, and domestic cats and dogs.
- the most preferred companion animal is a domestic cat.
- the renal disease is chronic renal failure.
- the calcium channel blocker is a dihydropyridine calcium channel blocker such as amlodipine, nifedipine, nitrendipine, nimodipine, nicardipine, felodipine, etc.
- the calcium channel blocker can be present as a pharmaceutically acceptable salt or solvate thereof.
- Pharmaceutically acceptable salts and solvates are non-toxic to the species being treated.
- Suitable pharmaceutically acceptable salts for dihydropyridine calcium channel blockers include acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, bisulphate, acid citrate, bitartrate, ethansulphonate, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzenesulphonate (besylate), p-toluenesulphonate (tosylate), methanesulphonate (mesylate), succinate, salicylate, nitrate, etc.
- the calcium channel blocker is amlodipine and the pharmaceutically acceptable salts thereof, including acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, bisulphate, acid citrate, bitartrate, ethansulphonate, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzenesulphonate (besylate), p-toluenesulphonate (tosylate), methanesulphonate (mesylate), succinate, salicylate, nitrate, etc.
- acid addition salts such as the hydrochloride, hydrobromide, hydroiodide, bisulphate, acid citrate, bitartrate, ethansulphonate, sulphate, phosphate or acid phosphate, acetate, maleate, fumarate, lactate, tartrate, citrate, gluconate, benzenesulphonate (
- amlodipine besylate salt Most preferred is the amlodipine besylate salt.
- Treatment refers to prevention, alleviation and/or cure of the condition.
- Another aspect of the invention is the administration, to a normotensive animal, of an efficacious amount of a calcium channel blocker, such as between 0.01 to 3mg/kg, preferably between 0.1mg/kg and 0.3mg/kg, more preferably between 0.12 and 0.25 mg/kg, amlodipine (preferably administered as the besylate salt) of the animal to treat renal disease such as chronic renal failure.
- a calcium channel blocker such as between 0.01 to 3mg/kg, preferably between 0.1mg/kg and 0.3mg/kg, more preferably between 0.12 and 0.25 mg/kg
- amlodipine preferably administered as the besylate salt
- amlodipine which comprises about 0.1-1.5 mg, preferably about 0.2-0.6, or about 0.8 to 1.5 mg, most preferably about 0.1 , 0.2, 0.4, 0.6, 0.8, 1.0, 1.2 or 1.5mg amlodipine per unit, where amlodipine is preferably present as its besylate salt, suitable for, or adapted for, the treatment of normotensive cats with renal disease, such as chronic renal failure.
- unit doses can also be used to treat-renal disease in animals with hypertension.
- the calcium channel blocker can be administered / formulated with an antihypertensive agent of a different class (i.e.
- Suitable agents include angiotensin converting enzyme (ACE) inhibitors such as those licensed for use in treating hypertension, such as benazepril, benazeprilat, captopril, enalapril, enalaprilat, fosinopril sodium, lisinopril, pentopril, perindopril, quinapril hydrochloride, quinaprilat, ramipril. ramiprilat, trandolapril, zofenopril calcium, and the like.
- ACE angiotensin converting enzyme
- co-administration may take place in a number of different ways, including: the active agents may be present in the same dosage form for single administration; the active agents may be administered in separate dosage forms, by the same or different administration routes, and at the same, substantially the same or at different times.
- a suitable ACE inhibitor for co-administration in the treatment of renal disease is thought to be benazepril, currently marketed as FortekorTM, which for cats is administered at about 0.5 to about 1 mg/kg per day for cats as a 2.5mg or 5mg dose.
- the calcium channel blockers can be administered alone but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
- a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of administration and standard pharmaceutical or veterinary practice.
- suitable pharmaceutical carriers, excipents, diluents, etc. can be found in Remington's Pharmaceutical Science, A. Osol, a standard reference text in the field.
- the calcium channel blocker (and/or other active agents) can be administered orally, buccally or sublingually in the form of tablets, capsules, ovules, elixirs, syrups, boluses, powders, pastes, drenches , medicated food or drinking water or other liquid, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-, pulsed- or controlled-release applications.
- Such tablets may contain excipients such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine, disintegrants such as starch (optionally pre-gelatinised, preferably corn, potato or tapioca starch), sodium starch glycollate, croscarmellose sodium and certain complex silicates, and granulation binders such as polyvinylpyrrolidone, hydroxypropylmethylcellulose (HPMC), hydroxypropylcellulose (HPC), sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.
- excipients such as microcrystalline cellulose, silicified microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine
- disintegrants such as starch (optionally pre-gelatinised, preferably corn
- cyclodextrin solublity modifiers may be included. Additionally antioxidants may be included. Agents to improve palatability, such as flavouring agents (e.g. yeast, yeast extract, pork liver) may also be included.
- flavouring agents e.g. yeast, yeast extract, pork liver
- the agents apart from the calcium channel blocker may be present in intimate mixture with the calcium channel blocker, or they may be separated, e.g. in a bilayer, trilayer or other multlayer tablet or coated tablet, or a microparticulate capsule.
- Solid compositions of a similar type may also be employed as fillers in gelatin capsules.
- Preferred excipients in this regard include lactose, starch, a cellulose, milk sugar or high molecular weight polyethylene glycols.
- the calcium channel blockers (and/or other active agents) may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents and with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.
- the calcium channel blockers can also be administered parenterally, for example, intravenously, intra-arterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion techniques.
- parenteral administration they are best used in the form of a sterile aqueous solution, or sterile aqueous or oil suspension, which may contain other substances, for example, enough salts or glucose to make the solution isotonic with blood.
- the aqueous solutions should be suitably buffered (preferably to a pH of from 3 to 9), if necessary.
- the preparation of suitable parenteral formulations under sterile conditions is readily accomplished by standard pharmaceutical techniques well-known to those skilled in the art.
- the calcium channel blockers can also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or an aerosol spray presentation from a pressurised container, pump, spray or nebuliser with the use of a suitable propellant, e.g.
- the dosage unit may be determined by providing a valve to deliver a metered amount.
- the pressurised container, pump, spray or nebuliser may contain a solution or suspension of the active compound, e.g.
- Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound and a suitable powder base such as lactose or starch.
- the calcium channel blocker (and/or other active agents) can be administered in the form of a suppository or pessary, or may be applied topically in the form of a gel, a pour-on, spot-on, dip, spray, mousse, shampoo, collar or powder formulation, ear tag, hydrogel, lotion, solution, cream, gel, paste, patch, ointment or dusting powder.
- the calcium channel blockers (and/or other active agents) may also be dermally or transdermally administered, for example, by the use of a skin patch. They may also be administered by the pulmonary or rectal routes.
- the calcium channel blocker (and/or other active agents) can be formulated as a suitable ointment containing the active compound suspended or dissolved in, for example, a mixture with one or more of the following: mineral oil, liquid petrolatum, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene compound, emulsifying wax and water.
- ком ⁇ онентs can be formulated as a suitable lotion or cream, suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, sorbitan monostearate, a polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax, cetearyl alcohol, 2- octyldodecanol, benzyl alcohol and water.
- the compounds may be administered with the animal feedstuff and for this purpose a concentrated feed additive or premix may be prepared for mixing with the normal animal feed.
- an oral formulation for a medicament comprising: a solid masticable portion and one or more reservoir portions encompassed by said solid masticable portion; the solid masticable portion consisting of a fully edible material, having a Young's modulus of 0.01-5MPa, and compressive strength in the range 10- 10,000 mJ, the reservoir portion or portions comprising a releasable dose of the medicament in a fluid (preferably a liquid) form, with a viscosity below 800mPa.s at body temperature (ca. 36-ca.40°C), such that on mastication, the masticable portion is ruptured and the unit dose of the medicament is released in a short space of time from the reservoir portion into the oral cavity.
- the calcium channel blockers (and/or other active agents mentioned above) can also be administered together with yet further active agents should the medical need arise.
- the physician or veterinarian in any event will determine the actual dosage which will be most suitable for any individual patient and it will vary with the age, weight and response of the particular patient.
- the dosages mentioned herein are exemplary of the average case. There can, of course, be individual instances where higher or lower dosage ranges are merited and such are within the scope of this invention.
- the skilled person will appreciate that, in the treatment of certain conditions the compounds may be taken as a single or multiple dose as needed or desired.
- the route of administration will depend on a number of factors, and in accordance with standard medical and veterinary practice, including the species of animal to be treated, size of the animal, ease of administration, etc. Based on the results disclosed herein, the envisioned dosage regime for amlodipine in the treatment of renal disease, such as chronic renal failure, in normotensive animals, is 0.125-0.25mg/kg/day.
- amlodipine dosage regime is 0.125 - 0.25 mg/kg / day, which translates to 0.4mg/cat/day for cats weighing from 1.6kg up to about 3kg, 0.8mg/cat/day for cats weighing between 3-6.5kg, and 1.2mg/cat/day for cats weighing about 6.5-9.5kg. Cats falling outside these weight ranges will of course be treatable in proportion to their weight.
- Oral administration is preferred, preferably of a tablet.
- Benazepril may be co-administered at 0.5 to 1 mg/kg per day, e.g. as a 2.5mg or 5mg dose for domestic cats (as in FortekorTM mentioned above).
- Other ACE inhibitors and/or endothelin-reducing agents may be co- administered with the calcium channel blocker such as amlodipine according to the medical need, efficacy, etc.
- the efficacy of calcium channel blockers such as amlodipine in the treatment of chronic renal failure, in the dosages mentioned and with the populations mentioned can be demonstrated by measurement of renal function (e.g. by GFR measurements or any other measurements known in the art such as renal plasma flow using appropriate markers such as creatinine, inulin, iohexol, radioisotopes and other validated markers of dynamic renal function, urine concentrations of analytes such as protein and/or protein indexed to urine creatinine concentration, etc.). Measurements can be made before treatment, during treatment and after treatment by methods well-known in the art. For control purposes, a similar population can be treated with a placebo instead of a calcium channel blocker.
- GFR measurements or any other measurements known in the art such as renal plasma flow using appropriate markers such as creatinine, inulin, iohexol, radioisotopes and other validated markers of dynamic renal function, urine concentrations of analytes such as protein and/or protein indexed to urine creatinine concentration, etc
- Amlodipine besylate at ca. 0.125 mg/kg to ca. 0.25 mg/kg was administered orally by tablet (0.2 mg, 0.4 mg, 0.8 mg and 1.2mg) to normotensive cats (systolic blood pressure of 160mm Hg or less as measured under standard conditions) once daily for a number of weeks, and measurements made at intervals to measure the effect on kidney function in cats presented as veterinary patients with renal problems.
- a number of cats were treated with an oral placebo tablet.
- Various breeds and crossbreeds of cats of approximately 6 months of age or older were used in the trial. Initial weights of 0.8kg to 9.6 kg were chosen, and the cats were either males or non-pregnant females (entire or neutered). For each animal, the body weight was used to select the appropriate tablet potency of amlodipine (0.125 to 0.25 mg/kg/day) according to the following table:
- amlodipine tablets used in the study were complemented by placebo tablets with the same excipients and which had the same dimensions and appearance.
- amlodipine besylate tablets used had the following compositions:
- the tablets were prepared using standard blending and direct compression techniques.
- the tablets described herein used the same excipients and manufacturing processes as the commercially available tablets.
- Chronic renal failure is generally considered an irreversible and progressive disease in cats.
- Chronic renal failure was diagnosed in each cat in this study.
- Cats were considered normotensive as defined by systolic arterial blood pressure less than 160 mm Hg prior to the onset of treatment.
- Cats were randomly assigned to treatment with either amlodipine besylate tablets at 0.125 to 0.25 mg/kg (as described above) or placebo tablets administered once daily by the oral route.
- Renal function was assessed by determining glomerular filtration rate (GFR).
- GFR glomerular filtration rate was estimated from plasma clearance of the exogenous marker, iohexol, approximately 7 days prior to the onset of treatment (day -7) and on approximately days 28, 56, 112, and 224 following onset of treatment.
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Abstract
Description
Claims
Applications Claiming Priority (3)
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GBGB0008332.9A GB0008332D0 (en) | 2000-04-04 | 2000-04-04 | Treament |
GB0008332 | 2000-04-04 | ||
PCT/IB2001/000518 WO2001074390A2 (en) | 2000-04-04 | 2001-03-28 | The use of a calcium channel blocker for treating renal disorders |
Publications (1)
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EP1284719A2 true EP1284719A2 (en) | 2003-02-26 |
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EP01914134A Withdrawn EP1284719A2 (en) | 2000-04-04 | 2001-03-28 | The use of a calcium channel blocker for treating renal disorders |
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EP (1) | EP1284719A2 (en) |
JP (1) | JP2003528927A (en) |
AR (1) | AR027763A1 (en) |
AU (1) | AU2001239510A1 (en) |
BR (1) | BR0109783A (en) |
CA (1) | CA2403950A1 (en) |
GB (1) | GB0008332D0 (en) |
MX (1) | MXPA02009819A (en) |
PA (1) | PA8514601A1 (en) |
PE (1) | PE20011163A1 (en) |
TN (1) | TNSN01051A1 (en) |
WO (1) | WO2001074390A2 (en) |
Families Citing this family (12)
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US7335380B2 (en) | 2000-12-29 | 2008-02-26 | Synthon Ip Inc. | Amlodipine free base |
CZ20031779A3 (en) * | 2000-12-29 | 2004-10-13 | Bioorganicsáb@V | Process for preparing amlodipine, its derivatives and precursors thereof |
AT5874U1 (en) * | 2000-12-29 | 2003-01-27 | Bioorg Bv | PHARMACEUTICAL PREPARATIONS CONTAINING AMLODIPINMALEAT |
RU2311903C2 (en) * | 2001-11-07 | 2007-12-10 | Синтон Б.В. | Tamzulosin tablets |
NL1019882C2 (en) * | 2002-02-01 | 2003-08-04 | Synthon Licensing | Pharmaceutical tablet composition useful for treating or preventing hypertension, angina or congestive heart failure comprises amlodipine free base |
CO5400144A1 (en) * | 2002-03-11 | 2004-05-31 | Novartis Ag | ORGANIC COMPOUNDS |
US7423009B2 (en) | 2002-09-30 | 2008-09-09 | Kowa Company, Ltd. | Method for treatment of kidney diseases |
EP1604664A4 (en) | 2003-01-31 | 2006-12-27 | Sankyo Co | Medicine for prevention of and treatment for arteriosclerosis and hypertension |
WO2006085208A2 (en) * | 2005-02-11 | 2006-08-17 | Ranbaxy Laboratories Limited | Stable solid dosage forms of amlodipine and benazepril |
US10130624B2 (en) | 2005-03-15 | 2018-11-20 | Lupin Limited | Pharmaceutical compositions of amlodipine and benazepril |
BRPI0611024A2 (en) * | 2005-04-29 | 2010-11-09 | Hills Pet Nutrition Inc | method for extending feline life, for delaying the onset of feline renal failure and for reducing morbidity and mortality from feline kidney disease, kit and means for communicating information or instructions related to the use of a diet having reduced levels of protein, phosphorus and sodium |
KR20180123021A (en) * | 2016-03-24 | 2018-11-14 | 다이이찌 산쿄 가부시키가이샤 | Medicines for the treatment of kidney disease |
Family Cites Families (6)
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GB8710493D0 (en) * | 1987-05-02 | 1987-06-03 | Pfizer Ltd | Dihydropyridines |
DK0459666T3 (en) * | 1990-05-31 | 1994-12-05 | Pfizer | Medicines for impotence |
NZ242724A (en) * | 1991-05-15 | 1994-09-27 | Du Pont | Synergistic composition comprising an angiotensin-ii receptor antagonist and a calcium channel blocker |
CA2124445A1 (en) * | 1991-11-26 | 1993-06-10 | James W. Young | Methods and compositions for treating hypertension, angina and other disorders using optically pure (-) amlodipine |
MX9706957A (en) * | 1995-03-16 | 1997-11-29 | Pfizer | Composition containing amlodipine, or a salt or felodipine and anace inhibitor. |
EP0795327A1 (en) * | 1996-03-13 | 1997-09-17 | Pfizer Inc. | Use of Amlodipine for the treatment and prophylaxis of congestive cardiac failure of non-ischaemic origin |
-
2000
- 2000-04-04 GB GBGB0008332.9A patent/GB0008332D0/en not_active Ceased
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2001
- 2001-03-28 CA CA002403950A patent/CA2403950A1/en not_active Abandoned
- 2001-03-28 MX MXPA02009819A patent/MXPA02009819A/en unknown
- 2001-03-28 AU AU2001239510A patent/AU2001239510A1/en not_active Abandoned
- 2001-03-28 WO PCT/IB2001/000518 patent/WO2001074390A2/en not_active Application Discontinuation
- 2001-03-28 JP JP2001572132A patent/JP2003528927A/en not_active Abandoned
- 2001-03-28 BR BR0109783-0A patent/BR0109783A/en not_active IP Right Cessation
- 2001-03-28 EP EP01914134A patent/EP1284719A2/en not_active Withdrawn
- 2001-04-02 PE PE2001000305A patent/PE20011163A1/en not_active Application Discontinuation
- 2001-04-03 PA PA20018514601A patent/PA8514601A1/en unknown
- 2001-04-03 TN TNTNSN01051A patent/TNSN01051A1/en unknown
- 2001-04-03 AR ARP010101580A patent/AR027763A1/en not_active Application Discontinuation
Non-Patent Citations (1)
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See references of WO0174390A2 * |
Also Published As
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PE20011163A1 (en) | 2001-11-12 |
MXPA02009819A (en) | 2003-03-27 |
PA8514601A1 (en) | 2002-08-26 |
BR0109783A (en) | 2003-01-21 |
GB0008332D0 (en) | 2000-05-24 |
CA2403950A1 (en) | 2001-10-11 |
AU2001239510A1 (en) | 2001-10-15 |
WO2001074390A2 (en) | 2001-10-11 |
AR027763A1 (en) | 2003-04-09 |
TNSN01051A1 (en) | 2005-11-10 |
WO2001074390A3 (en) | 2002-05-30 |
JP2003528927A (en) | 2003-09-30 |
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