CA1298784C - Pharmaceutical formulations with controlled release of the active substance - Google Patents
Pharmaceutical formulations with controlled release of the active substanceInfo
- Publication number
- CA1298784C CA1298784C CA000519302A CA519302A CA1298784C CA 1298784 C CA1298784 C CA 1298784C CA 000519302 A CA000519302 A CA 000519302A CA 519302 A CA519302 A CA 519302A CA 1298784 C CA1298784 C CA 1298784C
- Authority
- CA
- Canada
- Prior art keywords
- formulation according
- isradipine
- formulation
- controlled release
- fatty material
- 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.)
- Expired - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- 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
-
- 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
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2013—Organic compounds, e.g. phospholipids, fats
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/485—Inorganic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4858—Organic compounds
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
- A61K9/4841—Filling excipients; Inactive ingredients
- A61K9/4866—Organic macromolecular compounds
Abstract
Case 100-6717 Abstract of the Disclosure A controlled release formulation for oral administration comprising - an active substance chosen from the group of Pindolol and a 4-(2,1, 3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester, - a pharmaceutically acceptable hydrophilic swellable substance and containing optionally a pharmaceutically acceptable inert fatty material in addition.
The formulation has an excellent bioavailability and practically no food interaction after administration.
The formulation has an excellent bioavailability and practically no food interaction after administration.
Description
2 9 ~
Case 100-6717 Pharmaceutical formulations with controlled release of the active substance This invention relates to pharmaceutical formulations with controlled release of active substances having an influence on blood circulation, including the heart and chosen from the group of Pindolol and a 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester, especially Darodipine and Isradipine.
Darodipine is the generic name of diethyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.
10 ' It is disclosed in the British Patent GB 2.037766 B. For pharmaceutical use Darodipine is used as the free base.
The pharmacological and clinical properties have been extensively reviewed. Darodipine is a potent calcium antagonist on isolated coronary arteries and other peripheral blood vessels. Haemodynamic studies in healthy subjects show a reduction in total peripheral resistance and arterial blood pressure.
Darodipine is indicated for the treatment of angina pectoris, of hypertension, of stroke and of cerebral vasospasms.
Usual oral daily dosages are e.g. for the treatment of angina pectoris 75 to 300 mg, preferably given in 3 divided doses and for the treatment of hypertension 37.5 to 150 mg, given in 2 to 3 divided doses.
"~
, - 2 - Case 100-6717 Pindolol is the generic name of l-(lH-Indol-4-yloxy)-3-[(1-methyl ethyl)amino]-2-propanol and is described in the British Fatent No 1.138.969.
For pharmaceutical use Pindolol is preferably used in the form of the free base. The pharmacological and clinical properties have been extensively reviewed.
Pindolol is a ~-adrenoceptor antagonist (~-blocker). It acts on both ~1- and ~2-adrenoceptors. It protects the heart against excessive stimulation by catecholamines during physical and mental stress and also at rest; its intrinsic sympathomimetic activity (ISA), however, provides the heart with basal stimulation similar to that elicited by normal resting sympathetic activity. Heart rate and contractility at rest and intracardiac conduction are thus not unduly depressed.
As a consequence, the risk of bradycardia or of heart block is small and a non-elevated cardiac output is not reduced. The high vascular resistance of established hypertension is lowered by Pindolol and thus tissue and organ perfusion is not impaired.
Pindolol is indicated for the treatment of, inter alia - Arterial hypertension, - Angina pectoris (prevention of attacks).
- Sinus and atrial tachycardia, paroxysmal tachycardia, tachycardia in patients with atrial flutter or fibrillation.
supraventricular and ventricular extrasystoles, drug-induced extrasystoles (digitalis) and - Hyperkinetic heart syndrome and is normally administered orally.
lZ98784 - 3 - Case 100-6717 The oral dosage is adapted to the requirements of the individual patient and is usually within the range of 10-30 mg per day.
For arterial hypertension, S to 15 mg are given as a single daily dose in the morning. Alternatively 20-30 mg are divided into 2 or 3 doses per day.
For angina pectoris and cardiac arrhythmias, the daily dosage of 10-30 mg is generally divided into 2 or 3 single doses.
For hyperkinetic heart syndrome, the dosage is 10-20 mg, usually once a day, preferably in retard form.
Isradipine is the generic name of isopropyl methyl-4-(2,1,3-benzoxa-diazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate.
It is generally administered as the free base.
It is disclosed in the British Patent GB 2.037.766 B.
The pharmacological and clinical properties of Isradipine have been extensively investigated. It is a potent calcium antagonist and influences in particular the coronary and the peripheral arteries.
The drug is especially indicated for the treatment of e.g. hyper-tension, angina pectoris and cerebral insufficiency.
Usual oral daily dosages are 10 to 20 mg, preferably divided into smaller dosages of 5 to 10 mg two times a day.
The administration of the active substances mentioned above can occasionally be associated with adverse side effects, e.g. head-aches in case of Darodipine, tiredness, dizziness, gastrointestinal disturbances (mainly nausea), headache, sleep disturbances (e.g.
vivid dreams), when Pindolol and headache, flush, palpitation and lZ9878~
Case 100-6717 Pharmaceutical formulations with controlled release of the active substance This invention relates to pharmaceutical formulations with controlled release of active substances having an influence on blood circulation, including the heart and chosen from the group of Pindolol and a 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester, especially Darodipine and Isradipine.
Darodipine is the generic name of diethyl-4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridinedicarboxylate.
10 ' It is disclosed in the British Patent GB 2.037766 B. For pharmaceutical use Darodipine is used as the free base.
The pharmacological and clinical properties have been extensively reviewed. Darodipine is a potent calcium antagonist on isolated coronary arteries and other peripheral blood vessels. Haemodynamic studies in healthy subjects show a reduction in total peripheral resistance and arterial blood pressure.
Darodipine is indicated for the treatment of angina pectoris, of hypertension, of stroke and of cerebral vasospasms.
Usual oral daily dosages are e.g. for the treatment of angina pectoris 75 to 300 mg, preferably given in 3 divided doses and for the treatment of hypertension 37.5 to 150 mg, given in 2 to 3 divided doses.
"~
, - 2 - Case 100-6717 Pindolol is the generic name of l-(lH-Indol-4-yloxy)-3-[(1-methyl ethyl)amino]-2-propanol and is described in the British Fatent No 1.138.969.
For pharmaceutical use Pindolol is preferably used in the form of the free base. The pharmacological and clinical properties have been extensively reviewed.
Pindolol is a ~-adrenoceptor antagonist (~-blocker). It acts on both ~1- and ~2-adrenoceptors. It protects the heart against excessive stimulation by catecholamines during physical and mental stress and also at rest; its intrinsic sympathomimetic activity (ISA), however, provides the heart with basal stimulation similar to that elicited by normal resting sympathetic activity. Heart rate and contractility at rest and intracardiac conduction are thus not unduly depressed.
As a consequence, the risk of bradycardia or of heart block is small and a non-elevated cardiac output is not reduced. The high vascular resistance of established hypertension is lowered by Pindolol and thus tissue and organ perfusion is not impaired.
Pindolol is indicated for the treatment of, inter alia - Arterial hypertension, - Angina pectoris (prevention of attacks).
- Sinus and atrial tachycardia, paroxysmal tachycardia, tachycardia in patients with atrial flutter or fibrillation.
supraventricular and ventricular extrasystoles, drug-induced extrasystoles (digitalis) and - Hyperkinetic heart syndrome and is normally administered orally.
lZ98784 - 3 - Case 100-6717 The oral dosage is adapted to the requirements of the individual patient and is usually within the range of 10-30 mg per day.
For arterial hypertension, S to 15 mg are given as a single daily dose in the morning. Alternatively 20-30 mg are divided into 2 or 3 doses per day.
For angina pectoris and cardiac arrhythmias, the daily dosage of 10-30 mg is generally divided into 2 or 3 single doses.
For hyperkinetic heart syndrome, the dosage is 10-20 mg, usually once a day, preferably in retard form.
Isradipine is the generic name of isopropyl methyl-4-(2,1,3-benzoxa-diazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate.
It is generally administered as the free base.
It is disclosed in the British Patent GB 2.037.766 B.
The pharmacological and clinical properties of Isradipine have been extensively investigated. It is a potent calcium antagonist and influences in particular the coronary and the peripheral arteries.
The drug is especially indicated for the treatment of e.g. hyper-tension, angina pectoris and cerebral insufficiency.
Usual oral daily dosages are 10 to 20 mg, preferably divided into smaller dosages of 5 to 10 mg two times a day.
The administration of the active substances mentioned above can occasionally be associated with adverse side effects, e.g. head-aches in case of Darodipine, tiredness, dizziness, gastrointestinal disturbances (mainly nausea), headache, sleep disturbances (e.g.
vivid dreams), when Pindolol and headache, flush, palpitation and lZ9878~
- 4 - Case 100-6717 tachycardia, when Isradipine is administered.
We have now found it is preferred to keep the concentration of the active substance at a therapeutically active level between narrow limits and to avoid the usual drug burst just after administration of non-controlled release preparations, which leads to temporary high b100d levels and to proportionately strong adverse effects.
Therapy can be improved by administering two or three times a day smaller doses, the sum of which equals the total daily dosage.
However, this manner is cumbersome and still does not meet the requirement of providing blood levels of active substance only between narrow limits.
The present invention provides a controlled release formulation of the active substances having a prolonged action of the active substance to reduce the number of times the active substance has to be administered each day and to reduce certain adverse reactions.
Additionally the present formulations provide under the test conditions excellent bioavailability in food interaction studies, e.g. as described in Examples 3 and 18 hereinafter.
The present invention accordingly provides a controlled release formulation for oral administration comprising an active substance chosen from the - group of Pindolol and a 4-~2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6 -dimethyl-3,5-pyridine dicarboxylate ester - a pharmaceutically acceptable hydrophilic swellable substance and optionally - a pharmaceutically acceptable inert fatty material.
We have now found it is preferred to keep the concentration of the active substance at a therapeutically active level between narrow limits and to avoid the usual drug burst just after administration of non-controlled release preparations, which leads to temporary high b100d levels and to proportionately strong adverse effects.
Therapy can be improved by administering two or three times a day smaller doses, the sum of which equals the total daily dosage.
However, this manner is cumbersome and still does not meet the requirement of providing blood levels of active substance only between narrow limits.
The present invention provides a controlled release formulation of the active substances having a prolonged action of the active substance to reduce the number of times the active substance has to be administered each day and to reduce certain adverse reactions.
Additionally the present formulations provide under the test conditions excellent bioavailability in food interaction studies, e.g. as described in Examples 3 and 18 hereinafter.
The present invention accordingly provides a controlled release formulation for oral administration comprising an active substance chosen from the - group of Pindolol and a 4-~2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6 -dimethyl-3,5-pyridine dicarboxylate ester - a pharmaceutically acceptable hydrophilic swellable substance and optionally - a pharmaceutically acceptable inert fatty material.
- 5 - Case 100-6717 In other aspect the present invention provides a controlled release formulation for oral administration and containing Pindolol, and having a relative bioavailability of more than 85% compared with a non controlled release oral Pindolol formulation on administration to a subject in the fasted state.
In a further aspect the present invention provides a controlled re-lease formulation for oral administration and containing Isradipine, and having a relative bioavailability of more than 65% compared with a non controlled release oral Isradipine formulation on administration to a subject in the fasted state.
In an additional aspect the present invention provides a controlled release formulation for oral administration comprising an active substance chosen from the group of Pindolol and a 4-(2,1,3-benzoxa-diazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester), having bioavailability differences on administration to a subject in the fasted state and to a subject in the unfasted state of at most 20%.
~25~84 - 6 - Case 100-6717 Preferred amounts of Darodipine in unit dosage form are from 10 to 200 mg, especially 20 to 150, e.g. 100 mg.
Preferred amounts of Pindolol in unit dosage form are from 10 to 20 mg, especially 15 and 20 mg. Preferably Pindolol is in the base form, but an acid addition salt form is possible as well.
Preferred amDunts of Isradipine in unit dosage form are from 5 to 40 mg, especially 10 to 20 mg.
Preferred swellable substance is a cellulose compound, which in water turns into a colloid.
~ Hydrophilic swellable substances that are preferred include one or more natural, partially or totally synthetic, anionic or, preferably, nonionic hydrophilic gums, modified cellulose substances or protein aceous substances such as, for example, acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, agar, peptin, carrageen, soluble and insoluble alginates, methyl-cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxypoly-methylene, gelatin.
Preferred are cellulose hydrocolloids which include methylcellulose, hydroxypropylcellulose and especially hydroxypropylmethylcellulose and sodium carboxymethylcellulose.
Preferably the weight ratio of Darodipine to swellable substance is from 1:0.2 to 1:2, especially from 1:0.5 to 1, of Pindolol to swellable substance from 1:5 to 1:20 especially from 1:8 to 1:15 and of Isradipine to swellable substance from 1:2 to 1:20, especially from 1:4 to 1:10.
In a further aspect the present invention provides a controlled re-lease formulation for oral administration and containing Isradipine, and having a relative bioavailability of more than 65% compared with a non controlled release oral Isradipine formulation on administration to a subject in the fasted state.
In an additional aspect the present invention provides a controlled release formulation for oral administration comprising an active substance chosen from the group of Pindolol and a 4-(2,1,3-benzoxa-diazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester), having bioavailability differences on administration to a subject in the fasted state and to a subject in the unfasted state of at most 20%.
~25~84 - 6 - Case 100-6717 Preferred amounts of Darodipine in unit dosage form are from 10 to 200 mg, especially 20 to 150, e.g. 100 mg.
Preferred amounts of Pindolol in unit dosage form are from 10 to 20 mg, especially 15 and 20 mg. Preferably Pindolol is in the base form, but an acid addition salt form is possible as well.
Preferred amDunts of Isradipine in unit dosage form are from 5 to 40 mg, especially 10 to 20 mg.
Preferred swellable substance is a cellulose compound, which in water turns into a colloid.
~ Hydrophilic swellable substances that are preferred include one or more natural, partially or totally synthetic, anionic or, preferably, nonionic hydrophilic gums, modified cellulose substances or protein aceous substances such as, for example, acacia, gum tragacanth, locust bean gum, guar gum, karaya gum, agar, peptin, carrageen, soluble and insoluble alginates, methyl-cellulose, hydroxypropylmethylcellulose, hydroxypropylcellulose, hydroxyethylcellulose, sodiumcarboxymethylcellulose, carboxypoly-methylene, gelatin.
Preferred are cellulose hydrocolloids which include methylcellulose, hydroxypropylcellulose and especially hydroxypropylmethylcellulose and sodium carboxymethylcellulose.
Preferably the weight ratio of Darodipine to swellable substance is from 1:0.2 to 1:2, especially from 1:0.5 to 1, of Pindolol to swellable substance from 1:5 to 1:20 especially from 1:8 to 1:15 and of Isradipine to swellable substance from 1:2 to 1:20, especially from 1:4 to 1:10.
- 7 - Case 100-6717 Suitable pharmaceutically acceptable inert fatty materials include beeswax; fatty acidsi long chain fatty alcohols, such as, for example, cetyl alcohol, myristyl alcohol, stearyl alcohol, esters, e.g. glycerides such as glyceryl esters of fatty acids or hydrogenated aliphatic acids such as, for example, glyceryl mono-stearate, glyceryl distearate, glyceryl esters of hydrogenated castor oil and the like; oils such as mineral oil and the like. Fatty materials are preferably such with melting points between 30 and 90C.
Most preferably fatty materials have a melting point from 45C to 65C
and include glycerides such as glyceryl palmitates and stearates and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.
Preferably the weight ratio of Darodipine to the fatty material is from 10:10.2 to 10:5, especially 10:0.5 to 10:1; of Pindolol to the fatty material from 1:0.1 to 1:3, particularly 1:0.1 to 1:2, especially 1:0.25 to 1:1.4and of Isradipine to the fatty material from 1:0.3 to 1:2, especially 1:0.5 to 1:1.5, in particular 1:0.5 to 1:1.
The formulations contain preferably both hydroxypropyl-methyl-cellulose as a swellable agent and cetyl palmitate as a fatty material.
It is also convenient to incorporate in the formulation at least one of other soluble or insoluble pharmaceutical excipients such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silica, and magnesium stearate. Preferably a soluble excipient, especially lactose is present.
If these other excipients are present, then the weight ratio of Darodipine to the other excipients is conveniently fram 10:1 to ' .
, , , - 8 - Case 100-6717 1:2, especially 5:1 to 1:1; of Pindolol to the other excipients from 1:0.2 to 1:10 especially 1:0.3 to 1:5 and of Isradipine to the other excipients from 1:4 to 1:15, especially 1:5 to 1:10.
The formulation may be produced in conventional manner by mixing the ingredients together, preferably melting the fatty material.
The resultant mixture is in powder form. The powder can be pressed to form a tablet, but is preferably filled into a capsule.
If the fatty material is melted, the drug and additional excipients such as lactose, silica, calcium sulphate or calcium phosphate may be taken up in the molten fatty material. The mixture is the~
allowed to solidify and is then divided into small particles (granules).
The resultant granulate may be mixed with a, preferably porous, hydrophilic swellable substance and further excipients, e.g.
magnesium stearate, and the mixture may be pressed to form a tablet or may be preferably filled into a capsule.
In a preferred aspect the present invention accordingly provides a formulation containing the active substance in a fatty material matrix granulate, the granulate particles being in contact with a 2 0 hydrophilic swelling substance.
Preferably the swellable substance is present in a porous form.
We have surprisingly found that the formulations possess an excellent stability, despite the fact that the active substances are sensitive to many chemical reagents. Moreover, the formulations have a satisfactory pharmacodynamic and pharmacokinetic profile.
lZ98784 - 9 - Case lO0-67l7 The resultant formulations in general have comparable bio-availability in standard clinical trials to conventional non-retarded formulations containing the same amounts of active substances. The formulations of the invention, even if administered once a day, may produce a therapeutic effect for at least 24 hours and even as much as 35 hours. The formulation for Darodipine and Isradipine may be administeredonly once a day in the known indications of the active substances at approximately the same daily doses as employed in the conventional non-retarded forms. Steady state studies show a narrow range between maximum and minimum active substance levels in the blood.
The formulation for Pindolol may be administered twice a day.
The formulations of the present invention are well tolerated.
Moreover, the present formulations provide similar profiles of activity in food interaction studies, e.g. before and after administration of breakfast, with fasted subjects.
The once-a-day formulations may be formulated in conventional manner, e.g. to be a capsule or tablet and may contain from lO to 200 mg of active substance. Preferably they have the release profile as determined by in vivo or in vitro dissolution test, e.g. a release of about 34 percent of Darodipin, 50 to 75 percent of Pindolol and 50 to 65 percent of Isradipin over 6 hours in O.l NHCl, e.g. as in the experimental conditions in Examples l, 2 to 5, 16 and 17.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
Further information on the properties etc. of the pharmaceutical excipients named hereinafter may be obtained from the manufacturer, listed hereinafter, manufacturer's brochures or other sources, ~25~ 4 - 10 - Case 100-6717 especially H.P. Fiedler Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, 2nd Edition 1981, Edito Cantor, Aulendorf, W-Germany.
Silicon dioxide (silica) is e.g. brand Aerosil 200 available from Deutsche-Gold und Silberscheideanstalt, Frankfurt, W-Germany.
Glycerol ditripalmitostearat is e.g. brand Precirol Ato 5@'available from ETS Gattefosse 929100 Boulogne-Brillancourt, France.
Hydroxypropylmethylcellulose 15000 cps and 4000 cps are e.g. brands Methocel KlSM and Methocel 4EM available from Dow Chemical Company, 0 Michigan 48640 USA.
Cetyl palmitate is e.g. brand Cutina~'CPA available from Henkel 4000, Dusseldorf, W-Germany, or is available from Gattefosse or from A/S
Johan C. Martens and Company, Bergen, Norway.
12g~7~4 - 11 - Case 100-6717 Example 1:
Ingredient mg a) Darodipine 100 b) Lactose (200 mesh) 30 c) Cetyl palmitate 8 d) Hydroxypropylmethylcellulose ( 100 . 000 GpS ) 60 e) Mg stearate 2 10 P~reparation Ingredients a) and b) are sieved and mixed.
Ingredient c) is melted by heating to 60 and is added to the mixture which is heated to 55C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The rushed mass is broken up and sieved tthrough 250 micron openings). Ingredients d) and e) are sieved (through 360 micron openings) and mixed in over 10 minutes. The mixture is then encapsulated.
In vitro release Time (hours)Release of Darodipine 129878~
_ 12 Case l00-67l7 EXAMPLE 2: Capsule Ingredient mg a) Isradipine lO
b) Lactose 97 c) Glycerol ditripalmitostearatelO
d) Hydroxypropylmethylcellulose 4~00 cps 60 e) Silica f) ,~agnesium Stearate 2 Preparation (Charge of 6000 capsules) Ingredients a) and b) are sieved and mixed, Ingredient c) is melted by heating to 56C (m.p. 54C) and is added to the mixture , which is heated to 55C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The rushed mass is broken up and sieved (through 250 micron openings).
Ingredients d), e) and f) are sieved (through 360 micron openings) and mixed in over lO minutes. The mixture is then encapsulated.
In vitro release Time (hours) Release %
2 l9 24 l02 ~-fi= ":
-- , . ~
, 129~784 - 13 - Case 100-6717 EXAMPLE 3: Capsule Ingredients mg a) Isradipine 10 b) Microcristalline cellulose 97 c) Cetyl palmitate 5 d) Hydroxypropylmethylcellulose 4000 45 cps e) Silica f) Magnesium stearate 2 Preparation In analogous manner to that disclosed in Example.2 In vitro release Time (hours) Release %
20EXAMPLE 4: Capsule Ingredients mg In a clinical test a very good retard profile and a) Isradipine 10 relative bioavailability of the composition of b) Microcrystalline cellulose 47 Example 4 ln fasted and c) Cetyl palmitate 10 in non-fasted subjects could be established, d) Hydroxypropylmethyl cellulose 15000 compared with non-retarded cps 90 capsules containing the e) Silica 1 same amount of Isradipine.
f) Magnesium stearate 2 ~P
.:
~2~3~7~34 -14 - Case l00-67l7 Preparation In analogous manner to that disclosed in Example 2 .
In vivo release In a study to evaluate the bioavailability of the capsule of Example 4, this capsule and a reference capsule containing Isradipine in a non-prolonged release form were administered to fasting subjects.
The prolonged release capsule was additionally administered to non-fasted subjects.
The composition of the conventional reference capsule containing Isradipine in a non-prolonged release form was as follows:
Ingredients mg a) Isradipine lO
b) Lactose l67 c) Corn starch l28 d) Sodium laurylsulphate 5.5 e) Silica 1.5 f) Polyethylenglycol 6000 8.0 The study employed an open-label three~way randomized crossover desi~gn in 9 healthy male volunteers, $ubjects were given a single oral dose of either a non-prolonged release reference capsule (lO mg) in the fasted state or a prolonged release capsule according to Example 4 ~lO mg) in the fasted and in the non-fasted state. The intervals between the three different administration periods were at least 7 days.
.
~ . ~
~2~137l34 - 15 - Case 100-6717 Blood samples of each volunteer were collected from 0 to 48 hours after each dose and plasma was analysed for Isradipine by using a R~A technique (detection limit 0.1 nanogramlml).
The mean temporal plasma concentration data are plotted graphically in figure 2, in which O = 10 mg prolonged release capsule in the fasted state O = 10 mg prolonged release capsule in the non-fasted state and L~ = 10 mg conventional non~prolonged release capsule.
Plasmaconcentration in nanogram/ml vs. time in hours From the curves the following data are calculated:
Prolonged release Prolonged release Reference capsule (10 mg) capsule (10 mg) tablet (10 mg) non-fasted state fasted state fasted state AUCo8 34.73 34.67 49.65 in ng hlml Cmax 3,70 1.77 14,22 in ng/ml -Tmax 8,55 9 1,89 (in h~urs) Geometri.~c mean for n = 9 sub.jects, ~UC08 = .~erea under the curve from 0 to 48 hours.
Compared with the reference form the relative bioavailability is more than 65%.
. ~
Most preferably fatty materials have a melting point from 45C to 65C
and include glycerides such as glyceryl palmitates and stearates and fatty acids such as hydrogenated castor oil and fatty acid esters such as cetyl palmitate.
Preferably the weight ratio of Darodipine to the fatty material is from 10:10.2 to 10:5, especially 10:0.5 to 10:1; of Pindolol to the fatty material from 1:0.1 to 1:3, particularly 1:0.1 to 1:2, especially 1:0.25 to 1:1.4and of Isradipine to the fatty material from 1:0.3 to 1:2, especially 1:0.5 to 1:1.5, in particular 1:0.5 to 1:1.
The formulations contain preferably both hydroxypropyl-methyl-cellulose as a swellable agent and cetyl palmitate as a fatty material.
It is also convenient to incorporate in the formulation at least one of other soluble or insoluble pharmaceutical excipients such as calcium sulfate, calcium phosphate, lactose, mannitol, sucrose, sorbitol, colloidal silica, and magnesium stearate. Preferably a soluble excipient, especially lactose is present.
If these other excipients are present, then the weight ratio of Darodipine to the other excipients is conveniently fram 10:1 to ' .
, , , - 8 - Case 100-6717 1:2, especially 5:1 to 1:1; of Pindolol to the other excipients from 1:0.2 to 1:10 especially 1:0.3 to 1:5 and of Isradipine to the other excipients from 1:4 to 1:15, especially 1:5 to 1:10.
The formulation may be produced in conventional manner by mixing the ingredients together, preferably melting the fatty material.
The resultant mixture is in powder form. The powder can be pressed to form a tablet, but is preferably filled into a capsule.
If the fatty material is melted, the drug and additional excipients such as lactose, silica, calcium sulphate or calcium phosphate may be taken up in the molten fatty material. The mixture is the~
allowed to solidify and is then divided into small particles (granules).
The resultant granulate may be mixed with a, preferably porous, hydrophilic swellable substance and further excipients, e.g.
magnesium stearate, and the mixture may be pressed to form a tablet or may be preferably filled into a capsule.
In a preferred aspect the present invention accordingly provides a formulation containing the active substance in a fatty material matrix granulate, the granulate particles being in contact with a 2 0 hydrophilic swelling substance.
Preferably the swellable substance is present in a porous form.
We have surprisingly found that the formulations possess an excellent stability, despite the fact that the active substances are sensitive to many chemical reagents. Moreover, the formulations have a satisfactory pharmacodynamic and pharmacokinetic profile.
lZ98784 - 9 - Case lO0-67l7 The resultant formulations in general have comparable bio-availability in standard clinical trials to conventional non-retarded formulations containing the same amounts of active substances. The formulations of the invention, even if administered once a day, may produce a therapeutic effect for at least 24 hours and even as much as 35 hours. The formulation for Darodipine and Isradipine may be administeredonly once a day in the known indications of the active substances at approximately the same daily doses as employed in the conventional non-retarded forms. Steady state studies show a narrow range between maximum and minimum active substance levels in the blood.
The formulation for Pindolol may be administered twice a day.
The formulations of the present invention are well tolerated.
Moreover, the present formulations provide similar profiles of activity in food interaction studies, e.g. before and after administration of breakfast, with fasted subjects.
The once-a-day formulations may be formulated in conventional manner, e.g. to be a capsule or tablet and may contain from lO to 200 mg of active substance. Preferably they have the release profile as determined by in vivo or in vitro dissolution test, e.g. a release of about 34 percent of Darodipin, 50 to 75 percent of Pindolol and 50 to 65 percent of Isradipin over 6 hours in O.l NHCl, e.g. as in the experimental conditions in Examples l, 2 to 5, 16 and 17.
In the following examples all temperatures are in degrees Centigrade and are uncorrected.
Further information on the properties etc. of the pharmaceutical excipients named hereinafter may be obtained from the manufacturer, listed hereinafter, manufacturer's brochures or other sources, ~25~ 4 - 10 - Case 100-6717 especially H.P. Fiedler Lexikon der Hilfsstoffe fur Pharmazie, Kosmetik und angrenzende Gebiete, 2nd Edition 1981, Edito Cantor, Aulendorf, W-Germany.
Silicon dioxide (silica) is e.g. brand Aerosil 200 available from Deutsche-Gold und Silberscheideanstalt, Frankfurt, W-Germany.
Glycerol ditripalmitostearat is e.g. brand Precirol Ato 5@'available from ETS Gattefosse 929100 Boulogne-Brillancourt, France.
Hydroxypropylmethylcellulose 15000 cps and 4000 cps are e.g. brands Methocel KlSM and Methocel 4EM available from Dow Chemical Company, 0 Michigan 48640 USA.
Cetyl palmitate is e.g. brand Cutina~'CPA available from Henkel 4000, Dusseldorf, W-Germany, or is available from Gattefosse or from A/S
Johan C. Martens and Company, Bergen, Norway.
12g~7~4 - 11 - Case 100-6717 Example 1:
Ingredient mg a) Darodipine 100 b) Lactose (200 mesh) 30 c) Cetyl palmitate 8 d) Hydroxypropylmethylcellulose ( 100 . 000 GpS ) 60 e) Mg stearate 2 10 P~reparation Ingredients a) and b) are sieved and mixed.
Ingredient c) is melted by heating to 60 and is added to the mixture which is heated to 55C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The rushed mass is broken up and sieved tthrough 250 micron openings). Ingredients d) and e) are sieved (through 360 micron openings) and mixed in over 10 minutes. The mixture is then encapsulated.
In vitro release Time (hours)Release of Darodipine 129878~
_ 12 Case l00-67l7 EXAMPLE 2: Capsule Ingredient mg a) Isradipine lO
b) Lactose 97 c) Glycerol ditripalmitostearatelO
d) Hydroxypropylmethylcellulose 4~00 cps 60 e) Silica f) ,~agnesium Stearate 2 Preparation (Charge of 6000 capsules) Ingredients a) and b) are sieved and mixed, Ingredient c) is melted by heating to 56C (m.p. 54C) and is added to the mixture , which is heated to 55C. The mass is stirred for 2 minutes or until it is a homogenous mixture and cooled overnight. The rushed mass is broken up and sieved (through 250 micron openings).
Ingredients d), e) and f) are sieved (through 360 micron openings) and mixed in over lO minutes. The mixture is then encapsulated.
In vitro release Time (hours) Release %
2 l9 24 l02 ~-fi= ":
-- , . ~
, 129~784 - 13 - Case 100-6717 EXAMPLE 3: Capsule Ingredients mg a) Isradipine 10 b) Microcristalline cellulose 97 c) Cetyl palmitate 5 d) Hydroxypropylmethylcellulose 4000 45 cps e) Silica f) Magnesium stearate 2 Preparation In analogous manner to that disclosed in Example.2 In vitro release Time (hours) Release %
20EXAMPLE 4: Capsule Ingredients mg In a clinical test a very good retard profile and a) Isradipine 10 relative bioavailability of the composition of b) Microcrystalline cellulose 47 Example 4 ln fasted and c) Cetyl palmitate 10 in non-fasted subjects could be established, d) Hydroxypropylmethyl cellulose 15000 compared with non-retarded cps 90 capsules containing the e) Silica 1 same amount of Isradipine.
f) Magnesium stearate 2 ~P
.:
~2~3~7~34 -14 - Case l00-67l7 Preparation In analogous manner to that disclosed in Example 2 .
In vivo release In a study to evaluate the bioavailability of the capsule of Example 4, this capsule and a reference capsule containing Isradipine in a non-prolonged release form were administered to fasting subjects.
The prolonged release capsule was additionally administered to non-fasted subjects.
The composition of the conventional reference capsule containing Isradipine in a non-prolonged release form was as follows:
Ingredients mg a) Isradipine lO
b) Lactose l67 c) Corn starch l28 d) Sodium laurylsulphate 5.5 e) Silica 1.5 f) Polyethylenglycol 6000 8.0 The study employed an open-label three~way randomized crossover desi~gn in 9 healthy male volunteers, $ubjects were given a single oral dose of either a non-prolonged release reference capsule (lO mg) in the fasted state or a prolonged release capsule according to Example 4 ~lO mg) in the fasted and in the non-fasted state. The intervals between the three different administration periods were at least 7 days.
.
~ . ~
~2~137l34 - 15 - Case 100-6717 Blood samples of each volunteer were collected from 0 to 48 hours after each dose and plasma was analysed for Isradipine by using a R~A technique (detection limit 0.1 nanogramlml).
The mean temporal plasma concentration data are plotted graphically in figure 2, in which O = 10 mg prolonged release capsule in the fasted state O = 10 mg prolonged release capsule in the non-fasted state and L~ = 10 mg conventional non~prolonged release capsule.
Plasmaconcentration in nanogram/ml vs. time in hours From the curves the following data are calculated:
Prolonged release Prolonged release Reference capsule (10 mg) capsule (10 mg) tablet (10 mg) non-fasted state fasted state fasted state AUCo8 34.73 34.67 49.65 in ng hlml Cmax 3,70 1.77 14,22 in ng/ml -Tmax 8,55 9 1,89 (in h~urs) Geometri.~c mean for n = 9 sub.jects, ~UC08 = .~erea under the curve from 0 to 48 hours.
Compared with the reference form the relative bioavailability is more than 65%.
. ~
Claims (15)
1. A controlled release formulation for oral administration which comprises:
(a) an active substance comprising a 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester;
(b) a pharmaceutically acceptable hydrophilic swellable substance and (c) a pharmaceutically acceptable inert fatty material.
(a) an active substance comprising a 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester;
(b) a pharmaceutically acceptable hydrophilic swellable substance and (c) a pharmaceutically acceptable inert fatty material.
2. A formulation according to claim 1, wherein the active substance is Isradipine.
3. A formulation according to claim 1, wherein the swellable substance is a cellulose hydrocolloid.
4. A formulation according to claim 1, wherein the swellable substance is hydroxypropylmethylcellulose.
5. A formulation according to claim 1, 2, 3 or 4 wherein the fatty material is a hydrophobic material with a melting point between 30 and 90°C.
6. A formulation according to claim 1, 2, 3 or 4 wherein the fatty material is a fatty acid ester.
7. A formulation according to claim 1, 2, 3 or 4 wherein the fatty material is cetyl palmitate.
8. A formulation according to claim 1 or 2 containing of from 5 to 40 mg of Isradipine.
9. A formulation according to claim 1 or 2, wherein the weight ratio of Isradipine to the swellable substance is from 1:2 to 1:20.
10. A formulation according to claim 1 or 2, wherein the weight ratio of Isradipine to the fatty material is from 1:0.3 to 1:2.
11. A formulation according to claim 1 or 2 containing Hydroxypropylmethylcellulose as a swellable agent and cetyl palmitate as a fatty material.
12. A formulation according to claim 1 or 2 containing the active substance in a fatty material matrix granulate, the granulate particles being in contact with a hydrophilic swelling substance.
13. A formulation according to claim 1 or 2 for use in the treatment of disorders of the blood circulation, comprising a dosage unit containing 5 to 40 mg of Isradipine.
14. A controlled release formulation for oral administration according to claim 1 or 2 and containing Isradipine, and having a relative bioavailability of more than 65% compared with a non controlled release oral Isra-dipine formulation on administration to a subject in the fasted state.
15. A controlled release formulation for oral administration according to claim 1 or 2 comprising as active substance a 4-(2,1,3-benzoxadiazol-4-yl)-1,4-dihydro-2,6-dimethyl-3,5-pyridine dicarboxylate ester), having bioavailability differences on administration to a subject in the fasted state and to a subject in the unfasted state of at most 20%.
Applications Claiming Priority (10)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GB8524135 | 1985-10-01 | ||
| GB858524135A GB8524135D0 (en) | 1985-10-01 | 1985-10-01 | Darodipine compositions |
| GB858524653A GB8524653D0 (en) | 1985-10-07 | 1985-10-07 | Pharmaceutical formulations |
| GB8524653 | 1985-10-07 | ||
| GB858531419A GB8531419D0 (en) | 1985-12-20 | 1985-12-20 | Pindolol compositions |
| GB8531419 | 1985-12-20 | ||
| GB868603097A GB8603097D0 (en) | 1986-02-07 | 1986-02-07 | Pharmaceutical formulations |
| GB8603097 | 1986-02-07 | ||
| GB8605037 | 1986-02-28 | ||
| GB868605037A GB8605037D0 (en) | 1986-02-28 | 1986-02-28 | Oral pharmaceutical compositions |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1298784C true CA1298784C (en) | 1992-04-14 |
Family
ID=27516617
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000519302A Expired - Lifetime CA1298784C (en) | 1985-10-01 | 1986-09-29 | Pharmaceutical formulations with controlled release of the active substance |
Country Status (20)
| Country | Link |
|---|---|
| KR (1) | KR920008817B1 (en) |
| AT (1) | AT402257B (en) |
| BE (1) | BE905516A (en) |
| CA (1) | CA1298784C (en) |
| CH (1) | CH669524A5 (en) |
| DE (1) | DE3632201C2 (en) |
| DK (1) | DK170016B1 (en) |
| ES (1) | ES2002508A6 (en) |
| FR (1) | FR2589732B1 (en) |
| GR (1) | GR862457B (en) |
| HK (1) | HK392A (en) |
| HU (1) | HU197201B (en) |
| IE (1) | IE59589B1 (en) |
| IL (1) | IL80182A (en) |
| LU (1) | LU86615A1 (en) |
| NL (1) | NL194822C (en) |
| NZ (1) | NZ217732A (en) |
| PT (1) | PT83456B (en) |
| SE (1) | SE503222C2 (en) |
| SG (1) | SG103391G (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6440457B1 (en) | 1993-05-27 | 2002-08-27 | Alza Corporation | Method of administering antidepressant dosage form |
| ATE409475T1 (en) * | 2001-02-20 | 2008-10-15 | Dinan Timothy Gerard | TREATING FIBROMYALGIA WITH PINDOLOL |
| TW200616681A (en) * | 2004-10-05 | 2006-06-01 | Recordati Ireland Ltd | Lercanidipine capsules |
Family Cites Families (11)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CH630257A5 (en) * | 1975-03-17 | 1982-06-15 | Hoffmann La Roche | Sustained release formulation |
| CH639659A5 (en) * | 1978-12-18 | 1983-11-30 | Sandoz Ag | NEW 1,4-DIHYDROPYRIDINE DERIVATIVES, THEIR PRODUCTION AND USE. |
| DD145004A3 (en) * | 1978-09-25 | 1980-11-19 | Reinhard Huettenrauch | METHOD FOR PRODUCING SOLID A NOMENCLATES |
| CA1146866A (en) * | 1979-07-05 | 1983-05-24 | Yamanouchi Pharmaceutical Co. Ltd. | Process for the production of sustained release pharmaceutical composition of solid medical material |
| JPS6056122B2 (en) * | 1980-05-21 | 1985-12-09 | 塩野義製薬株式会社 | sustained release formulation |
| GB2084017B (en) * | 1980-09-18 | 1984-08-22 | Sandoz Ltd | Pharmaceutical compositions effective against coronary heat disease and hypertension |
| US4369172A (en) * | 1981-12-18 | 1983-01-18 | Forest Laboratories Inc. | Prolonged release therapeutic compositions based on hydroxypropylmethylcellulose |
| CA1208558A (en) * | 1982-10-07 | 1986-07-29 | Kazuo Kigasawa | Soft buccal |
| GB2154874B (en) * | 1984-02-29 | 1987-11-04 | Sandoz Ltd | Bromoscriptine compositions |
| AU4064285A (en) * | 1984-03-21 | 1985-10-11 | American Home Products Corporation | Sustained release pharmaceutical capsules |
| JPS6124516A (en) * | 1984-07-12 | 1986-02-03 | Fujisawa Pharmaceut Co Ltd | Long active tablet |
-
1986
- 1986-09-19 HU HU864004A patent/HU197201B/en unknown
- 1986-09-19 NL NL8602370A patent/NL194822C/en not_active IP Right Cessation
- 1986-09-22 CH CH3780/86A patent/CH669524A5/de not_active IP Right Cessation
- 1986-09-23 DE DE3632201A patent/DE3632201C2/en not_active Expired - Lifetime
- 1986-09-29 GR GR862457A patent/GR862457B/en unknown
- 1986-09-29 IE IE256586A patent/IE59589B1/en not_active IP Right Cessation
- 1986-09-29 NZ NZ217732A patent/NZ217732A/en unknown
- 1986-09-29 CA CA000519302A patent/CA1298784C/en not_active Expired - Lifetime
- 1986-09-29 PT PT83456A patent/PT83456B/en unknown
- 1986-09-29 DK DK464686A patent/DK170016B1/en not_active IP Right Cessation
- 1986-09-29 KR KR1019860008136A patent/KR920008817B1/en not_active IP Right Cessation
- 1986-09-29 SE SE8604112A patent/SE503222C2/en not_active IP Right Cessation
- 1986-09-29 IL IL80182A patent/IL80182A/en not_active IP Right Cessation
- 1986-09-30 AT AT0260486A patent/AT402257B/en not_active IP Right Cessation
- 1986-09-30 ES ES8602313A patent/ES2002508A6/en not_active Expired
- 1986-09-30 LU LU86615A patent/LU86615A1/en unknown
- 1986-09-30 BE BE1/011554A patent/BE905516A/en not_active IP Right Cessation
- 1986-10-01 FR FR868613668A patent/FR2589732B1/en not_active Expired
-
1991
- 1991-12-04 SG SG1033/91A patent/SG103391G/en unknown
-
1992
- 1992-01-02 HK HK3/92A patent/HK392A/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| HK392A (en) | 1992-01-10 |
| KR870003777A (en) | 1987-05-04 |
| ATA260486A (en) | 1996-08-15 |
| FR2589732B1 (en) | 1989-07-13 |
| ES2002508A6 (en) | 1988-08-16 |
| GR862457B (en) | 1987-01-29 |
| NZ217732A (en) | 1990-07-26 |
| SE503222C2 (en) | 1996-04-22 |
| CH669524A5 (en) | 1989-03-31 |
| HUT44701A (en) | 1988-04-28 |
| DK464686A (en) | 1987-04-02 |
| AT402257B (en) | 1997-03-25 |
| IL80182A0 (en) | 1986-12-31 |
| DK170016B1 (en) | 1995-05-01 |
| DE3632201A1 (en) | 1987-04-02 |
| HU197201B (en) | 1989-03-28 |
| IE862565L (en) | 1987-04-01 |
| IL80182A (en) | 1991-01-31 |
| PT83456A (en) | 1986-10-01 |
| KR920008817B1 (en) | 1992-10-09 |
| SG103391G (en) | 1992-01-17 |
| FR2589732A1 (en) | 1987-05-15 |
| PT83456B (en) | 1989-05-12 |
| LU86615A1 (en) | 1987-04-02 |
| NL194822C (en) | 2003-04-03 |
| IE59589B1 (en) | 1994-03-09 |
| DK464686D0 (en) | 1986-09-29 |
| SE8604112D0 (en) | 1986-09-29 |
| BE905516A (en) | 1987-03-30 |
| NL194822B (en) | 2002-12-02 |
| SE8604112L (en) | 1987-04-02 |
| NL8602370A (en) | 1987-05-04 |
| DE3632201C2 (en) | 1997-05-07 |
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