CA1327006C - Process for preparing a retard product containing diltiazem for a single daily administration - Google Patents
Process for preparing a retard product containing diltiazem for a single daily administrationInfo
- Publication number
- CA1327006C CA1327006C CA000559331A CA559331A CA1327006C CA 1327006 C CA1327006 C CA 1327006C CA 000559331 A CA000559331 A CA 000559331A CA 559331 A CA559331 A CA 559331A CA 1327006 C CA1327006 C CA 1327006C
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- 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
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- 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
- A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
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- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5073—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
- A61K9/5078—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core
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- 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
- A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
- A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
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- 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
- A61P9/08—Vasodilators for multiple indications
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- 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
- A61P9/10—Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
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- 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
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Abstract
ABSTRACT
A process is described for preparing a solid form for oral administration, in hard gelatin capsules which contain pellets based on diltiazem, possessing controlled release of the active substance "in vitro", such that a slow delivery and a prolonged absorption are possible "in vivo" with blood levels that are active following the administration of a single 180-mg dose every 24 hours, preferably in combination with a proportionately variable amount of immediate-delivery pellets in order to obtain good blood levels even in the initial phase of absorption.
A process is described for preparing a solid form for oral administration, in hard gelatin capsules which contain pellets based on diltiazem, possessing controlled release of the active substance "in vitro", such that a slow delivery and a prolonged absorption are possible "in vivo" with blood levels that are active following the administration of a single 180-mg dose every 24 hours, preferably in combination with a proportionately variable amount of immediate-delivery pellets in order to obtain good blood levels even in the initial phase of absorption.
Description
~32~
The present invention relates to a proces~ for preparing a retard product containiny diltiazem for single daily administration. Diltiazem [D-3-acetoxy-cis-2,3-dihydro-5-(2-dimethyl~minoethyl)-2-(p-methoxyphenyl)-1,5-benzothiazQpin-4(5H)-one~ is a drug belonging to the calcium-antagonistic group, having the following chemical structure:
~ OCU3 N 0, ~ 2CH2N(C~3)2 In the hydrochloride form, it is widely used in the treatment of coronary cardiopathies and arterial hyp~rtension. The average dosage of the oral preparation is 60 mg three timss per day. 90-mg retard preparations are commercially available, which p~rmit the admini~tration of one dose every 12 hours (twice per day); in these preparations, the active substance is released relatively slowly and constantly, enabling prolonged and effective blood levels of the drug to be obtained.
Calcium antagonists (nifedipine, diltia2em, verapamil) were employed very successfully, since they were ~ :1327~
first ;ntroduced in therapy, as antianginal drugs that were active in the different forms of coronary disease ~stable and unstable angina, Prinzmetal's angina, and the like)~
Only later was it demonstrated that these drugs are of decisive efficacy as hypotensives, that is to say substances that are active in the different forms of arterial hypertension. Nifedipine, in effect, was the first calciu~ antagonist used as an antihypertensive, and is employed today extensively in therapeutic treatments with this indication.
The other more important calcium ~ntagonist, diltiazem, introduced in ~herapy later than nifedipine, ~as itself~ and is at present, widely employed in the treatment of angina pectoris ~Rosenthal S.J. e~ al.:
"Efficacy of diltiazem ~or control of symptoms of coro-nary arterial spasm" - Am. J. Cardiol., 46: 1027-1032 1980); Schroeden J.S. et al.: "Multiclinic controlled trial of diltiazem for Prinzmetal's angina" - Am. J~ Med., ~0 7Z: 227-232 (1982); Petru M.A. et al.: "Short and long-t@rm effic3cy of high-dose oral diltiazem for angina due to coronary artery disease" - Circulation, 68: 139-147 (19833; Hoss~ck K. et al.: "Long-term study of highdose diltiazem in chronic stable e~ertional angina" Am.
25 Heart J., _ : 1215-1220 (1984~, but, during the last ~e~ years~ its use as an antihypertensiYe, lik~ nifedi-pine, has been increasingly e~t~nsive ~Aoki K~ et al.:
"Hy~otensive effects of dilti~ze~ to normaL and essential hypertensives" - Eur. J. Clin~ Ph~rmacol., 25: 475-480 ~ 3 ~ 7 ~ ~ ~
((1983); Safar ~.E. et al.: "Hemodynamic effects of diltiazem in hypertension" - Circ. Res., 52 (suppl. I~: 169-173 (1983); Trimarco B. et al.: "Diltiazem in the treatmant of mild to moderate essential hyperten~ionl' - J. Clin.
Pharmacol., 24: 218-227 (1984); Lewis J.E. et al.:
I'Diltiazem in hypertension, a preliminary dose-finding and efficacy multicenter study" - Curr. Ther. Res., 37: 566-579 (1985), Yamauchi et al.: "Effects of diltiazem hydrochloride on cardiovascular response, platel~t aggregation and coagulating activity during exercise testing in systemic hypertension" - Am. J. Cardiol., 57: 609-S12 (1986)].
In one aspect the invention provides a diltiazem delayed-release pellet consisting o~ a fast release pellet, said fast release pellet comprising diltiazem or a pharmaceutically acceptable salt thereof in association with a binderO and of an exterior membrane, wherein said ~ast release pellet comprises a ~entral neutral microgranule covered with a plurality of diltiazem- and binder-layers, and wherein said membrane is comprised of a plurality of layers of excipients, in powder form, and pol~mers, said membrane pe~mitting the release of diltiazem in an aqueous medium, said release having the following characteristics measured according to the Paddle method of ~S XX pharmacopee: A) release of 15 to 25~ of the total amount of diltiazem after two hours; B~ release of 25 to 40~ of the total amount of diltiazem after four hours: ~) release of 40 to 60% of the total amount cf diltiazem after six hours; D) release of 50 to 75% of the total amount of diltiazem after eight hours; E) release of 65 to 85% of the total amount o diltiaæem after twelve hour~, and the release curve having an essentially linear slope during the first six hours.
D
1327~
In preferred aspects the invention provides:
A diltiazem delayed-release pellet as defined above, wherein said release has the following charact~ristics:
a. release of 15% of the total amount of diltiazem after two hours;
b. release of 25% of the total amount of diltiazem after ~our hour~;
c. release of 40% of the total amount of diltiazem after six hours;
d. release of 50% of the total amount of diltiazem after eight hours; and e. release of 65% of the total amount of diltiazem after twelve hoursO
A diltiazem delayed-release pellet as dafined above, wherein said fast release pellet is obtained by a process comprising the ~ollowing steps:
a. rotating said microgranules in a coating-trough;
b. spraying at least one binder in solution in an organic solvent on said macrogranules;
c. sprinkling the sprayed microgranules with a powder comprising essentially diltiazem or a salt thereof; and ~ 4a --- ~ ~2~6 d. repeating steps b~ and c) alternatively in the range of 50 to 100 times; and wherein the material o~ said neutral microgranules is ~alected from the group consisting of starch and sucrose, wherein said organic solvent is selected from the group consisting of ethanol and ethanol-aceton mixtures, and wherein said binder is selected from the group consisting of shellac and polymetacrylates: and wherein said membrane is obtained by a process comprising the following steps:
e. spraying the rapid release pellets with a polymer dissolved in an organic solvent;
f. sprinkling the sprayad rapid release capsules w.ith an excipien~ in powder form: and g. repeating steps e) and f~ alternatively in the range of 20 to 25 times; and wherein the organic solvent is selected ~rom the group consisting of ethanol and ethanol-aceton mixtures, wherein said polymer is selected from the group consisting of shellac, acrylmetacrylates and cellulose polymers, and wherein said excipient in powdex form is talc.
The use of a diltiazem delayed-release pellet as defined above, for the treatment of coronary and hypertensive disorders by administering unique daily doses of a solid oral formulation having a circadian effect; and wherein said solid oral formulation is in the form of capsules containing from among 120 miligrams to 360 miligrams diltiazem; and more preferably wherein ~aid solid oral formulation contains about miligrams diltiazem.
4b -i_ ~327~6 A solid oral formulation for treatment of coronary disorders, comprising 60 to 95~ of a diltia~em delayed-;~ release pellet as defined above, and 40 to ~ of a rapid V release diltiazem ~ , and wherein the formulation contains from 120 to 360 miligrams diltiazem per capsule: and more preferably 180 miligrams diltiazem per capsule.
The invention will be further described by means of several examples, with reference to the attached figuresr ~0 -- ~9s G
~327~6 wherein:
Figure 1.1 shows the release curve for a typical experimental batch 15/S of Phase 1, together with the reference product.
Figures 1.2 and 1.3 show the "in vivo" absorption curve for, respectively, a 90-mg dose of the same batch and a 180-mg dose o~ the experimental product, compared with a dose of 2 90-mg tablets of the reference product.
Figure 2.1 shows the "in vitrot' release curve for a typical experimental batch 36/S of Phase 2, together with the re~erence productr Figure 2.2 shows the blood level curves for a single 90-mg dose and for the reference product.
Figure 2.3 shows the relative "in YiVo~ absorption curves.
Figure 3.1 shows the '7in vitro" release curve for a typical experimental preparation ~batch ll/c) of Phase 3, together with that ~or ~be reference product.
Figure 3.2 shows the curves for absorption of the drug in man.
Figure 4.1 ~hows the 'lin vitrol' release curves for a few e~perimental batches o~ Phase 4.
Figure 4.2 sho~s the curves for absorption of diltia~em in man.
Figure 4.3 shows the blood curves ~or the prinaipal metabolite.
13%7~
It is well-known that diltiaæem is subjected to a rapid metabolic conversion (first-pass effect), and the bioavailability of an oral dose is hence always less than 100~ and the blood peaks are not in linear proportion to the dose.
With a rapid-delivery preparation, for example, a 60 mg dose gives rise to a blood peak of 65 ~/- 9 ng/ml, whereas a 210-mg dose (3~5-fold higher) gives rise to a blood peak of 315 +/- 60 ng/ml (approximately 5-fold higher) (Rovei V. et alia: Acta Cardiologica, 35: 35-45, 1980). It is hence clear that, with high doses, the blood levels increase more than proportionally, v ry probably as a result of a metabolic saturation which partially neutralizes the first-pass effect.
For thi~ reasonj the development of the preparation o~ the present invention was carri~d out in several phases, u~ing different doses and different releasa curves from one occa-sion to the next, and checking the blood absorption curves and the bioavailability of the di~ferent preparations by means of ~'in vivo" studies in man~
All the prepara~ions of ~he pre~ent invention are composed of pellets contained in hard gelatin capsules. The preparation o~ the pellets consi~ts in covering, in purpose-designed troughs, small granules of inert excipient ~neutralcores) with the active principle mixed judiciously with bind1ng agents, and in the successive application of a variable layer of a polymeric me~brane ~327~6 which varies in composition, through ~hich the active princ;ple itself migrates by diffusion ~hen the pelL ts are present in an aqueous medium. In particular, as covering membranes, the follo~ing materials have been 5 used:
1) shellac (gum lac) 2) polymers based on acrylates/methacrylates 3) ceLlulose poLymers such as ethy(celLulose, hydroxy-ethylcellulose, and the like.
In all cases, the pellets were packaged in size 0, -1 or -2 hard gelatin capsules, depending on the dose.
PHASE 1: In this phase, the preparation was carried out of retard formulations containing 90 and 180 ~9 of dil-~iazem, with an "in vitro" release as similar as possible to that of a si~ilar 90-mg retard product which ~as ~dop-ted for all the tests as the reference product.
Figure 1.1 sho~s the release curve for a typical experimental batch 15/S of this phase, together with the reference product. In the next f;gure 1.2, it may be noted th~t the "in vivo" absorption curve for a 40-mg dose of the same batch is virtually coincident ~ith that of the reference product.
Figure 1.3 sho~s the "in vivo" absorption curves for a 180-~9 dose of the ~xper;~entaL product~ compared ~ith a dose of ~ ~0-og tablets tone tablet every 12 hours) of the r~ference product.
In this c~se~ in cvntrast to ~hat ~as noted in the preceding case, the blood curves for ~he experimental product denote a gr~ater bioav3il~biLity of the 3 ~ 2'P~
experimental batch, with levels which are more than pro-portional to the dose; nevertheless, all the blood curves are characterized by a fall ;n the levels from the 4th-6th hour after administration, with levels that are al-most negligible at Z4 hours~ For this reason, with theobject of obtaining a greater retard effect, with effec-tive levels up to 24 hours, the next phase ~as undertaken.
PHASE 2: In this phase, the preparation was carried out of retard formulations containing 90 mg and 180 mg of dilt;azem, with an "in vitro" release that was distinctly lower than that of the refer2nce product and also lower than that of ~he experimental batchPs of the preceding phase. Figure 2.1 shows the "in vitro" release curve for a typical experimental batch 36/S of this phase, together ~ith the ref~rence product. Figure 2~2 shows the blood level curves for a single 90-mg dose in ~an of the 90-mg form and of the reference product, boeh of them in a - single dose. It ~ay be noted from this that the greater retard effect of the experimental batch resuLts in prac-tice in some loss of bioavailability, since the lo~er rate of release gives rise to a slo~er absorption and henc~ to a ~ore effective ~nd relatively faster ~etabolism.
In oth~r ~ord~, the rate of releas~ tends to approach the rate of ~;rst-pass e~fect, and h~nce the blood curv2 stabili~es at a rather lo~ l~vel.
Dis~inctly ~ore favorable, in contrast, are the results obtained ~ith the 180-~9 do3e of the sa~e experi-~ental for~ulation, co~pared "in vivo" ~ith a dose of ?
~0-~9 tablets tone tablet every 12 hours~ of eh~ referenee _ ~ _ :~3270~
product.
Figure 2.3 shows the relative "in vivo" ab~orp-tion curves.
As may be noted from the development in the blood levels, the experiment~l formulaeion shows a distinctly greater retard effect than the reference product, and the levels are significant even at 24 hours; in ad~ition, the areas under the curve are virtually equivalent, which de-no~es that the rate of absorption of a sLow prepara~ion like that of 90 mg, but in a higher dose, that i5 to say 180 mg, distinctly exceeds that of metabolism, and the bioavaiLability is hence not imp~ired~ NevertheLess, in the cur~e of Figure 2.3, the experimental product shows an excessiveLy low deveLop~ent in the initial phase, and the uncertainty consequently ex;sts that the blood levels of product in the first 3-4 hours may be below the levels `~ of e~ficacy. For this reason, it ~as thsught expedient to prepare a fresh seriss ot e~peri~ntal preparations in ~hich a portion of the delayed-release pelle~s ~as replaced by im~ediate-release pellets.
PH~SE 3: In this phase, 180-mg "composite" retard formu-`~ lations ~ere pre~ared~ composed of a variable portion of 60 ~o 95X of deL~y~d-delivery pe~lets, ~ith the r~lease typical of thsse ot Phase 2, and, ~or the r~aining por~
25 tion, of 40 to 5% of i~edi3t~-delivery pellets, that is : to say nst cov~red ~ith th2 ret3rding ~brane. ln this particular phase, the "in vivo" co~parison ~as ~ade ~ith the reference product ad~inis~ered ~ith the dos~ of 290-9 table~ ~one t~blet ~very 12 hours)! Figur~ 3.1 s hoYs ; `
1327~G6 ~he "in vitro" release curve for a typical experi~ental preparation (batch 11/c) (70% delayed-release pellets +
30% rapid-reLease pellets), together ~ith that for the reference product, while Figure 3.2 shows the curves for absorption of the drug ;n man. The latter curves clearly show the early appearance of effective levels of diltia-zem, already 15-30 minutes after the administration of the experimental formulation, caused by the rapid absorp-tion of the drug from the immediate-release pellets, with a peak at 1 hour; there is then a short phase of decrease in the levels, followed by a rapid improvement and a new peak at 12 hours, and a further gradual decrease in the levels up to Z4 hours. At that point, the levels are stiLl sufficiently high and only slightly lower than those of the reference product àdministered in two succes-sive 90-mg doses e~ery 12 hours. In add;tion, it is clear from the same figure that the bioavailab;lity dur-ing the 24 hours (areas under the curve) of the exper;~
mental preparat;on adminis~er~d as a small dose ls equ;-valent to tha~ of the referense product adminis~ered int~o doses, one every 1? hours.
Very recently, ;n a study on nifed;pine, ;t ~as sho~n that, if the drug reaches the bLood slo~ly and gradually, its antihypertensiu~ efficacy is very pronoun-ced, ~here~s if significant blood levels are attainedrapidly~ the antihypertensi~Q eff~c~ is very feeble.
This de~onstrates, in fac~, that the an~ihyper~ensive action of a ca~ciu~ antagonisS, such as nifedipine, is f~r bet~er if th~ blood curve incr~3ses ~radually rather - lU -1327~6 ehan rapidly ~Kleinbloesem C~H. et al.: "Rate of increase in the plasma concentrations o~ nifedipine as a major determinant of its hemodynamic effect in humans" - Clin.
PharmacoL. Ther., 41: 26-~0 (1987)].
S It is hence clear, given the strict analogy be-tween the t~o drugs [Frish~an ~.H. et aL.: "Comparison of diLtiazem and nifedipine for both angina pectoris and systemic hypertension" - Am. J. Card;ol., 56: 41H-46H
(1985)], that a better antihypertensive efficacy may be expected in ~he case of diltiazem also when the blood levels show a slow and gradual increase.
It will be recalled that, already in Phase 2, satisfactory resuLts as regards bioavailability had been obtained, even with blood curves corresponding to slow trea~ment of anginal syndromes.
In the light of the abovementioned further obser-vations in the field of hypertensive diseases~ the prepa-rations aLready described in the abovementioned Phase 2 prove, nevertheless, to be altoge~her ~uitable for use ~0 in this particular tield of therapy.
In other ~ords~ the Phase 2 prepara~ions~ features of ~hich are vory good bioavailability and a slow and gradu~l rise in the blood curve, are especially ~ell suited to the treat~nt of the different for~s of arte-rial hyp~rtension~
To check ~nd confirm the da~a for the above~en-tion~d Phase 2, a ~urther series of tests ~as undertaken, c3lculated to ob~in preparations altogether ~i~ilar ~o those described therein, thae is to say hith si~ilar -`` 13~7~6 properties both "in v;tro" and "in vivo", and this fur-ther phase of development may be defined as the Fourth Phas~.
In the course thereof, preparations ~ere produced for experimental sampling, and also tests of bioavail-ability were carried out on healthy adult volunteers.
The results relating to these tests are described briefly below.
PHASE 4: In this phase, further formulations were prepar-ed, introducing a few variants into the processes forpreparing the pellets~ with the object of reproducing and improving the properties previously obtained with the formulat;ons produced in Phase 2.
Figure 4.1 shows the "in vitro" release curves for a fe~ experimental batches prepared in ~his way, in different variants which have undergone further techno-logical improvement, compared ~ith the curves for the same reference product already employed pr~viously in Phase 2. Healthy adult volunteers were tr~ated ~ith the 2C sa~e reference product, the voLunteers aiso being adminis-t~red one of the new experi~ental batches, ~ith a cross-~ over type treat-ent.
P Figure 4~ sho~s the curves for absorption of diltiaze~ in ~an atter such treatoants.
Figure 4.3 sho~s ~he blood curves for the prin~
cip~e ~etaboLite~ deac~tyldiltiaze~, in same su~jects as in the abov~ention~d test. The curve reprodu ed in Figure 4.2 de~onstrates ~hat ~he blood levels ot diltia-follo~ing a singl~ dose ot drug ad~inistered ~ith the ~32~
pellet for~ulation are very similar to those obtained ~ith t~o daily doses (one every 12 hours) of the reference product.
An almost identical development is sho~n by the levels o~ the metabolite deacetyldiltiazem (Fig. 4~3), although with distinctly lower absolute values.
The Phase 4 curves which have just been referred to prove to be altogether similar to those for Phase 2, and are hence appropriate for endo~ing ~he diltiazem pro-duct thus formulated with a d~cisive efficacy in thetreatment of arterial hypertension.
EXAMPLES
Th~ explanatory ~xamples which follow describe, without impli~d li~itationr the preparation of diltiazem pellets in the two forms~ rapid-reL~ase and delayed-release.
XAMPL~ A
A.1 DlLTIAZEM RAPID-2ELEASE PELLETS
The present invention relates to a proces~ for preparing a retard product containiny diltiazem for single daily administration. Diltiazem [D-3-acetoxy-cis-2,3-dihydro-5-(2-dimethyl~minoethyl)-2-(p-methoxyphenyl)-1,5-benzothiazQpin-4(5H)-one~ is a drug belonging to the calcium-antagonistic group, having the following chemical structure:
~ OCU3 N 0, ~ 2CH2N(C~3)2 In the hydrochloride form, it is widely used in the treatment of coronary cardiopathies and arterial hyp~rtension. The average dosage of the oral preparation is 60 mg three timss per day. 90-mg retard preparations are commercially available, which p~rmit the admini~tration of one dose every 12 hours (twice per day); in these preparations, the active substance is released relatively slowly and constantly, enabling prolonged and effective blood levels of the drug to be obtained.
Calcium antagonists (nifedipine, diltia2em, verapamil) were employed very successfully, since they were ~ :1327~
first ;ntroduced in therapy, as antianginal drugs that were active in the different forms of coronary disease ~stable and unstable angina, Prinzmetal's angina, and the like)~
Only later was it demonstrated that these drugs are of decisive efficacy as hypotensives, that is to say substances that are active in the different forms of arterial hypertension. Nifedipine, in effect, was the first calciu~ antagonist used as an antihypertensive, and is employed today extensively in therapeutic treatments with this indication.
The other more important calcium ~ntagonist, diltiazem, introduced in ~herapy later than nifedipine, ~as itself~ and is at present, widely employed in the treatment of angina pectoris ~Rosenthal S.J. e~ al.:
"Efficacy of diltiazem ~or control of symptoms of coro-nary arterial spasm" - Am. J. Cardiol., 46: 1027-1032 1980); Schroeden J.S. et al.: "Multiclinic controlled trial of diltiazem for Prinzmetal's angina" - Am. J~ Med., ~0 7Z: 227-232 (1982); Petru M.A. et al.: "Short and long-t@rm effic3cy of high-dose oral diltiazem for angina due to coronary artery disease" - Circulation, 68: 139-147 (19833; Hoss~ck K. et al.: "Long-term study of highdose diltiazem in chronic stable e~ertional angina" Am.
25 Heart J., _ : 1215-1220 (1984~, but, during the last ~e~ years~ its use as an antihypertensiYe, lik~ nifedi-pine, has been increasingly e~t~nsive ~Aoki K~ et al.:
"Hy~otensive effects of dilti~ze~ to normaL and essential hypertensives" - Eur. J. Clin~ Ph~rmacol., 25: 475-480 ~ 3 ~ 7 ~ ~ ~
((1983); Safar ~.E. et al.: "Hemodynamic effects of diltiazem in hypertension" - Circ. Res., 52 (suppl. I~: 169-173 (1983); Trimarco B. et al.: "Diltiazem in the treatmant of mild to moderate essential hyperten~ionl' - J. Clin.
Pharmacol., 24: 218-227 (1984); Lewis J.E. et al.:
I'Diltiazem in hypertension, a preliminary dose-finding and efficacy multicenter study" - Curr. Ther. Res., 37: 566-579 (1985), Yamauchi et al.: "Effects of diltiazem hydrochloride on cardiovascular response, platel~t aggregation and coagulating activity during exercise testing in systemic hypertension" - Am. J. Cardiol., 57: 609-S12 (1986)].
In one aspect the invention provides a diltiazem delayed-release pellet consisting o~ a fast release pellet, said fast release pellet comprising diltiazem or a pharmaceutically acceptable salt thereof in association with a binderO and of an exterior membrane, wherein said ~ast release pellet comprises a ~entral neutral microgranule covered with a plurality of diltiazem- and binder-layers, and wherein said membrane is comprised of a plurality of layers of excipients, in powder form, and pol~mers, said membrane pe~mitting the release of diltiazem in an aqueous medium, said release having the following characteristics measured according to the Paddle method of ~S XX pharmacopee: A) release of 15 to 25~ of the total amount of diltiazem after two hours; B~ release of 25 to 40~ of the total amount of diltiazem after four hours: ~) release of 40 to 60% of the total amount cf diltiazem after six hours; D) release of 50 to 75% of the total amount of diltiazem after eight hours; E) release of 65 to 85% of the total amount o diltiaæem after twelve hour~, and the release curve having an essentially linear slope during the first six hours.
D
1327~
In preferred aspects the invention provides:
A diltiazem delayed-release pellet as defined above, wherein said release has the following charact~ristics:
a. release of 15% of the total amount of diltiazem after two hours;
b. release of 25% of the total amount of diltiazem after ~our hour~;
c. release of 40% of the total amount of diltiazem after six hours;
d. release of 50% of the total amount of diltiazem after eight hours; and e. release of 65% of the total amount of diltiazem after twelve hoursO
A diltiazem delayed-release pellet as dafined above, wherein said fast release pellet is obtained by a process comprising the ~ollowing steps:
a. rotating said microgranules in a coating-trough;
b. spraying at least one binder in solution in an organic solvent on said macrogranules;
c. sprinkling the sprayed microgranules with a powder comprising essentially diltiazem or a salt thereof; and ~ 4a --- ~ ~2~6 d. repeating steps b~ and c) alternatively in the range of 50 to 100 times; and wherein the material o~ said neutral microgranules is ~alected from the group consisting of starch and sucrose, wherein said organic solvent is selected from the group consisting of ethanol and ethanol-aceton mixtures, and wherein said binder is selected from the group consisting of shellac and polymetacrylates: and wherein said membrane is obtained by a process comprising the following steps:
e. spraying the rapid release pellets with a polymer dissolved in an organic solvent;
f. sprinkling the sprayad rapid release capsules w.ith an excipien~ in powder form: and g. repeating steps e) and f~ alternatively in the range of 20 to 25 times; and wherein the organic solvent is selected ~rom the group consisting of ethanol and ethanol-aceton mixtures, wherein said polymer is selected from the group consisting of shellac, acrylmetacrylates and cellulose polymers, and wherein said excipient in powdex form is talc.
The use of a diltiazem delayed-release pellet as defined above, for the treatment of coronary and hypertensive disorders by administering unique daily doses of a solid oral formulation having a circadian effect; and wherein said solid oral formulation is in the form of capsules containing from among 120 miligrams to 360 miligrams diltiazem; and more preferably wherein ~aid solid oral formulation contains about miligrams diltiazem.
4b -i_ ~327~6 A solid oral formulation for treatment of coronary disorders, comprising 60 to 95~ of a diltia~em delayed-;~ release pellet as defined above, and 40 to ~ of a rapid V release diltiazem ~ , and wherein the formulation contains from 120 to 360 miligrams diltiazem per capsule: and more preferably 180 miligrams diltiazem per capsule.
The invention will be further described by means of several examples, with reference to the attached figuresr ~0 -- ~9s G
~327~6 wherein:
Figure 1.1 shows the release curve for a typical experimental batch 15/S of Phase 1, together with the reference product.
Figures 1.2 and 1.3 show the "in vivo" absorption curve for, respectively, a 90-mg dose of the same batch and a 180-mg dose o~ the experimental product, compared with a dose of 2 90-mg tablets of the reference product.
Figure 2.1 shows the "in vitrot' release curve for a typical experimental batch 36/S of Phase 2, together with the re~erence productr Figure 2.2 shows the blood level curves for a single 90-mg dose and for the reference product.
Figure 2.3 shows the relative "in YiVo~ absorption curves.
Figure 3.1 shows the '7in vitro" release curve for a typical experimental preparation ~batch ll/c) of Phase 3, together with that ~or ~be reference product.
Figure 3.2 shows the curves for absorption of the drug in man.
Figure 4.1 ~hows the 'lin vitrol' release curves for a few e~perimental batches o~ Phase 4.
Figure 4.2 sho~s the curves for absorption of diltia~em in man.
Figure 4.3 shows the blood curves ~or the prinaipal metabolite.
13%7~
It is well-known that diltiaæem is subjected to a rapid metabolic conversion (first-pass effect), and the bioavailability of an oral dose is hence always less than 100~ and the blood peaks are not in linear proportion to the dose.
With a rapid-delivery preparation, for example, a 60 mg dose gives rise to a blood peak of 65 ~/- 9 ng/ml, whereas a 210-mg dose (3~5-fold higher) gives rise to a blood peak of 315 +/- 60 ng/ml (approximately 5-fold higher) (Rovei V. et alia: Acta Cardiologica, 35: 35-45, 1980). It is hence clear that, with high doses, the blood levels increase more than proportionally, v ry probably as a result of a metabolic saturation which partially neutralizes the first-pass effect.
For thi~ reasonj the development of the preparation o~ the present invention was carri~d out in several phases, u~ing different doses and different releasa curves from one occa-sion to the next, and checking the blood absorption curves and the bioavailability of the di~ferent preparations by means of ~'in vivo" studies in man~
All the prepara~ions of ~he pre~ent invention are composed of pellets contained in hard gelatin capsules. The preparation o~ the pellets consi~ts in covering, in purpose-designed troughs, small granules of inert excipient ~neutralcores) with the active principle mixed judiciously with bind1ng agents, and in the successive application of a variable layer of a polymeric me~brane ~327~6 which varies in composition, through ~hich the active princ;ple itself migrates by diffusion ~hen the pelL ts are present in an aqueous medium. In particular, as covering membranes, the follo~ing materials have been 5 used:
1) shellac (gum lac) 2) polymers based on acrylates/methacrylates 3) ceLlulose poLymers such as ethy(celLulose, hydroxy-ethylcellulose, and the like.
In all cases, the pellets were packaged in size 0, -1 or -2 hard gelatin capsules, depending on the dose.
PHASE 1: In this phase, the preparation was carried out of retard formulations containing 90 and 180 ~9 of dil-~iazem, with an "in vitro" release as similar as possible to that of a si~ilar 90-mg retard product which ~as ~dop-ted for all the tests as the reference product.
Figure 1.1 sho~s the release curve for a typical experimental batch 15/S of this phase, together with the reference product. In the next f;gure 1.2, it may be noted th~t the "in vivo" absorption curve for a 40-mg dose of the same batch is virtually coincident ~ith that of the reference product.
Figure 1.3 sho~s the "in vivo" absorption curves for a 180-~9 dose of the ~xper;~entaL product~ compared ~ith a dose of ~ ~0-og tablets tone tablet every 12 hours) of the r~ference product.
In this c~se~ in cvntrast to ~hat ~as noted in the preceding case, the blood curves for ~he experimental product denote a gr~ater bioav3il~biLity of the 3 ~ 2'P~
experimental batch, with levels which are more than pro-portional to the dose; nevertheless, all the blood curves are characterized by a fall ;n the levels from the 4th-6th hour after administration, with levels that are al-most negligible at Z4 hours~ For this reason, with theobject of obtaining a greater retard effect, with effec-tive levels up to 24 hours, the next phase ~as undertaken.
PHASE 2: In this phase, the preparation was carried out of retard formulations containing 90 mg and 180 mg of dilt;azem, with an "in vitro" release that was distinctly lower than that of the refer2nce product and also lower than that of ~he experimental batchPs of the preceding phase. Figure 2.1 shows the "in vitro" release curve for a typical experimental batch 36/S of this phase, together ~ith the ref~rence product. Figure 2~2 shows the blood level curves for a single 90-mg dose in ~an of the 90-mg form and of the reference product, boeh of them in a - single dose. It ~ay be noted from this that the greater retard effect of the experimental batch resuLts in prac-tice in some loss of bioavailability, since the lo~er rate of release gives rise to a slo~er absorption and henc~ to a ~ore effective ~nd relatively faster ~etabolism.
In oth~r ~ord~, the rate of releas~ tends to approach the rate of ~;rst-pass e~fect, and h~nce the blood curv2 stabili~es at a rather lo~ l~vel.
Dis~inctly ~ore favorable, in contrast, are the results obtained ~ith the 180-~9 do3e of the sa~e experi-~ental for~ulation, co~pared "in vivo" ~ith a dose of ?
~0-~9 tablets tone tablet every 12 hours~ of eh~ referenee _ ~ _ :~3270~
product.
Figure 2.3 shows the relative "in vivo" ab~orp-tion curves.
As may be noted from the development in the blood levels, the experiment~l formulaeion shows a distinctly greater retard effect than the reference product, and the levels are significant even at 24 hours; in ad~ition, the areas under the curve are virtually equivalent, which de-no~es that the rate of absorption of a sLow prepara~ion like that of 90 mg, but in a higher dose, that i5 to say 180 mg, distinctly exceeds that of metabolism, and the bioavaiLability is hence not imp~ired~ NevertheLess, in the cur~e of Figure 2.3, the experimental product shows an excessiveLy low deveLop~ent in the initial phase, and the uncertainty consequently ex;sts that the blood levels of product in the first 3-4 hours may be below the levels `~ of e~ficacy. For this reason, it ~as thsught expedient to prepare a fresh seriss ot e~peri~ntal preparations in ~hich a portion of the delayed-release pelle~s ~as replaced by im~ediate-release pellets.
PH~SE 3: In this phase, 180-mg "composite" retard formu-`~ lations ~ere pre~ared~ composed of a variable portion of 60 ~o 95X of deL~y~d-delivery pe~lets, ~ith the r~lease typical of thsse ot Phase 2, and, ~or the r~aining por~
25 tion, of 40 to 5% of i~edi3t~-delivery pellets, that is : to say nst cov~red ~ith th2 ret3rding ~brane. ln this particular phase, the "in vivo" co~parison ~as ~ade ~ith the reference product ad~inis~ered ~ith the dos~ of 290-9 table~ ~one t~blet ~very 12 hours)! Figur~ 3.1 s hoYs ; `
1327~G6 ~he "in vitro" release curve for a typical experi~ental preparation (batch 11/c) (70% delayed-release pellets +
30% rapid-reLease pellets), together ~ith that for the reference product, while Figure 3.2 shows the curves for absorption of the drug ;n man. The latter curves clearly show the early appearance of effective levels of diltia-zem, already 15-30 minutes after the administration of the experimental formulation, caused by the rapid absorp-tion of the drug from the immediate-release pellets, with a peak at 1 hour; there is then a short phase of decrease in the levels, followed by a rapid improvement and a new peak at 12 hours, and a further gradual decrease in the levels up to Z4 hours. At that point, the levels are stiLl sufficiently high and only slightly lower than those of the reference product àdministered in two succes-sive 90-mg doses e~ery 12 hours. In add;tion, it is clear from the same figure that the bioavailab;lity dur-ing the 24 hours (areas under the curve) of the exper;~
mental preparat;on adminis~er~d as a small dose ls equ;-valent to tha~ of the referense product adminis~ered int~o doses, one every 1? hours.
Very recently, ;n a study on nifed;pine, ;t ~as sho~n that, if the drug reaches the bLood slo~ly and gradually, its antihypertensiu~ efficacy is very pronoun-ced, ~here~s if significant blood levels are attainedrapidly~ the antihypertensi~Q eff~c~ is very feeble.
This de~onstrates, in fac~, that the an~ihyper~ensive action of a ca~ciu~ antagonisS, such as nifedipine, is f~r bet~er if th~ blood curve incr~3ses ~radually rather - lU -1327~6 ehan rapidly ~Kleinbloesem C~H. et al.: "Rate of increase in the plasma concentrations o~ nifedipine as a major determinant of its hemodynamic effect in humans" - Clin.
PharmacoL. Ther., 41: 26-~0 (1987)].
S It is hence clear, given the strict analogy be-tween the t~o drugs [Frish~an ~.H. et aL.: "Comparison of diLtiazem and nifedipine for both angina pectoris and systemic hypertension" - Am. J. Card;ol., 56: 41H-46H
(1985)], that a better antihypertensive efficacy may be expected in ~he case of diltiazem also when the blood levels show a slow and gradual increase.
It will be recalled that, already in Phase 2, satisfactory resuLts as regards bioavailability had been obtained, even with blood curves corresponding to slow trea~ment of anginal syndromes.
In the light of the abovementioned further obser-vations in the field of hypertensive diseases~ the prepa-rations aLready described in the abovementioned Phase 2 prove, nevertheless, to be altoge~her ~uitable for use ~0 in this particular tield of therapy.
In other ~ords~ the Phase 2 prepara~ions~ features of ~hich are vory good bioavailability and a slow and gradu~l rise in the blood curve, are especially ~ell suited to the treat~nt of the different for~s of arte-rial hyp~rtension~
To check ~nd confirm the da~a for the above~en-tion~d Phase 2, a ~urther series of tests ~as undertaken, c3lculated to ob~in preparations altogether ~i~ilar ~o those described therein, thae is to say hith si~ilar -`` 13~7~6 properties both "in v;tro" and "in vivo", and this fur-ther phase of development may be defined as the Fourth Phas~.
In the course thereof, preparations ~ere produced for experimental sampling, and also tests of bioavail-ability were carried out on healthy adult volunteers.
The results relating to these tests are described briefly below.
PHASE 4: In this phase, further formulations were prepar-ed, introducing a few variants into the processes forpreparing the pellets~ with the object of reproducing and improving the properties previously obtained with the formulat;ons produced in Phase 2.
Figure 4.1 shows the "in vitro" release curves for a fe~ experimental batches prepared in ~his way, in different variants which have undergone further techno-logical improvement, compared ~ith the curves for the same reference product already employed pr~viously in Phase 2. Healthy adult volunteers were tr~ated ~ith the 2C sa~e reference product, the voLunteers aiso being adminis-t~red one of the new experi~ental batches, ~ith a cross-~ over type treat-ent.
P Figure 4~ sho~s the curves for absorption of diltiaze~ in ~an atter such treatoants.
Figure 4.3 sho~s ~he blood curves for the prin~
cip~e ~etaboLite~ deac~tyldiltiaze~, in same su~jects as in the abov~ention~d test. The curve reprodu ed in Figure 4.2 de~onstrates ~hat ~he blood levels ot diltia-follo~ing a singl~ dose ot drug ad~inistered ~ith the ~32~
pellet for~ulation are very similar to those obtained ~ith t~o daily doses (one every 12 hours) of the reference product.
An almost identical development is sho~n by the levels o~ the metabolite deacetyldiltiazem (Fig. 4~3), although with distinctly lower absolute values.
The Phase 4 curves which have just been referred to prove to be altogether similar to those for Phase 2, and are hence appropriate for endo~ing ~he diltiazem pro-duct thus formulated with a d~cisive efficacy in thetreatment of arterial hypertension.
EXAMPLES
Th~ explanatory ~xamples which follow describe, without impli~d li~itationr the preparation of diltiazem pellets in the two forms~ rapid-reL~ase and delayed-release.
XAMPL~ A
A.1 DlLTIAZEM RAPID-2ELEASE PELLETS
4.ûO kg of diLtiazem and 1.00 kg of talc, ~ith a particle size of 40 to 80 ~icrons, are mixed in a rot~ting-dru~ mixer.
; 1.50 kg of microgranul~s compos~d of succrose and starch, ~ith a p~rticle si~e of 0~500 to 0.710 M~, are rotatQd in ~ trough with a 45D-~ basket. The rotating ~ass is sprayed, by ~eans of ~ spscial ~embrane pump, ~;th 30 9 of a 40X strength solution of shellac ( ) in eehyl alcohol and sprinkled ~ith 100 9 of the above~ntioned ~i~ture.
The spra~ing and sprinkling operation-i~ alternated -` ~327~6 and ;s repeated 50 times in total.
( ) (Standard shellac: three circles extra dewaxed-bleached powder).
A.2 DILTIAZM DELAYED-RELEASE PELLETS
The quantity of pellets obtained (print A.1) is rotated in a trough 450 mm in diameter, and bathed with 40 9 of a sprayed solution of shellac in ethanol (40%) and sprinkled with 90 9 of talc.
The spraying and sprinkling operation is alterna-ted and is repeated 25 times in total.
B. 1 DILTIAZEM RAPID-RELEASE PELLETS
2.00 kg o~ microgranules co~posed of succrose and starch, ~ith a particle size of 0.500-û.710 mm, are rota-ted in a stainless steel trough 450 mm in diameterO Thero~ating mass is sprayed, by means of a special membrane-type proport;oning pump, with 42 9 of a lZ.5% strength sol-ution of polymethacrylates (Eudr3git L~ in acetone/ethanol and sprinkled ~ith 40 9 of diltiazem with a particle size o~ 40-80 microns. The spraying and sprinkling operation is alt~rnat~d and is repeated 100 times in total.
.2 bILTIA~EM DELAYED-RELEASE PLLETS
The quant;ty of peLlets obtained (point ~.1) is rotated in a trough 450 m~ in d;ameter, and baehed with a sprayed 14~5Z str~n~th so~ution of poly~etha~rylates (Eudragi~ S) in acetone/e~hanol and prinkl~d ~i~h 65 9 of talc.
The spraying and sprinkling operation is alt~rna-ted and is rep0~ted 20 ti~s in total.
~le~l~rl~
~327~Q~
EXAMPLE C
C.1 DILTIA~EM RAPID-RELEASE PELLETS
2.00 kg of microgranules composed of succrose and starch, ~;th a particle size of 0.500-0.710 mm~ are rota-ted in a trough with a stainless steel basket 450 mm indiameter~ The rotating ~ass is sprayed, by means of a membrane-type proportioning pump, ~ith 26 9 of a 40%
strength solution of shellac in ethanol and sprinkled with 80 9 of diltiazem with a particle size of 40-80 microns.
The spraying and sprinkling operation is alterna-ted and is repeated 50 times in total.
C.2 DILTIA~EM DELAYED-RELEAS PELLE~S
The quanti~y of pelLets obtained (point C.1) is rotated in a trough 450 mm in diameter, and bathed with 80 9 af a sprayed 5% strength soiution of Etho~yl N 100 in acetone/ethanol and sprinkled w;th 54 g of talc. The spraying and sprinkling operation is alternated and is repeaeed 25 times in totaL7 EXAMPLE D
DILTIA~~ PELLETS~ VARIANT 47/S
~.Q0 kg of diltiazem and 1.0D kg of talc~ ~ith a particle size of 40 ~o 80 ~icrons, are mixed in a rotat-ing-dr~ ~ixer.
2S 1.50 kg of neutral ~icrogranules composed of suc crose and starch, ~ith ~ particle siz~ of 0.500 to 0.710 mm, ~re rotat~d in a trough ~ieh ~ 450-m~ basket.
Th~ ~ot~ting oass is spray~d, by ~eans of a special ~e~brane-type pu~p, uith 25 g of a 20X strength Tr~ t~
13~7~01~
solution of KolLidon 30 in ethyl alcohol and sprinkled with S0 g of the abovementioned mixture.
The spraying and sprinkling operation is alterna-ted and ;s repeated 100 times ;n total. At th;s point, the rotat;ng mass ;s sprayed ~;~h B0 9 of a 5% strength sol-ution of Ethoxyl N 100 in acetone/ethanol and sprinkled with 50 9 of talc. The spraying and sprinkling operation is alternated and is repeated 20 t;mes ;n total~
EXAMPLE E
DILTIAZEM PELLETS, VARIANT 85/S
4.00 kg of dilt;azem and 1.00 kg of talc, ~ith a particle size of 40 to 80 microns, are mixed in a rotating-drum mixer.
1.S0 kg of neutral microgranules composed of suc-crose and starch~ uith a particle size of 0.500 to 0.710 ~m,are rota~ed in a trough with a 450 ~m basket.
The rotating mass is sprayed, by means of a spec;al m~brane-type pump, ~ith 25 9 of a 20% strength solution of Carbo~ax 4000 in e~hyl alcohol and sprinkled ~ith sa 9 of the above~entioned mixture~
The spraying and sprinkling operation is alterna-ted and is repe~ted 100 tim~s in total. At this point, the rotating ~ass is sprayed ~ith 100 9 of a 5X strength solution of Ethoxyl ~ 100 in acetone/ethanol and sprink-lod ~ith 50 ~ of talc. The spraying and sprinkling oper-ation is alt~rnated and is repea~d 20 ti~es in total~
~ ~d~ r~
; 1.50 kg of microgranul~s compos~d of succrose and starch, ~ith a p~rticle si~e of 0~500 to 0.710 M~, are rotatQd in ~ trough with a 45D-~ basket. The rotating ~ass is sprayed, by ~eans of ~ spscial ~embrane pump, ~;th 30 9 of a 40X strength solution of shellac ( ) in eehyl alcohol and sprinkled ~ith 100 9 of the above~ntioned ~i~ture.
The spra~ing and sprinkling operation-i~ alternated -` ~327~6 and ;s repeated 50 times in total.
( ) (Standard shellac: three circles extra dewaxed-bleached powder).
A.2 DILTIAZM DELAYED-RELEASE PELLETS
The quantity of pellets obtained (print A.1) is rotated in a trough 450 mm in diameter, and bathed with 40 9 of a sprayed solution of shellac in ethanol (40%) and sprinkled with 90 9 of talc.
The spraying and sprinkling operation is alterna-ted and is repeated 25 times in total.
B. 1 DILTIAZEM RAPID-RELEASE PELLETS
2.00 kg o~ microgranules co~posed of succrose and starch, ~ith a particle size of 0.500-û.710 mm, are rota-ted in a stainless steel trough 450 mm in diameterO Thero~ating mass is sprayed, by means of a special membrane-type proport;oning pump, with 42 9 of a lZ.5% strength sol-ution of polymethacrylates (Eudr3git L~ in acetone/ethanol and sprinkled ~ith 40 9 of diltiazem with a particle size o~ 40-80 microns. The spraying and sprinkling operation is alt~rnat~d and is repeated 100 times in total.
.2 bILTIA~EM DELAYED-RELEASE PLLETS
The quant;ty of peLlets obtained (point ~.1) is rotated in a trough 450 m~ in d;ameter, and baehed with a sprayed 14~5Z str~n~th so~ution of poly~etha~rylates (Eudragi~ S) in acetone/e~hanol and prinkl~d ~i~h 65 9 of talc.
The spraying and sprinkling operation is alt~rna-ted and is rep0~ted 20 ti~s in total.
~le~l~rl~
~327~Q~
EXAMPLE C
C.1 DILTIA~EM RAPID-RELEASE PELLETS
2.00 kg of microgranules composed of succrose and starch, ~;th a particle size of 0.500-0.710 mm~ are rota-ted in a trough with a stainless steel basket 450 mm indiameter~ The rotating ~ass is sprayed, by means of a membrane-type proportioning pump, ~ith 26 9 of a 40%
strength solution of shellac in ethanol and sprinkled with 80 9 of diltiazem with a particle size of 40-80 microns.
The spraying and sprinkling operation is alterna-ted and is repeated 50 times in total.
C.2 DILTIA~EM DELAYED-RELEAS PELLE~S
The quanti~y of pelLets obtained (point C.1) is rotated in a trough 450 mm in diameter, and bathed with 80 9 af a sprayed 5% strength soiution of Etho~yl N 100 in acetone/ethanol and sprinkled w;th 54 g of talc. The spraying and sprinkling operation is alternated and is repeaeed 25 times in totaL7 EXAMPLE D
DILTIA~~ PELLETS~ VARIANT 47/S
~.Q0 kg of diltiazem and 1.0D kg of talc~ ~ith a particle size of 40 ~o 80 ~icrons, are mixed in a rotat-ing-dr~ ~ixer.
2S 1.50 kg of neutral ~icrogranules composed of suc crose and starch, ~ith ~ particle siz~ of 0.500 to 0.710 mm, ~re rotat~d in a trough ~ieh ~ 450-m~ basket.
Th~ ~ot~ting oass is spray~d, by ~eans of a special ~e~brane-type pu~p, uith 25 g of a 20X strength Tr~ t~
13~7~01~
solution of KolLidon 30 in ethyl alcohol and sprinkled with S0 g of the abovementioned mixture.
The spraying and sprinkling operation is alterna-ted and ;s repeated 100 times ;n total. At th;s point, the rotat;ng mass ;s sprayed ~;~h B0 9 of a 5% strength sol-ution of Ethoxyl N 100 in acetone/ethanol and sprinkled with 50 9 of talc. The spraying and sprinkling operation is alternated and is repeated 20 t;mes ;n total~
EXAMPLE E
DILTIAZEM PELLETS, VARIANT 85/S
4.00 kg of dilt;azem and 1.00 kg of talc, ~ith a particle size of 40 to 80 microns, are mixed in a rotating-drum mixer.
1.S0 kg of neutral microgranules composed of suc-crose and starch~ uith a particle size of 0.500 to 0.710 ~m,are rota~ed in a trough with a 450 ~m basket.
The rotating mass is sprayed, by means of a spec;al m~brane-type pump, ~ith 25 9 of a 20% strength solution of Carbo~ax 4000 in e~hyl alcohol and sprinkled ~ith sa 9 of the above~entioned mixture~
The spraying and sprinkling operation is alterna-ted and is repe~ted 100 tim~s in total. At this point, the rotating ~ass is sprayed ~ith 100 9 of a 5X strength solution of Ethoxyl ~ 100 in acetone/ethanol and sprink-lod ~ith 50 ~ of talc. The spraying and sprinkling oper-ation is alt~rnated and is repea~d 20 ti~es in total~
~ ~d~ r~
Claims (13)
1. A diltiazem delayed-release pellet consisting of a fast release pellet, said fast release pellet comprising diltiazem or a pharmaceutically acceptable salt thereof in association with a binder, and of an exterior membrane, wherein said fast release pellet comprises a central neutral microgranule covered with a plurality of diltiazem- and binder-layers, and wherein said membrane is comprised of a plurality of layers of excipients, in powder form, and polymers, said membrane permitting the release of diltiazem in an aqueous medium, said release having the following characteristics measured according to the Paddle method of US XX pharmacopee: A) release of 15 to 25% of the total amount of diltiazem after two hours; B) release of 25 to 40% of the total amount of diltiazem after four hours; C) release of 40 to 60% of the total amount of diltiazem after six hours; D) release of 50 to 75% of the total amount of diltiazem after eight hours; E) release of 65 to 85% of the total amount of diltiazem after twelve hours, and the release curve having an essentially linear slope during the first six hours.
2. A diltiazem delayed-release pellet according to claim 1, wherein said release has the following characteristics:
a. release of 15% of the total amount of diltiazem after two hours:
b. release of 25% of the total amount of diltiazem after four hours;
c. release of 40% of the total amount of diltiazem after six hours;
d. release of 50% of the total amount of diltiazem after eight hours; and e. release of 65% of the total amount of diltiazem after twelve hours.
a. release of 15% of the total amount of diltiazem after two hours:
b. release of 25% of the total amount of diltiazem after four hours;
c. release of 40% of the total amount of diltiazem after six hours;
d. release of 50% of the total amount of diltiazem after eight hours; and e. release of 65% of the total amount of diltiazem after twelve hours.
3. A diltiazem delayed-release pellet according to claim 1, wherein said fast release pellet is obtained by a process comprising the following steps:
a. rotating said microgranules in a coating-trough;
b. spraying at least one binder in solution in an organic solvent on said macrogranules;
c. sprinkling the sprayed microgranules with a powder comprising essentially diltiazem or a salt thereof; and d. repeating steps b) and c) alternatively in the range of 50 to 100 times.
a. rotating said microgranules in a coating-trough;
b. spraying at least one binder in solution in an organic solvent on said macrogranules;
c. sprinkling the sprayed microgranules with a powder comprising essentially diltiazem or a salt thereof; and d. repeating steps b) and c) alternatively in the range of 50 to 100 times.
4. A diltiazem delayed-release pellet according to claim 3, wherein the material of said neutral microgranules is selected from the group consisting of starch and sucrose, wherein said organic solvent is selected from the group consisting of ethanol and ethanol-aceton mixtures, and wherein said binder is selected from the group consisting of shellac and polymetacrylates.
5. A diltiazem delayed-release pellet according to claim 3, wherein said membrane is obtained by a process comprising the following steps:
e. spraying the rapid release pellets with a polymer dissolved in an organic solvent;
f. sprinkling the sprayed rapid release capsules with an excipients in powder form; and g. repeating steps e) and f) alternatively in the range of 20 to 25 times.
e. spraying the rapid release pellets with a polymer dissolved in an organic solvent;
f. sprinkling the sprayed rapid release capsules with an excipients in powder form; and g. repeating steps e) and f) alternatively in the range of 20 to 25 times.
6. A diltiazem delayed-release pellet according to claim 5, wherein said organic solvent is selected from the group consisting of ethanol and ethanol-aceton mixtures, wherein said polymer is selected from the group consisting of shellac, acrylmetacrylates and cellulose polymers, and wherein said excipient in powder form is talc.
7. The use of a diltiazem delayed-release pellet as claimed in any one of claims 1 to 6, for the treatment of coronary and hypertensive disorders by administering unique daily doses of a solid oral formulation having a circadian effect.
8. The use of pellets as claimed in claim 7, wherein said solid oral formulation is in the form of capsules containing from 120 miligrams to 360 miligrams diltiazem.
9. The use as claimed in claim 8, wherein said solid oral formulation contains about 180 miligrams diltiazem.
10. A solid oral formulation for treatment of coronary disorders, comprising 60 to 95% of a diltiazem delayed-release pellet according to claim 1, and 40 to 5% of a rapid release diltiazem pellet.
11. The formulation of claim 10, containing from 120 to 360 miligrams diltiazem per capsule.
12. The formulation of claim 11, containing 180 miligrams diltiazem per capsule.
13 . Use of a formulation as defined in claim 10, 11 or 12, for treating coronary disorders.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CH00637/87-2 | 1987-02-20 | ||
| CH63787 | 1987-02-20 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1327006C true CA1327006C (en) | 1994-02-15 |
Family
ID=4191649
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000559331A Expired - Fee Related CA1327006C (en) | 1987-02-20 | 1988-02-19 | Process for preparing a retard product containing diltiazem for a single daily administration |
Country Status (12)
| Country | Link |
|---|---|
| EP (1) | EP0282698B1 (en) |
| JP (1) | JP2863528B2 (en) |
| KR (1) | KR960011232B1 (en) |
| AT (1) | ATE172112T1 (en) |
| AU (1) | AU1196988A (en) |
| BR (1) | BR8800763A (en) |
| CA (1) | CA1327006C (en) |
| DE (1) | DE3856258T2 (en) |
| DK (1) | DK173505B1 (en) |
| ES (1) | ES2125215T3 (en) |
| MX (1) | MX10490A (en) |
| ZA (1) | ZA881181B (en) |
Families Citing this family (16)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| DE3737741A1 (en) * | 1987-11-06 | 1989-05-18 | Goedecke Ag | ORAL MEDICAL FORM FOR THE ONLY DAILY TREATMENT OF HYPERTENSION WITH DILTIAZEMHYDROCHLORIDE |
| DE3922167A1 (en) * | 1988-04-16 | 1991-01-17 | Sanol Arznei Schwarz Gmbh | Oral diltiazem hydrochloride dosage forms - for admin. once a day, contg. fast- and delayed-release components |
| US5133974A (en) * | 1989-05-05 | 1992-07-28 | Kv Pharmaceutical Company | Extended release pharmaceutical formulations |
| SE8902699D0 (en) * | 1989-08-09 | 1989-08-09 | Lejus Medical Ab | DILTIAZEM CONTAINING PHARMACEUTICAL COMPOSITIOS |
| US5286497A (en) * | 1991-05-20 | 1994-02-15 | Carderm Capital L.P. | Diltiazem formulation |
| ZA923474B (en) * | 1991-05-20 | 1993-01-27 | Marion Merrell Dow Inc | Diltiazem formulation |
| JP3746315B2 (en) | 1994-07-07 | 2006-02-15 | ダイセル化学工業株式会社 | Separating agent |
| US5834024A (en) * | 1995-01-05 | 1998-11-10 | Fh Faulding & Co. Limited | Controlled absorption diltiazem pharmaceutical formulation |
| US5567441A (en) * | 1995-03-24 | 1996-10-22 | Andrx Pharmaceuticals Inc. | Diltiazem controlled release formulation |
| FR2742660B1 (en) * | 1995-12-22 | 1998-04-03 | Ethypharm Lab Prod Ethiques | NOVEL FORMS OF EXTENDED RELEASE MICROGRANULES CONTAINING DILTIAZEM AS ACTIVE INGREDIENT |
| CN100475210C (en) * | 1996-03-08 | 2009-04-08 | 尼科梅德丹麦有限公司 | Modified release multiple-units dosage composition |
| US5830503A (en) * | 1996-06-21 | 1998-11-03 | Andrx Pharmaceuticals, Inc. | Enteric coated diltiazem once-a-day formulation |
| FR2754710B1 (en) * | 1996-10-22 | 1998-12-31 | Prographarm Lab | PROCESS FOR THE PREPARATION OF A MULTIPARTICULAR PHARMACEUTICAL FORM WITH CONTROLLED RELEASE PLURISEQUENTIELLE |
| EP1010457A4 (en) | 1996-12-10 | 2006-03-22 | Asahi Chemical Ind | Porous polyvinylidene fluoride resin film and process for producing the same |
| US6162463A (en) * | 1997-05-01 | 2000-12-19 | Dov Pharmaceutical Inc | Extended release formulation of diltiazem hydrochloride |
| US7108866B1 (en) * | 1999-12-10 | 2006-09-19 | Biovall Laboratories International Srl | Chronotherapeutic diltiazem formulations and the administration thereof |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4173626A (en) * | 1978-12-11 | 1979-11-06 | Merck & Co., Inc. | Sustained release indomethacin |
| JPS5867616A (en) * | 1981-10-15 | 1983-04-22 | Tanabe Seiyaku Co Ltd | Enteric microcapsule and its preparation |
| JPS604120A (en) * | 1983-06-22 | 1985-01-10 | Shionogi & Co Ltd | Pharmaceutical preparation of pinacidil of long acting type |
| FR2554718B1 (en) * | 1983-11-14 | 1986-04-04 | Ethypharm Sa | NEW ORAL SULPIRIDE FORMS FOR SULPIRIDE |
| IE56999B1 (en) * | 1983-12-22 | 1992-03-11 | Elan Corp Plc | Pharmaceutical formulation |
| IT1178511B (en) * | 1984-09-14 | 1987-09-09 | Pharmatec Spa | PROCEDURE FOR THE PREPARATION OF A SOLID FORM FOR ORAL USE BASED ON NIFEDIPINE WITH RELEASE |
-
1988
- 1988-01-13 DK DK198800153A patent/DK173505B1/en not_active IP Right Cessation
- 1988-01-21 AT AT88100839T patent/ATE172112T1/en not_active IP Right Cessation
- 1988-01-21 ES ES88100839T patent/ES2125215T3/en not_active Expired - Lifetime
- 1988-01-21 EP EP88100839A patent/EP0282698B1/en not_active Expired - Lifetime
- 1988-01-21 DE DE3856258T patent/DE3856258T2/en not_active Expired - Fee Related
- 1988-02-15 JP JP63031018A patent/JP2863528B2/en not_active Expired - Fee Related
- 1988-02-19 AU AU11969/88A patent/AU1196988A/en not_active Abandoned
- 1988-02-19 ZA ZA881181A patent/ZA881181B/en unknown
- 1988-02-19 CA CA000559331A patent/CA1327006C/en not_active Expired - Fee Related
- 1988-02-19 BR BR8800763A patent/BR8800763A/en not_active Application Discontinuation
- 1988-02-19 MX MX1049088A patent/MX10490A/en unknown
- 1988-02-20 KR KR1019880001831A patent/KR960011232B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| MX10490A (en) | 1993-12-01 |
| DK15388D0 (en) | 1988-01-13 |
| DE3856258D1 (en) | 1998-11-19 |
| DK15388A (en) | 1988-08-21 |
| ZA881181B (en) | 1988-08-16 |
| BR8800763A (en) | 1988-10-04 |
| DE3856258T2 (en) | 1999-04-29 |
| KR960011232B1 (en) | 1996-08-21 |
| JPH01216934A (en) | 1989-08-30 |
| AU1196988A (en) | 1988-08-25 |
| DK173505B1 (en) | 2001-01-15 |
| EP0282698A1 (en) | 1988-09-21 |
| ES2125215T3 (en) | 1999-03-01 |
| EP0282698B1 (en) | 1998-10-14 |
| JP2863528B2 (en) | 1999-03-03 |
| ATE172112T1 (en) | 1998-10-15 |
| KR880009640A (en) | 1988-10-04 |
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| Date | Code | Title | Description |
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| MKLA | Lapsed |