ZA200006768B - Multiparticulate pharmaceutical form with programmed and timed release and preparation method. - Google Patents
Multiparticulate pharmaceutical form with programmed and timed release and preparation method. Download PDFInfo
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- ZA200006768B ZA200006768B ZA200006768A ZA200006768A ZA200006768B ZA 200006768 B ZA200006768 B ZA 200006768B ZA 200006768 A ZA200006768 A ZA 200006768A ZA 200006768 A ZA200006768 A ZA 200006768A ZA 200006768 B ZA200006768 B ZA 200006768B
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- South Africa
- Prior art keywords
- pharmaceutical form
- form according
- active ingredient
- coating
- polymer
- Prior art date
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- 238000002360 preparation method Methods 0.000 title claims description 9
- 229920000642 polymer Polymers 0.000 claims description 39
- 239000004480 active ingredient Substances 0.000 claims description 35
- 239000011248 coating agent Substances 0.000 claims description 26
- 238000000576 coating method Methods 0.000 claims description 26
- 239000000203 mixture Substances 0.000 claims description 19
- 230000007935 neutral effect Effects 0.000 claims description 13
- 230000035699 permeability Effects 0.000 claims description 12
- 239000000725 suspension Substances 0.000 claims description 11
- HSUGRBWQSSZJOP-RTWAWAEBSA-N diltiazem Chemical group C1=CC(OC)=CC=C1[C@H]1[C@@H](OC(C)=O)C(=O)N(CCN(C)C)C2=CC=CC=C2S1 HSUGRBWQSSZJOP-RTWAWAEBSA-N 0.000 claims description 8
- 229960004166 diltiazem Drugs 0.000 claims description 8
- 239000002245 particle Substances 0.000 claims description 7
- 239000011347 resin Substances 0.000 claims description 7
- 229920005989 resin Polymers 0.000 claims description 7
- PEDCQBHIVMGVHV-UHFFFAOYSA-N Glycerine Chemical compound OCC(O)CO PEDCQBHIVMGVHV-UHFFFAOYSA-N 0.000 claims description 6
- 230000003111 delayed effect Effects 0.000 claims description 6
- SGTNSNPWRIOYBX-UHFFFAOYSA-N 2-(3,4-dimethoxyphenyl)-5-{[2-(3,4-dimethoxyphenyl)ethyl](methyl)amino}-2-(propan-2-yl)pentanenitrile Chemical compound C1=C(OC)C(OC)=CC=C1CCN(C)CCCC(C#N)(C(C)C)C1=CC=C(OC)C(OC)=C1 SGTNSNPWRIOYBX-UHFFFAOYSA-N 0.000 claims description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 claims description 5
- 230000002496 gastric effect Effects 0.000 claims description 5
- 230000000968 intestinal effect Effects 0.000 claims description 5
- 150000007524 organic acids Chemical class 0.000 claims description 5
- 239000000454 talc Substances 0.000 claims description 5
- 229910052623 talc Inorganic materials 0.000 claims description 5
- 229960001722 verapamil Drugs 0.000 claims description 5
- NIXOWILDQLNWCW-UHFFFAOYSA-N acrylic acid group Chemical group C(C=C)(=O)O NIXOWILDQLNWCW-UHFFFAOYSA-N 0.000 claims description 4
- HQKMJHAJHXVSDF-UHFFFAOYSA-L magnesium stearate Chemical compound [Mg+2].CCCCCCCCCCCCCCCCCC([O-])=O.CCCCCCCCCCCCCCCCCC([O-])=O HQKMJHAJHXVSDF-UHFFFAOYSA-L 0.000 claims description 4
- 125000005395 methacrylic acid group Chemical group 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- 239000004014 plasticizer Substances 0.000 claims description 4
- 238000005507 spraying Methods 0.000 claims description 4
- 230000001419 dependent effect Effects 0.000 claims description 3
- 230000037406 food intake Effects 0.000 claims description 3
- 229920000036 polyvinylpyrrolidone Polymers 0.000 claims description 3
- 239000001267 polyvinylpyrrolidone Substances 0.000 claims description 3
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 claims description 3
- 230000003266 anti-allergic effect Effects 0.000 claims description 2
- 229940121363 anti-inflammatory agent Drugs 0.000 claims description 2
- 239000002260 anti-inflammatory agent Substances 0.000 claims description 2
- 230000003110 anti-inflammatory effect Effects 0.000 claims description 2
- 239000000043 antiallergic agent Substances 0.000 claims description 2
- 239000000739 antihistaminic agent Substances 0.000 claims description 2
- 229940125715 antihistaminic agent Drugs 0.000 claims description 2
- 210000000748 cardiovascular system Anatomy 0.000 claims description 2
- 229940000032 cardiovascular system drug Drugs 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 239000001866 hydroxypropyl methyl cellulose Substances 0.000 claims description 2
- 229920003088 hydroxypropyl methyl cellulose Polymers 0.000 claims description 2
- 235000010979 hydroxypropyl methyl cellulose Nutrition 0.000 claims description 2
- UFVKGYZPFZQRLF-UHFFFAOYSA-N hydroxypropyl methyl cellulose Chemical compound OC1C(O)C(OC)OC(CO)C1OC1C(O)C(O)C(OC2C(C(O)C(OC3C(C(O)C(O)C(CO)O3)O)C(CO)O2)O)C(CO)O1 UFVKGYZPFZQRLF-UHFFFAOYSA-N 0.000 claims description 2
- 235000019359 magnesium stearate Nutrition 0.000 claims description 2
- 230000000750 progressive effect Effects 0.000 claims description 2
- 239000002904 solvent Substances 0.000 claims 1
- FLKPEMZONWLCSK-UHFFFAOYSA-N diethyl phthalate Chemical compound CCOC(=O)C1=CC=CC=C1C(=O)OCC FLKPEMZONWLCSK-UHFFFAOYSA-N 0.000 description 11
- CSCPPACGZOOCGX-UHFFFAOYSA-N Acetone Chemical compound CC(C)=O CSCPPACGZOOCGX-UHFFFAOYSA-N 0.000 description 8
- 229920003159 Eudragit® RS 100 Polymers 0.000 description 6
- 229920003155 Eudragit® RL 100 Polymers 0.000 description 5
- 230000001225 therapeutic effect Effects 0.000 description 5
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 4
- KFZMGEQAYNKOFK-UHFFFAOYSA-N Isopropanol Chemical compound CC(C)O KFZMGEQAYNKOFK-UHFFFAOYSA-N 0.000 description 4
- 229910002012 Aerosil® Inorganic materials 0.000 description 3
- 238000004090 dissolution Methods 0.000 description 3
- 208000024891 symptom Diseases 0.000 description 3
- VBICKXHEKHSIBG-UHFFFAOYSA-N 1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 2
- 229920003139 Eudragit® L 100 Polymers 0.000 description 2
- 239000002775 capsule Substances 0.000 description 2
- 229940079593 drug Drugs 0.000 description 2
- 239000003814 drug Substances 0.000 description 2
- 230000000622 irritating effect Effects 0.000 description 2
- 229920006316 polyvinylpyrrolidine Polymers 0.000 description 2
- 239000008213 purified water Substances 0.000 description 2
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 2
- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
- 208000017667 Chronic Disease Diseases 0.000 description 1
- PYGXAGIECVVIOZ-UHFFFAOYSA-N Dibutyl decanedioate Chemical compound CCCCOC(=O)CCCCCCCCC(=O)OCCCC PYGXAGIECVVIOZ-UHFFFAOYSA-N 0.000 description 1
- 206010052804 Drug tolerance Diseases 0.000 description 1
- 108010010803 Gelatin Proteins 0.000 description 1
- CERQOIWHTDAKMF-UHFFFAOYSA-N Methacrylic acid Chemical compound CC(=C)C(O)=O CERQOIWHTDAKMF-UHFFFAOYSA-N 0.000 description 1
- VVQNEPGJFQJSBK-UHFFFAOYSA-N Methyl methacrylate Chemical compound COC(=O)C(C)=C VVQNEPGJFQJSBK-UHFFFAOYSA-N 0.000 description 1
- 241000940835 Pales Species 0.000 description 1
- 206010033546 Pallor Diseases 0.000 description 1
- 229920002472 Starch Polymers 0.000 description 1
- 229930006000 Sucrose Natural products 0.000 description 1
- CZMRCDWAGMRECN-UGDNZRGBSA-N Sucrose Chemical compound O[C@H]1[C@H](O)[C@@H](CO)O[C@@]1(CO)O[C@@H]1[C@H](O)[C@@H](O)[C@H](O)[C@@H](CO)O1 CZMRCDWAGMRECN-UGDNZRGBSA-N 0.000 description 1
- DOOTYTYQINUNNV-UHFFFAOYSA-N Triethyl citrate Chemical compound CCOC(=O)CC(O)(C(=O)OCC)CC(=O)OCC DOOTYTYQINUNNV-UHFFFAOYSA-N 0.000 description 1
- 239000003125 aqueous solvent Substances 0.000 description 1
- 206010003246 arthritis Diseases 0.000 description 1
- 208000006673 asthma Diseases 0.000 description 1
- 239000003405 delayed action preparation Substances 0.000 description 1
- 229940031954 dibutyl sebacate Drugs 0.000 description 1
- 235000013681 dietary sucrose Nutrition 0.000 description 1
- 239000012738 dissolution medium Substances 0.000 description 1
- 230000002526 effect on cardiovascular system Effects 0.000 description 1
- 230000000694 effects Effects 0.000 description 1
- 230000006870 function Effects 0.000 description 1
- 239000008273 gelatin Substances 0.000 description 1
- 229920000159 gelatin Polymers 0.000 description 1
- 235000019322 gelatine Nutrition 0.000 description 1
- 235000011852 gelatine desserts Nutrition 0.000 description 1
- YQEMORVAKMFKLG-UHFFFAOYSA-N glycerine monostearate Natural products CCCCCCCCCCCCCCCCCC(=O)OC(CO)CO YQEMORVAKMFKLG-UHFFFAOYSA-N 0.000 description 1
- SVUQHVRAGMNPLW-UHFFFAOYSA-N glycerol monostearate Natural products CCCCCCCCCCCCCCCCC(=O)OCC(O)CO SVUQHVRAGMNPLW-UHFFFAOYSA-N 0.000 description 1
- 230000026781 habituation Effects 0.000 description 1
- 239000007902 hard capsule Substances 0.000 description 1
- 238000004128 high performance liquid chromatography Methods 0.000 description 1
- 238000000338 in vitro Methods 0.000 description 1
- 230000005923 long-lasting effect Effects 0.000 description 1
- 230000002503 metabolic effect Effects 0.000 description 1
- 208000031225 myocardial ischemia Diseases 0.000 description 1
- 230000000422 nocturnal effect Effects 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 229940124531 pharmaceutical excipient Drugs 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 229920000193 polymethacrylate Polymers 0.000 description 1
- 230000033764 rhythmic process Effects 0.000 description 1
- 239000012488 sample solution Substances 0.000 description 1
- 238000005070 sampling Methods 0.000 description 1
- 239000000741 silica gel Substances 0.000 description 1
- 229910002027 silica gel Inorganic materials 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 229960004793 sucrose Drugs 0.000 description 1
- 238000011282 treatment Methods 0.000 description 1
- URAYPUMNDPQOKB-UHFFFAOYSA-N triacetin Chemical compound CC(=O)OCC(OC(C)=O)COC(C)=O URAYPUMNDPQOKB-UHFFFAOYSA-N 0.000 description 1
- 229960002622 triacetin Drugs 0.000 description 1
- 239000001069 triethyl citrate Substances 0.000 description 1
- VMYFZRTXGLUXMZ-UHFFFAOYSA-N triethyl citrate Natural products CCOC(=O)C(O)(C(=O)OCC)C(=O)OCC VMYFZRTXGLUXMZ-UHFFFAOYSA-N 0.000 description 1
- 235000013769 triethyl citrate Nutrition 0.000 description 1
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
- 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
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- 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
Description
oo -
MULTIPARTICULATE PHARMACEUTICAL FORM WITH PROGRAMMED
AND PULSED RELEASE AND PROCESS FOR ITS PREPARATION
The invention relates to a multiparticulate pharmaceutical form, with programmed and pulsed release, intended for oral administration. It also relates to the process for the preparation of the said pharmaceutical form.
Numerous pharmaceutical forms with delayed release for oral administration are available. The release of the active ingredient must be controlled as a function of the therapeutical purpose and of the pharmacological properties of the active ingredient. In consequence, it is not always desirable that the plasmatic rate be constant. On the contrary, in order to avoid any habituation and in order to 1imit the side effects provoked by the active ingredient, it would be absolutely advantageous for the plasmatic rate to follow the metabolic rhythm and the specific needs of the patient during certain periods of the nycthemer. For instance, in order to diminish the nocturnal symptoms or the symptoms upon awakening in the case of certain chronic diseases such as ischemic heart disease, asthma and arthritis, the drugs should be administered such a way that the desired therapeutical plasmatic level is reached only at the desired moment, that is to say during sleep or just at the moment of awakening.
In the article “An Organic Acid-Induced Sigmoidal
Release System for Oral Controlled-Release Preparations”,
Pharmaceutical Research, Vol. 11, No. 1 (1994), is disclosed a pharmaceutical form wherein the release of the active ingredient is of the sigmoidal type. However, it is indicated in this article that the sigmoidal release of the active ingredient can be obtained only if an organic acid is added to the pharmaceutical form. However, due to the presence of an organic acid, such pharmaceutical forms may have an irritating effect, which constitutes a major y . drawback especially in the case of long lasting treatments.
Consequently, there does not exist at present a multiparticulate pharmaceutical form free of organic acid, capable of making available high concentrations of active ingredient at the moment at which the patient needs them the most, while maintaining the minimal therapeutical plasmatic concentration throughout the day.
The Applicants have had the merit of finding unexpectedly and surprisingly that it is possible to obtain such pharmaceutical forms which are easy for administration and which do not present an irritating effect.
Thus, the multiparticulate pharmaceutical form according to the invention wherein the release of the active ingredient is delayed and pulsed and which enables to obtain the onset of the availability of the active ingredient within 4 to 8 hours after the ingestion of the pharmaceutical form, and then a progressive release of the totality of the active ingredient within the 8 to 20 following hours, is characterized by the fact that it is free of organic acid and that it is in the form of microgranules or medicinal spheroids consisting of a neutral spherical core comprising a first coating based on a mixture of at least one hydrosoluble polymer and of at least one non hydrosoluble polymer throughout which are uniformly distributed the constitutive particles of an active ingredient, the whole comprising a second coating based on at least two pH independent polymers presenting rates of permeability different from one another with respect to the gastric and intestinal mediums, optionally at least one pH dependent polymer, at least one plasticizer and at least one inert carrier uniformly distributed throughout the said coating.
The concentration of active ingredient is very high in the coating which envelops the neutral spherical core which makes it possible to obtain medicinal spheroids of
- f reduced size and thus definite pharmaceutical forms of low size which are easier and more pleasant to be ingested by the patient and which permit the administration of higher dosages per administered drug unit.
According to an advantageous embodiment, the pharmaceutical form according to the invention is thus characterized by the fact that the active ingredient represents from 20 to 100% by weight of the coating which envelops a neutral spherical core, preferably from 60 to 90% by weight and still more preferably from 80 to 90% by weight.
The hydrosoluble polymer which is part of the composition of the coating which envelops the neutral spherical core and which contains the active ingredient is selected from the group comprising especially polyvinylpyrrolidone, hydroxypropylmethyl cellulose, and their mixtures, and the non hydrosoluble polymer is selected from the group comprising especially acrylic and/or methacrylic resins, cellulosic polymers, and their mixtures.
The weight ratio between the hydrosoluble polymer and the non hydrosoluble polymer is from 0.1 to 0.9, preferably from 0.3 to 0.7, and still more preferably from 0.45 to 0.55.
The second coating of the pharmaceutical form according to the invention is based on at least two pH independent polymers which present permeability rates which are different from one another with respect to the gastric and the intestinal mediums, optionally at least one pH dependent polymer, at least one plasticizer and at least one inert carrier uniformly distributed throughout the said coating.
In this second coating, the proportion between the polymer which presents the lowest permeability and the polymer which presents the highest permeability, is from 97/3 to 80/20.
. f :
It is necessary to respect these proportions between the polymers of different permeability rates. As a matter of fact, in the case of proportions of polymer of low permeability higher than 97%, the release of the active ingredient can be too much delayed; on the contrary, in the case of proportions of polymer of low permeability lower than 80%, the release of the active ingredient is not sufficiently delayed.
The polymers of the second coating are selected from the group comprising especially acrylic and/or methacrylic resins, cellulosic polymers, and their mixtures.
The inert carrier which is uniformly distributed throughout the second coating is selected from the group comprising especially talc, anhydrous colloidal silicone dioxide, magnesium stearate, monostearate of glycerol and their mixtures.
The plasticizer which is part of the constitution of the second coating must be pharmaceutically acceptable; it is selected from the group comprising especially ethylphthalate, triethylcitrate, dibutylsebacate, triacetine and their mixtures.
According to an advantageous embodiment of the invention, the active ingredient is selected from the group comprising especially the molecules which are active on the cardio-vascular system, and more especially Diltiazem and
Verapamil, the anti-inflammatories, the antiallergics and the antihistamines.
The pharmaceutical form according to the invention is administered at bed-time.
Thus, the availability of the active ingredient begins about 4 to 8 hours after ingestion, that is to say at the moment of awakening of the patient, i.e. the moment at which certain of the symptoms among which the risks of cardio-vascular accidents are the highest.
The release continues regularly throughout the
- f . : following 8 to 20 hours.
The administration of the next pharmaceutical form being carried out several hours after the end of the total release of the active ingredient, the patient has the 5 benefit of the minimal therapeutical plasmatic concentration during the whole nycthemer.
The process according to the invention for the preparation of the pharmaceutical form according to the invention 1s characterized by a sequence of steps comprising: - the introduction of neutral spherical cores into a reaction vessel working on the principle of the fluidised- bed, - the spraying onto the said neutral spherical cores of particles of the active ingredient suspended in a solution of at least one hydrosoluble polymer and of at least one non hydrosoluble polymer in an organic and/or aqueous solvent, - the spraying on the coated particles obtained in the preceding step of a coating suspension comprising at least one inert carrier suspended in a solution of a mixture of at least two polymers having permeabilities different from one another with respect to the gastric and the intestinal mediums, - optionally the drying of the medicinal spheroids thus obtained.
In the following examples, the following pharmaceutical excipients are used: - EUDRAGIT RS 100: polyacrylic-polymethacrylic resin of low permeability marketed by ROHM, - EUDRAGIT RL 100: permeable polyacrylate-polymethacrylate resin marketed by ROHM, - PVP K 90: polyvinylpyrrolidone marketed by BASF,
- AEROSIL: silica gel marketed by DEGUSSA, ~ Alcohol for pharmaceutical use, - Talc for pharmaceutical use, - Ethyl phthalate marketed by SOLVAY,
S - Spherical neutral cores consisting of saccharose and of starch marketed by the Company WERNER'S, - INWITOR 900: glycerol monostearate marketed by the Company
UHLS, - EUDRAGIT L 100: resin based on methacrylic acid and on methyl methacrylate marketed by ROHM.
EXAMPLE 1
Preparation of medicinal spheroids constituted of the pharmaceutical form according to the invention and whose active ingredient is Diltiazem. 0.7 kg of neutral spherical cores having a diameter from 300 to 400 um are introduced in a fluidized air bed reaction vessel of the GPCGl type and on the said cores there is sprayed a suspension having the following composition:
EUDRAGIT RS 100 . . . . . . . . . . 0.525 kg
PVP K 90 . . . . . . . . « . . .. 0.525 kg
Diltiazem . . . . . . . . . . . . . 7.000 kg
Alcohol for pharmaceutical use . . 18.760 kg.
Then, a coating suspension is sprayed on the thus obtained particles, which suspension has the following composition:
EUDRAGIT RS 100 . . . . . . . . 2.000 kg
EUDRAGIT RL 100 . . . . . . . . 0.100 kg
Ethyl phthalate . . . . . . . . 0.192 kg
AEROSIL . . . . © + + « « « . . 0.320 kg
Talc for pharmaceutical use . . 0.400 kg
Alcohol for pharmaceutical use 10.500 kg
Acetone . . . . . . . oo... 4.500 kg. 400 to 500 of the thus obtained medicinal spheroids
. . ¥ 4 : are introduced in hard capsules of gelatin having a classical constitution.
A release test in vitro of the active ingredient is carried out as follows:
A conventional dissolumeter equipped with pales is used; purified water is used as dissolution medium; the use conditions of the dissolumeter are 900 ml of purified water and 100 rpm; the amount of introduced capsules corresponds to one therapeutical unit.
The amount of active ingredient released (expressed in percent by weight) with respect to the total amount of active ingredient comprised in the introduced capsules is measured as follows:
Sampling of the solution is carried out, every hour, from time 0 to 4 hours and then, every two hours, from the 4th to the 16th hour. The released Diltiazem in the sample solutions is determined by way of an HPLC device equipped with an UV detector at 240 nm.
The results obtained are collected in Table 1.
TABLE 1
ETT ET
IEE
EE ET
02 | a0 0s 1 sa
EEE
I SE SE TTA
HE EY
IE ET
| 2 | ea
EET "TE oo
EXAMPLE 2
Preparation of medicinal spheroids constituted of the pharmaceutical form according to the invention and whose active ingredient is Diltiazem.
Medicinal spheroids are prepared as indicated in example 1 using as coating suspension a suspension having the following composition:
EUDRAGIT RS 100 . . . . . . . . 3.060 kg
EUDRAGIT RL 100 . . . . . . . . 0.340 kg
Ethyl phthalate . . . . . . . . 0.340 kg
Inwitor 900 . . . . . . . . . . 0.170 kg
Isopropanol . . . . . . . . . . 14.28 kg
Acetone . . . . . . . . . . 9.52 kg.
According to the same way as in example 1, the dissolution is measured. The results are collected in table 2 hereafter.
TABLE 2
I EE TE swe 2 sen eer . 1036
EXAMPLE 3
Preparation of medicinal spheroids constituted of the pharmaceutical form according to the invention and whose active ingredient is Diltiazem.
Medicinal spheroids are prepared as indicated in
. ” . : example 1 using as coating suspension a suspension having the following composition:
EUDRAGIT RS 100 . . . . . . . . 3.612 kg
EUDRAGIT RL 100 . . . . . . . . 0.638 kg
Ethyl phthalate . . . . . . . . 0.425 kg
Inwitor 900 . . . . . . . . . . 0.213 kg
Isopropanol . . . . . . . . . . 17.850 kg
Acetone . . . . . . . . 11.900 kg.
According to the same way as in example 1, the dissolution is measured. The results are collected in table 3 hereafter.
TABLE 3
Hows | %ossoen
EE
5 IE EE TR
I EE 7 SE
I EE TE
IE
0s | er | 08 | eas
EC
ET ef est
ET
EXAMPLE 4
Preparation of medicinal spheroids constituted of the pharmaceutical form according to the invention and whose active ingredient is Verapamil.
Medicinal spheroids are prepared in the same way in example 1, Diltiazem being substituted as active ingredient by Verapamil, coating suspension consisting of a suspension having the following composition:
\ . » .
EUDRAGIT RS 100 . . . . . . . . 1.650 kg
EUDRAGIT RL 100 . . . . . . . . 0.87 kg
EUDRAGIT L 100 . . . . . . . . 0.063 kg
Ethyl phthalate . . . . . . . . 0.165 kg
AEROSIL . . . . . . . « + « . . 0.274 kg
Talc . . . . . . . CO 0. 0.343 kg
Alcohol for pharmaceutical use 9.000 kg
Acetone . . . . . . . . oo . 3.857 kg.
According to the same way as in example 1, the dissolution is measured, the released Verapamil being determined by way of a spectrophotometer UV at 278 nm. The results are collected in table 4 hereafter.
TABLE 4
HE
EEE ET
2 er 0s 1 es 4 ez] oe | ees es | er
ETE ees
I SE EZ SE
| we | es
Claims (15)
1. Multiparziculacte pharmaceutical form with delayed and pulsed release, enabling to obtain the onset: of the availzbility of the active ingredient within & +o 8 hours aftzsr the ingestion of the pharmaceutical form, and th2n & progressive release of the totality cf the active ingradient within the 8 to 20 following hours, wnerein it 1s Iree of organic acid and that it 1s in the form of medicinal spheroids consisting of a nautrel spherical core comprising a first coating basad on a mixture of at least onz hydrosoluzle polwvmer end of at least one non hvdrosoluble solymer throughout which are uniformly distributed the constitutive particles of an active ingredient, the wnhol2 comprising a second coating based on at least two pH independent polymers presenting rates of permeedility different from one another with respect to the gastric and intestinal mediums, optionally at l=2ast one pid dependent polymer, at least cn= plasticizer and at least one inert carrier uniformly distributed throughout the sald coating.
2. Pharmaceutical form according to claim 1, wherein the active ingredient represents from 20 to 100%, by weight of the coating which envelops the neutral spherical core.
3. Pharmaceutical form according to claim 2, wherein the active ingredient represents from 60 to 90%, by weight of the coating which envelops the neutral spherical core. AMENDED SHEET 19.11.2001 :
4. Pharmaceutical form according to claim 3, : wherein the active ingredient represents from 80 to 90%, by weight of the coating which envelops the neutral spherical core.
5. Pharmaceutical form according to claim 1 or claim 2, wherein the weight ratio between the hydrosoluble polymer and the non hydrosoluble polymer is from 0.1 to 0.9.
6. Pharmaceutical form according to claim 5, wherein the weight ratio between the hydrosoluble polymer and the non hydrosoluble polymer is from 0.3 to 0.7.
7. Pharmaceutical form according to claim 6, wherein the weight ratio between the hydrosoluble polymer and the non hydrosoluble polymer is from 0.45 to 0.55.
8. Pharmaceutical form according to any one of claims 1 to 7, wherein the hydrosoluble polymer is selected from the group comprising polyvinylpyrrolidone, hydroxy-propylmethyl cellulose and their mixtures, and the non hydrosoluble polymer is selected from the group comprising acrylic and/or methacrylic resins, cellulosic polymers and their mixtures.
9. pharmaceutical form according to any one of claims 1 to 8, wherein the proportion between the polymer which presents the lowest permeability and the polymer which presents the highest permeability, is from 97/3 to 80/20.
10. Pharmaceutical form according to any one of claims 1 to 9, wherein the polymers of the second AMENDED SHEET 19.11.2001 ]
2 13 coating are selected from the group comprising acrylic and/or methacrylic resins, cellulosic polymers and their mixtures.
11. Pharmaceutical form according to any one of claims 1 to 10, wherein the inert carrier which is uniformly distributed throughout the second coating is selected from the group comprising talc, anhydrous colloidal silicone dioxide, magnesium stearate, monostrearate of glycerol and their mixtures.
12. Pharmaceutical form according to any one of claims 1 to 11, wherein the active ingredient is selected from the group comprising the molecules which are active on the cardio-vascular system, the anti-inflammatories, the antiallergics and the 5 antihistamines.
13. Pharmaceutical form according to claim 12, wherein the active ingredient is selected from Diltiazem and Verapamil.
14. Process for the preparation of the pharmaceutical form according to one of the claims 1 to 13, comprising: - the introduction of neutral spherical cores into a reaction vessel working on the principle of the fluidised-bed, - the spraying onto the sald neutral spherical cores of particles of the active ingredient suspended in a solution of at least one hydrosoluble polymer and of at least one non hydrosoluble polymer in an organic and/or agueous solvent, - the spraying on the coated particles obtained in the preceding step of a coating suspension comprising at least one inert carrler AMENDED SHEET 19.11.2001 suspended in a solution of a mixture of at least two polymers having permeabilities different from one another with respect to tne gastric and the intestinal mediums. - optionally the drying of the medicinal spheroids thus obtained.
15. Multiparticulate pharmaceutical form with delayed and pulsed release, substantially as herein described with reference to any one of the illustrative examples. AMENDED SHEET 19.11.2001 i
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR9806384A FR2778848B1 (en) | 1998-05-20 | 1998-05-20 | MULTIPARTICULATE PHARMACEUTICAL FORMULA WITH PULSED RELEASE AND ITS PREPARATION METHOD |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200006768B true ZA200006768B (en) | 2001-11-20 |
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| Application Number | Title | Priority Date | Filing Date |
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| ZA200006768A ZA200006768B (en) | 1998-05-20 | 2000-11-20 | Multiparticulate pharmaceutical form with programmed and timed release and preparation method. |
Country Status (25)
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|---|---|
| EP (1) | EP1077687B1 (en) |
| JP (1) | JP2002515423A (en) |
| KR (1) | KR100583065B1 (en) |
| CN (1) | CN1186014C (en) |
| AT (1) | ATE214598T1 (en) |
| AU (1) | AU758299B2 (en) |
| BG (1) | BG64764B1 (en) |
| BR (1) | BR9910606A (en) |
| CA (1) | CA2333188C (en) |
| DE (1) | DE69901062T2 (en) |
| DK (1) | DK1077687T3 (en) |
| ES (1) | ES2173739T3 (en) |
| FR (1) | FR2778848B1 (en) |
| GE (1) | GEP20022750B (en) |
| HK (1) | HK1033271A1 (en) |
| HU (1) | HU224193B1 (en) |
| IL (1) | IL139774A (en) |
| MX (1) | MXPA00011364A (en) |
| NO (1) | NO330501B1 (en) |
| NZ (1) | NZ508392A (en) |
| PL (1) | PL192950B1 (en) |
| PT (1) | PT1077687E (en) |
| TR (1) | TR200100107T2 (en) |
| WO (1) | WO1999059557A1 (en) |
| ZA (1) | ZA200006768B (en) |
Families Citing this family (15)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US8071128B2 (en) | 1996-06-14 | 2011-12-06 | Kyowa Hakko Kirin Co., Ltd. | Intrabuccally rapidly disintegrating tablet and a production method of the tablets |
| US9358214B2 (en) | 2001-10-04 | 2016-06-07 | Adare Pharmaceuticals, Inc. | Timed, sustained release systems for propranolol |
| US8367111B2 (en) | 2002-12-31 | 2013-02-05 | Aptalis Pharmatech, Inc. | Extended release dosage forms of propranolol hydrochloride |
| US8802139B2 (en) | 2003-06-26 | 2014-08-12 | Intellipharmaceutics Corp. | Proton pump-inhibitor-containing capsules which comprise subunits differently structured for a delayed release of the active ingredient |
| US10624858B2 (en) | 2004-08-23 | 2020-04-21 | Intellipharmaceutics Corp | Controlled release composition using transition coating, and method of preparing same |
| US8747895B2 (en) | 2004-09-13 | 2014-06-10 | Aptalis Pharmatech, Inc. | Orally disintegrating tablets of atomoxetine |
| US9884014B2 (en) | 2004-10-12 | 2018-02-06 | Adare Pharmaceuticals, Inc. | Taste-masked pharmaceutical compositions |
| NZ589750A (en) | 2004-10-21 | 2012-07-27 | Aptalis Pharmatech Inc | Taste-masked pharmaceutical compositions with gastrosoluble pore-formers |
| US9161918B2 (en) * | 2005-05-02 | 2015-10-20 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
| AU2013273835B2 (en) * | 2005-05-02 | 2016-07-07 | Adare Pharmaceuticals, Inc. | Timed, pulsatile release systems |
| US10064828B1 (en) | 2005-12-23 | 2018-09-04 | Intellipharmaceutics Corp. | Pulsed extended-pulsed and extended-pulsed pulsed drug delivery systems |
| US10960077B2 (en) | 2006-05-12 | 2021-03-30 | Intellipharmaceutics Corp. | Abuse and alcohol resistant drug composition |
| WO2008136016A1 (en) * | 2007-05-08 | 2008-11-13 | Medreich Limited | A stable controlled release oral solid dosage form composition and a process thereof |
| AU2010325746B2 (en) | 2009-12-02 | 2016-02-25 | Adare Pharmaceuticals S.R.L. | Fexofenadine microcapsules and compositions containing them |
| FR2999432B1 (en) | 2012-12-17 | 2014-12-12 | Ethypharm Sa | ORODISPERSIBLE COMPRESSES OBTAINED BY COMPRESSION MOLDING |
Family Cites Families (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| JP2558396B2 (en) * | 1990-06-28 | 1996-11-27 | 田辺製薬株式会社 | Controlled release formulation |
| US5567441A (en) * | 1995-03-24 | 1996-10-22 | Andrx Pharmaceuticals Inc. | Diltiazem controlled release formulation |
| FR2754710B1 (en) * | 1996-10-22 | 1998-12-31 | Prographarm Lab | PROCESS FOR THE PREPARATION OF A MULTIPARTICULAR PHARMACEUTICAL FORM WITH CONTROLLED RELEASE PLURISEQUENTIELLE |
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1998
- 1998-05-20 FR FR9806384A patent/FR2778848B1/en not_active Expired - Lifetime
-
1999
- 1999-05-20 DK DK99920897T patent/DK1077687T3/en active
- 1999-05-20 WO PCT/FR1999/001201 patent/WO1999059557A1/en active IP Right Grant
- 1999-05-20 ES ES99920897T patent/ES2173739T3/en not_active Expired - Lifetime
- 1999-05-20 PL PL344314A patent/PL192950B1/en unknown
- 1999-05-20 HU HU0102027A patent/HU224193B1/en active IP Right Grant
- 1999-05-20 IL IL13977499A patent/IL139774A/en not_active IP Right Cessation
- 1999-05-20 PT PT99920897T patent/PT1077687E/en unknown
- 1999-05-20 AU AU38302/99A patent/AU758299B2/en not_active Expired
- 1999-05-20 MX MXPA00011364A patent/MXPA00011364A/en active IP Right Grant
- 1999-05-20 GE GEAP19995632A patent/GEP20022750B/en unknown
- 1999-05-20 JP JP2000549222A patent/JP2002515423A/en active Pending
- 1999-05-20 AT AT99920897T patent/ATE214598T1/en active
- 1999-05-20 NZ NZ508392A patent/NZ508392A/en not_active IP Right Cessation
- 1999-05-20 CN CNB998074322A patent/CN1186014C/en not_active Expired - Lifetime
- 1999-05-20 TR TR2001/00107T patent/TR200100107T2/en unknown
- 1999-05-20 KR KR1020007013020A patent/KR100583065B1/en not_active IP Right Cessation
- 1999-05-20 DE DE69901062T patent/DE69901062T2/en not_active Expired - Lifetime
- 1999-05-20 BR BR9910606-0A patent/BR9910606A/en not_active Application Discontinuation
- 1999-05-20 EP EP99920897A patent/EP1077687B1/en not_active Expired - Lifetime
- 1999-05-20 CA CA2333188A patent/CA2333188C/en not_active Expired - Lifetime
-
2000
- 2000-11-17 BG BG104963A patent/BG64764B1/en unknown
- 2000-11-17 NO NO20005838A patent/NO330501B1/en not_active IP Right Cessation
- 2000-11-20 ZA ZA200006768A patent/ZA200006768B/en unknown
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2001
- 2001-06-11 HK HK01103971A patent/HK1033271A1/en not_active IP Right Cessation
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