CA2218054C - Solid compositions containing polyethylene oxide and an active ingredient - Google Patents

Solid compositions containing polyethylene oxide and an active ingredient Download PDF

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Publication number
CA2218054C
CA2218054C CA 2218054 CA2218054A CA2218054C CA 2218054 C CA2218054 C CA 2218054C CA 2218054 CA2218054 CA 2218054 CA 2218054 A CA2218054 A CA 2218054A CA 2218054 C CA2218054 C CA 2218054C
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mg
composition according
mixing
composition
active ingredient
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CA 2218054
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CA2218054A1 (en
Inventor
Pawan Seth
Andre Stamm
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Valeant International Bermuda
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Biovail Laboratories Inc
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Priority to FR95/04520 priority Critical
Priority to FR9504520 priority
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Priority to PCT/FR1996/000574 priority patent/WO1996032097A1/en
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/495Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/505Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/519Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52Purines, e.g. adenine
    • A61K31/522Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/185Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic, hydroximic acids
    • A61K31/19Carboxylic acids, e.g. valproic acid
    • A61K31/195Carboxylic acids, e.g. valproic acid having an amino group
    • A61K31/197Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid, pantothenic acid
    • A61K31/198Alpha-aminoacids, e.g. alanine, edetic acids [EDTA]
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/21Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/275Nitriles; Isonitriles
    • A61K31/277Nitriles; Isonitriles having a ring, e.g. verapamil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/335Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin
    • A61K31/34Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/401Proline; Derivatives thereof, e.g. captopril
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/435Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/44221,4-Dihydropyridines, e.g. nifedipine, nicardipine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/55Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/554Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having at least one nitrogen and one sulfur as ring hetero atoms, e.g. chlothiapine, diltiazem
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/64Sulfonylureas, e.g. glibenclamide, tolbutamide, chlorpropamide
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2031Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyethylene oxide, poloxamers

Abstract

A solid composition is disclosed comprising an active ingredient that is not in amorphous form in association with polyethylene oxide and conventional additives, excluding basic compounds. Such compositions are suitable for use as pharmaceutical compositions. A method for their preparation is also disclosed.

Description

' CA 02218054 1997-10-10 SOLID COMPOSITIONS CONTAINING POLYETHYLENE OXIDE AND AN
ACTIVE INGREDIENT
The present invention relates to novel solid compositions, notably pharmaceutical compositions, containing polyethylene oxide and an active ingredient, and to methods for their preparation.
Certain medicaments need to be formulated in so-called delayed-release or sustained release form.
Polyethylene oxide referred to as PEO below is moreover known as a component of medicaments in tablet form designed to be administered by oral route. This compound is marketed by the Union Carbide Corporation under the commercial name Polyox~. The use of PEO for formulating medicaments has furthermore been the subject matter of many earlier patents.
EP-A-0 277 092, in the name of Ciba-Geigy relates to a composition comprising a casing in a material that is porous to water but not to the active ingredient, surrounding a central core consisting of a mixture of a substance that is weakly soluble in water, and a hydrophilic swelling material, said material consisting of a mixture of PEO and a vinyl pyrrolidone/vinyl acetate polymer. The composition in that patent is an example of current compositions in which a core which swells when exposed to water is surrounded by a water-porous material, release of the active ingredient being delayed or sustained as a result of the time necessary to expand the core, and for diffusion to take place through the casing following the penetration of water.
The abstract of the US-A-4,404,183 and US-A-4, 343,789 discloses two embodiments of a sustained release composition. In the first embodiment, the composition contains PEO, the active ingredient in an amorphous form, and a basic component. In the second embodiment, the active ingredient is nicardipine in an amorphous state, it being possible to omit the basic component.
It '.1= In n n ~ _'.775I nS=.UC7f' ~ L uuubri I ~JW _ I/34 ' CA 02218054 1997-10-10 Actually, the compositions according to the prior art are complex, require specific active ingredients or are provided in a specific form. Moreover, the results achieved are not always very good.
The present invention provides a simple composition which is suitable for use with a multiplicity of active ingredients, and has a remarkabledelaying or sustaining effect.
Thus, the present invention provides a solid composition comprising, by weight based on the total weight of the composition:
(a) from 1 to 700 of an active ingredient which is not in an amorphous form;
(b) from 10 to 950 of polyethylene oxide;
(c) the balance consisting of conventional additives, excluding basic components.
The expression "solid composition" means that the composition is in a tablet or mini-tablet form, these in their turn being able to be encapsulated using for example the conventional hard gelatin.
The expression "active ingredient" should be understood in its normal sense and, generally speaking, covers medicaments for treatment of the human or animal body as well as an association of one or several such medicaments. Active ingredients that are either hydrophilic or lipophilic are envisaged.
The expression "not in amorphous form" should be understood in its conventional meaning. Various sources give a definition of this term "amorphous" as meaning non-crystalline, lacking the lattice structure characterizing the crystalline state. The following references, which provide a definition of the term amorphous (or the opposite thereof) are, in a on-limiting manner . Hawley's, Condensed Chemical Dictionary, 12th Edition, p. 71; Handbook of Chemistry and Physics, 65th Edition, F-67; The Theory and Practice of Industrial Pharmacy, 1970, pp. 253-255; Remington's Pharmaceutical Sciences, 14th Edition, p. 182; General Chemistry 1992, ~e ~t_.mnr, m,msms~ mor _ ~ ~~z~~~~ > »n _ v2v _ pp.314-315; Encyclopedia of Pharmaceutical Technology, vol I, pp. 12-13.
The expression "excluding basic compounds" should be understood as excluding the presence of a compound or a group of compounds that confer a basic nature on the composition, in other words a pH greater than 7, when the composition is diluted in water at a rate of lOg per litre of water. In particular, this term should be taken as excluding the presence of one or several basic components) such as described in column 1, lines 38 to 62 of US-A-4,404,183 if no acid compound is counteracting the effect of said basic compound, or if the basic compound is present in a relatively large amount.
According to one preferred embodiment, the composition according to the invention, comprises:
(a) from 5 to 450 of an active ingredient;
(b) from 25 to 70% polyethylene oxide (c) the balance consisting of conventional additives, excluding basic components.
According to one preferred embodiment of the composition according to the invention, the active ingredient is a hydrophilic or lipophilic active ingredient, advantageously a hydrophilic ingredient.
According to another preferred embodiment of the composition according to the invention, the active ingredient is selected from the group comprising acyclovir, nifedipine, nicardipine, captopril, verapamil, diltiazem, oxybutynine, valacyclovir, glipizide, felodipine, isosorbide, carbidopa, levodopa, pentoxiphylline, and their pharmaceutically acceptable salts.
According to one alternative embodiment, in the composition according to the invention, the polyethylene oxide has a molecular weight which varies from 50,000 to 8,000,000, and preferably from 100,000 to 3,000,000. The required molecular weight for the PEO can be obtained by mixing PEO of differing molecular weights, that are available commercially.
H'111J1111'.1=J'cl 151.1117(.' _ G <.ct«lpre 1917 - T/2G

According to a further embodiment, in the composition according to the invention, the balance consisting of conventional additives comprises microcrystalline cellulose, lactose, ascorbic acid, pigments, plastifying agents, lubricants and so on. Obviously, other conventional additives known to those skilled in the art can be employed.
According to one embodiment of the invention, in a composition, the balance consisting of conventional additives comprises magnesium stearate and/or glycerol behenate and/or sodium stearyl fumarate, which is employed as a lubricant ensuring better compression of the composition when provided in tablet form, for example.
According to one or alternative embodiment, the composition is additionally coated. Surface coating is employed for the purposes of improving appearance making the drug more readily acceptable to the patient, or for dimensionally stabilising the compressed tablet. The coating can be a conventional coating suitable for enteral use. It is obtained using any conventional technique employing conventional ingredients. A surface coating can for example be obtained using a quick-dissolving film. It should be noted that the coating according to this invention is fundamentally different from the coating used in EP-A-0,277,092 as one does not encounter, in the invention, the dichotomy (water-swellable core)/(water-porous coating), and moreover, the coating in the invention dissolves and/or disintegrates whereas the coating in EP-A-0,277,092 does not dissolve.
The present solid compositions are suitable for the administration of medicaments. Thus, the invention also relates to pharmaceutical compositions deriving therefrom as well as to compositions thereof for use as medicaments.
The present composition can be obtained by any conventional method known to those skilled in the art such as, for example direct compression after simply H:1124!)1711=47S77.S=.UOC'-G Vc(oLrc 1917-4/2G

w mixing the dry ingredients, moist or wet granulation involving the use of a granulation liquid, and dry granulation involving a densification phase for the dry mixture.

5 However, use is preferably made of a process comprising the steps of:
( i ) mixing in the dry state and for a sufficient time, the active ingredient, polyethylene oxide and optionally, one or several additives;
(ii) optionally adding solvent when this is used, followed by mixing for a sufficient period of time;
(iii) granulation by passage through a suitable sieve;
(iv) ~ drying the granules thus formed for a sufficient period of time;
(v) optionally adding one of more additives, with mixing in the dry state for a sufficient time and passage through a suitable sieve;
(vi) optionally adding one or several additives and mixing in the dry state for a sufficient period of time;
(vii) compressing the mixture obtained from the preceding steps to obtain the desired compressed tablet; and (viii) optionally coating said compressed tablet_ The solvent employed, when use is made of a solvent, is preferably an alcohol. The solvent is eliminated by drying at one point or another in the process, and is substantially not encountered in the final composition.
The choice of mixing times, apparatus used, sieve mesh, and other operating conditions are within the province of the normal knowledge of those skilled in the art.
The invention will now be described in more detail, with reference to Fig. 1 which shows percentage in-vitro release of an active ingredient as a function of time for the solid compositions of examples 1 and 2.
~e.v=.~omn ~.am ~sz.UOC . a ~~z~~~~ 1997 _ snv x Without wishing to be bound by any theory, the applicant believes that the PEO, in the formulation, forms a hydrogel from contact with water. This hydrogel dissolves more or less rapidly as a function of the molecular weight of the PEO employed. Choosing the molecular weight of the PEO, in combination with a suitable choice of the weight concentrations of the active ingredient, of PEO, and of additives enables release of the active ingredient to be controlled.
Moreover, the present composition exhibits particularly surprising results. In a hydrophilic matrix, when the concentration of the hydrophilic active ingredient increases, one would expect that the rate of release of the active ingredient would increase. The present composition exhibits the opposite effect, in the case, for example, of acyclovir as active ingredient.
This is clearly shown in Fig. l, which gives in-vitro dissolution of the compositions of examples 1 and 2. The composition of example 1 has a lower concentration of the active ingredient (200 mg medicament in a 905 mg tablet) and shows a faster- in-vitro release of the drug as compared to the formulation of example 2 which has a higher concentration of the active ingredient (400 mg of medicament in a 905 mg tablet). This result is particularly surprising.
The examples below are provided as examples illustrating the invention and should not be considered as limiting its scope . In the examples, the amount of solvent employed is given in brackets, it being understood that the solvent is substantially absent in the final composition.
Example 1 The following composition was prepared:
Acyclovir - 200.0 mg PEO (M4~T = 100 000 ) 700 . 0 mg Magnesium stearate 5.0 mg Industrial alcohol (260.0 mg) I2 \I=alili\I=~i7G1 ~S=.U()(' . p m4nre 1997 _ G/2(, The acyclovir and PEO are weighed and added to a mixer kneader. Mixing in the dry state is performed for minutes. Alcohol is added to the mixture and followed by mixing by 5 minutes. GranL.lation is achieved by 5 passing through a sieve of 1.6 mm mesh. The granules are dried and are passed through a 0.8 mm mesh sieve. After weighing, the magnesium stearate is added and mixing in the dry state is performed during 2 minutes. Tabla_ts are obtained by compression using a Frogerais MR 15 machine.
Example 2 The following composition is prepared:
Acyclovir 400.0 mg PEO (MW = 100 000) 500.0 mg Magnesium stearate 5.0 mg Industrial alcohol (260.0 mg) The acyclovir and PEO are weighed and added in a mixer kneader. Mixing in the dry state is performed for 5 minutes. Alcohol is added to the mixture and followed by mixing by 5 minutes. Granulation is achie~red by passing through a sieve of 1.6 mm mesh. The granu7.es are dried and are passed through a 0.~3 mm mesh sieve. After weighing, the magnesium stearate is added and mixing in the dry state is performed during 2 minutes. Tablets are obtained by compression using a :rotary Frogerais MR 15*
type machine.
Example 3:
The following composition was prepared:
Nifedipine 60.0 mc~
Microcristalline cellulose 100.0 mg PEO (MW = 3 000 000) 336.0 mg Colloidal silicon dioxide 2.5 mg Magnesium stearate 2.5 mg Industrial alcohol (150.0 mg) The nifedipine, microcrystalline cellulose (ava.ilable from the company FMC under the commercial name Avicel PH
lOl~S and the PEO are weighed and added to a mixer kneader. They are mixed in the dry state for 5 minutes and the alcohol is added to the mixture with further *Trade-marks mixing for 5 minutes. Granulation is performed by passage through a 1.8 mm mesh sieve. The granules are dried. The colloidal silicon dioxide (available from Degussa under the commercial name Aerosil 200) is weighed and added and mixing is carried out in the dry state for 5 minutes followed by passage through a 0.6 mm mesh sieve. The magnesium stearate is weighed and added with mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15 type machine.
Example 4:
Core Nifedipine 60.0 mg Microcristalline cellulose 100.0 mg PEO (MW = 3 000 000) ~ 336.0 mg Colloidal silicon dioxide 2.5 mg Magnesium stearate 2.5 mg Industrial alcohol (150.0 mg) Coating:
Iron oxide 2.0 mg Titanium dioxide 1.0 mg Methylcellulose 12.0 mg Industrial alcohol (150.0 mg) The nifedipine, microcrystalli:ne cellulose (available from the company FMC under the commercial name Avi.cel PH
101'0 and the PEO are weighed and added to a mixer kneader. They are mixed in the d.ry state for S minutes and the alcohol is added to the mixture with further mixing for 5 minutes. Granulation is performed by passage through a 1.6 mm mesh siE_ve. The granules are dried. The colloidal silicon dioxide (available from Degussa under the commercial name .Aerosil 20~*)is weighed and added and mixing is carried out in the dry state for 10 minutes followed by passage through a 0.8 mm mesh 3S sieve. The magnesium stearate is weighed and added with mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15*type machine.
*Trade-marks Following tr:i s, t~~e mechylcel.lulose (availabl.e frcm _ciorccn under she commercial name Methocel*)is dissolved in the alcohol. The iron oxide and titanium diox_Lde are added to tre solution, followed by homogenization in an Ultra Turrax* apparatus for 10 minutes. The tablets are coated by spraying this suspension in a perforated pan coating apparatus of the "Glatt coater" type.
Example 5:
The following composition is prepared:
Core:
Nicardipine.HCl 60.0 mg Microcrystalline cellulose 77.0 mg PEO (MW = 2 000 000) 270.0 mg Magnesium stearate 3.0 mc~
Industrial alcohol (150.0 mg) Coat inct Iron oxide 2.0 mc~
Titanium dioxide 1.0 mg Methylcellulose 12.0 mg 2o Industrial alcohol (150.0 mg) The nicardipine.HCl, microcrystalline cellulose (Avicel PH 101*) and PEO are weighed and added to a kneader. Mixing in the dry state: is carried out for 5 minutes. The alcohol is added to the mixture with further kneading for 5 minutes. Granulation is carried out by passage through a 1.6 mm meah sieve. The granules are dried and passed through a 0.8 mm mesh sieve. The magnesium stearate is weighed and added followed by dry mixing for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15*type machine Following this, the methylce.llulose (Methocel*) is dissolved in the alcohol. The iron oxide and titanium oxide are added to the solution followed by homogenization in an Ultra Turrax* apparatus for 10 minutes. ~ The tablets are coated by spraying this suspension in a Glatt coater type coating apparatus.
ExamQle 6 The following composition is prepared:
* Trade-marks r Core:
Captop,ril 50.0 mg Microcrystalline cellulose 100.0 mg PEO (MW = 2 500 000) 300.0 mg S Ascorbic ar_i d (powder) 100 . 0 mg Magnesium stearate 3.0 mg Coating:
Titanium dioxide 1.0 mg Methylcellulose 10.0 mg 10 Industrial alcohol (150.0 mg) The captopril, microcristalline cellulose (Avicel 200*), ascorbic acid and PEO are weighed and added to a mixer kneader. Dry mixing is carried out during 5 _- minutes, followed by a passage through 1.6 mm mesh sieve.
The magnesium stearate is weighed and added with mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15*type machine.
Next, the methylcellulose (Me:thocel*) is dissolved in the alcohol. The titanium dioxide is added to the solution followed by homogenization in an Ultra Turrax*
apparatus for 10 minutes. The tablets are spray coated with this suspension in a Glat:t coater type coating apparatus.
Example 7 2S The following composition is prepared:
Verapamil . HC1 240 . 0 rng Lactose 100.0 rng PEO (MW = 1 000 000) 200.0 mg Magnesium stearate 5,0 mg Industrial alcohol (200.0 rng) The Verapamil.HCl, lactose (available from the company HMS under reference 80 mesh) and the PEO are weighed and added to a mixer kneader followed by mixing in the dry state for S minutes. The alcohol is added to 3S the mixture with further kne<~ding for S minutes.
Granulation is achieved by passage through a 1.6 mm mesh sieve. The granules are dried and passed through a 0.8 mm sieve. The magnesium stearate is weighed and added, * Trade-marks with mixing in the dry state for 2 minutes . -The tablets are obtained by compression in a rotary Frogerais MR 15*
type machine.
Example 8 The following composition is prepared:
Diltiazem HC1 180.0 mg Lactose 100.0 mg PEO (MW = 1 500 000) 160.0 mg Magnesium stearate 3.0 mg Industrial alcohol (150.0 mg) The diltiazem.HCl, lactose (HMS, 80 mesh) and PEO are weighed and added to a mixer kneader. Mixing is carried out in the dry state for 5 minutes. The alcohol is added to the mixture with mixing for 5 minutes. Granulation is achieved by passage through a 1.6 mm mesh sieve. The granules are dried and passed through a 0.8 mm mesh sieve. The magnesium stearate is weighed and added, followed by mixing in the dry state for 2 minutes. The tablets are obtained by compression in a rotary Frogerais MR 15*type machine.
Example 9.
The following composition is prepared:
Oxybutynine.HCl 15.0 mg Microcrystalline cellulose 75.0 mc~
PEO (MW = 1 000 000) 120.0 mg Colloidal silicon dioxide 1.5 mg Magnesium stearate 1.5 mq Industrial alcohol (110.0 mg) _ The oxybutynine.HCl, microcrystalline cellulose (Avicel PH 101*) and PEO are weighed and added to a mixer kneader. Mixing in the dry state is performed for 5 minutes. The alcohol is added to the mixture with further mixing for 5 minutes. Granulation is achieved by passage through a 1.6 mm mesh sieve. The granules are dried. The colloidal silicon dioxide (Aerosil 200) is weighed and added followed by mixing in the dry state for 10 minutes and passage through a 0.8 mm mesh sieve. The magnesium stearate is weighed and added, with mixing in * Trade-marks the dry state for 2 minutes. The tablets are.-obtained by compression in a rotary Frogerais MR 15* type machine.

Example 10:

The following composition was prepared:

S Core:

Nifedipine 60.0 mg Microcristalline cellulose 100.0 mg PEO (MW = 3 000 000) 336,0 rng Colloidal silicon dioxide 2.5 mg Magnesium stearate 2.5 mg Industrial alcohol (150.0 mg) Coating 1:

Ammonio methacrylate copolymer type A 160.0 mg Hydroxy propyl methyl cellulose 20.0 mg Water 30.0 g Industrial alcohol (150.0 mg) CoatincL2:

Iron oxide ~ 2.0 mg Titanium dioxide 1.0 mg Methylcellulose 12.0 mg Industrial alcohol (150.0 mg) The method of preparing the core is to that identical described in Example 4.

Coating 1 is prepared as follows.

The hydroxy propyl methyl is weighed and dissolved in the water/alcohol The amminio methacrylate copolymer (USP XXIII, 12.5 % solid vailable a from Rohm Pharma, German under the commerci al name Eudragit RL:*) is weighed and adde d followed mixing., by Coating is done in a Glatt coater type apparatus.

The method for preparing coating 2 and the application of the coating to the tablet obtained from the previous step are identical to those described in Example 4.

Example 11:

The following composition is prepared:

Valacyclovir_ 200.0 mg PEO (MW = 3U0 000) 700.0 mg * Trade-marks t Magnesium stearate 5.-0 mg Industrial alcohol (260.0 mg The valacyclovir and PEO are weighed and added in a mixer kneader. Mixing in the dry state is performed for S S minutes. Alcohol is added to the: mixture, followed by mixing by 5 minutes. Granulation is achieved by passing through a sieve of 1.6 mm mesh. The granules are dried and are passed through a 0.8 mm mesh sieve. After weighing, magnesium stearate is added and mixing in the l0 dry state is performed during 2 minutes. Tablets are obtained by compression using a 1~rogerais MR 15* type machine.
According to the general process disclosed in the previous examples, the following compositions are 15 prepared, where the active ingredient is a crystalline powder.
Example 12:
The following composition ways prepared:
Core:

20 Glipizide ~ 10.0 mg PEO 220.0 mg Microcristalline cellulose 55.0 mg Hydroxy propyl methyl cellulose 20.0 mg Lactose 50.0 mg 25 Sodium stearyl fumarate 1.7 mg Coatina:

Methacrylic acid copolymer 10.0 mg Polyethylene glycol 2.0 mg Talc 2.5 mg 30 Silicon dioxide 4.5 mg Example 13:

The following composition wa.s prepared:

Core:

Glipizide 10.0 mg 3S PEO 220.0 mg Microcristalline cellulose 55.0 mg Hydroxy propyl methyl cellulose 20.0 mg Lactose 50.0 mg * Trade-marks ' CA 02218054 1997-10-10 Sodium stearyl fumarate 1.7 mg Coating:

Ammonio methacrylate copolymer 10.0 mg Triethyl citrate 3.0 mg Polyethylene glycol 1.0 mg Hydroxypropylmethylcellulose 7.0 mg Example 14:

The following composition was prepared:

Core:

Glipizide 10.0 mg PEO 220.0 mg Microcristalline cellulose 55_0 mg Hydroxy propyl methyl cellulose 20.0 mg Lactose 50.0 mg Sodium stearyl fumarate 1.7 mg Coatincr Ammonio methacrylate copolymer 10.0 mg Lactose 10.0 mg Silicon dioxide 4.0 mg Example 15:

The following composition was prepared:

Core:

Glipizide 10.0 mg PEO 220.0 mg Microcristalline cellulose 55.0 mg Hydroxy propyl methyl cellulose 20.0 mg Lactose 50.0 mg Sodium stearyl fumarate 1.7 mg Coating:

30o polyacrylate dispersion 15.0 mg Silicon dioxide 6.0 mg Talc 2.0 mg Hydroxypropylmethylcellulose 6.0 mg Example 16:

The following composition was prepared:

Core:

Felodipine 10.0 mg PEO _ 220.0 mg 12 '.I ?411(1\I?J7G1 n.11-DC7C' . (, mlubre 1997 _ 7-1~=b Microcristalline cellulose 55.0 mg Hydroxy propyl methyl cellulose 20.0 mg Sodium stearyl fumarate 1.5 mg Coating:

5 Methacrylic acid copolymer 10.0 mg Polyethylene glycol 2.0 mg Talc 2.5 mg Silicon dioxide 4.5 mg Examt~le 17:

10 The following composition was prepared:

Core:

Felodipine 10.0 mg PEO 220.0 mg Microcristalline cellulose 55.0 mg 15 Hydroxy propyl methyl cellulose 20.0 mg Sodium stearyl fumarate 1.5 mg Coatincf Ammonio methacrylate copolymer 10.0 mg Triethyl citrate 3.0 mg Polyethylene glycol 1.0 mg Hydroxypropylmethylc~llulose 7.0 mg Example 18:

The following composition was prepared:

Core:

Felodipine 10.0 mg PEO 220.0 mg Microcristalline cellulose 55.0 mg Hydroxy propyl methyl cellulose 20.0 mg Sodium stearyl fumarate 1.5 mg 3 Coatinct Ammonio methacrylate copolymer 10.0 mg Lactose 10.0 mg Silicon dioxide 4.0 mg Example 19:

The following composition was prepared:

Core : .

Felodipine 10.0 mg PEO 220.0 mg R:\1240(1\12475[ V2.DOC - G octuLre 1997 - I5/2G

Microcristalline cellulose 55.0 mg Hydroxy propyl methyl cellulose 20.0 mg Sodium stearyl fumarate l.5 mg Coating:

30o polyacrylate dispersion 15.0 mg Silicon dioxide 6.0 mg Talc 2.0 mg Hydroxypropylmethylcellulose 6.0 mg Example 20:

The following composition was prepared:

Core:

Isosorbide mononitrate 60.0 mg PEO 100.0 mg Microcristalline cellulose 25.0 mg low substituted Hydroxypropylcellulose mg 5.0 Glycerol behenate 1_9 mg Coating:

Methacrylic acid copolymer 10.0 mg Polyethylene glycol 2.0 mg Talc 2.5 mg Silicon dioxide 4.5 mg Example 21:

The following composition was prepared:

Core:

Isosorbide mononitrate 60.0 mg PEO 100.0 mg Microcristalline cellulose 25.0 mg low substituted Hydroxypropylcell ulose 5.0 mg Glycerol behenate 1.9 mg 3 Coatinct Ammonio methacrylate copolymer 5.0 mg Triethyl citrate 1.5 mg Polyethylene glycol 0.5 mg Hydroxypropylmethylcellulose 3.5 mg Example 22:

The following composition was prepared:

Core:

Isosorbide mononitrate 60.0 mg R \1 ~J~L7\12J7W ~S2.DC7C' - v mGObrc 1 on7 . L(J=v ' CA 02218054 1997-10-10 PEO 100.0 mg MicrocYistalline cellulose 25_0 mg low substituted Hydroxypropylcellulose 5.0 mg Glycerol behenate 1.9 mg Coatinct Ammonio methacrylate copolymer 5.0 mg Lactose 5.0 mg Silicon dioxide 2.0 mg Example 23:

The following composition was prepared:

Core:

Isosorbide mononitrate 60.0 mg PEO 100.0 mg Microcristalline cellulose 25.0 mg low substituted Hydroxypropylcellulose 5.0 mg Glycerol behenate 1.9 mg Coatirig:

30o polyacrylate dispersion 7.5 mg Silicon dioxide 3.0 mg Talc 3.0 mg Hydroxypropylmethylcellulose 3.0 mg Example 24:

The following composition was prepared:

Core:

Carbidopa 25.0 mg Levodopa 100.0 mg Microcristalline cellulose 20.0 mg Povidone 4.0 mg Low substituted Hydroxypropylcellulose 8.0 mg PEO 20.0 mg Sodium stearyl fumarate 1.7 mg Coatin:cr Methacrylic acid copolymer 50.0 mg Polyethylene glycol 1.0 mg Talc 1.25 mg Silicon dioxide 2.25 mg Example 25:

The following composition was prepa red:

Itw.l?.Itlf1\I=-l7Sl IS_ 1)()C' ~ G mcmbm 1997 - 17/_v ' CA 02218054 1997-10-10 Core:

Carbidopa 25.0 mg Levodopa 100.0 mg Microcristalline cellulose 20.0 mg Povidone 4.0 mg Low substituted Hydroxypropylcellulose 8.0 mg PEO 20.0 mg Sodium stearyl fumarate 1.7 mg Coating:

Ammonio methacrylate copolymer 5.0 mg Triethyl citrate 1_5 mg Polyethylene glycol 0.5 mg Hydroxypropylmethylcellulose 3_5 mg Example 26:

The following composition was prepared:

Core:

Carbidopa 25.0 mg Levodopa 100.0 mg Microcristalline cellulose 20.0 mg Povidone 4.0 mg Low substituted Hydroxypropylcellulose 8.0 -mg PEO 20.0 mg Sodium stearyl fumarate 1.7 mg Coating:

Ammonio methacrylate copolymer 5.0 mg Lactose 5.0 mg Silicon dioxide 2.0 mg Example 27:

The following composition was prepared:

Core:

Carbidopa 25.0 mg Levodopa 100.0 mg Microcristalline cellulose 20.0 mg Povidone 4.0 mg Low substituted Hydroxypropylcellulose 8.0 mg PEO 20.0 mg Sodium stearyl fumarate 1.7 mg Coating:

li \I=~1(11111=~I7Cl IS=.DOC' . (, meliobre 1997 _ 18/16 ' CA 02218054 1997-10-10 30o polyacrylate dispersion 7.5 mg Silicon dioxide 3.0 mg Talc 1.0 mg Hydroxypropylmethylcellulose 3.0 mg Example 28:

The following composition was prepared:

Core:

Pentoxiphylline 400.0 mg PEO 150.0 mg Povidone 30.0 mg Glycerol behenate 6.0 mg Coating:

Methacrylic acid copolymer 20.0 mg Polyethylene glycol 4.0 mg Talc 5.0 mg Silicon dioxide 9.0 mg Example 29:

The following composition was prepared:

Core:

Pentoxiphylline 400.0 mg PEO 150.0 mg Povidone 30.0 mg Glycerol behenate 6.0 mg Coating:

Ammonio methacrylate copolymer 20.0 mg Triethyl citrate 6.0 mg Polyethylene glycol 2.0 mg Hydroxypropylmethylcellulose 14_0 mg Examt~le 30:

The following composition was prepared:

Core:

Pentoxiphylline 400.0 mg PEO 150.0 mg Povidone 30.0 mg Glycerol behenate 6.0 mg Coatincr Ammonio methacrylate copolymer 20.0 mg Lactose 20.0 mg R \12~1(tIt\I=~175I1S=.DOC - G ~ctubrc 1997 _ I9/2G

' CA 02218054 1997-10-10 Silicon dioxide - 8.0 mg Example 31:

The following composition was prepared:

Core:

5 Pentoxiphylline 400.0 mg PEO 150.0 mg Povidone - 30.0 mg Glycerol behenate 6.0 mg Coating:

l0 30o po.lyacrylate dispersion 30.0 mg Silicon dioxide 12.0 mg Talc 4.0 mg Hydroxypropylmethylcellulose 12.0 mg Example 32:

15 The following composition was prepared:

Core:

Nicardipine 30.0 mg PEO 150.0 mg Microcristalline cellulose 30.0 mg 20 Povidone 5.0 mg Magnesium stearate 2.0 mg Coating:

Methacrylic acid copolymer 6.0 mg Polyethylene glycol 1.2 mg Talc _ 1.5 mg Silicon dioxide 2.7 mg Example 33:

The following composition was prepared:

Core:

Nicardipine 30.0 mg PEO 150.0 mg Microcristalline cellulose 30.0 mg Povidone 5-.0 mg Magnesium stearate 2.0 mg Coating:

Ammonio methacrylate copolymer 6.0 mg Triethyl citrate l.g mg Polyethylene glycol 0.6 mg IL \I2~lllln.l=i7S~i5-.DOC-G UCIUI7fC 1997 -20/26 -' CA 02218054 1997-10-10 Hydroxypropylmethylcellulose 4_2 mg Example 34:

The following composition was prepared:

Core:

Nicardipine 30_0 mg PEO 150.0 mg Microcristalline cellulose 30.0 mg Povidone 5.0 mg Magnesium stearate 2.0 mg Coating:

Ammonio methacrylate copolymer 6.0 mg Lactose 6.0 mg Silicon dioxide 2.4 mg Example 35:

The following composition was prepared:

Core:

Nicardipine 30.0 mg PEO 150.0 mg Microcristalline cellulose 30.0 mg Povidone 5.0 mg Magnesium stearate 2.0 mg Coating:

30o po~lyacrylate dispersion 9.0 mg Silicon dioxide 3.6 mg Talc 1.2 mg Hydroxypropylmethylcellulose 3.6 mg R~\124UWI=.J7W'S_-DU<'-6uctubre 1997-21/26

Claims (47)

1. A solid pharmaceutical composition comprising, by weight based on the total weight of the composition:
(a) ~from 1 to 70% of active ingredient which is not in an amorphous form, (b) ~from 10 to 95% of polyethylene oxide, (c) ~the balance consisting of conventional additives, excluding basic components, said composition being obtained by the process comprising the steps of:
(i) ~mixing in the dry state and for a sufficient time, the active ingredient, polyethylene oxide and optionally, one or several additives;
(ii) ~optionally adding solvent when such is used, followed by mixing for a sufficient period of time;
(iii) ~granulation;
(iv) ~drying the granules thus formed for a sufficient period of time;
(v) ~optionally adding one of more additives, with mixing in the dry state for a sufficient time and passage through a suitable sieve;
(vi) ~optionally adding one or several additives and mixing in the dry state for a sufficient period of time;
(viii) ~compressing the mixture obtained from the preceding steps to obtain the desired compressed tablet; and (viii) ~optionally coating said compressed tablet.
2. ~The composition according to claim 1, comprising:
(a) from 5 to 45% of the active ingredient;
(b) from 25 to 70% polyethylene oxide;

(c) the balance consisting of conventional additives, excluding basic components.
3. The composition according to claim 1, in which the polyethylene oxide has a molecular weight which varies from 50,000 to 8,000,000.
4. The composition according to claim 3, in which the polyethylene oxide has a molecular weight which varies from 100,000 to 3,000,000.
5. The composition according the claim 1, in which the balance consisting of conventional additives comprises at least one conventional additive selected from the group consisting of magnesium stearate, glycerol behenate, and sodium stearyl fumarate.
6. The composition according to claim 1, wherein said composition is additionally coated.
7. The composition according to claim 2, in which the active ingredient is acyclovir or a pharmaceutically acceptable salt thereof.
8. The composition according to claim 2, in which the active ingredient is nifedipine or a pharmaceutically acceptable salt thereof.
9. The composition according to claim 2, in which the active ingredient is nicardipine or a pharmaceutically acceptable salt thereof.
10. The composition according to claim 2, in which the active ingredient is captopril or a pharmaceutically acceptable salt thereof
11. The composition according to claim 2, in which the active ingredient is verapamil or a pharmaceutically acceptable salt thereof.
12. The composition according the claim 2, in which the active ingredient is diltiazem or a pharmaceutically acceptable salt thereof.
13. The composition according the claim 2, in which the active ingredient is oxybutynine or a pharmaceutically acceptable salt thereof.
14. The composition according the claim 2, in which the active ingredient is valacyclovir or a pharmaceutically acceptable salt thereof.
15. The composition according the claim 2, in which the active ingredient is glipizide or a pharmaceutically acceptable salt thereof.
16. The composition according the claim 2, in which the active ingredient is felodipine or a pharmaceutically acceptable salt thereof.
17. The composition according the claim 2, in which the active ingredient is isosorbide or a pharmaceutically acceptable salt thereof.
18. The composition according the claim 2, in which the active ingredient is carbidopa or a pharmaceutically acceptable salt thereof.
19. The composition according the claim 2, in which the active ingredient is levodopa or a pharmaceutically acceptable salt thereof.
20. The composition according the claim 2, in which the active ingredient is pentoxiphylline or a pharmaceutically acceptable salt thereof.
21. A method for preparing a composition as defined in claim 1, comprising the steps consisting of:
(i) mixing in the dry state and for a sufficient time, the active ingredient, polyethylene oxide and optionally, one or several additives;
(