CA1285483C - Sustained release compositions - Google Patents
Sustained release compositionsInfo
- Publication number
- CA1285483C CA1285483C CA000520582A CA520582A CA1285483C CA 1285483 C CA1285483 C CA 1285483C CA 000520582 A CA000520582 A CA 000520582A CA 520582 A CA520582 A CA 520582A CA 1285483 C CA1285483 C CA 1285483C
- Authority
- CA
- Canada
- Prior art keywords
- weight percent
- formulation
- cellulose ether
- percent
- active ingredient
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Lifetime
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/20—Pills, tablets, discs, rods
- A61K9/2004—Excipients; Inactive ingredients
- A61K9/2022—Organic macromolecular compounds
- A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
- A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
- A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
Abstract
ABSTRACT
The release of one or more active ingredients from a tablet can be delayed by employing a fine par-ticle sized hydroxypropyl methylcellulose ether com-position.
34,506-F
The release of one or more active ingredients from a tablet can be delayed by employing a fine par-ticle sized hydroxypropyl methylcellulose ether com-position.
34,506-F
Description
8~83 SUSTAINED RELEASE COMPOSITIONS
This invention concerns sustained release tablets, and particularly solid pharmaceutical formu-lations comprised of a fine particle sized hydrophilic cellulose ether.
Polymeric compositions have been widely used as a matrix base for compressed tablets. Such tablets typically contain at least one medicament or vitamin whose xate of release into the system is delayed or controlled by the matrix base. Controlled release tablets are desirable because they provide a method of delivering a long-lasting dose in a single appli-cation without overdosing the system.
Typically, an effective amount of the polymeric matrix composition is employed. It is desirable to employ as little amount of polymeric composition as possible to provide the intended release profile, to obtain minimum dosage size or to obtain good compression properties. For such applications, a highly hydrophilic polymeric composition is suitably employed. Such a composition rapidly hydrates and forms a gel-like layer 34,506-F -1-. ~
~85~
in the tablet through which the active ingredient is released to the system. An example of a preferred hydrophilic polymeric composition is a cellulose ether sold as METHOCEL~ K4M and K15M by The Dow Chemical Company, which has a hydroxypropoxyl substitution of between 4 to 12 weight percent, and a methoxyl sub-stitùtion of between 19 to 25 weight percent.
U.S. Patent 4,369,172 discloses that hydroxy-propyl methylcellulose ethers having a hydroxypropoxyl content of from 9 to 12 percent and a number average molecular weight of less than about 50, 000 provide the best sustained release. Moreover, the effect of hydra-tion and gel formation is de-emphasized in favor of the chemical composition of the hydroxypropyl methylcel-lulose.
Cellulose ethers, such as METHOCEL~ K, aredesirable polymeric matrix compositions because they are derived from naturally occurring cellulose, and are free-flowing, readily compressible powders. Unfortun-ately, not all cellulose ethers hydrate rapidly, andtherefore do not provide a desirable release profile for compressed tablets.
Yet another factor affecting the performance of the tablet is the chemical characteristics of the active ingredient employed. Certain polymers can be employed beneficiallv for some active lnqredients, but not for others. The actlve ingredient's degree of water-solubility, molecular weight, and the diffusion coefficient in a hydrated polymer gel layer can be critical.
34,506-F -2-lZ8S483 It would be desirable to have additional cellulose ether polymeric matrix materials which would provide sufficient release profiles for use in pharmaceutical formulations such as particularly tablets.
The present invention provides a solid, compressed pharmaceutical formulation which, in powder form prior to compression, comprises:
(1) at least one active ingredient;
This invention concerns sustained release tablets, and particularly solid pharmaceutical formu-lations comprised of a fine particle sized hydrophilic cellulose ether.
Polymeric compositions have been widely used as a matrix base for compressed tablets. Such tablets typically contain at least one medicament or vitamin whose xate of release into the system is delayed or controlled by the matrix base. Controlled release tablets are desirable because they provide a method of delivering a long-lasting dose in a single appli-cation without overdosing the system.
Typically, an effective amount of the polymeric matrix composition is employed. It is desirable to employ as little amount of polymeric composition as possible to provide the intended release profile, to obtain minimum dosage size or to obtain good compression properties. For such applications, a highly hydrophilic polymeric composition is suitably employed. Such a composition rapidly hydrates and forms a gel-like layer 34,506-F -1-. ~
~85~
in the tablet through which the active ingredient is released to the system. An example of a preferred hydrophilic polymeric composition is a cellulose ether sold as METHOCEL~ K4M and K15M by The Dow Chemical Company, which has a hydroxypropoxyl substitution of between 4 to 12 weight percent, and a methoxyl sub-stitùtion of between 19 to 25 weight percent.
U.S. Patent 4,369,172 discloses that hydroxy-propyl methylcellulose ethers having a hydroxypropoxyl content of from 9 to 12 percent and a number average molecular weight of less than about 50, 000 provide the best sustained release. Moreover, the effect of hydra-tion and gel formation is de-emphasized in favor of the chemical composition of the hydroxypropyl methylcel-lulose.
Cellulose ethers, such as METHOCEL~ K, aredesirable polymeric matrix compositions because they are derived from naturally occurring cellulose, and are free-flowing, readily compressible powders. Unfortun-ately, not all cellulose ethers hydrate rapidly, andtherefore do not provide a desirable release profile for compressed tablets.
Yet another factor affecting the performance of the tablet is the chemical characteristics of the active ingredient employed. Certain polymers can be employed beneficiallv for some active lnqredients, but not for others. The actlve ingredient's degree of water-solubility, molecular weight, and the diffusion coefficient in a hydrated polymer gel layer can be critical.
34,506-F -2-lZ8S483 It would be desirable to have additional cellulose ether polymeric matrix materials which would provide sufficient release profiles for use in pharmaceutical formulations such as particularly tablets.
The present invention provides a solid, compressed pharmaceutical formulation which, in powder form prior to compression, comprises:
(1) at least one active ingredient;
(2) a substantially water-soluble hydroxypropyl methylcellulose ether having a hydroxypropoxyl substitution of from 7 to 12 weight percent and a methoxyl substitution of from 28 to 30 weight percent, and a number average molecular welght of at least 15,000, sald ether having a particle size diameter of at least 90 percent by weight of less than 100 mesh (150 micrometers), sald compressed formulation capable of sustained release of said active ingredient.
The formulation is prepared by intimately mixing an amount of the active ingredient(s) in the form of a powder with a functionally effective amount of a fine particle sized, ~ubstantially water-soluble hydroxypropyl methylcellulose ether.
The cellulose ether is in the form of a powder, has a hydroxypropoxyl substitution of from 7 to 12 weight percent, a methoxyl substitution of from 28 to 30 weight percent, and a number average molecular weight of at least 15,000. The intimate admixture is subjected to pressure conditions to form a solid tablet. The cellulose ether composition is sufficlently fine that ~: .
.
~.285483 -3a- 64693-3916 the release of active composltion from the solid tablet is delayed longer upon contacting an aqueous acidic environment at 37C, compared to a tablet formulated with a chemically identical but coarser cellulose ether composition.
B
.. ` . . -- . - . . ~ . .
.. . . .. .- . .
- - .
~ .
. .
~.28~83 This invention is useful in providing solid pharmaceutical formulations having at least one thera-peutically active ingredient with a cellulose ether which exhibits sustained release properties and optionally carriers and excipients.
The hydroxypropyl methylcellulose ether composition of this invention is within the USP spec-ification for HPMC 2910. It has a hydroxypropoxyl substitution of from 7 to 12 weight percent, a methoxyl substitution of from 28 to 30 weight percent, and a number average molecular weight of at least 15,000 or a 2 percent aqueous solution viscosity of at least 20 cps.
Preferably, the cellulose ether has a number average molecular weight of at least 50,000 or a 2 percent agueous solution viscosity of at least 800 cps. Most preferably, the cellulose ether has a number average molecular weight of at least 80,000 or a 2 percent agueous solution viscosity of at least 3,000 cps. Such a cellulose ether hydrates most rapidly and forms a thick viscous gel which can delay the release of the active ingredient(s).
Typically, the cellulose ether is prepared by the reaction of cellulose pulp with caustic to form alkali cellulose. The alkali cellulose is then reacted under control conditions with an alkyl halide and alkylene oxide to form the cellulose ether. Such a process is described, for example, in U.S. Patent 4,477,657.
The cellulose ether useful in this invention has a sufficiently fine particle size that the release 34,506-F -4-- .: -- . ': - ' :
.
; `- ~'.: : -'~ . ' .
.
~285483 of the active ingredient(s) from a tablet is delayed longer upon contacting an aqueous acidic environment at 37C; compared to the release from a tablet formulated with a chemically identical but coarser particle sized cellulose ether A cellulose ether is chemically iden-tical, for purposes of this invention, when it pos-sesses hydroxypropoxyl and methoxyl substitution within the ranges of USP HPMC 2910, and has a 2 percent a~ueous solution viscosity within 50 percent of the viscosity of the fine particle sized composition.~ A cellulose ether is coarse when the particle size distribution has a larger amount by weight of larger particles than the fine particle sized cellulose ether. A fine particle size is sufficient to increase the rate of hydration, and thereby delay the release of the active ingre-dient(s). Such particle size can vary, although any size sufficient to form a gel-like layer can be employed, and typically is sufficient when about 90 weight percent of the cellulose ether, and preferably at least about 95 weight percent, can pass through a -100 mesh screen. More preferably, the cellulose ether has a particle size sufficient that at least about 95 weight percent, and most preferably at least abaut 97 weight percent can pass through a -140 mesh screen.
The cellulose ether is substantially water-soluble. Substantially water-soluble ethers tend to spontaneously disperse their molecules throughout the molecules of water.
A functionally effective amount of the cellu-lose ether is employed. Such amount is an amount sufficient to delay the release of the therapeutically -34,506-F -5-' ~.~8548~
active ingredient. Preferably, the amount employed is the minimum amount required to provide the delayed release. Such an amount can vary and typically ranges from 5 to 90 weight percent, preferably from 5 to 25 weight percent, and most preferably from 10 to 17 weight percent based on weight of the tablet, although any functionally effective amount can be employed.
The solid pharmaceutical formulation can be administered orally to affect a condition such as, for example, a pharmaceutical drug or vitamin. The active ingredient(s) can be a water-soluble or a water-insoluble composition. A water-soluble composition is a composi-tion which spontaneously disperses its molecules in an aqueous medium, and a water-insoluble composition is a composition which does not exhibit that spontaneous dispersion. Suitable water-soluble compositions include ~ aspirin, theophylline, pseudoephedrine HCl, ascorbic I IL~ acid, riboflavin, 5 phosphate sodium and others.
Suitable water-insoluble compositions include naproxyn, ibuprofen and others. Water-soluble compositions especially find the formulation of this invention useful because they tend to dissolve and diffuse through the hydrated cellulose ether layer, during gel formation.
:
The therapeutically active ingredient(s) is (are) employed in any effective dosage amount. Such amount is an amount sufficient to affect the condition to be treated. The amount can vary according to the specific active ingredient employed, and such variations are within the knowledge of the skilled artisan. Typ-ically, the active ingredient can be employed up to about ale-~na~K
34,506-F -6-.
-~:
~ ~5483 95 weight percent of the compressed tablet, althoughany pharmaceu~tically effective weight percent can be employed.
Typically, tablets can contain one or more optional carriers or excipients such as diluents or fillers, binders, lubricants, distinegrants,and glid-ants. Diluents or fillers are agents which can provide bulk and binding properties. Examples of suitable diluents-or fillers are lactose, mannitol, sucrose, corn starch, and the like. Typically, such diluents or fillers can be employed in the formulation up to about 80 weight percent, and preferably up to about 60 weight percent. Binders are agents which can bind the compon-ents of the tablets together and are typically employed in a wet granulation process. Examples of suitable binders are hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, corn starch, gelatin, and polyvinyl-pyrrolidinone. Typically, such binders are employed in from 3 to 8 weight percent. Lubricants are agents which can prevent sticking to die walls or punch faces.
Examples of suitable lubricants are magnesium stearate, stearic acid and the like. Typically, such lubricants are employed in an amount from 0.5 to 3.0 weight percent. Disintegrants are agents that enable the tablet to break up at thP appropriate time. Examples of suitable disintegrants are corn starch, guar gum, potato starch, alginic acid, and the like. Glidants are agents which can aid powder flow. An example of a suitable glidant is fumed silica. Typically, such glidants are employed in an amount from 0.1 to 3.0 weight percent.
34,506-F -7-~85~83 The active ingredient(s), cellulose ether, and optional carriers and excipients are uniformly mixed together in powder form to provide a homogeneous mixture. The mixture is then subjected to compression to provide a solid tablet. Before compressing, the mixture can be subjected to a wet or dry granulation process. The powder or granulated mixture is fed to the die of a tablet press and sufficient pressure is applied to form a solid tablet. Such pressure can vary, and typically ranges from about 1,000 psi to about 6,000 psi, and preferably about 2,000 psi force.
A solid tablet can substantially retain its form under conventional storage and handling conditions. The tablet also maintains its solid form upon administra-tion, and provides sustained release of the activeingredient through diffusion and erosion.
Advantageously, the ingredients for the pharmaceutical formulation can be treated in a dry granulation process or a wet granulation process. In a dry granulation process, the mixture is precompressed and milled into the desired size prior to tableting.
In a wet granulation process, the mixture is combined and formed into granules with a polymeric binder solu-tion and then sized and/or dried at the desired par-ticle size prior to tableting. The size of the granu-lated mixture is not critical to the active ingredient release rate. The release rate is affected, according to this invention, by the particle size of the cellulose ether prior to granulating.
The tablets are suitable for administering one or more therapeutically active ingredients to 34,506-F -8-.. : :
g humans. Upon contacting the aqueous acidic environment typically present in humans, the tablets slowly dis-solve. Typically, the acidic environment is provided by gastric juices, and is at about 37C.
Solid tablets formulated with the small particle size cellulose ether composition of this invention surprisingly have a longer release profile compared to tablets formulated with a chemically iden-tical cellulose ether composition which has a larger particle size distribution. When the cellulose ether composition has a particle size sufficiently small that at least about 97 weight percent can pass through a -140 mesh screen, the tablets typically require at least one hour, preferably at least two hours, and more preferably at least four hours longer to release the active ingredient(s) compared to tablets formulated with a chemically identical cellulose ether composition having a particle size in which at least 97 weight percent can pass through a -140 mesh screen.
The following examples are illustrative only, and are not intended to limit the scope of the inven-tion.
ExamPle 1 A 780 mg tablet of aspirin is made in a 0.5-25 inch (1.2 cm) concave punch at 3,000 pounds compaction force. The tablet formulation is 82.6 weight percent B aspirin -100 mesh crystals, 16.5 weight percent METHOCEL~
E-50 Premium (i.e., HPMC 2910 USP, 50 cps), and 0.9 weight percent magnesium stearate lubricant. The HPMC
is ball milled for 24 hours to reduce the particle ~ T~le m~ .
34,506-F -9-,: . - :
.
- ' :, ', - '.
. - ~ . .
. ' ~ . --~ ~5483 size. About 95 weight percent of the HPMC passesthrough a -100 mesh screen. The tablet is placed in a USP dissolution device using the paddle method at 100 rpm in 0.1 N HCl at 37C. The release profile is provided in Table I, as Sample 1.
~ Comparative Sample 1 An aspirin tablet is prepared using the same amounts and ingredients employed in Exàmple 1, eXcept that the same HPMC is not ball milled, and about 84 weight percent of the particles fail to pass through a -100 mesh screen. The tablet is placed in the same USP
dissolution device as in Example 1. The release pro-file is provided in Table I as C-1 .
34,506-F -10-~ 285483 TABLE I
Sample ~ *(l) Time (Hours) (Percent) (Percent) O O O
0.5 13.2 95.9 1.0 18.4 100 1.5 22.7 --2.0 30.6 --3.0 38.2 --5.0 54-3 ~~
7.0 71.5 --9.O 100 Not an example of this invention.
(l)The amount of aspirin released into the environment.
This example illustrates the difference in release profiles provided to a formulation by employing a small particle sized (Sample 1) versus a large particle sized (C-1 ) cellulose ether as the release agent.
Example 2 Aspirin tablets are prepared using the amounts and ingredients of Example 1. The cellulose ether (HPMC 2910, 50 cps) has the following particle size distribution.
Percent of HPMC
Mesh Size Retained -60 0.88 -80 1.07 -100 2.34 -140 12.30 -200 16.11 -325 28.61 thru -325 36.23 34,506-F -11-8S4~33 Tablets are prepared using the fraction whichpasses through the -140 mesh screen. The release profile is provided in Table II, under "Sample 2".
Comparative tablets are prepared using the entire range S of particle sizes. The release profile of these tablets is provided in Table II, under C-2 .
TABLE II
*
Sample 2 C-2 Time Hours (Percent) (Percent) 0.5 29.6 95.9 1.0 53.8 100 1.5 71.8 --2.0 80.3 --3.0 87.2 --5.0 100 __ Not an example of this invention.
This example illustrates the surprising benefits of employing a cellulose ether which exclu-sively has a small particle size (Sample 2) versus therelease profile provided by a formulation employing a small amount (about 16 percent~ of larger particle size (C-2 j.
ExamPle 3 Solid tablets are prepared from a formulation of 52.6 weight percent lactose, 26.7 weight percent theophylline USP, 20.0 weight percent METHOCEL~ E-4M
Premium (HPMC 2910, USP) and 0.7 weight percent magne-sium stearate. The tablet is a 750 mg tablet and is 34,506-F -12-128548~
made using a 0.5-inch (1.2 cm) concave punch at about 3,000 psi compressional force. About 99 weight percent of the particles of the cellulose ether pass through a -100 mesh screen. The release profile is determined in the same dissolution device and environment used in Examples 1 and 2. The release profile is provided in Table III, under Sample 3.
*
comParative SamPle 3 Tablets of theophylline are prepared in the same formulation as in Example 3. The cellulose ether composition has a substantially larger particle size (about 85 weight percent fail to pass through a -140 mesh screen). The release profile is measured as in Example 3, and is provided in Table 3, under C-3 .
Table III
Sample 3 C-3 Time (Hours) (Percent) (Percent) O O O
0.5 17 21 1.5 21 38 3.0 35 55 5.0 47 69 7.0 59 80 9.0 67 92 11.0 77 100 13.0 81 --Not an example of this invention.
This example illustrates that smaller particle size can extend the sustained release properties of tablets which typically exhibit an effective sustained release profile.
34,506-F -13-:, - . ...
'
The formulation is prepared by intimately mixing an amount of the active ingredient(s) in the form of a powder with a functionally effective amount of a fine particle sized, ~ubstantially water-soluble hydroxypropyl methylcellulose ether.
The cellulose ether is in the form of a powder, has a hydroxypropoxyl substitution of from 7 to 12 weight percent, a methoxyl substitution of from 28 to 30 weight percent, and a number average molecular weight of at least 15,000. The intimate admixture is subjected to pressure conditions to form a solid tablet. The cellulose ether composition is sufficlently fine that ~: .
.
~.285483 -3a- 64693-3916 the release of active composltion from the solid tablet is delayed longer upon contacting an aqueous acidic environment at 37C, compared to a tablet formulated with a chemically identical but coarser cellulose ether composition.
B
.. ` . . -- . - . . ~ . .
.. . . .. .- . .
- - .
~ .
. .
~.28~83 This invention is useful in providing solid pharmaceutical formulations having at least one thera-peutically active ingredient with a cellulose ether which exhibits sustained release properties and optionally carriers and excipients.
The hydroxypropyl methylcellulose ether composition of this invention is within the USP spec-ification for HPMC 2910. It has a hydroxypropoxyl substitution of from 7 to 12 weight percent, a methoxyl substitution of from 28 to 30 weight percent, and a number average molecular weight of at least 15,000 or a 2 percent aqueous solution viscosity of at least 20 cps.
Preferably, the cellulose ether has a number average molecular weight of at least 50,000 or a 2 percent agueous solution viscosity of at least 800 cps. Most preferably, the cellulose ether has a number average molecular weight of at least 80,000 or a 2 percent agueous solution viscosity of at least 3,000 cps. Such a cellulose ether hydrates most rapidly and forms a thick viscous gel which can delay the release of the active ingredient(s).
Typically, the cellulose ether is prepared by the reaction of cellulose pulp with caustic to form alkali cellulose. The alkali cellulose is then reacted under control conditions with an alkyl halide and alkylene oxide to form the cellulose ether. Such a process is described, for example, in U.S. Patent 4,477,657.
The cellulose ether useful in this invention has a sufficiently fine particle size that the release 34,506-F -4-- .: -- . ': - ' :
.
; `- ~'.: : -'~ . ' .
.
~285483 of the active ingredient(s) from a tablet is delayed longer upon contacting an aqueous acidic environment at 37C; compared to the release from a tablet formulated with a chemically identical but coarser particle sized cellulose ether A cellulose ether is chemically iden-tical, for purposes of this invention, when it pos-sesses hydroxypropoxyl and methoxyl substitution within the ranges of USP HPMC 2910, and has a 2 percent a~ueous solution viscosity within 50 percent of the viscosity of the fine particle sized composition.~ A cellulose ether is coarse when the particle size distribution has a larger amount by weight of larger particles than the fine particle sized cellulose ether. A fine particle size is sufficient to increase the rate of hydration, and thereby delay the release of the active ingre-dient(s). Such particle size can vary, although any size sufficient to form a gel-like layer can be employed, and typically is sufficient when about 90 weight percent of the cellulose ether, and preferably at least about 95 weight percent, can pass through a -100 mesh screen. More preferably, the cellulose ether has a particle size sufficient that at least about 95 weight percent, and most preferably at least abaut 97 weight percent can pass through a -140 mesh screen.
The cellulose ether is substantially water-soluble. Substantially water-soluble ethers tend to spontaneously disperse their molecules throughout the molecules of water.
A functionally effective amount of the cellu-lose ether is employed. Such amount is an amount sufficient to delay the release of the therapeutically -34,506-F -5-' ~.~8548~
active ingredient. Preferably, the amount employed is the minimum amount required to provide the delayed release. Such an amount can vary and typically ranges from 5 to 90 weight percent, preferably from 5 to 25 weight percent, and most preferably from 10 to 17 weight percent based on weight of the tablet, although any functionally effective amount can be employed.
The solid pharmaceutical formulation can be administered orally to affect a condition such as, for example, a pharmaceutical drug or vitamin. The active ingredient(s) can be a water-soluble or a water-insoluble composition. A water-soluble composition is a composi-tion which spontaneously disperses its molecules in an aqueous medium, and a water-insoluble composition is a composition which does not exhibit that spontaneous dispersion. Suitable water-soluble compositions include ~ aspirin, theophylline, pseudoephedrine HCl, ascorbic I IL~ acid, riboflavin, 5 phosphate sodium and others.
Suitable water-insoluble compositions include naproxyn, ibuprofen and others. Water-soluble compositions especially find the formulation of this invention useful because they tend to dissolve and diffuse through the hydrated cellulose ether layer, during gel formation.
:
The therapeutically active ingredient(s) is (are) employed in any effective dosage amount. Such amount is an amount sufficient to affect the condition to be treated. The amount can vary according to the specific active ingredient employed, and such variations are within the knowledge of the skilled artisan. Typ-ically, the active ingredient can be employed up to about ale-~na~K
34,506-F -6-.
-~:
~ ~5483 95 weight percent of the compressed tablet, althoughany pharmaceu~tically effective weight percent can be employed.
Typically, tablets can contain one or more optional carriers or excipients such as diluents or fillers, binders, lubricants, distinegrants,and glid-ants. Diluents or fillers are agents which can provide bulk and binding properties. Examples of suitable diluents-or fillers are lactose, mannitol, sucrose, corn starch, and the like. Typically, such diluents or fillers can be employed in the formulation up to about 80 weight percent, and preferably up to about 60 weight percent. Binders are agents which can bind the compon-ents of the tablets together and are typically employed in a wet granulation process. Examples of suitable binders are hydroxypropyl methylcellulose, hydroxypropyl cellulose, acacia, corn starch, gelatin, and polyvinyl-pyrrolidinone. Typically, such binders are employed in from 3 to 8 weight percent. Lubricants are agents which can prevent sticking to die walls or punch faces.
Examples of suitable lubricants are magnesium stearate, stearic acid and the like. Typically, such lubricants are employed in an amount from 0.5 to 3.0 weight percent. Disintegrants are agents that enable the tablet to break up at thP appropriate time. Examples of suitable disintegrants are corn starch, guar gum, potato starch, alginic acid, and the like. Glidants are agents which can aid powder flow. An example of a suitable glidant is fumed silica. Typically, such glidants are employed in an amount from 0.1 to 3.0 weight percent.
34,506-F -7-~85~83 The active ingredient(s), cellulose ether, and optional carriers and excipients are uniformly mixed together in powder form to provide a homogeneous mixture. The mixture is then subjected to compression to provide a solid tablet. Before compressing, the mixture can be subjected to a wet or dry granulation process. The powder or granulated mixture is fed to the die of a tablet press and sufficient pressure is applied to form a solid tablet. Such pressure can vary, and typically ranges from about 1,000 psi to about 6,000 psi, and preferably about 2,000 psi force.
A solid tablet can substantially retain its form under conventional storage and handling conditions. The tablet also maintains its solid form upon administra-tion, and provides sustained release of the activeingredient through diffusion and erosion.
Advantageously, the ingredients for the pharmaceutical formulation can be treated in a dry granulation process or a wet granulation process. In a dry granulation process, the mixture is precompressed and milled into the desired size prior to tableting.
In a wet granulation process, the mixture is combined and formed into granules with a polymeric binder solu-tion and then sized and/or dried at the desired par-ticle size prior to tableting. The size of the granu-lated mixture is not critical to the active ingredient release rate. The release rate is affected, according to this invention, by the particle size of the cellulose ether prior to granulating.
The tablets are suitable for administering one or more therapeutically active ingredients to 34,506-F -8-.. : :
g humans. Upon contacting the aqueous acidic environment typically present in humans, the tablets slowly dis-solve. Typically, the acidic environment is provided by gastric juices, and is at about 37C.
Solid tablets formulated with the small particle size cellulose ether composition of this invention surprisingly have a longer release profile compared to tablets formulated with a chemically iden-tical cellulose ether composition which has a larger particle size distribution. When the cellulose ether composition has a particle size sufficiently small that at least about 97 weight percent can pass through a -140 mesh screen, the tablets typically require at least one hour, preferably at least two hours, and more preferably at least four hours longer to release the active ingredient(s) compared to tablets formulated with a chemically identical cellulose ether composition having a particle size in which at least 97 weight percent can pass through a -140 mesh screen.
The following examples are illustrative only, and are not intended to limit the scope of the inven-tion.
ExamPle 1 A 780 mg tablet of aspirin is made in a 0.5-25 inch (1.2 cm) concave punch at 3,000 pounds compaction force. The tablet formulation is 82.6 weight percent B aspirin -100 mesh crystals, 16.5 weight percent METHOCEL~
E-50 Premium (i.e., HPMC 2910 USP, 50 cps), and 0.9 weight percent magnesium stearate lubricant. The HPMC
is ball milled for 24 hours to reduce the particle ~ T~le m~ .
34,506-F -9-,: . - :
.
- ' :, ', - '.
. - ~ . .
. ' ~ . --~ ~5483 size. About 95 weight percent of the HPMC passesthrough a -100 mesh screen. The tablet is placed in a USP dissolution device using the paddle method at 100 rpm in 0.1 N HCl at 37C. The release profile is provided in Table I, as Sample 1.
~ Comparative Sample 1 An aspirin tablet is prepared using the same amounts and ingredients employed in Exàmple 1, eXcept that the same HPMC is not ball milled, and about 84 weight percent of the particles fail to pass through a -100 mesh screen. The tablet is placed in the same USP
dissolution device as in Example 1. The release pro-file is provided in Table I as C-1 .
34,506-F -10-~ 285483 TABLE I
Sample ~ *(l) Time (Hours) (Percent) (Percent) O O O
0.5 13.2 95.9 1.0 18.4 100 1.5 22.7 --2.0 30.6 --3.0 38.2 --5.0 54-3 ~~
7.0 71.5 --9.O 100 Not an example of this invention.
(l)The amount of aspirin released into the environment.
This example illustrates the difference in release profiles provided to a formulation by employing a small particle sized (Sample 1) versus a large particle sized (C-1 ) cellulose ether as the release agent.
Example 2 Aspirin tablets are prepared using the amounts and ingredients of Example 1. The cellulose ether (HPMC 2910, 50 cps) has the following particle size distribution.
Percent of HPMC
Mesh Size Retained -60 0.88 -80 1.07 -100 2.34 -140 12.30 -200 16.11 -325 28.61 thru -325 36.23 34,506-F -11-8S4~33 Tablets are prepared using the fraction whichpasses through the -140 mesh screen. The release profile is provided in Table II, under "Sample 2".
Comparative tablets are prepared using the entire range S of particle sizes. The release profile of these tablets is provided in Table II, under C-2 .
TABLE II
*
Sample 2 C-2 Time Hours (Percent) (Percent) 0.5 29.6 95.9 1.0 53.8 100 1.5 71.8 --2.0 80.3 --3.0 87.2 --5.0 100 __ Not an example of this invention.
This example illustrates the surprising benefits of employing a cellulose ether which exclu-sively has a small particle size (Sample 2) versus therelease profile provided by a formulation employing a small amount (about 16 percent~ of larger particle size (C-2 j.
ExamPle 3 Solid tablets are prepared from a formulation of 52.6 weight percent lactose, 26.7 weight percent theophylline USP, 20.0 weight percent METHOCEL~ E-4M
Premium (HPMC 2910, USP) and 0.7 weight percent magne-sium stearate. The tablet is a 750 mg tablet and is 34,506-F -12-128548~
made using a 0.5-inch (1.2 cm) concave punch at about 3,000 psi compressional force. About 99 weight percent of the particles of the cellulose ether pass through a -100 mesh screen. The release profile is determined in the same dissolution device and environment used in Examples 1 and 2. The release profile is provided in Table III, under Sample 3.
*
comParative SamPle 3 Tablets of theophylline are prepared in the same formulation as in Example 3. The cellulose ether composition has a substantially larger particle size (about 85 weight percent fail to pass through a -140 mesh screen). The release profile is measured as in Example 3, and is provided in Table 3, under C-3 .
Table III
Sample 3 C-3 Time (Hours) (Percent) (Percent) O O O
0.5 17 21 1.5 21 38 3.0 35 55 5.0 47 69 7.0 59 80 9.0 67 92 11.0 77 100 13.0 81 --Not an example of this invention.
This example illustrates that smaller particle size can extend the sustained release properties of tablets which typically exhibit an effective sustained release profile.
34,506-F -13-:, - . ...
'
Claims (7)
1. A solid, compressed pharmaceutical formulation which, in powder form prior to compression, comprises:
(1) at least one active ingredient;
(2) a substantially water-soluble hydroxypropyl methylcellulose ether having a hydroxypropoxyl substitution of from 7 to 12 weight percent and a methoxyl substitution of from 28 to 30 weight percent, and a number average molecular weight of at least 15,000, said ether having a particle size diameter of at least 90 percent by weight of less than 100 mesh (150 micrometers), said compressed formulation capable of sustained release of said active ingredient.
(1) at least one active ingredient;
(2) a substantially water-soluble hydroxypropyl methylcellulose ether having a hydroxypropoxyl substitution of from 7 to 12 weight percent and a methoxyl substitution of from 28 to 30 weight percent, and a number average molecular weight of at least 15,000, said ether having a particle size diameter of at least 90 percent by weight of less than 100 mesh (150 micrometers), said compressed formulation capable of sustained release of said active ingredient.
2. The formulation of claim 1 in a tablet form.
3. The formulation of claim 1, wherein at least 95 weight percent of the cellulose ether particles can pass through a -100 mesh screen.
4. The formulation of claim 3, wherein at least 95 weight percent of the cellulose ether particles can pass through a -140 mesh screen.
5. The formulation of claim 1 or 4, wherein the cellulose ether has a 2 percent solution viscosity of at least 800 cps.
6. The formulation of Claim 1, further comprising an exci-pient which is a lubricant.
7. The formulation of Claim 1 or 2 when the active ingre-dient is present up to about 95 weight percent, the cellulose ether is present from 5 to 90 weight percent, and further compris-ing carriers or excipients which are present up to about 3 weight percent.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US06/791,675 US4734285A (en) | 1985-10-28 | 1985-10-28 | Sustained release compositions |
| US791,675 | 1985-10-28 |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CA1285483C true CA1285483C (en) | 1991-07-02 |
Family
ID=25154448
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CA000520582A Expired - Lifetime CA1285483C (en) | 1985-10-28 | 1986-10-16 | Sustained release compositions |
Country Status (6)
| Country | Link |
|---|---|
| US (1) | US4734285A (en) |
| JP (1) | JPH0751516B2 (en) |
| KR (1) | KR890004685B1 (en) |
| AU (1) | AU599925B2 (en) |
| CA (1) | CA1285483C (en) |
| NZ (1) | NZ218046A (en) |
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-
1985
- 1985-10-28 US US06/791,675 patent/US4734285A/en not_active Expired - Lifetime
-
1986
- 1986-10-15 AU AU63947/86A patent/AU599925B2/en not_active Expired
- 1986-10-16 CA CA000520582A patent/CA1285483C/en not_active Expired - Lifetime
- 1986-10-23 NZ NZ218046A patent/NZ218046A/en unknown
- 1986-10-27 JP JP61253879A patent/JPH0751516B2/en not_active Expired - Lifetime
- 1986-10-27 KR KR1019860008977A patent/KR890004685B1/en not_active IP Right Cessation
Also Published As
| Publication number | Publication date |
|---|---|
| JPH0751516B2 (en) | 1995-06-05 |
| NZ218046A (en) | 1990-04-26 |
| KR870003781A (en) | 1987-05-04 |
| JPS62149632A (en) | 1987-07-03 |
| KR890004685B1 (en) | 1989-11-25 |
| AU599925B2 (en) | 1990-08-02 |
| US4734285A (en) | 1988-03-29 |
| AU6394786A (en) | 1987-04-30 |
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