MULTI-LAYERED, MULTIPLE UNIT PHARMACEUTICAL COMPOSITIONS
Technical Field of the Invention
The present invention relates to pharmaceutical compositions comprising multilayered multiple
units and processes for the preparation thereof.
Background of the Invention
This application is a patent of addition of IN 1587/DEL/2009 which has a priority of July 31,
2009.
Oral controlled release formulations provide maxImum patient compliance and reduce the
frequency of dosing to attain effective therapy. The intention of controlled release formulations
is to provide an extended duration of the pharmacological response after administration of the
dosage form, than is ordinarily experienced after the administration of an immediate release
dosage form. The purpose of these formulations is to provide a constant concentration of the
active substance in body fluids for a certain time period. However, the demand on controlled
release dosage forms is immense, the maximal therapeutic effect is to be reached using a
minimum amount of active substance with reduced frequency of dosing and lesser degree of side
effects, as well as minimized inter and intra individual effect variations. The dosage form could
be single unit or multiple unit dosage form.
Single unit controlled release dosage forms of drugs have known disadvantages. Such dosage
forms either pass undisintegrated through the gastrointestinal tract or release the entire drug in a
burst (dose dumping). These dosage forms are dependent upon gastric emptying rates and transit
times and are also associated with a lot of intra and inter-individual variations.
Multiple unit dosage forms comprise a multiplicity of individual units contained within a rapid
dissolving capsule, or compressed into a tablet, and soon after ingestion upon its dissolution are
available as individual units in the GJ.T.
Several advantages with multiple unit dosage forms comprising a large number of small units
have been described in the literature. It is, for example, possible to obtain a reproducible
emptying of the units from the stomach into the small intestine when the particles are less than
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1-2 mm. Dispersion over a large area in the gastrointestinal tract can give a more reproducible
time for the passage, which is of advantage for the absorption process. In addition a multiple
unit preparation is preferable to one single drug unit as the dose is spread out in the intestine.
The risk of local irritation and accumulation of several doses due to constriction in the
alimentary canal are also considered to be lower.
u.s. Patent Nos. 4,927,640 and 5,246,714 describe controlled release insoluble beads coated
with a membrane controlling drug release. Examples of insoluble inert material used are silicon
dioxide, glass, or plastic resin particles. The core materials have a standardized size and shape,
preferably spherical with an even surface with size of 0.15 - 0.25mm. The preparation has
several advantages, e.g. the particles contain a high percentage of active ingredient and are not
contaminated by soluble inert compounds, which is the case, when cores of e.g. lactose or sugar
are covered by a therapeutically active compound. By using small dense particles of e.g. silicon
dioxide as the core material, it is possible to obtain highly concentrated beads (granules) of the
active compound which is an advantage for high dosage preparations, e.g. magnesium chloride.
Dosage forms containing multiple layers have several advantages over the prior discussed arts.
For example, u.s. Patent No. 5,783,215 describes the multiple unit dose preparation capable of
withstanding the mechanical stress, i.e. during compaction. This has been done by using inert
and non-soluble cores of glass or sand particles or soluble cores such as sugar spheres capable of
withstanding mechanical stress, in combination with a plasticizing layer. The active substance is
dispersed in a solution of the hydrophilic polymer and applied to the core, which is again
covered with controlled release membrane. These beads have excellent mechanical and release
characteristics.
A co-assigned peT publication No. WO 200411 05735 refers to a controlled release composition
containing units, wherein each unit includes a core, a first layer, and a second layer. In this
application it has been disclosed that inert core (soluble or swellable or insoluble) is first layered
with active and one or more hydrophilic polymers, and is further layered with one or more
polymers that are effective for controlled release of active.
u.s. Patent No. 8,110,226 discloses a controlled release drug composition comprising a bead,
said bead comprising: an inert core; a seal layer positioned on said core layer, said seal layer
comprising a non-polymeric hydrophobic material; a layer containing at least one active
ingredient positioned on said seal layer; and a layer of at least one release-controlling polymer
positioned on said layer containing at least one active ingredient; wherein said seal layer does
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not contain any polymeric material.
peT Publication No. WO 2012/101653 discloses a modified release pharmaceutical composition
comprising: (a) a plurality of sustained release components comprising memantine or salts
thereof and one or more rate controlling polymers; (b) at least one immediate release component
comprising memantine or salts thereof coated over the sustained release components; and (c)
more than 3% by weight of one or more pharmaceutically acceptable binders, wherein the
composition exhibits a biphasic release profile.
u.s. Patent No. 5,229,135 discloses a sustained release diltiazem pellet formulation having, a
central inactive sphere; a plurality of alternating first and second layers surrounding the sphere
to form a core, the first layer comprising a water soluble pharmaceutically acceptable polymeric
material and the second layer comprising diltiazem or a pharmaceutically acceptable salt
thereof; and an outer coating comprising first inner membrane layers applied to said core, said
first inner membrane layers comprising a first water insoluble pharmaceutically acceptable
polymer, and a single outer membrane forming a relatively thick and homogeneous layer
surrounding said first inner membrane layers and comprising a second water insoluble
pharmaceutically acceptable polymeric material different from said first water insoluble
pharmaceutically acceptable polymer.
Applying polymer layer over the inert core before the active layer has few advantages. For
examples, the amount of time that the solution within the bead would be saturated with respect
to drug may be maximized. Thus, by preventing the soluble core from being a reservoir for drug
dissolution, the relative time that a saturated solution would remain within the bead during the
release period can be increased considerably. This means that a substantially longer zero order
drug release phase (the phase when the drug release rate is essentially constant) will be obtained
(and less in the undesirable declining release rate phase). By varying the thickness of the first
polymeric layer, drug release profile can be altered in a predictable fashion, in particular for
drugs with a moderate to high water solubility.
Similar type of dosage form is disclosed in u.S. Patent No. 6,911,217. It describes a bead
comprising (i) a core unit of a substantially water-soluble or water-swellable inert material, (ii) a
first layer on the core unit of a substantially water-insoluble polymer, (iii) a second layer
covering the first layer and containing an active ingredient, and (iv) a third layer of polymer on
the second layer effective for controlled release of the active ingredient. The first layer of waterinsoluble
polymer is meant to control water penetration into the core. u.S. '217 patent describes
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that in order to achieve water penetration into the core, aqueous polymeric dispersions are used
in the first and third layers. However, aqueous based system requires high heat of vaporization
that might require lengthy processing times leading to economic disadvantages. In addition to
this, multiple units coated with aqueous based polymeric system can easily agglomerate in the
coating process due to low inertia and momentum.
Hence, it would be desirable to have a controlled release composition in the form of
multilayered multiple units that will deliver a constant and controlled release of water soluble
drugs. Further it is desired to have an advantageous process that would be less time consuming
and economical. The processing time for the present formulation would be less due to nonaqueous
based system. In the present invention combination of hydrophobic and pH dependent
components in the polymeric seal coating on the core, helps in modulating the drug release.
Summary of the Invention
In one aspect, the present invention relates to a multilayered multiple unit composition
compnsmg:
(i) an inert core;
(ii) a first layer on the inert core, comprising
a) at least one hydrophobic polymer or hydrophobic substance and
b) at least one pH-dependent polymer or pH-dependent substance;
(iii) a second layer onto the first layer, compnsmg at least one active ingredient;
(iv) a third layer onto the second layer, compnsmg one or more pharmaceutically
acceptable polymers effective for controlling or modifying the release of active
ingredient; and
(v) optionally, a fourth layer onto the third layer compnsmg one or more
pharmaceutically acceptable polymers;
wherein the first layer is applied as a solution or dispersion in a non-aqueous based solvent
system.
Embodiments of the composition may include one or more following features. For example, a
seal layer comprising one or more pharmaceutically acceptable polymers may optionally be
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applied between the second active layer and the third controlled release or modified release
layer.
In one embodiment, the hydrophobic polymer or hydrophobic substance present in the first layer
amounts to 0.1 - 20% of the total weight of the composition. Particularly the amount is 0.1 10%
and more particularly the amount is 0.1 - 5%.
In another embodiment, the pH-dependent polymer or pH-dependent substance present in the
first layer amounts to 0.1 - 20% of the total weight of the composition. Particularly the amount is
0.1 - 10% and more particularly the amount is 0.1 - 5%.
In yet another embodiment, the ratio of the hydrophobic polymer or hydrophobic substance to
the pH-dependent polymer or pH-dependent substance in the first layer may be from about 99:1
to 1:99 by weight.
In yet another embodiment, the active ingredient may include, but are not limited to, antiulcers,
analgesics, antihypertensives, antibiotics, antipsychotics, anticancer agents, antimuscarinics,
diuretics, antimigraines, antivirals, anti-inflammatory agents, sedatives, antidiabetics,
antidepressants, antihistaminics, antiparasitics, antiepileptics, anti alzheimer's drugs and lipid
lowering drugs. Particularly the active ingredient is antimuscarinic or anti alzheimer's drugs and
more particularly the antimuscarinic is tolterodine and its acceptable salts and anti alzheimer's
drug is memantine.
In another aspect the present invention relates to a process for preparing a multilayered multiple
unit composition comprising the steps of:
(i) providing an inert core;
(ii) applying a first layer on the inert core, comprising
(a) at least one hydrophobic polymer or hydrophobic substance and
(b) at least pH-dependent polymer or pH-dependent substance;
(iii) applying a second layer onto the first layer, comprising at least one active
ingredient;
(iv) applying a third layer onto the second layer, compnsmg one or more
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pharmaceutically acceptable polymers effective for controlling or modifying the
release of active ingredient; and
(v) optionally applying a fourth layer onto the third layer compnsmg one or more
pharmaceutically acceptable polymers;
wherein the first layer is applied as a solution or dispersion or suspenSIOn m a non
aqueous based solvent system.
In yet another aspect the present invention relates to a process for preparing a multilayered
multiple unit composition comprising the steps of:
(i) providing an inert core;
(ii) applying a first layer on the inert core, comprising
(a) at least one hydrophobic polymer or hydrophobic substance and
(b) at least one pH-dependent polymer or pH-dependent substance;
(iii) applying a second layer onto the first layer, comprising at least one active
ingredient;
(iv) applying a seal layer onto the second layer, compnsmg one or more
pharmaceutically acceptable polymers;
(v) applying a third layer onto
pharmaceutically acceptable polymers
release of active ingredient; and
the seal
effective
layer, compnsmg one or more
for controlling or modifying the
(vi) optionally applying a fourth layer onto the third layer, compnsmg one or more
pharmaceutically acceptable polymers;
wherein the first layer is applied as a solution or dispersion or suspenSIOn m a non
aqueous based solvent system.
In one embodiment the seal layer onto the second layer may optionally further include one or
more organic acids as stabilizers to prevent any inter-reactions between the drug and the release
controlling or modifying layer.
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In yet another aspect the pharmaceutical composition of the present invention relates to method
of treating urinary disorders including overactive urinary bladder.
Embodiments of the composition may include one or more pharmaceutically acceptable
excipients, which act in one or more capacities as diluents, binders, plasticizers, lubricants,
glidants, colorants or flavoring agents.
The details of one or more embodiments of the inventions are set forth in the description below.
Other features and objects of the invention will be apparent from the description and examples.
Description of the Invention
Formulating a controlled release pharmaceutical composition for water soluble drugs, that too in
the form of multiple units is not so easy. In this invention the inventors have developed a
multilayered multiple unit composition, that is robust and stable, to deliver the active ingredient
in a controlled manner.
The invention relates to a multilayered multiple unit controlled release composition comprising:
(i) an inert core;
(ii) a first layer on the inert core, comprising
(a) at least one hydrophobic polymer or hydrophobic substance and
(b) at least one pH-dependent polymer or pH-dependent substance;
(iii) a second layer onto the first layer, comprising at least one active ingredient;
(iv) a third layer onto the second layer, comprising one or more pharmaceutically
acceptable polymers effective for controlling or modifying the release of active
ingredient;
(v) a seal layer between the second and third layer, compnsmg one or more
pharmaceutically acceptable polymers; and
(vi) optionally, a fourth layer onto the third layer compnsmg one or more
pharmaceutically acceptable polymers; - wherein the first layer is applied as a solution or
dispersion or suspension in a nonaqueous based solvent system.
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The term "multiple unit composition" indicates a pharmaceutical composition that includes one
or more individual coated units contained in the formulation in such a form that the individual
units will be available from the formulation upon disintegration of the formulation in the
stomach. The multiple unit pharmaceutical composition or formulation may be a capsule or a
tablet that disintegrates in the stomach to give individual units. The multiple units may be
formulated as granules, pellets or beads.
The inert core of the composition may include one or more of an inert insoluble, swellable or
soluble core. The insoluble or swellable inert core may include one or more of dicalcium
phosphate, microcrystalline cellulose or any of the marketed inert cores, for example glass
beads, silicate beads, sugar spheres, non-pareils and celphere. The soluble core may include one
or more of glucose, mannitol, lactose, xylitol, dextrose, and sucrose.
The first layer of the composition comprises (a) at least one hydrophobic polymer or
hydrophobic substance and (b) at least one pH-dependent polymer or pH-dependent substance;
Suitable examples of hydrophobic polymer or hydrophobic substance include, but are not
limited to ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl
methylcellulose phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic
acid esters, waxes, shellac, hydrogenated vegetable oils; or mixtures thereof. Ethylcellulose is
available as a dry powder (Ethocel®. of Dow, U.S.A.) or as aqueous dispersion marketed under
the trade name Aquacoat®. of FMC, USA or Surelease® of Colorcon, USA, Ethylcellulose of
various available viscosities grades ranging from 3 mpas to 50 mpas can be used.
Suitable examples of pH-dependent polymer or pH-dependent substances include, but are not
limited to cellulose acetate phthalate, polymethacrylates, and sodium carboxymethylcellulose.
Chitosan, sodium alginate, oleic acid. Polymethacrylate is selected form Poly(methacrylic acid,
methyl methacrylate) 1:1 marketed under the trade name of Eudragit® L of Rohm Pharma,
Germany, Poly (methacrylic acid, ethyl acrylate) 1:1 marketed under the trade name of
Eudragit®L 30D-55 and Eudragit® LIOO-55 of Rohm Pharma, Germany, Poly(methacrylic
acid, methyl methacrylate) 1:2 marketed under the trade name of Eudragit®S of Rohm Pharma,
Germany.
The ratio of the hydrophobic polymer or hydrophobic substance to the pH-dependent polymer or
pH-dependent substance in the first layer may be from about 99: 1 to 1:99 by weight.
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The first layer controls the penetration of water inside the core depending on the pH of the
environment. pH-dependent polymer dissolves at a specific pH and leads to the formation of
pores in the first layer leading to the water absorption by the osmotic core and which controls
the drug release through push-pull mechanism.
The second layer of the composition comprise at least one water-soluble active ingredient
selected from the group including, but are not limited to, antiulcers, analgesics,
antihypertensives, antibiotics, antipsychotics, anticancer agents, antimuscarinics, diuretics,
antimigraines, antivirals, anti-inflammatory agents, sedatives, antidiabetics, antidepressants,
antihistaminics, antiparasitics, antiepileptics, anti alzheimer's drugs and lipid lowering drugs.
The active ingredients are water-soluble or water-insoluble. Particularly, the active ingredient is
water-soluble.
Suitable examples of water-soluble active ingredient include, but are not limited to, tolterodine
tartrate, memantine, diltiazem hydrochloride, verapamil hydrochloride, bupropion
hydrochloride, metformin hydrochloride, propranolol hydrochloride, dextromethorphan
hydrobromide, diphenhydramine hydrochloride, disopyramide hydrochloride, tramadol,
fluoxetine hydrochloride, paroxetine hydrochloride, pentoxifylline hydrochloride and the like.
The second layer may additionally comprise a hydrophilic polymer along with the active
ingredient that gives plasticity properties to the units and acts as a binder.
Suitable hydrophilic polymers may include, but are not limited to, pharmaceutically acceptable
materials like starch, gums, alginates, polysaccharides, polyvinylprrolidone, polyethylene
glycol, acrylic acid derivatives, and cellulose derivatives like hydroxypropyl cellulose,
hydroxypropyl methylcellulose, hydroxyethylcellulose, hydroxymethylcellulose,
carboxymethylcellulose, methylcellulose, sodium carboxy methylcellulose and mixtures thereof.
The third layer of the composition comprises one or more polymers effective for controlling or
modifying the release active ingredient.
The release controlling polymers may be selected from the group comprising hydrophilic
polymers, hydrophobic polymers, or combinations thereof.
Suitable examples of hydrophilic release controlling polymers include, but are not limited to
cellulose derivatives such as hydroxypropylcellulose, hydroxypropylmethylcellulose,
hydroxyethylcellulose, hydroxymethylcellulose, carboxymethylcellulose, methylcellulose,
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sodium carboxy methylcellulose or combinations thereof; polyvinylpyrrolidone, polyvinyl
acetate, copolymer of vinylpyrrolidone and vinyl acetate, polysaccharides, polyalkylene glycols,
starch and derivatives; or mixtures thereof.
Suitable examples of hydrophobic release controlling polymers include, but are not limited to
ethyl cellulose, cellulose acetate, cellulose acetate butyrate, hydroxypropyl methylcellulose
phthalate, poly (alkyl) methacrylate, and copolymers of acrylic or methacrylic acid esters,
waxes, shellac and hydrogenated vegetable oils. The hydrophobic release controlling polymers
may be water-based dispersions of ethyl cellulose and is commercially available as Surelease®
or AquaCoat®.
The ratio of the hydrophobic polymer to the hydrophilic polymer in the third layer may be from
about 99: I to I :99 by weight.
The release modifying polymers may be the enteric polymers and may be selected from any
such pharmaceutically acceptable enteric polymers, which would facilitate erosion and
breakdown of the pellets in the pH of the lower GI tract. These enteric polymers may be selected
from the group consisting of cellulose acetate phthalate, hydroxypropylmethylcellulose
phthalate, and additional cellulose ether phthalates, any or the acrylic acid derivates phthalates
(available commercially as Eudragits), shellac, zein, or mixtures thereof.
The third layer of release controlling or modifying layer may also include one or more release
regulators which are hydrophilic or having pH dependent solubility. The release regulators may
include, but are not limited to, hydroxypropyl methylcellulose, hydroxyethyl cellulose,
hydroxypropyl cellulose, methylcellulose, carboxymethylcellulose, polyethylene glycol,
polyvinylpyrrolidone, polyvinyl alcohol, polymers with pH-dependent solubility, such as
cellulose acetate phthalate or ammonio-methacrylate copolymer and methacrylic acid
copolymer; or mixtures thereof.
The seal layer between the second and third layers of the composition comprises one or more
pharmaceutically -acceptable polymers that include, but are not limited to, ethyl cellulose,
hydroxypropyl methylcellulose, hydroxypropyl cellulose, methyl cellulose,
carboxymethylcellulose, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl
phthalate, cellulose acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; Waxes
such as polyethylene glycol; methacrylic acid polymers such as Eudragit® E, L, S, FS, NE, RL
and RS; or mixtures thereof. Alternatively, commercially available coating compositions
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comprising film-forming polymers marketed under various trade names, such as Opadry® may
also be used for coating.
The seal layer may further include one or more organic acids as stabilizers to prevent any interreactions
between the drug and the release controlling or modifying layer.
Suitable examples of organic acids used as stabilizers include, but are not limited to tartaric acid,
lactic acid, salicylic acid, citric acid, acetic acid, gluconic acid, succinic acid, and oxalic acid.
Particularly the organic acid is tartaric acid.
The optional fourth layer, onto the third layer of the composition comprises one or more
pharmaceutically acceptable polymers. The polymers may comprise one or more film forming
agents and/or pharmaceutically acceptable excipients.
Examples of film forming agents include, but are not limited to ethyl cellulose, hydroxypropyl
methylcellulose, hydroxypropyl cellulose, methyl cellulose, carboxymethylcellulose,
hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropyl methyl phthalate, cellulose
acetate, cellulose acetate trimelliatate, cellulose acetate phthalate; Waxes such as polyethylene
glycol; methacrylic acid polymers such as Eudragit® RL and RS; or mixtures thereof.
Alternatively, commercially available coating compositions comprising film-forming polymers
marketed under various trade names, such as Opadry® may also be used for coating.
The composition may further include one or more pharmaceutically acceptable excipients act in
one or more capacities as fillers, binders, plasticizers, lubricants, glidants, colorants and
flavoring agents.
Suitable examples of fillers include, but are not limited to com starch, lactose, white sugar,
sucrose, sugar compressible, sugar confectioners, glucose, sorbitol, calcium carbonate, calcium
phosphate-dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose,
silicified microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose, fructose,
kaolin, lactitol, mannitol, sorbitol, starch, starch pregelatinized, sucrose, and mixtures thereof.
Examples of binders include, but are not limited to methyl cellulose, hydroxypropyl cellulose,
hydroxypropyl methylcellulose, polyvinylpyrrolidone, poloxamer, gelatin, gum Arabic, ethyl
cellulose, polyvinyl alcohol, pullutan, pregelatinized starch, agar, tragacanth, sodium alginate,
propylene glycol, and mixtures thereof.
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Examples of plasticizers include, but are not limited to propylene glycol, triethylene glycol,
oleic acid, ethyleneglycol monoleate, triethyl citrate, triacetin, diethyl phthalate, glyceryl
monostearate, dibutyl sebacate, acetyl triethylcitrate, castor oil, medium chain triglycerides and
mixtures thereof.
Examples of lubricants and glidants include, but are not limited to colloidal anhydrous silica,
stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters
of fatty acids, microcrystalline wax, yellow beeswax, white beeswax, and mixtures thereof.
The coloring agents of the present invention may be selected from any FDA approved colors for
oral use.
The non-aqueous solvents used for the preparation of solution, dispersion, or suspension may
include, but are not limited to alcohols, ethyl alcohol, isopropyl alcohol; ketones, acetone,
ethylmethylketone; halogenated hydrocarbons, dichloroethane, trichloroethane and mixtures
thereof. The non-aqueous solvent based system includes completely non-aqueous solvents (for
example solvent system comprising organic solvents, inorganic solvents or mixture of both).
The non-aqueous solvent based system also includes substantially non-aqueous solvent
comprising at most 20% by weight of water. The remainder of the solvent (Le. at least 80% by
weight) is non-aqueous.
The pharmaceutical compositions of the present invention comprising multilayered multiple
units may provide a controlled, extended or a pulsatile delivery.
The coating of the layers may be done using a conventional coating pan, a spray coater, a
rotating perforated pan, or an automated system, such as a centrifugal fluidizing (CF) granulator,
a fluidized bed process, or any other suitably automated coating equipment.
The coated multiple units are filled into hard gelatin capsules or compressed into tablets that
disintegrate in the stomach to make available a multiplicity of individually coated units.
The pharmaceutical composition of the present invention relates to method of treating urinary
disorders including overactive urinary bladder.
The overactive bladder condition gives rise to urmary frequency, urgency and/or urge
incontinence. Overactive bladder disorders also include nocturia, i.e. awakening at night to
urinate. While overactive bladder is often associated with detrusor muscle instability, disorders
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of bladder function may also be due to neuropathy of the central nervous system (detrusor
hyperreflexia) including spinal cord and brain lesions, such as multiple sclerosis and stroke.
Overactive bladder symptoms may also result from, for example, male bladder outlet obstruction
(usually due to prostatic hypertrophy), interstitial cystitis, local edema and irritation due to focal
bladder cancer, radiation cystitis due to radiotherapy to the pelvis, and cystitis. The compounds
also have spasmolytic activity and may be useful for treating gastrointestinal disorders,
including gastrointestinal hyperactivity.
The present invention is illustrated below by reference to the following example. However, one
skilled in the art will appreciate that the specific methods and results discussed are merely
illustrative of the invention, and not to be construed as limiting the invention.
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Example 1:
Ingredients Percentw/w
Ethyl cellulose 4.93
Methacrylic acid copolymer 1.64
Dibutyl sebacate 0.15
Isopropyl alcohol Q.S
Methylene Chloride Q.S
Tolterodine L-tartarate
Hydroxypropyl methyl cellulose
Purified water
2.33
0.88
Q.S
Hydroxypropyl methyl cellulose
Talc
Purified water
2.51
0.83
Q.S
Ethyl cellulose
Hydroxypropyl methyl cellulose
Purified water
10.34
1.82
Q.S
I. Ethyl cellulose and Methacrylic acid copolymer were dispersed in isopropyl alcohol with
stirring and methylene chloride was added to this dispersion to form a clear solution.
2. Then dibutyl sebacate was added to solution of step 1 and this solution was coated over
sugar spheres, to form first layer
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3. Tolterodine tartarate and hydroxypropyl methyl cellulose were dissolved in water and
sprayed over the cores of step 2, to form second layer.
4. Hydroxypropyl methyl cellulose and talc were dispersed in water and coated over cores
of step 3, to form an optional seal coat.
5. Ethyl cellulose and hydroxypropyl methyl cellulose were dispersed in water and coated
over cores of step 4, to form third layer.
6. The coated beads were dried and lubricated with talc and finally filled into capsules.
Example 2:
Ingredients Percentw/w
Ethyl cellulose 4.99
Methacrylic acid copolymer 1.66
Dibutyl sebacate 0.31
Isopropyl alcohol Q.S
Methylene Chloride Q.S
Tolterodine L-tartarate
Hydroxypropyl methyl cellulose
Purified water
2.41
0.92
Q.S
Hydroxypropyl methyl cellulose 2.60
16
Talc
Purified water
0.87
Q.S
Ethyl cellulose
Hydroxypropyl methyl cellulose
Purified water
7.83
1.17
Q.S
Talc 0.99
1. Ethyl cellulose and Methacrylic acid copolymer were dispersed in isopropyl alcohol with
stirring and methylene chloride was added to this dispersion to form a clear solution.
2. Then dibutyl sebacate was added to solution of step 1 and this solution was coated over
sugar spheres, to form first layer
3. Tolterodine tartarate and hydroxypropyl methyl cellulose were dissolved in water and
sprayed over the cores of step 2, to form second layer.
4. Hydroxypropyl methyl cellulose and talc were dispersed in water and coated over cores
of step 3, to form an optional seal coat.
5. Ethyl cellulose and hydroxypropyl methyl cellulose were dispersed in water and coated
over cores of step 4, to form third layer.
6. The coated beads were dried and lubricated with talc and finally filled into capsules.
Example 3:
Ingredients Percentw/w
Sugar spheres 73.57
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Ethyl cellulose 5.04
Oleic acid 0.67
Medium chain triglycerides 0.84
Hydroxypropyl methyl cellulose 0.17
Isopropyl alcohol Q.S
Methylene Chloride Q.S
Tolterodine L-tartarate
Hydroxypropyl methyl cellulose
Purified water
2.33
0.88
Q.S
Hydroxypropyl methyl cellulose
Talc
Purified water
2.51
0.83
Q.S
Ethyl cellulose
Hydroxypropyl methyl cellulose
Purified water
Talc
10.34
1.82
Q.S
0.99
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I. Ethyl cellulose, oleic acid, Hydroxypropyl methyl cellulose and medium chain
glycerides were dispersed in isopropyl alcohol with stirring and methylene chloride was
added to this dispersion to form a clear solution.
2. The solution of step I was coated over sugar spheres, to form first layer
3. Tolterodine tartarate and hydroxypropyl methyl cellulose were dissolved in water and
sprayed over the cores of step 2, to form second layer.
4. Hydroxypropyl methyl cellulose and talc were dispersed in water and coated over cores
of step 3, to form an optional seal coat.
5. Ethyl cellulose and hydroxypropyl methyl cellulose were dispersed in water and coated
over cores of step 4, to form third layer.
6. The coated beads were dried and lubricated with talc and finally filled into capsules.
While several particular forms ofthe invention have been illustrated and described, it will be
apparent that various modifications and combinations of the invention detailed in the text can be
made without departing from the spirit and scope of the invention.
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WE CLAIM:
1. A multilayered multiple unit composition comprising:
(i) an inert core;
(ii) a first layer on the inert core, comprising
a) at least one hydrophobic polymer or hydrophobic substance and
b) at least one pH-dependent polymer or pH-dependent substance;
(iii) a second layer onto the first layer, comprising at least one active ingredient;
(iv) a third layer onto the second layer, comprising one or more pharmaceutically
acceptable polymers effective for controlling or modifying the release of active
ingredient; and
(v) optionally, a fourth layer onto the third layer comprising one or more
pharmaceutically acceptable polymers;
wherein the first layer is applied as a solution or dispersion in a nonaqueous based solvent
system.
2. The multilayered multiunit composition according to claim 1, wherein the hydrophobic
polymer or hydrophobic substance is present in the first layer in an amount of about
0.1% to 20% ofthe total weight of the composition.
3. The multilayered multiunit composition according to claim 1, wherein the pH-dependent
polymer or pH-dependent substance is present in the first layer in an amount of about
0.1% to 20% of the total weight of the composition.
4. The multilayered multiunit composition according to claim 1, wherein the ratio of the
hydrophobic polymer or hydrophobic substance to the pH-dependent polymer or pHdependent
substance in the first layer varies from about 99: 1 to 1:99 by weight.
5. The multilayered multiunit composition according to claim 1, wherein a seal layer
comprising one or more pharmaceutically acceptable polymers is optionally applied
between the second active layer and the third controlled release or modified release
layer.
6. The multilayered multiunit composition according to claim 1, wherein said composition is
prepared using a process comprising the steps of:
(i) providing an inert core;
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(ii) applying a first layer on the inert core, comprising
(a) at least one hydrophobic polymer or hydrophobic substance and
(b) at least pH-dependent polymer or pH-dependent substance;
(iii) applying a second layer onto the first layer, comprising at least one active
ingredient;
(iv) applying a third layer onto the second layer, compnsmg one or more
pharmaceutically acceptable polymers effective for controlling or modifying the
release of active ingredient; and
(v) optionally applying a fourth layer onto the third layer comprising one or more
pharmaceutically acceptable polymers;
wherein the first layer is applied as a solution or dispersion or suspenSIOn in a non
aqueous based solvent system.
7. The multilayered multiunit composition according to claim 5, wherein said composition is
prepared using a process comprising the steps of:
(i) providing an inert core;
(ii) applying a first layer on the inert core, comprising
a) at least one hydrophobic polymer or hydrophobic substance and
b) at least one pH-dependent polymer or pH-dependent substance;
(iii) applying a second layer onto the first layer, comprising at least one active
ingredient;
(iv) applying a seal layer onto the second layer, compnsmg one or more
pharmaceutically acceptable polymers;
(v) applying a third layer onto the seal layer, comprising one or more
pharmaceutically acceptable polymers effective for controlling or modifying the
release ofactive ingredient; and
(vi) optionally applying a fourth layer onto the third layer, comprising one or more
pharmaceutically acceptable polymers;
wherein the first layer is applied as a solution or dispersion or suspenSIOn in a non
aqueous based solvent system.
7. The multilayered multiunit composition according to claim 5, wherein the seal layer onto
the second layer optionally includes one or more organic acids.
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8. The multilayered multiunit composition according to claim 1, wherein the said
composition includes one or more pharmaceutically acceptable excipients, which act in
one or more capacities as di1uents, binders, plasticizers, lubricants, glidants, colorants or
flavoring agents.
9. The multilayered multiunit composition according to claim 1, wherein the said
composition is used to treat urinary disorders including overactive urinary bladder.
10. A multilayered multiple unit composition as described and illustrated herein.