Water insoluble polymer based sustained release formulation

Sustained release drug formulations contain the pharmaceutical itself and a three component release rate controlling matrix composition. The three components of the matrix composition are (1) water insoluble polymer, such as ethyl cellulose, (2) pH dependent gelling polymer, such as sodium alginate, and (3) a pH independent gelling polymer, such as hydroxypropyl methylcellulose. The drug release rate can be adjusted by changing the amount of one or more of these components of the composition.

FIELD OF THE INVENTION
 The present invention is directed to formulations for preparing sustained
 release drug dosage forms useful for releasing pharmaceuticals at
 controlled rates for oral administration.
 BACKGROUND OF THE INVENTION
 A controlled release profile from a drug dosage form is sometimes desirable
 in clinical use to reduce side effects and improve patient compliance. The
 technology used to formulate sustained release dosage forms is well
 documented. The entrapment of a drug in a polymer based matrix is a common
 approach to formulate sustained release tablets with a desirable release
 profiles.
 It has been reported that depot drug formulations for controlled release of
 pharmaceutical drugs may be prepared using alginates alone (see U.S. Pat.
 No. 5,132,295), using combinations of alginates and polyacrylates (see
 U.S. Pat. No. 5,230,901) and using combinations of alginates and a pH
 independent gelling agent, such as, for example, hydroxypropyl
 methylcellulose (see U.S. Pat. No. 4,792,452). It is also known that the
 use of alginates alone for this purpose often presents difficulties in
 tableting, film coating and storage.
 It also has been reported that a sustained release dosage form useful in
 providing once-a-day medication consists of the admixture of hydroxypropyl
 methylcellulose (viscosity of 80 to 120 cps in a 2% aqueous solution) and
 ethylcelluose with etodolac (see U.S. Pat. No. 4,966,768). Using a low
 viscosity of hydroxypropyl methylcellulose with ethylcellulose as rate
 controlling agents in the formulation may give a shorter T.sub.max (time
 to peak blood concentration) after oral administration due to a fast
 tablet erosion.
 Adding polyacrylates to the alginate formulation overcomes these
 difficulties to some extent; however, tablets formed using alginates and
 polyacrylates often have a pH dependent dissolution profile. In a low pH
 environment, alginates and polyacrylates do not swell and/or dissolve
 properly. This leads to drug release by a diffusion mechanism through
 non-viscous capillaries resulting in a different dissolution rate than in
 a high pH environment. On the other hand, in a high pH environment,
 alginates swell and become soluble while polyacrylates may or may not do
 the same. This leads to drug release both by erosion and diffusion at a
 rate which is different than the low pH release rate.
 In formulations which contain an alginate and a pH independent gelling
 polymer such as, for example, hydroxypropyl methylcellulose, hydration at
 low pH levels forming a viscous gel layer for drug release. At high pH
 levels, however, tablets become smaller and smaller during drug release
 due to erosion of the swollen polymer layer, leading to a reduction in
 surface area which may affect the dissolution rate of a tablet.
 The novelty of the present invention is the provision of a sustained
 release formulation which reduces, and perhaps eliminates the
 aforementioned problems completely. In particular the invention provides a
 controlled release drug formulation which includes novel formulations
 containing three different types of polymers. These three different types
 of polymers include: 1) a water insoluble polymer, such as ethylcellulose;
 2) a pH independent gelling polymer, such as hydroxypropyl
 methylcellulose; and 3) a pH dependent gelling polymer, such as sodium
 alginate. These three different types of polymers must be used together to
 achieve a controlled release rate of the selected drug. Such a combination
 of polymers facilitates manufacturing processes and improves drug release
 and absorption profiles.
 In accordance with the present invention, the combination of the three
 polymers provides an excellent matrix drug depot system with desirable
 controlled release characteristics. During dissolution at low pH levels,
 such as in the stomach, the pH independent gelling polymer e.g.,
 hydroxypropyl methylcellulose, hydrates and swells to form a hydrogel
 which controls drug release from the matrix system. Drug release may be
 due to the gel layer erosion or drug diffusion through the gel layer or a
 combination of both. The water insoluble polymer e.g., ethylcellulose, and
 the pH dependent gelling polymer e.g., sodium alginate, are dispersed in
 the gel layer as insoluble parties to block the diffusion pathway or
 adjust the erosion rate of the gel layer. All the three polymers play
 important roles to control drug release at a low pH environment. As the
 matrix system moves to a higher pH environment e.g. in the intestinal
 tract, the tablet surface area becomes smaller due to the gel layer
 erosion, which may lead to a reduction of drug release rate. However, the
 pH dependent gelling polymer dispersed in the gel layer starts to hydrate
 and swell. Meanwhile, the insoluble particles dispersed in the gel layer
 will be reduced due to the hydration of pH dependent gelling polymer,
 resulting of the opening of additional diffusion channels. Therefore,
 hydration of the pH dependent polymer and concomitant reduction of the
 insoluble particles in the hydrogel in high pH environment, will
 compensate the reduction tendency of the drug release rate due to the
 surface area changes resulting from erosion. Thus, drug release rate is
 maintained regardless of the pH and tablet size changes. Thus, the
 formulations of the present invention provide improved drug release
 profiles compared with the prior art formulations described above.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
 The present invention provides sustained release tablets formulated with a
 mixture of three different types of polymers; a water insoluble polymer, a
 pH dependent gelling polymer and pH independent gelling polymer, from
 which the pharmaceutical active may be released at a controlled rate.
 One or more suitable water insoluble polymers may be selected to be used in
 the invention, which include, but are not limited to, ethylcellulose and
 co-polymers of acrylic and methacrylic acid esters (Eudragit.RTM. RS or
 RL). One or more suitable pH dependent gelling polymer may be selected to
 be used in the invention, which includes, but not limited to, alginates
 and sodium carboxymethylcellulose. One or more suitable pH independent
 gelling polymers may be selected to be used in the invention, which
 include, but are not limited to, carboxypolymethylene, hydrxpropyl
 methylcellulose, hydroxypropyl cellulose, hydroxypropyl ethylcellulose,
 hydroxyethylcellulose, methylcellulose, xanthum gum and polyethylene
 oxide.
 Suitable pharmaceutical compositions include those having an active
 ingredient selected from the group consisting of antihistamines,
 antibiotics, antituberculocis agents, cholinergic agents, antimuscarinics,
 sympathominetics, sympatholytic agents, autonomic drugs, iron
 preparations, haemostatics, cardiac drug, antiinflammatory agents, opiate
 agonists, anticonvulsants, tranquilizers, stimulants, barbiturates,
 sedatives, expectorants, antiemetics, gastrointestinal drugs, heavy metal
 antagonists, antithyroid agents, genitourinary smooth muscle relaxants and
 vitamins. The invention is applicable to active ingredients regardless of
 their solubility.
 The overall tablet formulation should include a mixture of three types of
 polymers in an amount so as to establish a weight percentage of from about
 6% to about 60% based on the total tablet weight, preferably from about
 10% to about 50% in the formulation. The three type of polymers should
 include 1) water insoluble polymer in an amount of from 2% to 30% of the
 total tablets weight, preferably from about 3% to about 25%; 2) pH
 dependent gelling polymer in an amount of from about 2% to about 40% of
 the total tablet weight, preferably from about 3% to about 30%; and 3) pH
 independent gelling in an amount of from about 2% to about 30%, preferably
 from about 3% to about 25%.
 In a preferred form, the formulation of the invention should contain 1)
 water insoluble polymer component, such as ethylcellulose; 2) pH dependent
 gelling polymer, such as sodium alginate, having a viscosity range of from
 about 50-10,000 centipoises in a 2% by weight water solution at 25.degree.
 C., preferably from about 100 to about 7,000 centipoises, measured using a
 Brookfield LV viscometer; and 3) pH independent gelling polymer, such as
 hydroxypropyl methylcellulose, having a viscosity range of from about 50
 to about 150,000 centipoises, preferably from about 200 to about 120,000
 centipoises in a 2% by weight water solution at 25.degree. C., measured
 using a Brookfield LV viscometer.
 Other ingredients which may be optionally included in the formulation of
 the invention are: 1) tablet filler; 2) binder; 3) lubricant; 4) colorant,
 and 5) film forming polymer for coating. The amounts of all these common
 ingredients selected in the formulation should be in a pharmaceutically
 acceptable range.
 The following examples are set forth to illustrate the claimed invention
 and are not to be construed as a limitation thereof.