Link:  Pharm/Biotech Resources

Title:  Hydrogel-driven layered drug dosage form

United States Patent:  6,899,896

Issued:  May 31, 2005

Inventors:  Curatolo; William J. (Niantic, CT); Waterman; Kenneth C. (East Lyme, CT); Thombre; Avinash G. (East Lyme, CT); Fergione; Michael B. (Stonington, CT); Roy; Michael C. (Gales Ferry, CT); Appel; Leah A. (Bend, OR); Supplee; Danni (Bend, OR); Friesen; Dwayne T. (Bend, OR); Chidlaw; Mark B. (Bend, OR); Beyerinck; Ronald A. (Bend, OR)

Assignee:  Pfizer Inc (New York, NY)

Appl. No.:  745096

Filed:  December 20, 2000

A controlled release dosage form for sertraline has a core comprising a sertraline-containing composition and a water-swellable composition wherein the water-swellable composition is in a separate region within the core. A coating around the core is water-permeable, water-insoluble, and has at least one delivery port therethrough. In one embodiment, the dosage form releases sertraline to the use environment at an average rate of 6 to 10 wt % per hour from the second to the twenth hour after introduction to a use environment and less than about 25 wt % for the first two hours and at least 70 wt % by the twelfth hour, where the percentages correspond to the mass of drug released from the tablet divided by the total mass of drug originally present in the tablet. In another embodiment, the dosage form releases less than about 25 wt % of sertraline to the use environment by the second hour after introduction of the dosage form to the use environment, and delivers at least 25 wt % from the eighth to the twenty-fourth hour.

BACKGROUND OF THE INVENTION

The present invention relates to a dosage form that provides a controlled release of sertraline to an environment of use.

Sertraline is a selective serotonin reuptake inhibitor which is useful, inter alia, as an antidepressant and anorectic agent, and in the treatment of obsessive-compulsive disorder, premenstrual dysphoric disorder, post-traumatic stress disorder, chemical dependencies, anxiety-related disorders, panic and premature ejaculation. See, for example, U.S. Pat. Nos. 4,536,518, 5,130,338, 4,971,998, 5,061,728, 4,940,731, and 4,962,128. The IUPAC name for sertraline is (1S-cis)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine, its empirical formula is C₁₂H₁₇NCl₂.

Sertraline is most commonly prescribed for therapy of depressive illness, in the general dose range 50-200 mgA/day wherein "mgA" refers to active sertraline in the free base, or neutral form. Sertraline has an elimination half-life of 23 hours, and is conventionally dosed once daily with immediate-release tablets.

Patients are generally initiated on sertraline at a dose of 50 mgA/day or less. Patients who do not respond at the 50 mgA dose are given higher doses. Initiation at doses greater than 50 mgA is generally avoided, when possible, because side effects such as dizziness, tremor, sweating, and gastrointestinal upset are generally believed to be more severe at higher doses. If necessary to achieve efficacy, higher doses may be reached by gradual increases in dosage.

Improved sertraline dosage forms which exhibit a lower incidence and/or severity of side effects would be advantageous because patient comfort and thus, compliance, would be improved and dosing could be initiated at doses higher than 50 mgA without the need for gradual increases. Initiation at higher starting doses would, in turn, be useful by potentially effecting a shorter onset of antidepressive action. Thus, such an improved sertraline dosage form which permits oral dosing of high doses of sertraline (e.g., 60 mgA and higher) with relatively reduced side effects would permit wider therapeutic application of sertraline therapy, and would accordingly provide a significant improvement in dosing compliance and convenience. Similarly, a dosage form which lowers the incidence and/or severity of side effects at lower doses would also be of significant value.

While such a once-a-day dosage form with reduced incidence or severity of side effects at a given dose is desirable, there are practical difficulties attendant to the development of such a dosage form. There is an upper limit on the size a dosage form may take. It is desired that a dosage form have a mass of less than 1 g, preferably less than about 800 mg, and more preferably no more than about 600 mg. In some cases, particularly when treating children or elderly patients, even lower mass tablets are desirable. Otherwise, the dosage form becomes so large that it is difficult to swallow.

The sertraline dose in an individual dosage form must be about 20 to 200 mgA, and preferably about 40 mgA to 150 mgA. This amount of active sertraline requires that an amount of sertraline salt (e.g., chloride, lactate, acetate, aspartate) be included in the core such that the desired amount of active agent is delivered. Assuming complete release of the drug, this means that to deliver 150 mgA, the core must contain 168 mg sertraline chloride, 194 mg sertraline lactate, 215 mg sertraline aspartate, or 179 mg sertraline acetate. Because sertraline occupies such a large portion of the core, the remaining excipients must be capable of providing the desired release profile using a minimum amount of material. Although this is most true at higher dose levels, it is often desirable to have a range of dosage forms that vary in dose with their size, but have a common composition. Thus, the tablet composition can be limited by the magnitude of the highest dose tablet.

Sertraline also has poor aqueous solubility, particularly at pH values above 6 to 7. This can result in low bioavailability, where bioavailability is the fraction of drug orally dosed that is absorbed into the blood stream, particularly in controlled-release dosage forms. Bioavailability from controlled release sertraline formulations can be significantly less than 100%, particularly at high drug doses and when a significant portion of the drug is delivered in the lower GI tract where the pH is relatively high and drug solubility is relatively low. While the solubility of sertraline is relatively high at low pH, e.g., 6 mgA/mL at pH 2.0, the solubility is much lower at higher pH. Thus, at a pH of 6.5 (generally corresponding to the pH in the duodenum), the solubility of sertraline is only about 1 mgA/mL, while at a pH of about 7.0 (generally corresponding to the pH of the small intestine), the solubility is about 0.2 mgA/mL, while at a pH of about 7.5 (generally corresponding to the pH in the colon), the solubilty is about 0.05 mgA/mL. While the lower pH in the stomach is ideal for solubilizing sertraline, it has been found that the incidence or severity of side effects such as nausea can be minimized by avoiding the release of excessive sertraline within the stomach. Thus, while the solubility of sertraline in the stomach is high, it is desired to limit the amount of sertraline released into the stomach to an acceptable level. However, the steadily decreasing solubility of sertraline as it proceeds down the GI tract (as pH increases) can result in low bioavailability if release is delayed too long.

As a result, to achieve the combined goals of (1) reduced incidence or severity of side effects (e.g., nausea), (2) high bioavailability, and (3) therapeutic blood levels over as long a time period as possible, a narrow range of drug release profiles is desired, which not only limits the amount of sertraline released into the stomach to an acceptable level, but also provides good absorption of sertraline either by (1) insuring that most of the sertraline is delivered prior to reaching the colon, or (2) delivering sertraline to the colon in such a manner that it is substantially absorbed. In addition, because the dose of sertraline may be high (e.g., 100 mgA to 200 mgA) and it is ideal to deliver a single tablet each day, it is desired that the dosage form deliver a substantial amount of the drug, leaving relatively low residual drug and that the amount of drug be a high fraction of the overall weight of the dosage form.

Under certain conditions, and in the presence of certain excipients used for formulation of conventional controlled-release dosage forms, sertraline may undergo adverse reactions that can alter its bioavailability or lead to undesirable impurities within a relatively short time, thus giving it a poor shelf life. Commercially acceptable controlled release dosage forms must provide patients with all of the desired attributes mentioned above while providing patients with a supply of sertraline that may be stored for relatively long periods of time and over a reasonably wide range of temperature and humidity conditions and still remain stable.

It is known that osmotic and hydrogel delivery devices of a bi-layer design, having a drug-containing composition and a water-swellable composition, may be used to provide controlled release of drugs through a surrounding coating having one or more delivery ports in the coating. However, a common problem encountered by such osmotic and hydrogel dosage forms is that residual drug remains within the dosage form after the dosage form exits that portion of the GI tract where drug absorption occurs. Such residual drug is not available for absorption and, accordingly, such dosage forms require increased amounts of drug to compensate for the failure of the dosage form to deliver all of the drug into the environment of use. In addition, the amount of such residual drug can be variable and may lead to variability of sertraline blood levels from patient to patient and from day to day.

Such bi-layer osmotic and hydrogel devices by definition contain water-swellable materials that occupy significant space within the core that otherwise would be available for sertraline. The water-swellable materials that provide delivery of the drug must be capable of providing a highly efficient delivery of sertraline, since very little of the mass of the dosage form may be available for the water-swellable material.

In addition, to maximize the bioavailability of the drug it is often desirable to have the dosage form begin delivery of sertraline immediately upon entering an aqueous environment of use. However, many bi-layer delivery systems exhibit a time lag before the onset of drug delivery. Several techniques have been proposed to overcome the time lag, but each has its own drawback. One technique has been to provide thin coatings around the dosage form. While this technique provides a quicker uptake of aqueous fluid, the thin coating often provides insufficient protection to the dosage form which becomes susceptible to damage during handling. Such thin coatings are also inherently weak and upon ingestion can rupture, causing uncontrolled release of drug. Yet another technique for eliminating the delivery time lag has involved providing holes or channels that allow communication of the water-swellable composition with the exterior fluid, but this often leads to unacceptable amounts of residual drug. Another technique involves coating the core with an immediate release drug formulation, but this requires additional processing steps, and is problematic in that the drug is often not stable in such coatings.

Yet another problem encountered with conventional bi-layer osmotically-driven and hydrogel-driven drug delivery systems is that conventionally such dosage forms require the presence of osmagents. These osmagents are often necessary, particularly when low water permeability coatings are used, to increase the drug release rate, but have the drawback of increasing the weight of the dosage form, thus further limiting the amount of sertraline which may be contained in the dosage form. Another drawback of inclusion of an osmagent is that it can potentially interact adversely with sertraline, thereby accelerating its degradation (in the case of certain sugars) or reducing its dissolution (in the case of salts such as chlorides). In addition, the presence of such osmagents increases the costs of manufacture due to the need to insure uniform concentrations of such ingredients throughout the composition.

Sustained and delayed release dosage forms of sertraline as well as a variety of sertraline compositions have been disclosed in commonly assigned U.S. patent application Ser. No. 09/380,885 filed Sep. 7, 1999 now abandoned, U.S. patent application Ser. No. 09/380,825 filed Sep. 7, 1999, and U.S. patent application Ser. No. 09/380,900 filed Sep. 7, 1999. However, none of these disclose a dosage from where the drug is in the form of an amorphous dispersion or a bi-layer osmotic dosage form that permits high drug loading, stability and optimum drug release profiles, and high bioavailability, all of which are possible with the present invention.

In addition, a variety of bi-layer osmotic and hydrogel-driven devices for many different drugs have been disclosed. See, e.g. Wong et al., U.S. Pat. No. 5,082,668; Eckenhoff, U.S. Pat. No. 4,865,598; Courtese et al., U.S. Pat. No. 4,327,725; and Ayer et al., U.S. Pat. No. 5,126,142. Nonetheless, the prior art bi-layer dosage forms do not disclose the means by which sertraline, a poorly soluble, hydrophobic, and potentially reactive drug, may be optimally delivered to a use environment in a controlled release fashion.

Accordingly, there is still a need in the art for a controlled release dosage form of sertraline that results in a highly efficient delivery of sertraline to an environment of use with very little residual drug, that allows high drug loading so as to decrease the dosage form size, that begins delivering drug soon after entering a desired environment of use, that limits the number of other components in the dosage form, that reduces the frequency or severity of negative side effects by limiting the release of sertraline to the stomach to an acceptable level, and that simultaneously achieves high bioavailability. Obtaining such high bioavailability may require that either the sertraline release profile be carefully controlled so that substantially complete release is achieved prior to entering the colon or, when delivery is continued in the colon, modifying the material released such that the absorption of sertraline in the colon is enhanced. These needs and others which will become apparent to one skilled in the art are met by the present invention, which is summarized and described in detail below.

BRIEF SUMMARY OF THE INVENTION

The present invention overcomes the drawbacks of the prior art by providing a dosage form for the controlled release of sertraline. The basic dosage form common to all aspects of the present invention has a core comprising a sertraline-containing composition and a water-swellable composition wherein the water-swellable composition is in a separate region within the core. A coating around the core is water-permeable, water-insoluble and has at least one delivery port therethrough.

In referring to the precentage of the core, or composition that the sertraline comprises, percentages given in wt % refer to the mass of sertraline form present divided by the total mass of the core or composition multiplied by 100. Release rates, given in wt %, refer to the mass of sertraline released divided by the total mass of sertraline multiplied by 100. As used here and in the claims, the average rate of sertraline release per hour for a time period is defined as the wt % sertraline released during the time period divided by the duration (in hours) of the time period. For example, a dosage form that delivers 10 wt % of sertraline by 2 hours and 90 wt % by 12 hours following delivery to a use environment would have an average rate of sertraline release of 8 wt % per hour for the second to the twelfth hours. It should be noted that this same dosage form may release much of the sertraline prior to the twelfth hour (for example, 80 wt % of the sertraline by the fourth hour) and thus may have a release rate for the 2-hour to 4-hour time period that is much higher than the average release rate of 8 wt % per hour, which is the average from the 2- to 12-hour period.

In a first aspect of the invention, the sertraline-containing composition contains sertraline and an entraining polymer. The dosage form has a high drug loading, with sertraline being present in an amount of at least 20 mgA and making up at least about 20 wt %, preferably 30 wt %, more preferably 40 wt % or higher of the sertraline-containing composition. Sertraline is present in the form of a pharmaceutically acceptable salt, and following introduction of the dosage form to a use environment, the dosage form releases sertraline to the use environment at an average rate of from about 4.5 to 10 wt % per hour from the second to the twelfth hour and less than about 25 wt % for the first two hours and at least 70 wt % by the twelfth hour.

In a second aspect of the invention, the sertraline-containing composition also comprises polyethylene oxide (PEO) having a molecular weight of at least 500,000, and a fluidizing agent. The dosage form has the same sertraline release profile as the first aspect of the invention.

In a third aspect of the invention, the water-swellable composition contains substantially no osmotically effective agent. The sertraline-containing composition comprises sertraline and a polymeric entraining agent. The dosage form has the same sertraline release profile as the first aspect of the invention.

In a fourth aspect of the invention, the sertraline-containing composition comprises sertraline and a polymeric entraining agent. The coating is a hydrophilic cellulosic polymeric coating that is porous. The dosage form has the same sertraline release profile as the first aspect of the invention.

In a fifth aspect of the invention, the dosage form has an extended sertraline release profile. The dosage form is like that of the first aspect of the invention mentioned above, except that the dosage form delivers less than about 25 wt % of sertraline to the use environment by the second hour after introduction of the dosage form to the use environment, and delivers at least about 40 wt % by the eighth hour and delivers at least about 25 wt % from the eighth to the twenty-fourth hour. Thus, the dosage form releases sertraline to the use environment at an average rate of from about 3 to about 13 wt % per hour from the second to the eighth hour. At least a portion of the sertraline is delivered such that improved absorption in the lower GI tract is observed.

In a sixth aspect of the invention, sertraline is present in the form of an amorphous dispersion.

In a seventh aspect of the invention, the sertraline-containing composition contains sertraline, PEO, and a binder. The sertraline-containing composition is wet-granulated using a mixture of a lower alcohol and water.

In an eighth aspect of the invention, the sertraline-containing composition comprises sertraline, an entraining polymer, and a concentration-enhancing polymer. The dosage form provides a maximum concentration of sertraline in a use environment that is at least 1.25-fold higher than the equilibrium concentration of sertraline in the use environment provided by a control dosage form, and a concentration of sertraline in the use environment that exceeds the equilibrium concentration for a longer time than a concentration provided by the control dosage form exceeds said equilibrium concentration, where the control dosage form is free from the concentration-enhancing polymer and comprises an equivalent quantity of sertraline. The dosage form provides an elevated sertraline concentration above the equilibrium concentration relative to the control dosage form for at least 15 minutes, and more preferably for longer than 30 minutes.

A ninth aspect of the invention comprises a method of treating a disorder in a patient that is susceptible to treatment by administering a therapeutic amount of sertraline, comprising introducing a sertraline-containing dosage form of the invention to an environment of use in the patient.

The various aspects of the present invention have one or more of the following advantages. The dosage forms of the present invention release sertraline at certain rates and amounts so as to reduce the incidence or severity of side effects resulting from the delivery of excessive sertraline to the stomach. In addition, the dosage forms either deliver a large fraction of the total sertraline dose prior to entry of the dosage form into the colon, or enhance the absorption of sertraline from the large intestine or colon by increasing the concentration of dissolved sertraline. The dosage forms are also capable of delivering relatively high doses of sertraline while minimizing the amounts of other materials needed for controlled release, thus minimizing tablet size and weight. The dosage forms are also capable of delivering greater amounts of drug to the desired environment of use, resulting in less residual drug than is the case with conventional dosage forms. In addition, the dosage forms are capable of higher drug loadings compared to conventional compositions of poorly soluble, hydrophobic drugs.

The present invention also allows for the control of the time lag in the delivery of sertraline. Thus, where sertraline is desired to be almost completely released prior to entering the colon, the dosage forms may begin releasing sertraline to the use environment soon after introduction to the use environment. This allows the achievement of high bioavailability while still keeping the amount of sertraline released to the stomach sufficiently low that adverse GI side effects are generally avoided. Alternatively, where the concentration of dissolved sertraline is improved at high pH, the dosage forms are capable of delaying release of sertraline so as to minimize the amount of sertraline released into the stomach and also extend the absorption time to achieve more constant sertraline blood levels.

In addition, the present invention prevents or retards the decomposition of sertraline during storage of the sertraline controlled-release dosage form.

The foregoing and other objectives, features, and advantages of the invention will be more readily understood upon consideration of the following detailed description of the invention, taken in conjunction with the accompanying drawings.

Claim 1 of 144 Claims

1. A dosage form for the controlled release of sertraline, comprising:

(a) a core comprising a sertraline-containing composition and a water-swellable composition wherein said water-swellable composition is in a separate region within said core;

(b) said sertraline-containing composition comprising sertraline and polyethylene oxide wherein sertraline makes up at least about 20 wt % of said sertraline-containing composition; and

(c) a coating around said core that is water-permeable, water-insoluble and has at least one delivery port therethrough;

wherein sertraline is in the form of a pharmaceutically acceptable salt thereof and, following introduction of said dosage form to an environment of use, said dosage form releases sertraline to said environment of use at an average rate of from about 6 to 10 wt % per hour from the second to the twelfth hour and releases less than about 25 wt % for the first two hours and releases at least 70 wt % by the twelfth hour.

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