HK1027982B - Delayed-release dosage forms of sertraline - Google Patents

Description

Sustained release dosage forms of sertraline

Technical Field

The present invention relates to sustained release dosage forms of sertraline which peak plasma concentrations in a relatively short period of time after oral administration. The invention also relates to dosage forms that can improve the side effect profile, and methods of treating psychosis and other disorders comprising administering sertraline in such sustained release dosage forms to a mammalian (including human) patient in need of treatment.

Background

Sertraline is a selective 5-hydroxytryptamine reuptake inhibitor (SSRI) which is used as an antidepressant and anorectic for the treatment of obsessive-compulsive disorders, post-traumatic stress disorders, anxiety-related disorders and panic. Sertraline is also used to treat premature ejaculation, chemical dependency, premenstrual dysphoria, and obesity.

Sertraline is the most commonly prescribed for the treatment of depression, and is typically administered in a dosage range of 50-200 mg/day. The elimination half-life of sertraline is 23 hours, and thus, administration is once a day.

Patients with depression are initially treated with sertraline, usually at a dose of 50 mg/day. The dose is increased in patients who do not respond to the 50mg dose. However, doses above 50mg are generally avoided at the initial stage of administration, since higher doses may exacerbate side effects such as nausea, diarrhea and regurgitation. If a higher dose is necessary to achieve efficacy, the higher dose can be achieved by increasing gradually from the lower dose. The improved sertraline dosage form results in a reduction in the incidence and/or severity of side effects and, therefore, would be advantageous (1) to improve patient experience and (2) to start the dosage of over 50mg without the need for titration. Secondly, higher doses used in the initial stages of treatment are beneficial in producing an effect of antidepressant action in a shorter period of time. Thus, such improved dosage forms of sertraline that allow for oral administration of high doses of sertraline (e.g., 200mg) with relatively low side effects would allow for broader application of sertraline for treatment, and thus a significant improvement in dosing compliance and convenience. Furthermore, improved dosage forms are of great value in reducing the incidence of side effects when used at low doses.

For sertraline in a known immediate release dosage form, the time T to reach the maximum plasma concentration of sertraline if such dosage form is taken orally_maxAbout 6-7 hours. In general, this T_maxIs relatively long. It has now been determined that oral dosage forms, with sertraline contained therein, exiting the stomach and entering the small intestine, are capable of being dispensed more than conventionalMore rapid, i.e. T_maxThe shorter the delivery of sertraline to the systemic circulation, the conventional dosage forms begin to disintegrate immediately upon ingestion and are dissolved upon ingestion. The delayed dissolution of the drug in the gastrointestinal tract results in a faster appearance of the drug in the bloodstream, which is surprising and surprising.

There are other unexpected benefits of delivering sertraline in dosage forms with minimal exposure to the stomach. It will be demonstrated herein (see examples) that certain side effects of sertraline, such as nausea, regurgitation and diarrhea, are mediated in part or primarily by direct contact of sertraline with the upper gastrointestinal tract, primarily the stomach, rather than by the systemic system, i.e., by exposure of sertraline to the bloodstream following absorption. The locally mediated nature of these three sertraline side effects was unknown prior to the human clinical studies disclosed herein. It is noted that these side effects are generally not locally mediated for all drugs that cause them. For example, cancer chemotherapeutic agents administered by injection can cause the same side effects.

Summary of The Invention

The present invention provides an oral sustained release dosage form of sertraline. T relative to currently known delivered equivalent unit dose immediate release sertraline tablets_maxOral sustained release dosage forms of sertraline which reduce T_max. The present invention also reduces the incidence and/or severity of gastrointestinal and/or other side effects relative to immediate release dosage forms. The sustained release period is followed by immediate release, and such dosage forms are sometimes referred to for convenience as "sustained release plus immediate release" forms, as described below. If the sustained release is added to the immediate release dosage form, T can be reduced_maxOr to alleviate any of the above mentioned side effects, are within the scope of the present invention.

Sustained release dosage forms can work by being sensitive to the environment in which they are used, so that they release sertraline after it enters the small intestine. Such sustained release dosage forms, which release sertraline independently of time depending on the location in the gastrointestinal tract, are referred to herein as "spatial" dosage forms, or exhibit "spatial sustained release". The dosage form releases the remainder of sertraline in an immediate manner upon entry into the small intestine. By "immediate release" is meant that no effective ingredient or means is present in such a dosage form that intentionally delays or slows release once the delay period has expired. In general, such dosage forms should release at least 70% of the sertraline remaining therein within 1.5 hours, preferably within 1 hour, after entering the small intestine. Examples of spatially sustained release dosage forms are (1) pH-triggered dosage forms, i.e., dosage forms that release sertraline upon entry into the small intestine environment at pH6.0 or above, and (2) small intestine enzyme-triggered dosage forms, i.e., dosage forms that release sertraline until the coating of the dosage form changes due to interaction with lipases, esterases, or proteases, as the case may be, in the small intestine lumen. The spatially sustained release dosage forms of the present invention generally begin releasing sertraline immediately within about 30 minutes (preferably 15 minutes) after exiting the stomach into the small intestine.

Accordingly, in one aspect, the present invention provides a spatially sustained release oral dosage form suitable for oral administration to a mammal, comprising sertraline or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. The dosage form releases no more than 10% of the contained sertraline in the stomach of said mammal upon ingestion by said mammal. Moreover, the remaining contained sertraline is released immediately upon entry into the small intestine of said mammal.

Dosage forms which release sertraline in the stomach in amounts less than 10% of the above also fall within the scope of the present invention, and even shorter Ts are obtainable_maxAnd/or a better side effect profile. Thus, dosage forms that release only 5% or less of the sertraline contained therein before immediate release is achieved once in the small intestine may exhibit a release profile within the scope of the present invention and may more effectively shorten T_maxAnd/or to ameliorate side effects. Dosage forms that release a lesser amount of sertraline in the stomach are preferred, dosage forms that release no more than 3% of the sertraline contained therein are more preferred, and dosage forms that release substantially no sertraline in the stomach are most preferred.

As noted above, the spatial sustained release dosage form may be enzyme-initiated or pH-initiated. The two dosage forms can be administered by performing solubility tests in vitro, which provide excellent approximations of in vivo behavior, whereby it can be determined whether they fall within the scope of the present invention. Thus, in another aspect, the invention provides a pH-triggered sustained release dosage form suitable for oral administration to a mammal, for pH triggering in an in vitro assay, comprising (1) an immediate release core comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and (2) a pH sensitive coating surrounding said core, which when tested for solubility in vitro releases no more than 10% of the sertraline contained therein within 2 hours in 750ml of 0.1N HCl and after 2 hours releases the remainder of the sertraline immediately in 1 liter of 0.05M sodium phosphate buffer (pH6.8) containing 1% Tween 80. As used herein, "immediate release" generally means at least 70% release within 1.5 hours, preferably 1 hour.

In another aspect, the invention provides an enzyme-triggered sustained release dosage form suitable for oral administration to a mammal for in vitro testing of the enzyme-triggering type, comprising (1) an immediate release core comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and (2) an enzymatically degradable coating surrounding said core, which when tested for solubility in vitro releases no more than 10% of the contained sertraline within 2 hours in 750ml 0.1N HCl, after 2 hours the remainder of sertraline is immediately released in the presence of an enzyme suitable for enzymatic degradation of said coating in 1 liter 0.05M sodium phosphate buffer (pH6.8) containing 1% Tween 80. The actual enzyme used in the assay depends on whether the enzyme-initiated coating is sensitive to duodenal enzymes or to small intestinal enzymes.

Note that the acid medium in the in vitro assay mimics the gastric environment; the buffer mimics the small intestine environment.

In addition to the spatially sustained release dosage forms described above, the dosage forms of the present invention may also function by delaying the release of sertraline over a set period of time, reducing the time of gastric exposure to sertraline. Such dosage forms are referred to herein as "time" dosage forms, or exhibit "time-release" or the like. Time delay refers to the delay that occurs after the dosage form is ingested, regardless of the spatial location of the dosage form in the gastrointestinal tract. It is believed that the time delayed dosage form is due to the presence of water to initiate release and that there is a means to delay release of sertraline at a particular time after the dosage form enters an aqueous environment.

Thus, in another aspect, the present invention provides a time delayed dosage form suitable for oral administration to a mammal, comprising (1) an immediate release core comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, and (2) a coating surrounding said core. The dosage form releases substantially no sertraline within the first about 10 minutes after ingestion by said animal; releasing no more than 10% of the contained sertraline during a second phase up to 2 hours after the first phase; the remaining contained sertraline is then immediately released. The dosage form generally functions in a manner that (1) dissolves the coating, disintegrates or otherwise renders sertraline more permeable to an aqueous environment for a predetermined period of time (i.e., a delay period), and thereafter releases sertraline in an immediate manner, or (2) imbibes water through the coating (e.g., a semipermeable coating) until the core and coating rupture, physically breaking the core and coating combination, thereby immediately releasing sertraline.

Note that the first phase of "about 10 minutes" of the dosage form refers to the natural lag time characteristic of most, if not all, solid dosage forms, including pure immediate release forms, or the induction period following swallowing (i.e., ingestion), during which the dosage form is wetted and/or hydrated. The length of this stage may of course vary, with "about" meaning on the order of 2-20 minutes. The second phase refers to the delay period that has actually been purposefully designed into the dosage form. For spatially delayed dosage forms, the lag time of the first stage is classified as the delay period during which no more than 10% of the sertraline contained therein is released.

A time-delayed dosage form that "does not substantially release sertraline" during the first phase means that the dosage form releases nearly 0% sertraline, although "substantially" allows some minor release, preferably 1% or less than 1%. It is also noted that the second phase described above may last "at most 2 hours" meaning that this phase does not exceed 2 hours.

Time delayed dosage forms may also be tested for solubility in an in vitro test that mimics or approximates in vivo behavior to determine whether the dosage form is within the scope of the invention. Thus, in another aspect, for a time delay dosage form for in vitro testing, the present invention provides a time delay dosage form suitable for administration to a mammal comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, which dosage form releases substantially no sertraline during the first phase of about 10 minutes when subjected to an in vitro solubility test in a USP-2 apparatus containing 900ml of an acetate/acetate buffer solution (ph4.0, 0.075M in NaCl); releasing only no more than 10% of the contained sertraline during a second phase up to 2 hours after said first phase, and then releasing the remaining sertraline immediately after said second phase.

As mentioned above, the present invention is surprising in that the dosage forms of the present invention shorten T_maxEven though the dosage form provides delayed release of sertraline in the Gastrointestinal (GI) tract, wherein T_maxThe time required for sertraline to reach a maximum in the blood. Shortening of T of sertraline_maxIs a novel invention and is another feature of the present invention. Accordingly, the present invention also provides a sustained release dosage form suitable for oral administration to a mammal comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier. The dosage form expresses in vivo plasma T_maxT as measured after ingestion of an equivalent amount of sertraline by an immediate release dosage form (i.e., a dosage form in which no delay period is designed or implemented)_maxShort. Preferred sustained release dosage forms exhibit T relative to an immediate release dosage form containing an equivalent amount of sertraline_maxThe reduction is at least 1/2hr, preferably at least 1 hr.

It is well known that the residence time of a dosage form in the stomach depends on whether the patient has eaten. Some dosage forms, e.g., non-disintegrating tablets, will remain in the stomach until food substantially passes through the stomach into the duodenum, with a residence time in the stomach of up to 3 hours. Multiparticulate dosage forms take longer in the fed stomach than in the fasted stomach, although the increased duration in this case is reflected in the longer gastric emptying half-life of these smaller multiparticulates, which are about 50 μm to 0.3cm in diameter. Thus, for reducing T of dosage form_maxCharacteristically, it is preferred that the dosage form of the present invention is consumed when the patient is in a fasted state, e.g., more than 1 hour prior to a meal or more than 2 hours after a meal. For T_maxShortening property, the dosage form of the invention is used in patients with food intakeThe effect will vary depending on the choice of the relative times of taking the medicine and the meal, and also on the amount of heat contained in the meal. Spatially delayed dosage forms exhibit fed/fasted independence with respect to side-effect modifying properties. For side effect improving properties, the time delayed dosage form of sertraline is preferably administered in the fasted state and the effect varies greatly in the fed state.

The content of sertraline in the sustained release dosage form is at least 10mg, and can be as high as 300mg or more than 300 mg; preferably 10-250 mg. The dosage form may be unitary or divided, e.g., consisting of two or more units (e.g., sachets or tablets combined to form the dosage form) which are ingested at or about the same time.

Sertraline may be used in the dosage forms of the present invention as the free base or a pharmaceutically acceptable salt thereof, e.g., as the hydrochloride, aspartate, acetate or lactate salt, as well as in anhydrous or hydrated forms. All of these forms may be used within the scope of the present invention.

These salts can generally be prepared by combining sertraline free base with the corresponding stoichiometric amount of acid (i.e., aspartic acid, acetic acid, or lactic acid), as described in commonly assigned Pfizer docket No.9337 ajtjj, assigned to the united states of the PCT applications, which are incorporated herein by reference in their entirety. The sertraline used is preferably in the form of the free base, hydrochloride, aspartate, acetate or lactate. Reference in the claims to a therapeutic amount or rate of release of "sertraline" is to active sertraline, referred to herein simply as "mgA", which is a non-salt, non-hydrated free base having a molecular weight of 306.2. The amount expressed in mgA can be easily converted to any salt equivalent.

As mentioned above, the dosage forms forming the subject of the present invention are sustained release formulations. The dosage form may be in the form of a tablet, capsule, multiparticulate, or unit dose packet (sometimes referred to in the art as a "sachet"). Also included are combination dosage forms, for example, those containing one or more sustained release tablets in a capsule shell, such as a gelatin capsule shell.

The term "tablet" includes compressed tablets coated with a material that achieves the desired sustained release effect. Tablet dosage forms may be "single dose", i.e. the total dose is concentrated in one tablet, or "multiple dose", i.e. the total dose is divided in several tablets; they may be ingested substantially simultaneously or they may be contained in a capsule which is dissolved after ingestion and releases multiple tablets after dissolution of the capsule. Since the production and coating of tablets in the prior art has been greatly developed, tablets contain the preferred dosage forms of the present invention.

The term "capsule" includes capsules in which the capsule body disintegrates after ingestion to release particles in the capsule which exhibit the desired sustained release properties, as well as capsules in which the sustained release mechanism is provided by the capsule body. Also included are hard or soft gelatin capsules containing sertraline solutions or suspensions. Sustained release dosage forms containing sertraline solution are preferred because they provide sertraline solution directly, allowing the dosage form to reduce T_maxThe properties of (2) can be exerted to the maximum extent.

The term "multiparticulate" includes dosage forms comprising a plurality of microparticles, the total number of microparticles representing the desired therapeutically effective dose of sertraline. The diameter of the particles is generally about 50 μm to 0.3cm, preferably 100 μm to 2 mm. Multiparticulate formulations are preferred in the examples because they facilitate the sizing (sizing) of the dosage form based on the weight of various animals (e.g., dogs) in a simple manner by programming the number of microparticles in the dosage form to fit the animal weight. Another reason that multiparticulates are preferred is that they undergo a more repetitive gastric emptying process than larger single dosage forms (e.g. tablets), especially for differences in gastric emptying between fed and fasted states. The capsule is preferably filled with fine particles with diameter of 0.4-2 mm. Preferably, microparticles having a diameter of 0.2 to 1mm are compressed into tablets. Preferably, microparticles having a diameter of 0.1 to 0.8mm are used as powders for the preparation of oral suspensions or single dose packets ("sachets").

The multiparticulate, granule or other particulate dosage form may be mixed in a gelatin capsule or may be compressed into a tablet.

In another aspect of the invention there is provided a method of treatment of psychosis or other disorders comprising administering to a mammal (including a human being) in need of such treatment a therapeutically effective amount of sertraline in the form of an oral sustained release dosage form which releases sertraline according to the release profile described above. Such psychiatric disorders include those known in the art to be treatable with sertraline, including those described above. Obesity, premenstrual dysphoric disorder, chemical dependencies and premature ejaculation may also be treated with the sustained release plus immediate release formulations of the present invention.

It is an object of the present invention to provide T in a more conventional sertraline dosage form_maxShort, thereby allowing sertraline to appear faster in the bloodstream, and facilitating sertraline dosage forms that exhibit therapeutic effects faster. Faster presentation of therapeutic effects is particularly important for acute indications, such as improvement of panic or premature ejaculation. It is another object of the present invention to reduce the incidence and severity of sertraline-induced gastrointestinal side effects. This is important for all doses, especially high doses, such as 200mg and above 200mg, since the incidence of gastrointestinal side effects can be relatively high at high doses. This objective is achieved by minimizing the extent and duration of gastric exposure to sertraline, thereby reducing the overall incidence and severity of sertraline-induced nausea, regurgitation or diarrhea.

Using conventional immediate release tablets (Zosoft)^Pfizer inc. registered trademark) oral administration of sertraline results in excessive exposure of the drug to the stomach. It is therefore another object of the present invention to provide a dosage form that delivers a therapeutically effective amount of sertraline while reducing the extent to which sertraline is intensively exposed to the upper gastrointestinal tract, particularly the stomach, and reducing the T_maxAnd faster exposure of the systemic circulation to sertraline for treatment, and more favorable reduction of nausea, regurgitation or diarrhea.

Brief Description of Drawings

FIG. 1 is a PK/PD plot showing the relationship between plasma concentrations of sertraline and the mean self-reported visual simulation scores for study nausea presented in the examples.

Detailed Description

In principle, the invention may be practiced by coating (preferably completely) an immediate release core containing sertraline and a pharmaceutically acceptable carrier with a coating that provides the desired sustained release profile, either spatially or temporally. Thus, any immediate release sertraline dosage form may be used as a drug core, which in turn is coated with a coating of the desired sustained release properties. Such dosage forms constitute preferred examples within the scope of the present invention.

Spatially delayed pH-triggered dosage forms

The first spatially delayed release example of the present invention is a "pH-dependent coated tablet" comprising an immediate release tablet or a core coated with a material comprising a polymer which at the pH of the stomach does not substantially allow sertraline permeation but which at the pH of the small intestine becomes permeable to sertraline. By "substantially impermeable" is meant that the spatially retarded dosage form allows very small amounts of sertraline to be released through the coating, provided that the amount released in the stomach does not exceed 10% of the sertraline contained in the dosage form, even if it is substantially impermeable. These polymers become permeable by dissolving or disintegrating or being broken up so that sertraline can pass freely. The tablets or cores may further contain excipients such as disintegrants, lubricants, fillers, and/or other common formulation ingredients. All of these ingredients and/or excipients, regardless of the dosage form, are collectively referred to herein as a pharmaceutically acceptable "carrier". The core is surrounded by a material, preferably a polymer, which is substantially insoluble and impermeable at the pH of the stomach, but is more permeable at the pH of the small intestine. Preferred coating polymers are substantially insoluble and impermeable at pH < 5.0 and water soluble or water disintegrable at pH > 5.0. Mixtures of pH sensitive polymers with water insoluble polymers may be used. The tablets are coated with a polymer in an amount of 3-70% by weight of the tablet core containing sertraline. Preferred tablets are coated with 5-50% polymer by weight of the sertraline containing core.

pH sensitive polymers which are less soluble and impermeable at the pH of the stomach but are more soluble or disintegratable or permeable at the pH of the small intestine and colon include polyacrylamides, phthalate derivatives, such as acid phthalates of carbohydrates, amylose acetate phthalate, cellulose acetate phthalate, other cellulose ester phthalates, cellulose ether phthalates, hydroxypropyl cellulose phthalate, hydroxypropyl ethyl cellulose phthalate, hydroxypropyl methyl cellulose phthalate, polyvinyl acetate hydrogen phthalate, sodium cellulose acetate phthalate, starch acid phthalate, cellulose acetate 1, 2, 4-trimellitate, styrene-maleic acid dibutyl phthalate copolymers, styrene-maleic polyvinyl acetate phthalate copolymers, styrene and maleic acid copolymers, polyacrylic acid derivatives, such as acrylic acid and acrylate copolymers, polyisomethacrylic acid and its esters, polyacrylic acid-methacrylic acid copolymers, shellac, and vinyl acetate and crotonic acid copolymers.

Preferred pH sensitive polymers include shellac, phthalate derivatives, especially cellulose acetate phthalate, polyvinyl acetate phthalate and hydroxypropyl methyl cellulose phthalate; cellulose acetate 1, 2, 4-trimellitate; polyacrylic acid derivatives, in particular copolymers containing acrylic acid and at least one acrylic ester; polymethyl methacrylate blended with acrylic acid and acrylate copolymers; and vinyl acetate and crotonic acid copolymers.

Particularly preferred pH sensitive polymers include cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, anionic acrylic copolymers of methacrylic acid and methyl methacrylate, and copolymers containing acrylic acid and at least one acrylate.

Cellulose Acetate Phthalate (CAP) can be administered to sertraline tablets such that release of sertraline is delayed until the sertraline-containing tablets leave the stomach. The CAP coating solution may contain one or more plasticizers such as diethyl phthalate, polyethylene glycol 400, triacetin citrate, propylene glycol, and other plasticizers known in the art. Preferred plasticizers are diethyl phthalate and triacetin. The CAP coating formulation may also contain one or more emulsifiers, such as Tween 80.

Anionic acrylic copolymers of methacrylic acid and methyl methacrylate are also particularly useful coating materials which allow the tablet to be moved to a location in the gastrointestinal tract remote from the stomach before releasing sertraline from the sertraline-containing tablet. Such copolymers are commercially available from RohmPharma Corp under the trademark Eudragit^-L and Eudragit^-S。Eudragit^-L and Eudragit^-S is an anionic copolymer of methacrylic acid and methyl methacrylate. Eudragit^The ratio of free carboxyl groups to ester in L is approximately 1: 1, whereas in Eudragit^in-S, the ratio is about 1: 2. Eudragit can also be used^-L and Eudragit^-a mixture of S. As for the coating of sertraline-containing tablets, these acrylic coating polymers may be dissolved in an organic solvent or a mixture of organic solvents, or suspended in an aqueous medium. Useful solvents for this purpose are acetone, isopropanol and dichloromethane. It is generally desirable to include 5-20% plasticizer in the acrylic copolymer coating formulation. Useful plasticizers include polyethylene glycol, propylene glycol, diethyl phthalate, dibutyl phthalate, castor oil and triacetin. Preferred is Eudragit^L, because it dissolves relatively rapidly at the pH of the intestinal tract.

The content of the above coating may be 3 to 70%, preferably 5 to 50%, more preferably 5 to 40% by weight of the bare chip core.

An example of a spatially retarded sertraline dosage form is a "pH dependent coated granule" comprising sertraline and particles having a carrier diameter of 0.4 to 2.0mm coated with one or more of the above pH sensitive polymers. Such coated granules may be placed in capsules or compressed into tablets, but care should be taken during compression to avoid damaging the polymer coating on each granule. Preferred coated particles are those which have the above-described characteristics that allow substantially no (i.e., less than 10%) sertraline to be released from the dosage form until the particles are removed from the stomach, thereby ensuring that only minimal amounts of sertraline are released in the stomach. The content of the cladding is 5 to 200%, preferably 10 to 100%, based on the weight of the bare particle core.

An example of a multi-microparticulate spatially retarded sertraline dosage form is the "pH dependent encapsulated microparticle", which is composed of small sertraline plus carrier microparticles having a diameter of 0.1-0.4 mm. The microparticles are coated with one or more of the above-mentioned pH sensitive polymers. The coated particles may be used to form unit dose packs or placed in capsules or compressed into tablets, but care is taken during compression to avoid damaging the polymer coating on each particle. Preferred coated microparticles are those having the above characteristics that substantially no sertraline (i.e., less than 10%) is released from the dosage form until the microparticles are removed from the stomach, thereby ensuring that only minimal sertraline is released in the stomach. Also included are mixtures of pH polymers with water insoluble polymers. Preferred sertraline-containing microparticles are coated with 15-200% of a polymer, by weight, based on the weight of the sertraline-containing bare particle core.

Also included are mixtures of pH sensitive polymers with water insoluble polymers. Sertraline-containing tablets, microparticles and granules can be coated with a mixture of polymers, with mixtures of different solubilities being selected for different pH. For example, preferred coatings include Eudragit^L, or Eudragit from 9: 1 to 1: 4^-L and Eudragit^-a mixture of S.

Another example of a spatially retarded sertraline dosage form is a modification of the examples of pH-dependent coated tablets, pH-dependent coated granules and pH-dependent coated microparticles. The sertraline-containing tablet, granule or microparticle core is first coated with an isolation layer and then coated with a pH-dependent coating. The function of the barrier coating is to isolate sertraline from the pH-dependent coating. Since sertraline is a base, hydration of sertraline in the core raises the pH in the microenvironment of the pH-dependent coating, thus making the pH-dependent coating permeable or soluble prematurely, resulting in premature release of some or all of the sertraline dose in the stomach. The barrier layer may prevent such premature release. Suitable barrier coatings are composed of water soluble materials, sugars such as sucrose, or water soluble polymers such as hydroxypropyl cellulose, hydroxypropyl methylcellulose, and the like. Hydroxypropyl cellulose, hydroxypropyl methylcellulose and polyvinylpyrrolidone are preferred polymers. The content of the coating of the isolating layer may correspond to 1-20%, preferably 2-15% by weight of the sertraline-containing naked tablet core, naked granule core or naked microparticle core.

Another example of a spatially retarded sertraline dosage form is the formation of a solution, suspension or powder of sertraline in a solvent, followed by encapsulation in a water-soluble capsule, e.g., a hard or soft gelatin capsule as known in the art, which is then coated with a pH-dependent polymer as described above for the pH-dependent coated tablet. For the preparation of sertraline solutions in capsules, solvents such as triglyceride oils and glycols may be used. Useful and preferred sertraline solvents are disclosed in the commonly assigned pending provisional application [ Pfizer Docket 9838JTJ ], filed on the same date as the present application, which is incorporated herein by reference. Useful and preferred solvents also include those listed below.

Preferred solvents are water-immiscible solvents including water-immiscible oils including triglyceride vegetable oils such as safflower oil, sesame oil, olive oil, corn oil, castor oil, coconut oil, cottonseed oil, soybean oil and the like. Also included are synthetic and semi-synthetic medium chain triglyceride oils, e.g. as Miglyol^(HulsAmerica, Piscataway, New Jersey) or Captex^Oil sold under the trademark (Abitec Corp., Columbus, Ohio). Examples are triglycerides of caprylic/capric acid (Miglyol)^-810，Miglyol^-812，Captex^-300，Captex^-355), and triglycerides of caprylic/capric/linoleic acid (Miglyol)^-818). Also included are long chain triglyceride oils, such as triolein, and other mixed chain triglycerides that are liquid at room temperature.

The water-immiscible solvent also includes mono-and diglycerides, e.g. as Capmul^(ABITEC, Columbus, Ohio) and Imwitor^Esters sold under the trade mark (HulsAmerica, Piscataway, New Jersey). Examples are glycerol monooleate (Capmul)^-GMO), and mono-and diglycerides of caprylic/capric acid (Imwitor)^-742，Capmul^-MCM), and monocapraxin (Imwitor)^308), etc.

Preferred oils are liquid at room temperature. Preferred mono-, di-and triglycerides are those having an average acyl chain length of C₄-C₁₈An ester of (a).

Useful carriers also include various liquid esters of short chain alcohols, such as propylene glycol caprylate/caprate (Miglyol)^-840，Captex^-200). Fatty acids that are liquid at room or body temperature, such as caprylic acid, capric acid, lauric acid, oleic acid or linoleic acid, may also be used.

Other useful carriers include semi-solid carriers, such as Gelucire^The article of commerce of (1). Examples are PEG-32-glyceryl laurate (Gelucire)^44/14) and glycerol esters of fatty acids (Gelucire)^33/01)。

Other useful carriers also include surfactants and emulsifiers that are capable of solubilizing sertraline. These surfactants and emulsifiers form micelles when they are mixed with an aqueous medium. Examples are polyethoxyether, nonylphenoxypolyoxyethylene, dioctyl sodium sulfosuccinate, PEG-6-glycerol monooleate (Labrafil)^M-1944-CS), PEG-6 glyceryl linoleate (Labrafil)^M-2125-CS), etc.

Preferred carriers are those which dissolve sertraline or one of its pharmaceutically acceptable salts at a concentration of 16.7mgA/ml or greater. Some encapsulated carriers have a greater ability to retain sertraline in solution than others after the formulation is mixed with the simulated parenteral substance. More preferred vectors are those that inhibit sertraline precipitation in the presence of 0.1N HCl or phosphate buffered saline (pH 5.8). These encapsulating carriers are more preferred because they minimize sertraline precipitation and gelation in the environment of use, i.e., the gastrointestinal lumen, and thus, allow sertraline to appear in the bloodstream at the fastest rate after administration. Although these preferred carriers do not completely or almost completely prevent the precipitation of sertraline when mixed with chlorine-containing physiological fluid models, the effect on sertraline precipitation rate is beneficial. In vivo, the intestinal wall has a high capacity to rapidly absorb sertraline, expressed as the high absorption constant (ARC). Any formulation that enables sertraline to remain in solution, even in the time-form, is useful because precipitation and absorption compete for the soluble sertraline available.

According to this guideline, more preferred carriers are vegetable oils, such as safflower oil and olive oil; medium chain triglycerides, such as caprylic/capric triglyceride; mono-and diglycerides, including medium chain mono-and diglycerides; acylated polyols such as propylene glycol dicaprylate/caprate; fatty acids, such as oleic acid; and surfactants, such as tween 80.

More preferred carriers are those which inhibit sertraline precipitation in 0.1N HCl or phosphate buffered saline (pH5.8), including medium chain triglycerides, such as caprylic/capric triglyceride; mono-and diglycerides, including medium chain mono-and diglycerides; acylated polyols such as propylene glycol dicaprylate/caprate; fatty acids, such as oleic acid; and surfactants, such as tween 80. The most preferred carrier is one that is capable of solubilizing the sertraline hydrochloride salt in the environment of use, thereby minimizing precipitation of said salt in a chlorinated physiological solution, whether the sertraline is the free base, hydrochloride, or other pharmaceutically acceptable salt at the time of initial administration. Most preferred carriers, in addition to providing sertraline in any form with a solubility greater than 16.7mgA/ml (thereby allowing for 10mgA or more of the medicament in a 0.8ml gelatin capsule), provide sertraline hydrochloride solubility in excess of 0.3mgA/ml (to inhibit sertraline precipitation in physiological fluids).

The water-immiscible solvent may be mixed with the surfactant and emulsifier so that when the water-immiscible solvent/emulsifier carrier is mixed with water, as in the gastrointestinal tractIn (b), fine or micro-carrier droplets (e.g., microemulsions) may form spontaneously. Such mixtures include mixtures of triglycerides or mono-and diglycerides with tweens, e.g., Capmul^-mixture of MCM and tween 80, or Miglyol^A mixture of 812 and tween 80 in a ratio of 99/1 to 50/50, respectively. Other useful mixtures include mixtures of mono-, di-and tri-glycerides with tweens, e.g., Capmul^-MCM/Miglyol^-812, wherein Capmul^-MCM constitutes 40-80% of the support, the remainder being Miglyol^-812 and tween 80. Other useful mixtures also include vegetable oils and surfactants, e.g., olive oil/tween 80 in a ratio of 99: 1 to 50: 50, or corn oil/Labrafil^-M-2125-CS in a ratio of 99: 1 to 50: 50. Polyethylene glycol and other water-miscible sertraline solvents such as glycerol, ethanol, propylene glycol may also be present in the carrier in proportions up to 30% in order to optimize the solubility of sertraline in the carrier or to improve the viscosity of the carrier to facilitate capsule filling.

Solutions of sertraline in carriers of the above type are encapsulated in soft gelatin capsules, or in hard gelatin capsules. If encapsulated in a hard gelatin capsule, the gap between the two-piece capsule shells is preferably sealed, for example with a strip of gelatin, to prevent leakage. Methods of encapsulating soft gelatin capsules are known and described in The Theory and practice of The pharmaceutical industry (The Theory and practice of Industrial Pharmacy), L.Lachman, H.Lieberman and J.Kanig, Lea and Febiger.

The pH sensitive polymer may be any of the polymers disclosed such as, but not limited to, cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, copolymers of methacrylic acid and methyl methacrylate, and copolymers containing acrylic acid and at least one acrylate.

Tablets, granules, capsules and microparticles containing sertraline may be coated using equipment known in the art. For example, sertraline-containing tablet cores and capsules may be coated with a pan-Coater, such as a Hi-Coater (Freund Corp.), or Accela-Cota (Manesty Corp., Liverpool). The sertraline-containing granules and microparticles are preferably coated with a fluid bed coating machine, such as a Wurster coater, available coating equipment, for example, from Glatt corporation (Ramsey, NJ). The granules may also be coated using a rotary granulator, such as the CF granulator sold by Freund corporation.

Advantageously, inter-patient variability in gastric emptying is not a significant problem because of the mechanism by which the pH-induced spatial delay dosage form is perceived as being after it has been removed from the stomach.

Spatially delayed enzyme-triggered dosage forms

Another example of a spatially retarded sertraline dosage form "enzyme primer-supported liquid film dosage form" includes sertraline dosage forms of the type described in International application PCT/US93/07463, published in WO 94/12159 on 9/6 of 1994, which is hereby incorporated by reference. This example is typically in the form of an immediate release tablet core or multiparticulate (preferably granules) containing sertraline plus a carrier, the tablet core or granules being at least partially, and preferably fully, surrounded by a microporous hydrophobic membrane, the hydrophobic liquid being entrapped within the pores of the membrane. Alternatively, the sertraline loading bodies can be loaded together into a capsule shell which is composed of a microporous hydrophobic membrane and the capsule shell confines the hydrophobic liquid within the pores. The hydrophobic liquid is substantially impermeable to the aqueous environment and to the sertraline tablet core or granule core formulation. The hydrophobic liquid may be modified to allow penetration into an aqueous environment or into a sertraline formulation. The release of sertraline in the gastrointestinal system of a mammal, including a human, after ingestion of such a dosage form will be delayed until the dosage form moves out of the stomach and into the small intestine.

The hydrophobic liquid entrained in a liquid film dosage form supported by the sertraline enzyme trigger is an enzymatically altered liquid which is altered in the small intestine lumen, but not in the stomach, to render the pores (in the film) permeable to water and sertraline. The drug core may also optionally contain an osmotic agent (osmagent), a swelling agent or a bursting material to help accelerate the release rate of sertraline as the dosage form passes through the small intestine. Examples of hydrophobic liquids are triglycerides, fatty acid anhydrides, fatty acid esters of cholesterol, hydrophobic amino acid esters, and the like. Preferred triglycerides include trioleoyl glyceride, trioctyl glyceride, trilauryl glyceride, olive oil, palm oil, coconut oil, sesame seed oil, corn oil, peanut oil, soybean oil, and the like. Preferred fatty acid anhydrides include caprylic anhydride, lauric anhydride, myristic anhydride, and the like. Mixtures of hydrophobic liquids may also be used. Examples of materials useful as microporous hydrophobic carrier films include cellulose esters, polycarbonates, polyolefins, polystyrenes, polyvinylesters, polysiloxanes, polyacrylates, and polyethers. The preferred hydrophobic microporous membrane with entrained hydrophobic liquid is impermeable to sertraline until the gastrointestinal enzyme catalyzes a change in the hydrophobic oil, as described below.

In the environment of use, i.e., in the lumen of the small intestine, lipases and esterases degrade the hydrophobic oils, releasing surfactant products in the pores of the microporous membrane of this example, thereby creating aqueous channels through which sertraline in the core can exit through the microporous hydrophobic carrier membrane. Release of sertraline can be achieved by simple diffusion, osmotic pumping, osmotic rupture, or by bursting as a result of the presence of a swellable material such as a hydrogel in the sertraline-containing core of the dosage form.

Hydrophobic oils may be used as substrates for small intestine proteases, such as carboxypeptidases and chymotrypsin, in the liquid film dosage forms supported by the above enzyme triggers of sertraline. Examples of oils are hydrophobic esters of amino acid derivatives.

In other examples of spatially retarded sertraline dosage forms, the sertraline tablet, capsule, granule or powder is coated with a coating containing ingredients that are enzymatically degradable in the small intestine but not in the stomach. The coating material comprises a natural or synthetic wax or triglyceride that is solid at body temperature. In preferred embodiments, materials that are 2-20% liquid at body temperature and are degraded by small intestinal enzymes (e.g., trypsin, chymotrypsin, elastase, lipase) are also included. Suitable enzymatically labile liquids are those described above in connection with the "liquid film dosage form supported by an enzyme primer". The preferred amount of wax coating is 3-20% by weight of the sertraline caplet, capsule, granule or powder.

Time delay dosage form

In a first example of a time delayed dosage form of sertraline, a "ruptured osmotic core dosage form", sertraline is incorporated into an osmotic ruptured dosage form consisting of a core of tablets or granules containing sertraline and one or more osmotic agents. Such dosage forms are disclosed in U.S. Pat. No. 3,952,741 to Baker, which is incorporated herein by reference. Examples of osmotic agents are sugars such as glucose, sucrose, mannitol, lactose, and the like; and salts such as sodium chloride, potassium chloride, sodium carbonate, etc.; water-soluble acids such as tartaric acid, fumaric acid, and the like. The sertraline-containing tablet or granule core is coated with a polymer which forms a semipermeable membrane which is permeable only to water and not to sertraline. Among the polymers that can provide a semipermeable membrane are cellulose acetate, cellulose acetate butyrate and ethyl cellulose, with cellulose acetate being preferred. Mixtures of polyethylene glycol, such as polyethylene glycol 6000, with hydrogenated oils, such as hydrogenated castor oil, which melt, may also be used as coatings, as discussed by Yoshino in the paper on isoniazid tablets (Series of monograph papers for capsules; present situation on targeted Delivery of drugs to the Gastrointestinal Tract (Capsugel Symposia Series; Current state on targeted Drug Delivery to the Gastrointestinal Tract), 1993, pp.185-190). Preferred semipermeable coatings are cellulose esters and cellulose ethers, polyacrylic acid derivatives, such as polyacrylates and polyacrylates, and polyvinyl alcohols and polyolefins, such as ethylene vinyl alcohol copolymers. Particularly preferred semipermeable coating materials are cellulose acetate and cellulose acetate butyrate.

When the above-described rupture permeable core coated tablet or granule is placed in an aqueous environment of use, water permeates the semipermeable membrane into the core, causing a portion of the sertraline and osmotic agent to dissolve, creating an osmotic pressure of the colloid, thereby causing rupture of the semipermeable membrane and release of sertraline into the aqueous environment. By selecting the size and geometry of the particle or tablet core, the identity and quantity of osmotic agents, and the thickness of the semipermeable membrane, the time lag between entry of the dosage form into the aqueous environment of use and release of the contained sertraline can be rationally arranged. It will be appreciated by those skilled in the art that increasing the surface area to volume ratio of the dosage form and increasing the permeability of the osmotic agent may reduce the lag time, while increasing the coating thickness will increase the lag time. A preferred osmotic-breaking dosage form of the present invention is one in which sertraline is not substantially released from the dosage form (i.e., less than 10%) until the dosage form is removed from the stomach, thereby ensuring minimal release of sertraline in the stomach. A tablet or granule having a core comprising 15-80% sertraline, 5-60% of the above osmotic agent and 5-20% other pharmaceutical adjuvants, such as binders and lubricants. The semipermeable membrane coating on the tablet is preferably a cellulose acetate coating material in an amount corresponding to 2-30%, preferably 3-20% of the weight of the tablet core. The semipermeable membrane coating on the granule is preferably a cellulose acetate coating material in an amount of 2-80%, preferably 3-40% by weight of the granule core.

The ruptured osmotic core dosage form does not have the ability to sense that the dosage has moved out of the stomach into the small intestine. Thus, such dosage forms are time delayed dosage forms, i.e., dosage forms that release sertraline at a predetermined time upon entry into an aqueous environment, i.e., upon swallowing. In the fasted state, indigestible non-disintegrating solids, such as the "ruptured osmotic core dosage form" of the present invention, empty from the stomach during the third phase of inter-digestive phase shift complex myoelectricity (IMMC). For humans, this occurs approximately every 2 hours. Depending on the stage of IMMC on fasting administration, the ruptured osmotic core dosage form may migrate out of the stomach almost immediately after administration, or within 2 hours after administration. In the fed state, indigestible, non-disintegrating solids, less than 11mm in diameter, will slowly drain from the stomach with food (Khosla and Davis, journal of international pharmacology (int.j. pharmaceut.), 62(1990) R9-R11). If the diameter of the indigestible non-disintegrating solid is more than 11mm, i.e. typical tablet size, it is left in the stomach to undergo a process of digesting food, and then,after waiting for all of the food to be digested and removed from the stomach, it is emptied from the stomach during the third phase of IMMC. A split osmotic core dosage form that releases sertraline from 10 minutes to 2 hours after ingestion reduces the T of sertraline_maxAnd the incidence and severity of nausea, regurgitation and diarrhea in most patients taking such dosage forms. Preferred ruptured osmotic core dosage forms are those which, when administered in the empty film state, enter an aqueous environment, i.e., begin releasing sertraline from 15 minutes to 1.5 hours after ingestion, to more reliably ensure release of sertraline after removal from the stomach.

In another example of a time delayed sertraline dosage form, "burst coated swelling cores," 25-70% of sertraline-containing tablets or granules prepared according to the method described by Milosovich in US3,247,066 are swellable materials, such as swellable colloids (e.g., gelatin), which is incorporated herein by reference. Preferred intumescent core materials are hydrogels, i.e. hydrophilic polymers which swell with water, such as polyethylene oxide, polyacrylic acid derivatives, such as polymethyl methacrylate, polyacrylamide, polyvinyl alcohol, poly-N-vinyl-2-pyrrolidone, carboxymethyl cellulose, starch, etc. The preferred swelling hydrogels of this example are polyethylene oxide, cross-linked polyacrylate and carboxymethyl cellulose. The sertraline-containing tablet or granule core containing the colloid/hydrogel is at least partially surrounded by a semipermeable membrane. Examples of polymers capable of providing a semipermeable membrane are cellulose acetate, cellulose acetate butyrate and ethyl cellulose. Mixtures of polyethylene glycol, such as polyethylene glycol 6000, with hydrogenated oils, such as hydrogenated castor oil, which melt, may also be used as coatings, as discussed by Yoshino in the paper on isoniazid tablets (Series of monograph papers for capsules; present situation on targeted Delivery of drugs to the Gastrointestinal Tract (Capsugel Symposia Series; Current state on targeted Drug Delivery to the Gastrointestinal Tract), 1993, pp.185-190). Preferred semipermeable coatings are cellulose esters and cellulose ethers, polyacrylic acid derivatives, such as polyacrylates and polyacrylates, and polyvinyl alcohols and polyolefins, such as ethylene vinyl alcohol copolymers. Particularly preferred semipermeable coating materials are cellulose acetate and cellulose acetate butyrate.

When the coated tablet or granule having an expanded core surrounded by a disruptive substance is placed in an aqueous environment of use, water permeates the semipermeable membrane and enters the drug core, causing the core to expand, resulting in rupture of the semipermeable membrane and release of sertraline into the aqueous environment. The time lag between entry into the aqueous environment of use and release of the contained sertraline may be selected by selection of the size and geometry of the particle or core, the identity and amount of the swelling agent, and the thickness of the semipermeable membrane. Preferred ruptured substance encapsulated expanded core dosage forms of the present invention release substantially no sertraline (i.e., less than 10%) from the dosage form prior to removal from the stomach, thereby ensuring minimal release of sertraline in the stomach.

A tablet or granule of an expandable core surrounded by a disintegrating substance has a core or granule comprising 15-80% sertraline, 15-80% expanding material, such as a hydrogel, 0-15% optionally an osmotic agent and 5-20% other pharmaceutical adjuvants, such as binders and lubricants. The semipermeable membrane coating on the tablet is preferably a cellulose acetate coating material in an amount corresponding to 2-30%, preferably 3-20% of the weight of the tablet core. The semipermeable membrane coating on the granule is preferably a cellulose acetate coating material in an amount of 2-80%, preferably 3-40% by weight of the granule core.

The burst-material-coated swelling core dosage form does not have the function of sensing that the medicament has moved out of the stomach into the small intestine. Thus, such dosage forms release sertraline at a predetermined time upon entry into an aqueous environment, i.e., after swallowing, as discussed above with respect to the ruptured osmotic core dosage forms, the same considerations and references apply to the preparation of an expanded core dosage form surrounded by a ruptured substance.

In a preferred embodiment of the time delayed sertraline dosage form, the immediate release sertraline tablet, granule or microparticle is formed into a core and surrounded by a water soluble and/or water disintegrable delay layer. Preferred delayed coatings include hydroxypropyl cellulose (HPC), hydroxypropyl methylcellulose (HPMC), polyethylene oxide and polyvinylpyrrolidone. For tablets the coating process may be carried out on a tablet coating machine, such as a HCT-30, HCT-60 or HCT-130 coating machine (Freund Corp.). The core is coated with an aqueous solution of HPMC or other suitable polymer such that the weight of the final coating is 5-50% of the weight of the final coated tablet. The heavier coating weight results in a longer delay time before sertraline begins to be released to the environment of use (gastrointestinal tract lumen). The delay time can also be increased by adding small to moderate amounts of poorly water soluble polymers including, but not limited to, Ethyl Cellulose (EC), Cellulose Acetate (CA) and cellulose acetate butyrate to the coating formulation. For example, the coating formulation may consist of 95: 5HPMC/EC to 50: 50HPMC/EC, or 95: 5HPMC/CA to 50: 50 HPMC/CA. In the case of such a hybrid polymer clad system, it is necessary to adjust the solvent composition to dissolve the mixture of the water-soluble polymer and the poorly water-soluble polymer. For example, a mixture of acetone and water, or a mixture of ethanol and water, may be used as necessary. Granules and microparticles may similarly be coated using a fluidized bed coating machine, such as the GlattGPCG-5 coating machine. For the particles, the cladding is present in an amount corresponding to 10-100% by weight of the bare particle core. For sertraline particles, the amount of cladding is 15-200% by weight of the bare particle core.

In another example of a time delayed sertraline dosage form, a solution or suspension of sertraline in a solvent is encapsulated in a soft or hard gelatin capsule and then coated with a water-soluble and/or water-disintegrable polymer as described with respect to the coating of other types of drug cores. Useful and preferred solvents for sertraline include all those solvents described above for use in the sterically retarded encapsulation solutions. Coating polymers include, for example, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyethylene oxide, polyvinyl pyrrolidone, cellulose acetate, and ethyl cellulose.

It will be appreciated by those skilled in the art that the various coated sertraline tablets, granules and microparticles described above may be coated using standard coating equipment, such as pan coaters (e.g., Hi-Coater, available from Freund, Inc., or Accela-Cota, available from Manesty, Inc. (Liverpool)); fluidized bed coaters, such as Wurster coaters (available from Glatt corporation (Ramsey, NJ) and Aeromatic corporation (Columbia, MD)); and a rotary granulator, such as a CF granulator (available from Freund corporation). The tablet cores may be made on a standard tablet press, such as a Kilian tablet press. Sertraline-containing granules and granules can be made in fluid bed granulators, rotary granulators and extruder/ball mills (spheronizers).

In the preferred embodiment of the present invention, in order to shorten T as much as possible_maxSertraline rapidly dissolves after a spatial or temporal delay to achieve the goal of increased therapeutic efficiency. In formulating sustained release dosage forms of sertraline, it may be advantageous to use highly soluble salts, formulations that increase the solubility of sertraline, or a combination of both, collectively referred to as "highly soluble forms". In addition, the addition of excipients is advantageous in increasing the rate of dissolution of sertraline, and this protocol is preferred. Solubilizers and compositions are disclosed in copending provisional application [ Pfizer Docket 9835JTJ ]]The filing date is the same as the present application, which is incorporated herein by reference.

Whatever salt form or specific excipient is employed in the dosage form, the highly soluble form should provide sertraline water solubility of at least 5 mg/ml. The use of a highly soluble salt or form is advantageous because (a) it dissolves faster than a less soluble salt or form (e.g., sertraline base, sertraline hydrochloride without solubilizing excipients present) and (b) it provides a higher sertraline concentration in the lumen of the gastrointestinal tract, allowing a higher sertraline concentration gradient across the intestinal wall, thereby allowing a more rapid absorption of the sertraline dose.

Solubilization for T_maxMinimization of sertraline dosage forms can be very important because some sertraline forms, especially the highly soluble salt forms of sertraline, may form gels in many aqueous solutions, especially solutions containing chloride ions, such as in the gastrointestinal tract.

Sertraline gels can be formed by simply introducing chloride ions into a solution of sertraline lactate or sertraline acetate. Similar gels can also be formed by incorporating an acid, such as tartaric acid, or a combination of an acid and a surfactant, such as succinic acid and sodium lauryl sulfate, into a sertraline solution. However, other acid and/or surfactant-like compounds may provide solubilization, minimize gel formation, and provide a formulation basis for delivering sertraline to aqueous solutions containing chloride ions, such as intestinal fluids.

The gelling of sertraline in certain forms is surprising, and the ability of certain additives to prevent such gelling is both surprising and unpredictable.

Therefore, it would be highly advantageous to utilize these methods in sustained release dosage forms to increase the ability of sertraline to dissolve rapidly in the environment of use. One way to obtain more soluble sertraline is to make sertraline salts with higher solubility, such as sertraline lactate, sertraline acetate and sertraline aspartate. Preferred salts have a solubility in water of more than two times that of sertraline hydrochloride, which is about 3 mgA/ml.

Another method of increasing the solubility of sertraline is the use of an agent, referred to herein as a "solubilizing agent," whose actual effect of adding the solubilizing agent is to increase and preferably maintain the solubility of sertraline (or a salt thereof) in the same use environment relative to the solubility of sertraline in the use environment without the use of the solubilizing agent.

Many of the solubilizing agents used in the present invention can be divided into several broad categories:

1. organic acids and organic acid salts;

2. partial glycerides, i.e., incompletely esterified derivatives of glycerol, including mono-and diglycerides;

3. a glyceride;

4. a glyceride derivative;

5. polyethylene glycol esters;

6. polypropylene glycol ester;

7. a polyol ester;

8. polyoxyethylene ethers;

9. sorbitan esters; and

10. a polyoxyethylene sorbitan ester,

11. a carbonate salt.

The amount of solubilizer to be used will depend on the particular solubilizer used.

For the case where the solubilizing agent is an organic acid, the amount of solubilizing agent should be multiplied by the amount of sertraline to be used, which is the ratio of the solubility of the organic acid to the solubility of the sertraline salt, i.e.: (solubility of organic acid or salt/solubility of sertraline or sertraline salt). times.sertraline amount, wherein solubility is expressed in mg/ml. The above expressions are approximate and are well-suited for optimization. In summary, the above expression will give a quantity, the final quantity used being this plus ± 25%. Although larger amounts of solubilizer may be used, it does not add any particular benefit. In addition, organic acid salts may be added to improve the pH and/or solubility of the organic acid, effectively optimizing the solubilization of the solubilizing agent.

For the other types of solubilizing agents listed, the typical amount of solubilizing agent in the dosage form will be from 1 to 150%, preferably from 1 to 100%, more preferably from 3 to 75% of the amount of sertraline used. The amount of solubilizer may be higher than 150%, although amounts in excess of 150% are considered to be of no particular benefit in most cases.

Examples of the organic acid used in the present invention include malic acid, citric acid, isoascorbic acid, adipic acid, glutamic acid, aspartic acid, maleic acid, aconitic acid and ascorbic acid. Preferred acids are citric acid, erythorbic acid, ascorbic acid, glutamic acid and aspartic acid. Organic acid salts, such as alkaline earth metal (magnesium, calcium) salts and alkali metal (lithium, potassium, sodium) salts, and mixtures of organic acids and their salts may also be used. Calcium salts, such as calcium carbonate, calcium acetate, calcium ascorbate, calcium citrate, calcium gluconate monohydrate, calcium lactobionate, calcium glucoheptonate, calcium levulinate, calcium pantothenate, calcium propionate, calcium hydrogen phosphate, calcium glucarate are preferred organic acid salts.

Examples of such other classes of compounds are summarized in table 1.

TABLE 1

Solubilizer

Categories	Example, chemical name	Example, trade name (supplier)
			Partial glyceride	Glyceryl monocaprylate	Monocaprylin(Sigma)，CapmulMCM(Abitec)，Imwitor308(Huls)
	C8-C10 partial glyceride	CapmulMCM(Abitec)，Imwitor742(Huls)，Imwitor988(Huls)
				Monooleic acid glyceride	Myverol18-19(Eastman)，CalgeneGMO(calgene)，CapmulGMO(Abitec)
	Linoleic acid glyceride	Myverol18-92(Eastman)
				Glyceryl monostearate	Imwitor191(Huls)，CalgeneGSO(Calgene)
	Monolaurin	Imwitor312(Huls)，CalgeneGLO(Calgene)
				Glycerol dilaurate	CapmulGDL(Abitec)
Glycerides	Triacetyl glyceride	Triacetyl glyceride (Sigma)
			Glyceride derivatives	PEG-derivatized glycerides	CremophorRH40，CremophorRH60(BASF)，Acconon CA5，CA-9，CA-15，W230，TGH(Abi tec)
	Pegylated glycerides	Gelucire44/14，42/12，50/13，53/10，35/10，48/09，46/07，62/05，50/02；Labrasol(Gattefosse)；Capmul3GO；3GS，6G20，6G2S，10G40，10G100(Abitec)
			Polyethylene glycol esters	PEG200 monolaurate PEG400 monolaurate PEG600 monolaurate	Calgene20-L，Calgene40-L，Calgene60-L
	PEG200 Monostearate PEG400 Monostearate PEG600 Monostearate	Calgene20-S，Calgene40-S，Calgene60-S
				PEG200 dilaurate PEG400 dilaurate PEG600 dilaurate	Calgene22-L，Calgene42-L，Calgene62-L

Polypropylene glycol ester	Polypropylene glycol dicaprylate	Captex200(Abitec)
			Polyol esters	Diethylene glycol monolaurate	CalgeneDGL
	Propylene glycol monolaurate	CalgenePGML
				Ascorbyl palmitate	Ascorbyl palmitate (Sigma)
Polyoxyethylene ethers	PEG lauryl ether	Nonionic L-4(Calgene)
				PEG stearyl ether	Non-ionic S-20(Calgene)，Myrj 45，52，53，59(Sigma)
Sorbitan esters	Sorbitan monolaurate	CalgeneSML，Span20(Sigma)
				Sorbitan monooleate	CalgeneSMO，Span80(Sigma)
Polyoxyethylene sorbitan esters	POE-20 sorbitan monolaurate	CalgenePSML-20，Span20(Sigma)，Tween20(Sigma)，CapmulPOE-L(Abitec)
				POE-20 monooleate	Tween80，PSMO-20
Sugar esters	Sucrose monolaurate	Ryoto LW-1540(ChemService)
			Phospholipids	Phosphatidylcholine	Lecithin (Sigma)
	Mixed phospholipids	Emphos D70-30C(Witco)
			Block copolymer	PEO-PPO block copolymer	PluronicF-68，F127，L-62(BASF)
Polyethylene glycol	PEG3350	From various sources

In addition, other compounds which may be used as solubilizers according to the invention are ethyl propionate, methyl paraben, propyl gallate, nicotinic acid amide, ethyl vanillin, p-aminobenzoic acid, butylated hydroxyanisole, iminourea (iminourea) and glycine. It should also be noted that preferred compositions include mixtures of organic acids or corresponding organic acid salts with one or more of the non-organic solubilizing agents described above or listed in table 1. It should also be noted that it has been generally observed that the solubility of the solubilizer in the aqueous use environment containing chloride ions should be at least 1mg/ml, preferably more than 5mg/ml, for best results.

In addition to the preferred organic acids described above, the preferred various solubilizing agents include those listed in table 2.

TABLE 2

Preferred solubilizers

Categories	Example, chemical name	Example, trade name (supplier)
			Partial glyceride	Glyceryl monocaprylate	Monocaprylin(Sigma)，CapmulMCM(Abitec)，Imwitor308(Huls)
	C8-C10 partial glyceride	CapmulMCM(Abitec)，Imwitor742(Huls)，Imwitor988(Huls)
				Glyceryl monostearate	Imwitor191(Huls)，CalgeneGSC(Calgene)
	Monolaurin	Imwitor312(Huls)，CalgeneGLO(Calgene)
			Glycerides	Triacetyl glyceride	Triacetyl glyceride (Sigma)
Sorbitan esters	Sorbitan monolaurate	CalgeneSML，Span20(Sigma)
				Sorbitan monooleate	CalgeneSMO，Span80(Sigma)
Phospholipids	Phosphatidylcholine	Lecithin (Sigma)
				Mixed phospholipids	EmphosD70-30C(Witco)
Block copolymer	PEO-PPO block copolymer	PluronicF-68，F127，L-62(BASF)
			Polyethylene glycol	PEG3350	From various sources

Note: the above supplier details are as follows:

Abitec Corp.，Janesville，WI

BASF，Parsippany，NJ

Calgene Chemical Inc.，Skokie，IL

Chem Service，Inc.，West Chester，PA

Huls America，Piscataway，NJ

Sigma，St.Louis，MO

Witco，Houston，TX

preferred combinations of solubilizing agents include (1) salts of organic acids plus the same or different organic acids, (2) organic acids plus nonionic solubilizing agents, such as those listed in table 1, and (3) salts of organic acids plus the same or different organic acids plus nonionic solubilizing agents.

Particularly preferred individual solubilizers include aspartic acid, glycerol monocaprylate, calcium acetate, ascorbic acid, citric acid, glutamic acid and calcium carbonate. Aspartic acid, glyceryl monocaprylate and calcium acetate are most preferred.

Also preferred are combinations of preferred acids with preferred surfactant-based compounds. Screening assays for candidate solubilizing agents for testing co-use with low solubility sertraline salts, such as sertraline hydrochloride, are described in the examples.

Preferred examples of sustained release dosage forms include a granular or tablet core comprising sertraline hydrochloride and one or more solubilizing acids, preferably maleic acid, L-aspartic acid, tartaric acid, L-glutamic acid, malic acid, citric acid, isoascorbic acid and adipic acid; more preferred are malic acid, citric acid, isoascorbic acid and adipic acid.

Preferred examples of sustained release dosage forms include a core comprising sertraline lactate or sertraline acetate or sertraline aspartate and an acid, preferably ascorbic acid, erythorbic acid, citric acid, glutamic acid or aspartic acid. More preferred examples are those containing sertraline lactate or sertraline acetate.

Another preferred example of a sustained release dosage form comprises a core containing sertraline lactate or sertraline acetate, an acid such as ascorbic acid, erythorbic acid, citric acid, glutamic acid or aspartic acid and a surfactant-based material such as partial glycerides, glycerol esters, sorbitan esters, phospholipids, polyethylene oxide-polypropylene oxide block copolymers and polyethylene glycol.

Another preferred embodiment of the sustained release dosage form comprises a core containing sertraline lactate or sertraline acetate and a surfactant-based material, such as partial glycerides, glycerol esters, sorbitan esters, phospholipids, polyethylene oxide-polypropylene oxide block copolymers and polyethylene glycol.

These "high solubility" cores are further coated with a space delay coating or a time delay coating as described herein.

The spatially delayed release dosage form of the present invention is a solid dosage form or an encapsulated solution for oral administration comprising sertraline and a pharmaceutically acceptable carrier, which dosage form releases no more than 10% of the contained sertraline upon entry into the stomach of a mammal and 70% or more of the remaining sertraline contained therein within 1.5 hours after entry into the small intestine of said mammal. The time delayed release dosage form of the present invention is a solid dosage form or an encapsulated solution for oral administration comprising sertraline and a pharmaceutically acceptable carrier, which dosage form delays release of sertraline contained therein within 10 minutes to 2 hours, preferably 15 minutes to 1.5 hours, after ingestion. At least 70% of the remaining sertraline contained is released immediately (i.e., within 1.5 hours) after the delay period of the dosage form has elapsed.

The release time of sertraline in the stomach or small intestine may be tested by various means including, but not limited to, X-ray evaluation, magnetic resonance imaging, gamma scintigraphy, or direct sampling from the stomach and duodenum by insertion of a catheter. These tests are certainly feasible, but sometimes difficult to perform for humans.

A more convenient method of testing the spatially delayed release dosage forms of the present invention is an improved version of a two-part in vitro dissolution test described in the section 1995 United states pharmacopoeia (USP23), [724] section, "extended release (enteric coating) project-standard for general drug release" which is first tested for sertraline release in simulated gastric fluid for 2 hours ("acid test") and then tested for drug release in simulated intestinal fluid ("neutral test"). For tablets or capsules that do not contain multiparticulates or do not rapidly disintegrate into multiparticulates, agitation is performed with a paddle at 100 rpm. For multiparticulates, whether the dosage form is a capsule, tablet, or unit dose packet, the agitation is also performed with a paddle at 100 rpm. If gelatin capsules are used, 0.1mg/ml trypsin must be added to the (neutral assay, second stage) buffer. These two phases of the in vitro test can be modified for use in evaluating the spatially retarded dosage forms of the present invention, as now described.

For the pH-triggered spatial delay dosage forms, in vitro testing was conducted as described above in USP "enteric test" and required that the dosage forms of the present invention release (a) no more than 10% of the contained sertraline alone in the 2 hour "acidic" portion of the test and (b) 70% or more of the contained sertraline remaining in the 1.5 hour "neutral" portion of the test. The acidic part of the experiment was run in 750ml of 0.1n hcl for 2 hours. After 2 hours, 250ml of 0.2M trisodium phosphate containing 10mg of Tween 80 are added to the acidic medium (containing the dosage form) and the pH is adjusted to 6.8 with 2M HCl or 2M NaOH as required. Thus, the volume of solution in the neutral fraction is about 1 liter. The solubility of sertraline in the second stage phosphate buffer (pH6.8) is low. Thus, 1% tween 80 was added to the neutral phosphate medium (ph6.8) to increase the solubility of sertraline, thereby providing "soak conditions" for dissolution.

For the enzyme-triggered spatial delayed release dosage forms of the present invention, the assay was performed in the manner described above for the pH-triggered dosage forms, except that sertraline release was triggered by the presence of enzymes in the small intestine, such as pancreatic lipase, esterase or protease. Thus, in vitro assays typically use enzymes at a concentration of 5mg/ml suitable for initiating the enzymatic degradation corresponding to or of the same type as that which is released in the human small intestine. For in vitro evaluation of lipase-induced sustained release dosage forms, the phosphate buffer dissolution medium used in the second stage of the dissolution test contains lipase, such as 5mg/ml porcine pancreatic lipase (Sigma chem., st. For esterase or protease initiated sustained release systems, the second phase of the in vitro assay will contain an appropriate esterase or protease (e.g., trypsin, chymotrypsin, elastase), e.g., at a concentration of 5 mg/ml.

If the esterase, protease or lipase is denatured with tween 80, the first hour of the "neutral" phase is carried out in the presence of the enzyme and in the absence of tween 80. After 1 hour of "neutral" phase 10g tween 80 was added.

For the time delayed dosage form, the in vitro dissolution test was performed at 37 ℃ using a USP dissolution apparatus with paddle agitation at 100 rpm. The dissolution test medium was 900ml of acetate buffer (0.13M acetic acid) containing 0.075M sodium chloride and adjusted to pH4.0 with potassium hydroxide. If gelatin capsules are used, 0.1mg/ml trypsin is added to the dissolution medium. The dosage forms of the present invention released substantially no sertraline (about 1% or less than 1% released) within the first 10 minutes of the test. The dosage forms of the invention released no more than 10% of the total sertraline contained during the second test phase from 10 minutes to 2 hours in an acidic test medium. Then, at least 70% of the remaining sertraline was released during the third test period, which lasted 1.5 hours.

The test conditions were as described in USP.

In the in vitro assay, sertraline may be quantified by HPLC using a reversed phase C-18 column with UV detection at 230nm, or by other suitable methods for the quantitative analysis of sertraline as well.

For oral administration, the preferred sustained release sertraline dosage forms of the invention will deliver T_maxReduced by 0.5 hours or more, preferably 1 hour or more, or reduced incidence or severity of nausea, diarrhea or regurgitation. To examine whether the dosage forms could reduce T_maxCrossover clinical studies can be conducted in a population of healthy, fasting volunteers, typically 12 or more. One half of the volunteers received the sertraline test dosage form of the present invention, and the other half received the immediate release sertraline dosage form at the same dosage (e.g., Zoloft)^Tablets). Blood samples were collected before and at appropriate times after the test and the blood concentration of sertraline was determined by appropriate methods as described in the examples below. Two groups of volunteers received dosage forms were exchanged after at least one week of washout and blood concentrations of sertraline were determined using the method described above. Determination of T for each test object_max(immediate release dosage form) with T_maxDifference of (test dosage form). The differences are then averaged to obtain an average T_maxThe difference value. If the value is greater than 0.5 hours, the dosage form is a dosage form of the present invention. Analysis of sertraline in blood was performed by quantifying sertraline in plasma, as fully disclosed in example 1 below.

The reduction of side effects can be determined as follows. Two parallel groups of healthy fasting human subjects (at least 15 subjects per group) were administered 200mg sertraline. One group received the dose of the test dosage form and the other group received the same dose of the immediate release dosage form (e.g., two 100mg Zolosoft tablets)^). The administration is carried out in a blinded form, i.e. each subject is receivingThe sertraline-containing dosage forms received placebo of other dosage forms as well. The placebo should not contain any excipients known to cause or ameliorate nausea, regurgitation or diarrhea. Questionnaires were filled out hourly within 12 hours after dosing to assess the severity of nausea, regurgitation and diarrhea in subjects one hour prior to dosing. A visual-analogue scale (visual-analogue scale) in the range of 0-10 was used, with 0 representing no effect and 10 representing the worst possible effect. For each treatment (e.g., test dosage form or immediate release dosage form), for each side effect (e.g., regurgitation), all scores are added for each subject to give a cumulative score for that side effect in the subject receiving treatment. For each treatment (e.g., trial dosage form), the cumulative scores for 15 (or more) subjects were added for each side effect (e.g., regurgitation) and then divided by the number of subjects receiving treatment to give the Mean Cumulative Score (MCS).

If for any side effect, such as nausea, regurgitation or diarrhea, the MCS achieved by administration of the immediate release dosage form is higher than that of the test dosage form, then the test dosage form is a dosage form of the present invention.

For clarity, the following information is provided:

1. the percentages (%) indicating the amount size are expressed as percentages by weight based on the total weight, unless otherwise indicated.

2.“Eudragit^"is a trademark registered by Rohm Pharma GmbH, Germany for enteric polymerized methacrylates.

3.“Opadry^"Colorcon inc., West Point, PA is a registered trademark of plasticized cellulose ether based drugs, including hydroxypropyl methylcellulose, hydroxypropyl cellulose and methylcellulose, which are powdered and reconstituted in water upon application.

"use environment" refers to the aqueous environment of the gastrointestinal tract in vivo, or the test medium used to quantify sertraline release from a dosage form in the in vitro test described above.

Example 1

This example discusses the difference in absorption of sertraline when it is administered directly to various sites of the gastrointestinal tract. In particular, this example demonstrates that the delivery of sertraline directly to the duodenum (upper small intestine) allows sertraline to reach peak plasma concentrations more rapidly than the usual oral route of delivering the drug to the stomach. This means that an oral sertraline dosage form which does not release sertraline until it is removed from the stomach into the duodenum will allow blood to absorb sertraline faster than a dosage form without the delay effect.

Volunteers were divided into two groups (group A and group B), 6 persons each, and 200mg sertraline or placebo was administered to each group on a different 4-crossover schedule. Administration is by (1) oral tablet, or (2) infusion of the solution into the stomach or duodenum, or the ileocecal region of the small intestine via a nasointestinal tube, or (3) infusion into the transverse colon via an anal cannula.

For group a, 4 different regimens were group a receiving (1) oral sertraline immediate release tablet plus infusion placebo solution to the stomach, or (2) oral placebo tablet plus infusion sertraline solution to the stomach, or (3) oral placebo tablet plus infusion sertraline solution to the ileocecal junction of the small intestine, or (4) oral placebo tablet plus infusion placebo solution to the ileocecal junction of the small intestine. For group B, 4 different regimens were group B receiving (1) oral sertraline immediate release tablet plus perfused placebo solution to the duodenum, or (2) oral placebo tablet plus perfused sertraline solution to the duodenum, or (3) oral placebo tablet plus perfused sertraline solution to the transverse colon, or (4) oral placebo tablet plus perfused placebo solution to the transverse colon.

The oral sertraline dose is two 100mg tablets. Perfusion is the administration of a 2mg/ml solution at a rate of 20 ml/min for 5 minutes.

Blood samples were drawn prior to dosing and at 0.5, 1, 1.5, 2, 4, 6, 8, 10, 12, 16, 24, 36, 48, 72, 96, 120, 144, 192 and 240 hours post-dose. Sertraline is first removed from alkaline human bodyPlasma concentration of sertraline was determined by extraction into methyl tert-butyl ether, followed by derivatization to form the trifluoroacetyl adduct. Analysis was performed by capillary gas chromatography with electron capture detection. The overall sertraline exposure system is determined by measuring the area under the sertraline plasma concentration-time curve (AUC) for each subject in a given test group and then calculating the mean AUC for that group. C_maxIs the maximum value of the measured sertraline plasma concentration achieved in the subject. T is_maxIs to reach C_maxThe time required. The plasma pharmacokinetic data for this example are presented in table 1.

Table 1 lists the mean C measured under various dosing regimens_max，T_maxAnd AUC. Perfusing the stomach to obtain C_max，T_maxAnd AUC values similar to those obtained after oral tablets (group a). This means that the perfusion technique itself does not alter the pharmacokinetics of sertraline to any substantial degree. Perfusion into the duodenum also gave a C similar to that measured after oral tablets_maxAnd AUC values. But perfused into the duodenum to obtain T_maxMuch shorter than the T measured after oral tablet administration_max(3.7 hours vs. 6.7 hours) (group B).

T measured by perfusing sertraline solution into the stomach_max(7.0 hours) is longer than that obtained by perfusion into the duodenum (3.7 hours), which means that there are some restrictions on the release of sertraline solution from the stomach through the pylorus into the duodenum relative to the release of water from the stomach, which typically occurs when the emptying half-life is about 10 minutes. While not wishing to be bound by theory, an explanation for this unexpected measurement is that sertraline inhibits its own gastric emptying. Another theory is that sertraline in solution, initially in the stomach at a lower pH, begins to precipitate (possibly as a free base) as it enters the duodenum, then slowly dissolves again and is slowly absorbed in its entirety. Alternatively, as described above in the present invention, sertraline may form a slow-dissolving gel in the high-chlorine environment of the stomach. However, if the sertraline solution is able to enter the small intestine (duodenum), it may be rapidly hemolyzedAnd (4) absorbing the flow.

TABLE 1-1

Pharmacokinetics of 200mg sertraline delivered to various parts of the gastrointestinal tract

Group A
				Route of administration	Cmax(ng/ml)	Tmax(hr)	AUCFinally, the(ng·hr/ml)
Oral tablet	39.9	7.0	1174.5
				Gastric perfusion fluid	35.6	7.0	923.1
Ileocecal perfusion fluid	27.3	5.0	727.1
				Group B
Route of administration	Cmax(ng/ml)	Tmax(hr)	AUCFinally, the(ng·hr/ml)
				Oral tablet	44.7	6.7	1153.4
Duodenal perfusate	48.8	3.7	1270.3
				Colon perfusate	10.9	4.4	179.4

Example 2

This example demonstrates that certain sertraline side effects (such as nausea, regurgitation and diarrhea) are mediated in part or primarily by exposure of orally administered sertraline to the upper gastrointestinal tract, rather than by sertraline present in the circulatory system following absorption. Thus, oral administration of sertraline via the stomach in a sustained release dosage form may ameliorate the side effects of local modulation of sertraline.

In a larger group of double-blind randomized, placebo-controlled parallel studies, healthy male subjects were divided into two groups (study I). Group A received a single 200mg administration of sertraline, i.e., two 100mg tablets of sertraline (100 mg commercial tablets of Zoloft) ("bolus administration" group). The tablets were taken down with 50ml of water. Group B received two placebo tablets. All subjects were dosed after an overnight fast.

Blood samples were drawn prior to dosing and at 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 18, 20, 22, 24, 36, 48, 72, 96, 120, 144, 168, 192 and 240 hours post-dose. Sertraline is first extracted from alkaline human plasma into methyl tert-butyl ether, then derivatized to form a trifluoroacetyl adduct, and the plasma concentration of sertraline is determined. Analysis was performed by capillary gas chromatography with electron capture detection. The overall sertraline exposure system is determined by measuring the area under the sertraline plasma concentration-time curve (AUC) for each subject in a given test group and then calculating the mean AUC for that group. C_maxIs the maximum value of the measured sertraline plasma concentration achieved in the subject. T is_maxIs to reach C_maxThe time required. Mean C after 200mg sertraline administration_maxIs 74ng/ml, mean T_maxIs 6 hours and the mean AUC is 1646ng · hr/ml (mean of 15 subjects).

A similar second study (study II) was performed. Mean C after 200mg sertraline administration_maxIs 75ng/ml, mean T_maxIs 5.4 hours and the mean AUC is 1744ng · hr/ml (mean of 11 subjects). 4 subjects in the 200mg dose group vomited at 2.6, 2.8 and 3.8 hours, respectively. The data obtained from these 4 subjects were not included in the pharmacokinetic averages.

Before administration and each blood draw, each subject is filled with a questionnaire consisting of a series of visual analogue scales, each subject being asked to assess the severity of a potential side effect on a scale of 0-10. Each object is informed that "0" represents no effect and "10" represents the worst possible effect. Subjects were also informed to interpolate between 0 and 10 for moderate side effects.

All 30 subjects completed study I: group A and group B were 15 persons each. Each side effect was evaluated at 30 time points, resulting in 900 individual visual analog scale estimates. All 29 subjects completed study II: 14 in group A and 15 in group B. Each side effect was evaluated at 30 time points, yielding a total of 870 individual visual analog scale estimates.

Figure 1 shows the relationship between sertraline plasma concentration and mean self-reported visual analogue scores for nausea in study I. This figure is a well-known pharmacokinetic-pharmacokinetic profile ("PK/PD profile") that can be obtained using the following method. For group a of 15 subjects, the sertraline plasma concentrations were averaged at each time point of blood draw to obtain the mean sertraline plasma concentration for group a at each time point. Likewise, for group a 15 subjects, the visual analogue scores for nausea were averaged at each time point. Mean nausea scores (y-axis) for each time point were plotted against sertraline plasma concentrations (x-axis) at the corresponding time point. The arrows on the graph indicate the progression of the PK/PD relationship over time. The PK/PD plot in figure 1 shows "clockwise lag" for a 200mg bolus. Thus, both the nausea score and the sertraline plasma concentration increased over time until the nausea score reached a maximum at which time the sertraline plasma concentration was at the maximum sertraline plasma concentration C_maxThe following. When reaching C_max(about 70ng/ml), the nausea score dropped to a lower value. Since sertraline plasma concentrations subsequently also decreased, the hypothetical nausea score was lower than the score obtained from the same sertraline plasma concentrations at earlier time points. This "clockwise lag" (or "proteresis") is consistent with the explanation that direct sertraline contact with the gastrointestinal tract can significantly modulate sertraline-induced nausea, and that the presence of sertraline in the systemic blood does not completely modulate sertraline-induced nausea, since the mean nausea score is not related solely to sertraline plasma concentrations. At the first few time points (0-3 hours) after administration, orally administered sertraline primarily contacts the stomach and may inhibit its own emptying into the duodenum (as described in example 1). Since nausea is not simply directly related to sertraline plasma concentrations and apparently is mediated locally primarily through contact with the gastrointestinal tract, where sertraline is released in lower amounts, e.g., in the duodenum or jejunum, which results in faster absorption and reduced contact time with the upper gastrointestinal tract, and thus reduced exposure timeLess nausea.

In study 1, diarrhea was also manifested as a clockwise lag on the plot of its side effect score versus sertraline plasma concentration. The maximum diarrhea score was achieved 3 hours after dosing, and the mean plasma T at 6 hours in these subjects_maxLong before it is reached. Thus, the delay of orally administered sertraline release through the stomach may reduce nausea.

As described above, in study 2, 4 subjects exhibited regurgitation. For the regurgitation side effects, the individual PK/PD patterns of these subjects showed clockwise retardation. Thus, the delay in the release of orally administered sertraline through the stomach may reduce regurgitation.

Example 3

This example discusses a method of making sertraline sustained release tablets. The process comprises (1) wet granulating sertraline with hydroxypropyl cellulose; (2) drying, grinding and mixing the granules; (3) mixing the granules with all the remaining ingredients except magnesium stearate; (4) adding and mixing magnesium stearate; (5) pressing the finally stirred mixture into tablets; and (6) coating the tablet with a pH sensitive sustained release coating. This example also demonstrates the in vitro release profile of sertraline from enteric coated tablets by in vitro testing as described herein.

A4 kg portion of sertraline was mixed with hydroxypropyl cellulose (Klucel EF)^TMAqualon) were mixed in a suitable mixer for 5 minutes. After the initial mixing, water is added to the mixture, which acts as a granulating agent while continuing to stir until the desired end point is reached. Next, the wetted particles were dusted in a polyethylene lined dish and dried in an oven at 50 ℃ until the dry loss percentage (LOD) was less than 0.5%. The particles were then milled (Fitzpatrick JT mill) and mixed in a stainless steel twin shell mixer for 10 minutes. Next, the remaining ingredients, except magnesium stearate, were added to the mixer and mixing was continued for 30 minutes. Magnesium stearate was then added to the mixture and mixed for 5 minutes. Standard circular shapes were made using a Manesty beta press (Manesty Machines, Liverpool, England) and 7/16 inchesThe resulting blend was compressed into 600mg tablets using a concave tableting die. The components of the die are listed in Table 3-1.

TABLE 3-1 composition of extended release core tablet prepared on beta press with dosage strength of 200 mgA/tablet

Components	Gram/batch	%/tablet
			Example No. 12A
Sertraline hydrochloride hydroxypropyl cellulose (a) calcium phosphate (b) microcrystalline cellulose (c) sodium glycolate starch (d) magnesium stearate	1492.1120.0640.01197.9500.050.0	37.33.016.030.012.51.2
			In total 4000 g600 mg

(a) The hydroxypropyl cellulose is Klucel^EF^TM，Aqualon

(b) Calcium phosphate refers to calcium hydrogen phosphate dihydrate, Emcompress^，Edward Mendell Co.Inc.

(c) The microcrystalline cellulose is Avicel^PH101，FMC Corporation

(d) The sodium glycolate starch is Explotab^，Edward Mendell Co.Inc.

Next, the sertraline core was spray coated with pH sensitive slow release coating in a coating pan (Freund Model HCT-30, Vector Corporation, Marion, IA) until the desired endpoint was reached (coating weight%). The slow release coating material contained 16.0% of a methacrylic acid copolymer (Eudragit)^L30D-55, Rohm Pharma), 4.0% talc as antiblocking agent, 1.6% triethyl citrate as plasticizer and 78.4% water. The cores were coated to make tablets with both 6% and 10% coating content (table 3-2).

Tables 3-2 composition of sertraline extended release tablets containing core formulation coated with 6% and 10% pH sensitive coating

Components	mg solid/tablet	mg solid/tablet
			Coating content (wt%)	6％	10％
Tablet core sertraline hydrochloride hydroxypropyl cellulose (a) calcium phosphate (b) microcrystalline cellulose (c) sodium glycolate starch (d) magnesium stearate tablet core Total weight	223.818.096.0180.075.07.2600mg	223.818.096.0180.075.07.2600mg
			Coated EudragitL30D-55 (a) Total weight of Talc triethyl citrate coating	6％26.76.72.636mg	10％44.511.14.460mg

(a)Eudragit^L30D-55 consisted of a 30% aqueous dispersion.

The extended release tablets containing a 10% pH sensitive coating described in example 3A (shown in tables 3-3) were subjected to an in vitro extended release solubility test and sertraline was quantitated by reverse phase High Performance Liquid Chromatography (HPLC) analysis to determine the percentage of sertraline released as a function of total dose as described below.

Sustained release dosage form testing of sertraline is performed on a standard USP rotary paddle apparatus as described in united states pharmacopoeia xxiii (USP), chapter 711 dissolution test, apparatus 2. The sustained release dissolution test procedure involves paddle rotation at 100rpm, dissolution being carried out in two stages, contained in a lidded vessel to prevent evaporation, maintaining all media at 37 ℃. The first stage, the acid phase, places the dosage form in 750ml of 0.1N HCl for 2 hours, during which a certain amount (typically 2 or 10ml) of medium is withdrawn from the test medium and analyzed for sertraline by the HPLC assay described below. In the second stage, the buffered phase with solubilizer, the first stage acid phase was converted to the second stage buffer at pH6.8 and containing 1% solubilizer by adding 250mL of 0.2M trisodium phosphate with an additional 10 grams of tween 80 to the acid phase and then adjusting the pH to 6.8 with 2M hydrochloric acid or 2M sodium hydroxide. A certain amount (typically 2 or 10ml) of the filtered test medium is withdrawn over a certain period of time after addition of phosphate buffer and analyzed for sertraline by the HPLC method described below.

Quantitative analysis of sertraline was performed by reverse phase high performance liquid chromatography as follows. mu.L of a fixed volume was injected onto an analytical column (150mm long by 3.9mm diameter Nova-Pac C-18 column). The isocratic mobile phase consisted of aqueous acetate buffer, methanol and acetonitrile in a volume ratio of 40/15/45. The aqueous acetate buffer was prepared as follows: (1) 2.86ml of glacial acetic acid are added to a 1000ml Erlenmeyer flask with a magnetic stir bar placed in an ice bath; (2) 3.48ml of triethylamine was added to the flask while stirring; and (3) fill the flask and mix well. To an aqueous acetate buffer (40%) were added HPLC grade methanol (15% v/v) and HPLC grade acetonitrile (45% v/v). After thorough mixing, the mobile phase was filtered under vacuum and degassed with a 0.45 μm PTFE filter (Lid-X305 disposable solid/liquid separator). The flow rate of the mobile phase was 1.8 ml/min and sertraline UV was detected at 254 nm.

The results for tablets coated with 10% appear in tables 3-3 (data representing 3 separate tests with a content of 200 mgA/unit, n being the average of 3). This example meets the dissolution criteria and is an example of a sustained release dosage form of the present invention.

Tables 3-3 in vitro test, where sertraline is released slowly from enteric-coated tablets to 750ml of 0.1N HCl over 2 hours, then performed on USP 2# apparatus using 1000ml of enteric buffer medium (pH6.8) containing 1% Tween 80, 37 ℃, with paddle speed set at 100rpm (N ═ 3 tablets)

Example enteric coated acid phase Q2 buffer phase Q3.5- > Q6 (%) (%) (%) 3108.193.397.1

Q2 is% released at 2 hours; q3.5 is% released at 3.5 hours.

Example 4

This example discusses a method of making multiparticulates for use in the preparation of sustained release dosage forms designed to release sertraline substantially only in the area below the stomach. The method comprises (1) preparing a naked sertraline multiparticulate core; (2) coating with pH sensitive slow release coating.

The multisicro core containing sertraline was prepared as follows: the preparation of sertraline compounds with microcrystalline cellulose (Avicel)^PH101, FMC Corp, Philadelphia, PA) in a ratio of 85: 15(w/w), wet aggregating the mixture in a Hobart mixer with water in an amount corresponding to about 27% of the weight of the mixture, passing through a mixerA multi-well plate (Luwa EXKS-1 extruder, FujiPaudal Co., Osaka Japan) extrudes the wet mass, spheronizes the extrudate (Luwa QJ-230marumerizer, Fuji Paudal Co., Ltd.), and finally, dries a granular core of about 1mm in diameter.

The delayed release layer coating was performed using a Wurster bottom spray fluid bed processor (Glatt GPCG-1). The amount of the sustained release coating is typically 5-50% in order to ensure compliance with the sustained release dissolution standard. The sustained release coating contained 12.3% methacrylic acid copolymer (Eudragit)^L30D-55), 6.2% talc, 1.5% triethyl citrate and 80% water.

Since the extended release coating is soluble in environments with a pH greater than 5.5, the multiparticulate formulation thus prepared can release sertraline from the encapsulated microparticle core in the sub-gastric area, since the pH is greater than 5.5 there.

Example 5

This example discusses a method of making multiparticulates for use in the preparation of sustained release dosage forms designed to release sertraline substantially only in the area below the stomach. The method comprises (1) preparing a naked sertraline multiparticulate core; (2) coating a protective coating on the particle core; and (3) coating the first layer with a second pH sensitive slow release coating.

The multiparticulate cores containing the drug were prepared using a fluid bed processor with rotating inserts (Model GPCG-1). First, 400g of sertraline drug was added to a rotating bowl and sprayed into a rotating bed containing 5% poly (ethyl acrylate, methyl acrylate) (Eudragit)^NE-30-D), 5% plasticized hydroxypropyl methylcellulose (Opadry)^) And 90% water until a particle core with an average diameter of about 250 μm is obtained.

A spray of hydroxypropyl methylcellulose (Opadry) containing 5% plasticization was sprayed on the bare particle cores in the same fluidized bed processor with rotating insert^) Binder solution of the solution until the cladding reaches 10%. The intermediate coating can improve the particle core and the final sustained-release coatingThe adhesive force of the garment.

The same fluid bed processor as described above was used for the extended release coating (extended release coating of 5-50% is generally required to meet the extended release standard). The sustained release coating contained 12.3% methacrylic acid copolymer (Eudragit)^L30D-55), 6.2% talc, 1.5% triethyl citrate and 80% water. The final product is a sustained release multiparticulate having microparticles with an average diameter of about 300 μm.

Example 6

This example discusses the preparation of pH-induced spatially retarded sertraline coated tablets coated with cellulose acetate phthalate.

Sertraline tablet cores were prepared according to the formulation set forth in table 3-1 of example 3 and the method described in example 3. Placing the tablet core in HCT-60Hi-Coater^Spray coating was performed with a solution of Cellulose Acetate Phthalate (CAP) in acetone in a spray coater (Freund ind. corp., Tokyo). CAP was plasticized with 25% by weight diethyl phthalate (DEP). Sufficient CAP is sprayed onto the core tablet so that the weight of the final dried coating polymer is 5-50 wt% relative to the weight of the bare tablet.

Example 7

This example discusses the preparation of pH-triggered spatially retarded sertraline CAP coated tablets with a barrier layer.

Sertraline tablet cores were prepared according to the formulation set forth in table 3-1 of example 3 and the method described in example 3. In HCT-60Hi-Coater^Wherein core tablets are spray coated with an aqueous solution of hydroxypropyl methylcellulose (HPMC; Colorcon, Inc.). The tablets were coated in the same manner with a 5% by weight HPMC release layer corresponding to the initial tablet weight and then, in HCT-60Hi-Coater^Further spray-coated with Cellulose Acetate Phthalate (CAP) and DEP plasticizer as described in example 6. Sufficient CAP is sprayed onto the tablets to provide a final dried coating polymer weight of 5-50 wt% relative to the weight of the bare die. HPThe MC cladding acts as a barrier between the sertraline and pH sensitive CAP cladding. The barrier layer prevents premature dissolution (or weakening) of the CAP coating which may be caused by the local high pH within the tablet due to the presence of sertraline, for example, in the low pH environment of the stomach.

Example 8

This example discusses the preparation of pH-induced sterically retarded acrylic resin coated sertraline tablets with a barrier layer.

Sertraline tablet cores were prepared according to the formulation set forth in table 3-1 of example 3 and the method described in example 3. In HCT-60Hi-Coater^Wherein core tablets are spray coated with an aqueous solution of hydroxypropyl methylcellulose (HPMC; Colorcon, Inc.). The tablets were coated in the same manner with an HPMC release layer corresponding to 5 wt% of the initial tablet weight. The formulations of the cladding were formulated according to the formulations of tables 3-3.

Using HCT-60Hi-Coater from Freund^The coating solution was sprayed onto the HPMC-coated tablet cores.

The total weight of the acrylic polymer used is 5-50 wt% of the base weight of the die. The HPMC dark layer acts as a barrier between the sertraline and pH sensitive CAP coatings. This barrier layer prevents the potential occurrence of a locally higher pH within the tablet, due to the presence of sertraline, which could cause premature dissolution (or weakening) of the CAP coating, for example, in the low pH environment of the stomach.

Example 9

This example discusses the preparation of time delayed (water activated) sertraline tablets.

Sertraline tablet cores were prepared according to the formulation set forth in table 3-1 of example 3 and the method described in example 3. On a tablet coating machine, such as HCT-30, HCT-60 or HCT-130 coating machine (Freund Corp.). The core tablet is coated with an aqueous HPMC solution so that the weight of the coating is 5-50% of the weight of the final coated tablet. The heavier coating weight results in a longer delay time between entry of sertraline into the environment of use (gastrointestinal lumen) and the onset of release. Time lag may also be increased by adding small to moderate amounts of poorly water soluble polymers (including, but not limited to, Ethyl Cellulose (EC), Cellulose Acetate (CA), and cellulose acetate butyrate) to the cladding formulation. For example, the formulation of the clad may consist of 95: 5HPMC/EC to 50: 50HPMC/EC, or 95: 5HPMC/CA to 50: 50 HPMC/CA. In the case of such a hybrid polymer clad system, it is necessary to adjust the composition of the solvent to dissolve the mixture of the water-soluble polymer and the poorly water-soluble polymer. For example, a mixture of acetone and water, or a mixture of ethanol and water, may be used as necessary. In the environment of use, the dosage forms of this example exhibited delayed sertraline release during which the coating polymer dissolved from the surface of the sertraline core. The sertraline core releases at least 70% of the remaining contained sertraline within 1.5 hours after the delay.

Example 10

This example discusses organic acids having the ability to increase the solubility of sertraline hydrochloride. The candidate acids were screened by dissolving them in water and then stirring the acid solution of excess sertraline hydrochloride for at least 8 hours. The concentration of sertraline in the surfactant was then determined by HPLC analysis. The test results are shown in the following Table 10-1. Most of the acids listed in the table successfully increased the solubility of sertraline hydrochloride (normal solubility was 2.5 mg/ml).

TABLE 10-1

Excipient	Approximate concentration of excipient (mg/ml)	Solubility of sertraline (mg/ml)
			D, L-malic acid	900	21
Citric acid	600	20
			Isoascorbic acid	400	19
Adipic acid	14	12
			Maleic acid	700	6.4
L-aspartic acid	10	5.5
			Tartaric acid	1400	5.5
L-glutamic acid	12	5.4
			Fumaric acid	11	3.1
Tannic acid	2000	2.8
			D, L-tyrosine	600	2.2

Preferred acids according to this screening test are malic acid, citric acid, isoascorbic acid and adipic acid. Maleic acid, L-aspartic acid, tartaric acid and L-glutamic acid also significantly improved the solubility of sertraline hydrochloride. Sustained release dosage forms with such acids in the drug core will be more effective than dosage forms without such acids.

Example 11

This example discusses organic acids having the ability to increase the solubility of sertraline acetate by a process similar to that used for the hydrochloride salt described in example 10. The excipients, excipient concentrations, and solubility of sertraline are listed in Table 11-1 below. According to this result, the preferred acids included in the dosage form for increasing the solubility of sertraline acetate are ascorbic acid, isoascorbic acid, citric acid, lactic acid, aspartic acid, glutamic acid and aconitic acid.

TABLE 11-1

Excipient	Excipient concentration (mg/ml)	Solubility of sertraline (mg/ml)
			Ascorbic acid	400	＞425
Isoascorbic acid	400	＞330
			Citric acid	600	146
Lactic acid	213	＞294
			Aspartic acid	7	110
Glutamic acid	12	108
			Aconitic acid	500	＞92
Itaconic acid	150	72
			Succinic acid	77	28
Is free of	-	64

Example 12

This example discusses the organic acid and three calcium salts having the ability to increase the water solubility of sertraline lactate by a process similar to that used for the hydrochloride salt described in example 10. The excipients, the excipient concentrations in the aqueous solutions and the solubilities of sertraline acetate in the test solutions are listed in Table 12-1 below. The solubility of sertraline acetate in water is about 125 mg/ml. The following data show that the following 8 organic acid solutions resulted in a solubility of sertraline lactate equal to or greater than 125 mg/ml: adipic acid, erythorbic acid, itaconic acid, citric acid, aspartic acid, glutamic acid, histidine and ascorbic acid. Moreover, a mixed solution of two of these acids also has high solubility: ascorbic acid and aspartic acid. The solubility of sertraline lactate in calcium salt solutions, alone (calcium citrate) or in mixtures with ascorbic acid is also high.

TABLE 12-1

Excipient	Excipient concentration (mg/ml)	Solubility of sertraline lactate (mg/ml)
			Adipic acid	14	360
Isoascorbic acid	400	＞217
			Itaconic acid	150	＞202
Citric acid	600	162
			Aspartic acid	7	＞155
Glutamic acid	12	＞125
			Histidine	42	＞116
Ascorbic acid/aspartic acid	400/7	116
			Ascorbic acid	400	102
Glycine	250	66
			Aconitic acid	200	＜59
Tartaric acid	1400	12
			Fumaric acid	11	＜9
Sorbic acid	3	＜9
			Calcium lactate/ascorbic acid	50/400	160
Calcium citrate	10	165
			Calcium carbonate/ascorbic acid	50/400	176
Is free of	-	125

Example 13

The low solubility of the chloride salt of sertraline and all sertraline lactate and sertraline acetate in the presence of high concentrations of chlorine indicates that the core formulation is preferably one that allows sertraline to be left in solution in which the core does not precipitate or form a gelatinous mass when chlorine is present in the environment of use. It has been found by the following screening tests that certain organic acids and salts can inhibit precipitation or gelation of sertraline in the presence of chlorine. Sertraline lactate alone (as a control) or together with candidate excipients was dissolved in water. Sodium chloride (as a concentrated solution) was added and the results were observed. This excipient is considered advantageous for use if the solution remains clear and fluid. The more chlorine added to the excipient solution and keeping the solution clear, the more advantageous the excipient. The results of this screening test are shown in Table 13-1 below and show that all excipients tested increased the concentration of sertraline in the chloride solution.

TABLE 13-1

Excipient	Excipient concentration (mg/ml)	NaCl concentration (mM)	Final sertraline concentration (mg/ml)	Observed value after NaCl addition
					Is free of	-	38	22	Gel/precipitate
Ascorbic acid/aspartic acid	400/7	152	162	Solutions of
					Aspartic acid	77	114152	162100	Solution gels
Ascorbic acid	400	100	102	Precipitation of
					Ascorbic acid/calcium lactate	400/50	150	165	Solutions of
Ascorbic acid/calcium carbonate	400/50	150	170	Slightly cloudy
					Citric acid/calcium lactate	600/50	150	162	Solutions of
Histidine	42	150	110	Slightly precipitated

Example 14

Organic compounds (solubilizers) that increase the ability of sertraline salts to dissolve in aqueous solutions with or without the presence of chlorine were screened. An excess of sertraline lactate is added to an aqueous solution of the candidate solubilizer and, in most cases, the organic acid. The organic acids were saturated in these solutions and the additional solubilizers and their concentrations are listed in Table 14-1. Equilibrium sertraline solubility was determined. Then, sodium chloride was added to the saturated solution, and the final concentration of sertraline was determined. The results of these screening tests are summarized in Table 14-1.

TABLE 14-1

Serial number	Solubilizer	Solubilizer concentration (mg/ml)	Organic acids	Solubility of sertraline (mg/ml)	NaCl concentration (mM)	Sertraline concentration (with NaCl)
							1	None (control)	-	Is free of	125	150	5
2	Glyceryl monocaprylate	10	Ascorbic acid	160	150	160
							3	Glycerol triacetate	100	Ascorbic acid	170	150	170
4	Monobutyric acid glyceride	50	Is free of	120	150	120
							5	Glycerol diacetate	50	Ascorbic acid	120	150	120
6	Imwitor 312	10	Ascorbic acid	120	150	120
							7	Imwitor 375	10	Ascorbic acid	120	150	120
8	Imwitor 742	50	Is free of	120	150	120
							9	Imwitor 988	50	Is free of	140	100	140
10	Citric acid triethyl ester	50	Ascorbic acid	160	150	160
							11	Pluronic L31	50	Is free of	120	100	120
12	Cremophore EL	50	Ascorbic acid	120	150	120
							13	Sucrose acetate isobutyrate	50	Ascorbic acid	120*	150	120
14	Sodium decyl lactate	50	Ascorbic acid	120	150	120
							15	Sucrose monolaurate	50	Is free of	150	150	150
16	Sodium lauryl lactate	50	Ascorbic acid	120	150	120
							17	Span 80	50	Ascorbic acid	120	150	120

Example 15

This example demonstrates that solubility enhancers for sertraline also increase the rate of dissolution of sertraline. The effect of candidate excipients on sertraline dissolution rate can be determined by the following method. The solid drug, candidate solubilizing excipient, and in some cases other excipients, such as organic acids and osmotic agents (e.g., sugar) were added to a 1.8ml centrifuge tube. The sample tubes were centrifuged at 14K G for 5 minutes in a microcentrifuge to compact the powder. To the compacted powder, 150. mu.l of gastric buffer was added and the sample was gently agitated and then centrifuged at 14KG for 2 minutes in a microcentrifuge. The sample was removed from the microcentrifuge and then allowed to stand until the solution was removed. The solution was removed from the sample after 10 minutes of completion after the gastric buffer was added to the powder mass and then analyzed by HPLC to determine the concentration of sertraline.

The dissolution rate (mg sertraline/ml-min) was calculated from the change in dissolved concentration of sertraline in the supernatant over time measured the first 10 minutes after dissolution. These dissolution rates and the excipient mixtures to be measured are summarized in Table 15-1 below. As shown in the table, several excipient mixtures containing solubilizing agents significantly (about 3-fold or more) increased the dissolution rate of sertraline compared to sertraline alone and sertraline and ascorbic acid.

TABLE 15-1

Candidate excipient name	Excipient concentration (wt%)	Organic acids	Organic acid concentration (wt%)	Penetrant	Concentration of penetrant (wt%)	Other excipients	Other excipient concentrations (wt%)	Lactate concentration with triptyline (wt%)	Dissolving speed of the containing Qulin (mg/ml-min)
										Is free of	-	Is free of	-	Is free of	-	Is free of	-	100	0.9
Is free of	-	Ascorbic acid	51.0	Lactose	20	Is free of	-	14	3.5
										Imwitor312	5.0	Ascorbic acid	49.5	Lactose	12.5	CaCO3	5	14	20.9
Lecithin	5.0	Ascorbic acid	51.0	Lactose	15	Is free of	-	14	10
										PEG 3550	5.0	Ascorbic acid	51.0	Lactose	15	Is free of	-	14	9.3
Capmul MCM	5.0	Ascorbic acid	71.0	Is free of	-	Is free of	-	24	14.5
										Capmul MCM	4.7	Is free of	Is free of	Lactose	17	CaCO3Calcium citrate	4.747	13.1	4.3
Imwitor191	5.0	Ascorbic acid	49.5	Lactose	12.5	CaCO3	1.0	14	8.0
										Myrerol(18-99)	5.0	Ascorbic acid	49.5	Lactose	12.5	Is free of	-	14	6.4
Span 60	5.0	Ascorbic acid	51.0	Lactose	15	Is free of	-	14	9.5
										Ascorbyl palmitate	6.8	Is free of	Is free of	Lactose	74.2	Is free of	-	19	4.3
Methylparaben/propylparaben/propylgallate	0.5/0.5/1.0	Ascorbic acid	50.0	Lactose	17.5	Is free of	-	14	11.5
										Imwitor312	6.8	Ascorbic acid	74.2	Is free of	-	Is free of	-	19	5.3

Claims (7)

1. A spatially extended release oral dosage form suitable for oral administration to a mammal, comprising an immediate release core comprising sertraline or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier, surrounded by a material comprising a polymer selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, anionic acrylic copolymers of methacrylic acid and methyl methacrylate, and copolymers comprising acrylic acid and at least one acrylate.

2. A dosage form as defined in claim 1 which is pH-triggered.

3. A dosage form as defined in claim 1, wherein said drug core is a multiparticulate.

4. A dosage form as defined in claim 1, wherein said drug core is a tablet.

5. A dosage form as defined in claim 1, wherein said drug core is a capsule.

6. A dosage form as defined in claim 5, which is a gelatin capsule encapsulated by a polymer, wherein said polymer is selected from the group consisting of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropyl methylcellulose phthalate, cellulose acetate trimellitate, anionic acrylic copolymers of methacrylic acid and methyl methacrylate, and copolymers containing acrylic acid and at least one acrylate.

7. A dosage form as defined in claim 1, wherein said mammal is a human.