OA11243A

OA11243A - Solubilized sertraline compositions

Info

Publication number: OA11243A
Application number: OA9900301A
Authority: OA
Inventors: Dwayne Thomas Friesen; Ravi Mysore Shanker Sco Herbig; James Blair West
Original assignee: Pfizer Prod Inc
Priority date: 1997-07-01
Filing date: 1999-12-21
Publication date: 2003-07-24
Also published as: BG103918A; SK181099A3; KR20010013365A; AP1192A; PL337804A1; UA67741C2; AR015917A1; HUP0002236A2; CA2290974C; IL133076A; ZA985708B; YU68299A; NO996520L; EA199900962A1; KR100366373B1; PE97199A1; IL133076A0; CA2290974A1; UY25071A1; AR040279A2

Abstract

Compositions of matter comprising sertraline and a solubilizing agent which increases the solubility of sertraline in aqueous chloride ion-containing use environments.

Description

1

Solubilized Sertraline Compositions

Field of the Invention

This invention relates to a composition comprising sertraline or a pharmaceu-tically acceptable sait thereof and a solubilizing agent which prevents gel formation orotherwise maintains the solubîlity of sertraline in a use environment containingchloride ions. The invention further relates to a method of treating a psychiatrie orother illness comprising administering sertraline in such a solubilized composition to amammal, including a human patient, in need of such treatment

Background of the Invention

Sertraline is a sélective serotonin reuptake inhibitor (SSRI), which is useful asan antidepressant and anorectic agent, and in the treatment of obsessive-compulsivedisorder, premenstrual dysphorie disorder, post-traumatic stress disorder, Chemicaldependencies, anxiety-related disorders, panic and prématuré éjaculation.

Sertraline is most commonly prescribed for therapy of dépressive illness, inthe general dose range 50-200 mg/day. Sertraline has an élimination half-life of 23 hrand is dosed once daily. Commercially, sertraline is available as the hydrochloridesait which is undeniably therapeuticaily effective, many patients having availedthemselves of the benefits ofthis drug.

Some forms of sertraline, particulariy salts which exhibit high solubîlity, can beprobiematic, however. Such salts, generally those having an aqueous solubîlity inexcess of 10 mg/mL, can exhibit a tendency to form a gel and/or exhibit reducedsolubîlity (e.g., precipitate as a sait or as the free base having a lower solubîlity in theenvironment of use than the sait form originally administered) when exposed to a useenvironment containing chloride ions such as the gastrointestinal tract The gel itselftends to dissolve slowly and otherwise releases sertraline at a slow rate, therebyaffecting absorption. It is not known whether gélation is the only mechanism whichimpacts the solubîlity of sertraline in a use environment. However, therapeuticdifficulties can accordingly arise from administering an immediate-release dosageform in vivo if solubîlity is affected, regardless of mechanism. Probiems can similariyarise in the case of controlled-release dosage forms since the controlled releaseprofile of the dosage form can be altered in vivo by factors affecting solubîlity. The 2 011243 unanticipated phenomerton of gélation of sertraline salts in a chloride ion-containing environment can thus create therapeutic difficulties by unexpectedly altering the release profile of a dosage form, whether immediate-release or controlled-release.

The mechanism of sertraline gélation is not wel! understood, and can be ail the moreproblematic therapeutically since the release characteristics of a gel formed in situmay not be anticipated.

In particular, geliing of sertraline in sustained-release dosage forms can bedetrimental in those sustained release Systems known as non-eroding matrixSystems, réservoir Systems, and osmotic Systems. In each of these types ofsustained release formulations release of the drug is dépendent on transport of thedrug across a distance w'rthin the device (matrix or coating layer) to the surroundingfluid. This drug transport can occur by diffusive or convective mechanisms. in bothmechanisms, formation of a gel can reduce transport by an order of magnitude ormore and in some cases can resuit in devices that exhibit incomplète drug release(e.g., less than 70% of the total drug in the formulation).

Summarv Of The Invention

This invention provides a composition of matter, suitable for administration toa mammal, including a human, comprising sertraline or a pharmaceuticailyacceptable sait thereof and an amount of an excipient, herein termed a “solubilizingagent” suffirent to effect a concentration of dissolved sertraline in a use environmentcontaining chloride ions which is at least 1.5 times higher, preferably 2 timés higher,more preferably 3 times higher than the concentration effected by a comparativecomposition of matter (i.e„ a control) identical thereto but for the inclusion of saidsolubilizing agent. The use environments mainly intended are the aqueous in vivodigestive fluids of the gastrointestinal (GI) tract including the stomach, small intestineand large intestine, and aqueous in vitro chloride ion-containing test media, as furtherdescribed beiow. The compositions are suitable for formulating into oral dosageforms including tablets, capsules, multiparticulates, powders for oral suspension, andunit dose packets (sometimes referred to in the art as a “sachet”). In addition thecompositions can be used in liquid dosage forms such as oral solutions orsuspensions and injectable formulations. For making the compositions of thisinvention into oral dosage forms, conventional techniques known to the art can be 3 011243 employed. The composition can additionally comprise other conventional pharmaceutical ingrédients and/or a pharmaceutically acceptable carrier.

By this invention, it has been determined that in cases of dosage formscontaining sertraline saits which form gels or which otherwise exhibit reducedsolubility in a use environment, solubility may advantageously be increased, and insome cases solution viscosity may be advantageously decreased, by empioying thesertraline sait together with a solubilizing agent which increases the sertraline'ssolubility. The solubilizing agent preferably also maintains solubility, meaning thatthe level of dissolved sertraline in a use environment, regardless of the saitemployed, is held at a concentration greater than or equal to 1.5 times theconcentration of sertraline in a iike formulation without solubilizing excipient, for atleast 2 hours. For many dosage forms it may be advantageous to maintain thesertraiine concentration greater than or equal to 1.5 times the concentration ofsertraline in Iike formulations without solubilizing excipient for longer periods of timesuch as 4 hours, 8 hours, 16 hours, or 20 hours, and this can be effected by thechoice and amount of solubilizing agent. It has otherwise been determined that in achloride ion-containing use environment without a solubilizing agent, for example atest environment such as 0.075M sodium chloride solution, sertraline solubility isgenerally less than 10 mgA/mL, usually less than 5 mgA/mL, regardless of the saitemployed, and despite the fact that many of the salts themselves exhibit solubilities inpure water (i.e., no chloride ions) well in excess of 10 mgA/mL Solubilizirig agentsthus could also be construed to be compounds that maintain sertraline concentrationsof 10mgA/ml or greater in chloride-ion-containing environments of use.

Reference herein to “a solubilizing agent" herein, including the daims, shall beunderstood as also including the use of more than one solubizing agent in acomposition, added separately or as a mixture.

As mentioned above, the term “use environment" can refer to the aqueous invivo chloride ion-containing digestive fluids of the stomach, or to an in vitro chlorideion-containing aqueous environment used to test a dosage form for its sertraiinerelease characteristics. A useful in vitro test environment for purposes of thisinvention is 0.075M sodium chloride. 0.075M sodium chloride is preferred as a testmedium because of its ready availability and simiiar chloride ion concentration to the 4 011243 iower ievels of chloride ions found in the fluids in the Gl tract. Blood & Other BodvFluids, Dorothy S. Dittmer, ed., Fédération of American Societies for ExperimentalBiology, Washington, D.C., 1961, pp. 404-419. Thus, as an additional feature, thisinvention provides an in vitro test to détermine whether a dosage form is within thescope of the invention. That is, the invention provides a composition of mattercomprising sertraiine or a pharmaceutically acceptable sait thereof and an amount ofa solubilizing agent sufficient to produce and to maintaîn, for at least 2 hours in0.075M sodium chloride, a concentration of dissolved sertraiine which is at least 1.5times higherthan.the concentration effected by a comparative composition of matteridentical thereto but for the inclusion of said solubilizing agent. Agitation should beemployed during the test although, as explained beiow, the degree or type ofagitation is not critical. Sait solution température is not beiieved to be particuiariycritical so long as it is about 37°C, plus or minus 3°C, throughout the test Excipients,including the solubilizing agent(s) should be at the desired concentration in theaqueous test solution prior to adding sertraiine and sodium chloride. Sertraiine isthen added to a concentration ranging between 80% to 100% of its saturationconcentration in the test solution. This solution should be decanted off or filteredaway from any solids. To this solution a 3M NaCl solution is slowiy added withstirring until the NaCl concentration in the test solution is 0.075M. The sertraiineconcentration in this test solution after 2 hours is compared with a control solutionmade in the same manner and consisting of the same components except thesolubilizing agent

Altematively, a solubilizing excipient can be identified in an in vivo test suchas a crossover study. In an in vivo crossover study a solubiiized sertraiine-containing dosage form is dosed to half a group of 12 or more humans and, after anappro’priate washout period (e.g., one week) the same subjects are dosed with adosage form otherwise identical but for inclusion of the solubilizing agent. The otherhalf of the group is dosed with the non-solubilized dosage form first, followed by thesolubiiized dosage form. Maximum concentration in the blood (Cmax) and/orbioavailability, measured as the area under the curve (AUC) for a plot of theconcentration of sertraiine in blood versus time, is determined for each group. Bycomparison, assessment of the solubiiized dosage form can be made. If the average 5 011243 Cæax or AUC for the formulation containing the solubilizing agent is greater by 10% ormore than the formulation without the solubilizing agent, then the solubilizingexcipient is an embodiment of this invention. It is preferred that the C^ and/or AUCbe greater by at least 15%, and more preferred either or both be greater by at least20%. The détermination of AUC's is a well known procedure and is described, forexample, in “Pharmacokinetics; Processes and Mathematics," by Peter Welling (ACSMonograph 185, Amer. Chem. Soc., Wash. D. C., 1986). Thus, as an additionalfeature of the invention, the invention provides a composition of matter comprisingsertraline or a pharmaceutically acceptable sait thereofand an amount of asolubilizing agent sufficient to effect, in vivo, a C^ and/or an AUC which is greaterby at least 10% than the Cmax and/or AUC effected by a comarison composition ofmatter (i.e., a control) identical thereto but for the inclusion of said solubilizing agent.

The invention further provides a method of increasing the soiubiiity ofsertraline in an aqueous chloride ion-containing environment, comprisingadministering said sertraline in a composition of matter comprising sertraline and asolubilizing agent.

The invention is surprising in that, prior to the invention, it was not known that(1 ) the phenomenon of reduced sertraline soiubiiity in chloride ion-containingenvironments existed, nor that (2) any Chemical agent existed which would reduce orprevent sertraline gélation or reduced sertraline soiubiiity in chloride ion-containinguse environments or otherwise operate to increase sertraiine’s soiubiiity in such useenvironments. The term “solubilized sertraline’ is used herein to refer to acomposition comprising sertraline or a sertraline sait plus an excipient (i.e. thesolubilizing agent) which prevents gélation or otherwise increases, and preferablymaintains, the soiubiiity of the sertraline sait in an in vivo or in vitro chloride ion-containing use environment. Likewise, the term “solubilize" is used to dénoté that thesoiubiiity of a sertraline sait is being increased by at least 1.5 times in a useenvironment over what it would be in the absence of a solubilizing agent.

The invention is preferred for use with the aspartate, acetate, and lactate saltswhich are salts that exhibit high solubilities in water relative to the free base. Thesesalts are disclosed in commonly assigned co-pending application PC9337JTJ, filed 6 011243 as a PCT application designating the United States, and herein incorporated by référencé.

For convenience and consistency, référencé to "sertraiine" in terms of thera-peirtic amounts herein, including the ciaims, is to active sertraiine, abbreviated hereinas “mgA”, Le., the non-salt, non-hydrated free base having a molecuiar weight of306.2. Amounts in mgA can convenientiy be converted to équivalent weights forwhatever sait form is desired.

Many solubilizing agents useful herein can be grouped into several broadcategories: 1. Organic acids and organic acid salis; 2. Partial Glycerides, i.e., less than fully esterified dérivatives of glycerin,including monoglycerides and diglycerides; 3. Glycerides; 4. Glyceride dérivatives; 5. Polyethylene glycol esters; 6. Polypropylene glycol esters; 7. Polyhydric alcohol esters; 8. Poiyoxyethylene ethers; 9. Sorbitan esters; and 10. Poiyoxyethylene sorbitan esters. 11. Carbonate salts

Detailed Description

The amount of solubilizing agent employed in a composition according to theinvention dépends on the particular solubilizing agent employed.

In the case of solubilizing agents which are organic acids the prefenedamount of solubiiizer can be calculated as a ratio multiplied by the quantity ofsertraiine to be used, wherein the ratio is of organic acid solubility to solubility ofsertraiine sait: (organic acid or sait solubifity/sertraline or sertraiine sait solubility) x quantity ofsertraiine 7 011243 where the solubïirties referred to are in mg/ml. The above expression is approximate,and some adjustment may be advantageous for optimization. Generally the aboveexpression will give a quantity which is plus or minus 25% of the final valueemployed, although higher quantities of solubilizing agent can be incorporatedwithout any particuiar additional advantage. In addition, organic acid salts can beadded to modify the pH and/or solubility of the organic acid, effectively optimizing thesolubilization effect of the agents.

For other types of solubilizing agents listed, typically the amount of solubilizingagent employed in the dosage form will be 1 to 150% by weight of the amount ofsertraline employed therein, preferably 1 to 100%, more preferably 3 to 75%.Amounts of solubilizing agent higher than 150% may be employed, although it isbelieved that in most cases no particuiar advantage would be provided.

Salts of sertraline or excipients that in combination with sertraline aid insolubilizing sertraline can be bénéficiai to virtualiy any type of sertraline dosage formsintended for oral administration, including immédiate reiease as well as controliedrelease Systems, including (1) sustained-release dosage forms which meter outsertraline as they progress through the gastrointestinal System and (2) delayedreiease Systems which reiease sertraline after an initial delay period following ingestion, lmmediate-release Systems are well known and commercially available in ! both solid and liquid formulations. Controlied release dosage forms of sertraline arediscussed and disclosed in commonly assigned co-pending applications PfizerDocket PC9337JTJ and PC9824JTJ, each of which is a PCT application designatingthe United States and each herein incorporated by référencé in rts entirety.Solubilized sertraline can enhance release from the dosage form by increasing theconcentration gradient for diffusive based Systems such as matrix dosage forms andréservoir dosage forms. Solubilized sertraline can also enhance delivery fromosmotic dosage forms in that a more soluble sertraline can increase the osmoticpressure in the core and increase the sertraline concentration in the fluid that ispumped or extruded out of the dosage form. In addition, solubilized sertraline canbenefit sustained-release formulations by aiding absorption of drug from the G.l. 8 J1'I 2 4 ό , u. 011243 tract. For example, higher concentrations of drug in the colon can increaseabsorption due to a higher concentration gradient across the intestinal wall.

It is noted that currently available commercial dosage forms of sertraline areimmediate-release dosage forms containing sertraline hydrochloride. Even though 5 the hydrochloride has proven to be very effective, it is possible that dosage formscontaining the hydrochloride can also benefit by the addition of a solubilizing agent.

Exampies of organic acids useful in the invention include malic, citric,erythorbic, adipic, glutamic, aspartic, maleic, aconitic, and ascorbic acid. Preferredacids are citric, erythorbic, ascorbic, glutamic, and aspartic. Salts of organic acids 10 such as alkalkine earth métal (magnésium, calcium) salts and alkaii métal (lithium,potassium, sodium) salts are also effective as well as mixtures of organic acids andtheir salts. Calcium salts such as calcium carbonate, calcium acetate, calciumascorbate, calcium citrate, calcium gluconate monohydrate, calcium lactobionate,calcium gluceptate, calcium levulinate, calcium pantothenate, calcium proprionate, 15 calcium phosphate dibasic, and calcium saccharate are preferred organic acid salts.Examples of compounds within the other categories mentioned above are summarized in Table 1. 9 01 1 24ό

Table 1

Solubilizing Agents

Class Examples, Chemical Name Examples, Trade Désignation, (Vendor) Partial Glycerides Glyceryl Monocapryiate Monocaprylin® (Sigma), Capmur MCM(Abitec), Imwitor® 308 (Hüls) C8-C10 Partial Glycerides Capmul® MCM (Abitec), Imwitor" 742-------- (Huis), Imwitor® 988 (Hüls) Glyceryl Monooleate Myverol® 18-99 (Eastman), Calgene" GMO (Calgene), Capmul® GMO(Abitec) Glyceryl Monoiinoleate Myverol® 18-92 (Eastman) Glyceryl Monostearate Imwitor® 191 (Hüls) Calgene'*’ GSO(Calgene) Glycery Monoiaurate Imwitor'*’ 312 (Hüls) Calgene'*’ GLO (Calgene) Glyceryl Dilaurate Capmul® GDL (Abitec) Glycerides Triacetin Triacetin (Sigma) Glyceride Dérivatives PEG-Derivitized Glycerides Cremophor® RH40, Cremophor" RH60 (BASF), Acconon CA5, CA-9, CA-15, W230, TGH (Abitec) Polyglycolized Glycerides Gelucire® 44/14,42/12, 50/13, 53/10, 35/10, 48/09, 46/07, 62/05, 50/02;Labrasol® (Gattefosse); Çapmul® 3GO;3GS, 6G2O, 6G2S, 10G4O, 10G100(Abitec) Poiyethyleneglycol Esters PEG 200 Monoiaurate, PEG 400 Monoiaurate, PEG 600 Monoiaurate Calgene1*120-L, Calgene" 40-L, Calgene® 60-L PEG 200 Monostearate,PEG 400 Monostearate,PEG 600 Monostearate Calgene" 20-S, Calgene® 40-S, Calgene® 60-S PEG 200 Dilaurate, PEG 400 Dilaurate, PEG 600Dilaurate Calgene® 22-L, Calgene" 42-L Calgene® 62-L PolypropyleneGlycol Esters Propylene Glycol Dicaprylate Captex® 200 (Abitec) PolyhydricAlcohol Esters Diethylene GlycolMonoiaurate Calgene® DGL 10 011243

Propylene GlycolMonolaurate Calgene^ PGML Ascorbyi Palmitate Ascorbyi Palmitate (Sigma) Polyoxyethylene Ethers PEG Lauryl Ether Nonionic L-4 (Calgene) PEG Stearyl Ether Nonionic S-20 (Calgene), Myrj 45, 52, 53, 59 (Sigma) Sorbitan Esters Sorbitan Monolaurate Calgene* SML, Span1* 20 (Sigma) Sorbitan Monooleate Calgene® SMO, Span® 80 (Sigma) PolyoxyethyleneSorbitan Esters POE-20 SorbitanMonolaurate Calgene* PSML-20, Span* 20(Sigma), Tween 20 (Sigma), Capmul® POE-L(Abitec) POE-20 Monooleate Tween1* 80, PSMO-20 ” Saccharide Esters Sucrose Monolaurate Ryoto LW-1540 (Chem Service) Phosphoiipids Phosphatidyl choline Lecithin (Sigma) Mixed phosphoiipids Emphos D70-30C (Witco) Block Co-polymers PEO-PPO Biock Copoiymers Pluronic* F-68, F127, L-62 (BASF) Polyethylene Glycols PEG 3350 Various sources ln addition other compounds useful as solubilizing agents in the invention areethyl propionate, methyl paraben, propyl paraben, propyl gallate, niacinamide, ethylvaniliin, paraaminobenzoic acid, butyiated hydroxyanisoie, imidurea, and glycine. It is 5 also noted that preferred compositions include mixtures of an organic acid with orwithout a corresponding organic acid sait, and one or more of the non-organicsolubilizers iisted above or in Table 1. It is also noted that it has generally beenobserved that in order to be most effective the solubilizer should hâve a solubility inthe aqueous chloride-ion containing use environment of at least 1 mg/ml, and 10 preferabiy greater than 5mg/ml. A preferred group of solubilizing agents, in addition to the preferred organicacids previously mentioned, includes those in Table 2. 11

Table 2 011243

Preferred Solubilizing Agents

Class Examples, ChemicalName Examples, Trade Names (source) Partial Glycerides Glyceryl monocaprylate Monocapryiirt" (sigma), CapmurMCM(Abitec), Imwitor® 308 (Hüls) C8-C10 Partial Glycerides Capmul® MCM (Abitec), imwitor" 742 (Hüls) Imwitor 988 (Hüls) Glyceryl Monostearate Imwitor® 191 (Hüls) Calgene" GSO(Calgene) Glyceryl Monolaurate Imwitor® 312 (Hüls) Calgene" GLO (Calgene) Glycerides Triacetin Triacetin® (Sigma) Sorbitan Esters Sorbitan Monolaurate Calgene" SML, Spart" 20 (Sigma) Sorbitan Monooieate Calgene® SMO, Span® 80 (Sigma) Phospholipids Phosphatidyl choline Lecithin" (Sigma) Mixed phospholipids Emphos D70-30C (Witco) Block Co-polymers PEO-PPO BlockCopolymers Pluronic" F-68, F127, L-62 (BASF) Polyethylene Glycols PEG 3350 Various sources

Note: Commercial vendors shown above are as follows:

Abitec Corp. Janesville, Wl

BASF, Parsippany, NJ

Calgene Chemical Inc. Skokie, IL

10 Chem Service, Inc., West Chester, PAHüls America, Piscataway, NJSigma, St. Louis, MOWitco, Houston, TX 12 <Α4Ι Ά όΜ'ό01 124;.

Preferred combinations of solubiiizing agents inciude (1) an organic acid plus a sait of the same or a different organic acid, (2) an organic acid plus a non-ionic solubilizing agent such as any of those listed in Table 1, and (3) an organic acid plus a sait of the same or a different organic acid plus a non-ionic solubiiizing agent.

Particularly preferred individual solubilizing agents inciude aspartic acid,glyceryl monocaprylate, glyceryl monoiaurate, calcium acetate, ascorbic acid, citricacid, glutamic acid, and calcium carbonate. Aspartic acid, glyceryl monocaprylate,glyceryl monoiaurate and calcium acetate are most preferred.

As previously discussed, a dosage form can be tested in vitro to déterminewhether an excipient has a solubilizing effect on sertraline in a chloride-ion containinguse environment and thus is useful as a solubilizing agent. A 0.075M NaCI solutionis preferred for use as a test medium although other chloride-ion containing solutionswith équivalent or higher chloride ion concentration than 0.075M (e.g., 0.1 N HCl orisotonie saline) may be used to détermine the solubilizing effect of a test excipient. Insome cases reduced solubîiity is évident simply by adding a dosage form such as apowder to the test medium because gélation is visible. Similar probiems may beévident in a dosage form such as a tablet if the tablet is, for exampie, eut open andgélation is visible on its open face. A recommended procedure is to initially make asolution containing the desired excipients, including solubilizing agent(s). Theexcipients can be at any concentration relevant to the intended dosage form, but are

I typically for organic acids and soluble salts or sugars 80-100% of saturation. Forother surfactant-like compounds, concentrations typically range from 1 to 150% of thesertraline concentration in the test solution. Sertraline is added to this excipient-containing solution at a concentration typically 80-100% of saturation. The solution isfiltered or decanted to remove any solids and then a 3M solution of sodium chloride isadded until the sodium chloride concentration is 0.075M. The concentrated sodiumchloride solution should be added dropwise with stirring. This test medium should bekept at a température on the order of 37°C for at least 2 hours at which time thesertraline concentration in solution is determined. It is preferred that the sertralineconcentration be maintained for 4 hours, more preferably for 8 hours, still morepreferably for 16 hours, and most preferably for at least 20 hours. The amount ofagitation is not critical. When sampling the test medium, filtration or centrifugation 13 011246 can be employed to obtain solution that is free of any solids or gel material, and alsoto avoid inclusion of particulates (which may contain sertraiine) in the sample.Analysis of the samples to détermine sertraiine concentration can be accomplishedvia several conventional analytical methods, such as by high performance liquidchromatography (HPLC). For example, sertraiine concentrations can be determinedusing reverse phase HPLC with a ULTRACARB® 5 ODS 4.6 x 250 mm column(Phenomonex, Torrance, CA), and a mixture of acetic acid, triethylamine, acetonitrile,and water as mobile phase, with UV détection at 230 nm. For example, the mobilephase can be prepared by combining, with stirring, 2.86 ml of glacial acetic acid, 3.48ml of triethylamine, diluting to a liter with water, and filtering and degassing. Fiowrates are typically on the order of 1.5 ml/min, and rétention times about 4 minutes.

Dosage forms with solubilizing agent can be formulated by conventional tech-niques. Immédiate release dosage forms can be capsules, tablets, multipartic-ulates, liquid solutions or suspensions. Capsule formulations can be either softgelatin capsules where the sertraiine is either dissolved or suspended within thecapsule corë or hard gelatin capsules filled with multiparticuiates, tablets or a liquid(solution or suspension) fill. Immédiate release tablets can be by techniquesstandard in the industry by simply including the solubilizing agent as one or more ofthe tabiet excipients. Likewise immediate-release multiparticuiates can be made thatinciude solubilizing agents by techniques such as extension spheronization, rotarygranulation, coating seed cores or other methods common in the pharmaceuticalindustry. Liquid formulations consisting of a solution or suspension or both can bemade by methods common in the pharmaceutical industry.

Controlled-release dosage forms can also be made that inciude solubilizingagents by methods common in the pharmaceutical industry. Controlied releasedosage forms inciude a wide variety of dosage forms that impart control overthedissolution rate or rate of release of sertraiine from the dosage form. Such dosageforms inciude but are not limited to sustained release, delayed and then immédiaterelease, delayed and then sustained release and a dosage form with a small portionof sertraiine released immediately and then foliowed by the majority of the sertraiinein the dosage release at a sustained rate. Other algorithme of release can also be 14 011243 attained such as pulsitile release. Many such formulations are described in aforementioned co-pending applications PC9337JTJ and PC9824JTJ.

Standard techniques can be used to make controlled release dosage forms.For example, tablets can be made by commonly used direct compression methodsthat contain sertraiine and a solubilizing agent. To provide delayed release, a pH-sensitive coating can be applied to these tablets via a side-vented pan coater (e.g.,HCT-60 tablet coater, Vector Corp.). The pH sensitive coating is résistant to low pHenvironments such as typically in the stomach and then dissolves, releasingsertraiine, in neutral pH environment such as typically in the small intestine. Suchcoating materials (e.g., cellulose acetate phthalate or methacrylic acid copolymer) arecommon in the pharmaceutical industry. Altematively, the tablets can be coated witha porous or semipermeable membrane coating to provide sustained release of thetablet cores, A particularly useful process for applying a membrane coatingcomprises dissolving the coating polymer in a mixture of solvents chosen such thatas the coating dries, a phase inversion takes place in the applied coating solution,resuiting in a membrane with a porous structure. Numerous examples of this type ofcoating System are given in European Patent Spécification 0 357 359 B1, publishedMarch 7,1990, herein incorporated by reference. Many other types of controlledrelease dosage forms can also be made that benefit from the inclusion of solubilizingagents such as matrix Systems which inciude but are not iimited to 1) non-erodingmatrices, tablets, multiparticulates and hydrogel-based Systems; 2) hydrophiliceroding, dispersible or dissolvable matrix Systems, tablets and multiparticulates; and3) coated matrix Systems. Another ciass of controlied-release dosage forms consistsof réservoir Systems where release of the drug is modulated by a membrane, such ascapsules and coated tablets or multiparticulates. A third ciass consists of osmotic-based Systems such as 1) coated bilayer tablets; 2) coated homogeneous tabletcores; 3) coated multiparticulates; and 4) osmotic capsules. A fourth ciass consistsof swellable Systems where drug is release by a swelling and then extrusion of thecore components out through a passageway in a coating or surrounding Shell orouter layer.

The invention is further illustrated by the foliowing examples, which are not to be taken as limiting. 15

Example 1 01124ό

This example illustrâtes that organic acids hâve the ability to raise thesolubility of the hydrochloride sait of sertraline. The acids were tested by dissolving 5 the candidate acid in water and then stirring excess sertraline hydrochloride in theacid solution for at least 8 hours. The concentration of sertraline in the supematantwas then measured by HPLC analysis. The results of this test are shown in Table 1- 1, below. Most of the acids iisted in the table successfully raised the solubility ofsertraline hydrochloride (normal solubility 2.5 mg/ml). 10 Table 1-1

Excipient Approximate ExcipientConcentration (mg/ml) Sertraline Solubility (mg/ml) D,L-malic acid 900 21 Citric acid 600 20 Erythorbic 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, based on the above-described test, are malic, citric, erythorbic, andadipic acids. Maleic, L-aspartic, tartane, and L-glutamic acids also significantiy 15 improved sertraline hydrochloride solubility. Some controlled-release dosage formswith such acids in the core will perform better than those without such acids. This isparticularily true for osmotic-based formulations that deiiver a solution of drug.

Example 2 20 This example illustrâtes that organic acids hâve the ability to raise the solubility of the acetate sait of sertraline by a test method similarto that used for thehydrochloride sait described in Example 1. The solubiiizing agent, its concentration,and resulting sertraline solubility are shown in Table 2-1 below. Based on theseresults, preferred acids to include in a dosage form where increased sertraline 16 011243 acetate solubility is desired are ascorbic, erythorbic, citric, lactic, aspartic, glutamic,and aconitic acids.

Table 2-1

Excipient Excipient Concentration(mg/ml) Sertraline Solubility(mg/ml) Ascorbic acid 400 >425 Erythorbic 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 None — 64

Example 3

This example illustrâtes that organic acids and three calcium salts hâve the 10 ability to raise the aqueous solubility of the lactate sait of sertraline using a methodsimilar to that used for the hydrochloride sait described in Example 1. Thesolubilizing agent, its concentration in the aqueous test solution, and the sertralinelactate solubility in the test solution are listed in Table 3-1 below. Solubility ofsertraline lactate in water is approximately 125 mg/ml. The data below shôw that 15 eight organic acids effected sertraline lactate solubilities about the same as or higherthan 125 mg/ml; adipic, erythorbic, itaconic, citric, aspartic, glutamic, histidine, andascorbic. Also, a solution of a mixture of two of these acids also had high solubility;ascorbic and aspartic. Sertraline lactate solubility was also high in calcium saitsolutions, either alone (calcium citrate) or mixed with ascorbic acid. 17

Table 3-1 011243

Excipient Excipient Concentration(mg/ml) Sertraline Lactate Solubility(mg/ml) Adipic acid 14 360 Erythorbic acid 400 >217 Itaconic acid 150 >202 Citric acid 600 162 Aspartic acid 7 >155 Glutamic acid 12 >125 Histidine 42 >116 Ascorbic/Aspartic 400/7 116 Ascorbic 400 102 Glycine 250 66 Aconitic acid 200 <59 Tartaric acid 1400 12 Fumaric acid 11 <9 Sortie acid 3 <9 Calcium lactate/Ascorbic acid 50/400 160 Calcium citrate 10 165 Calcium carbonate/Ascorbic acid 50/400 176 None — 125

Example 4 5 The lower solubility of the sertraline chloride sait and of ail sertralîne lactate and sertraline acetate salts in the presence of high chloride concentrations.suggestthat core formulations are preferred for which sertraline stays in solution that is, itdoes not precip'rtate or form a gel-like material when chloride is présent Certainorganic acids and salts were found to inhibit précipitation or gélation of sertaline when 10 chloride is présent via the foliowing screening test Sertraline lactate was dissolved inwater-either alone (as a contrai) or with a candidate solubilizing agent. Sodiumchloride was then added (as a concentrated solution) and the resuit observed. Anexcipient was considered bénéficiai if the solution remained clear and fluid. Themore chloride that could be added to an excipient solution with the solution remaining 15 clear, the more bénéficiai was the excipient. Table 4-1 below shows the results ofthis screening test, indicating that ail the excipients tested increased sertralineconcentration in the chloride solutions. 18

Table 4-1 011243

Excipient Excipient Concentration (mg/ml) ConcentrationNaCI (mM) Final SertralineConcentration(mg/ml) Observation AfterNaCI Addition None — 38 22 gel/precipitate Ascorbic/Aspartic acids 400/7 152 162 solution Aspartic acid 7 7 114 152 162 100 solution gel Ascorbic acid 400 100 102 precipitate Ascorbic acid/calcium lactate 400/50 150 165 solution Ascorbic acid/ calcium carbonate 400/50 150 170 slightly turbid Citric acid/calcium lactate 600/50 150 162 solution Histidine 42 150 110 slight precipitate

Example 5 5

Organic compounds (soiubilizers) were screened for their ability to enhancethe solubility of sertraline lactate in aqueous solutions with or without the presence ofchioride. Excess sertraline lactate was added to an aqueous solution of the candidate solubilizer and, in most cases an organic acid. The organic acids were ! 10 saturated in these solutions and the additional solubiiizing agents were at theconcentration shown in Table 5-1. The equilibrium sertraline solubility wasmeasured. Then, sodium chioride was added to the saturated solution and the finalsertraline concentration was measured. The resuits of these screening tests aresummarized in Table 5-1. 19 011243 ïableJhl

SertralineConcentrationwith NaCI(mg/ml) m 160 O h- 120 120 o CM X— O CM x— l 120 I | 140 | O co 120 | 120 I 120 120 150 o CM x— o CM x— NaCI Concentration (mM) o w X— 150 O m X- o LO x— o IO x— O m X— 150 | o LO X— | 100 I o LO x— | 100 | o LO x— o in x— 150 150 O LO X— C5 LO x— Sertraline Solubîlity (mg/ml) 125 o CO X— I 170 O CM x— O CM O CM X— o CM x— [ 120 | I 140 i O <0 o CM x— I 120 j « O CM o CM X— 150 | 120 j O CM Organic Acid none ascorbic I ascorbic none ascorbic I ascorbic | ascorbic <D C O c I none | | ascorbic j [ none | ascorbic | ascorbic I i ascorbic | none , ascorbic | ascorbic Soiubilizer Concentration (mg/ml) 1 1 O o o 50 50 O r* o I_50 I_50_I o •n I os | O LO 50 50 [ 50 50 I 50 J Soiubilizer None (control) Monocaprylin | Triacetin Monobutyrin Diacetin CM τ- Ο δ·_ o E lmwitorw 375 Imwitor8' 742 | Imwitor*'988 j Trrethyl citrate | x— CO c 2 3 CL _J LU δ 2 o JZ Q. O E 05 L·. O Sucrose acetateisobutyrate Sodium capryl lactate Sucrose monolaurate Sodium lauryl lactate | Span 80 j - CM CQ LD CD Γ'- CO 05 O t— V* T* CM CO T— r~ LO CO h- T* 20 011243

Example 6

This example illustrâtes that solubilizers for sertraiine also can increase therate of dissolution of sertraiine. The effect of a candidate excipient on sertraiine 5 dissolution rate was determined by adding solid drug, the candidate solubilizingexcipient, and, in some cases, other excipients such as an organic acid and anosmagent (such as a sugar) to a 1.8 ml centrifuge tube. The sample tubes werespun at 14K G for 5 minutes in a microcentrifuge to pack the powder. 150 μΙ gastricbuffer was added to the packed powder and the samples were gently agitated, then 10 spun at 14K G in a microcentrifuge for 2 minutes. The samples were then removedfrom the microcentrifuge and allowed to stand undisturbed until the solution wasremoved. The solution was removed from the samples after a total of 10 minutesafter gastric buffer was added to the powder pack, and analyzed by HPLC todétermine the sertraiine concentration. 15 The dissolution rate (mg sertraline/ml-min) was calculated from the measured concentration of dissolved sertraiine in the supematant as a function of time over thefirst 10 minutes of dissolution. These dissolution rates and the excipient mixtures forwhich they were measured are summarized in Table 6-1 below. As shown, severalexcipient mixtures containing solubilizers significantly (about 3X or greater) increased 20 the dissolution rate of sertraiine, compared with sertraiine alone and compared withsertraiine and ascorbic acid. 21 011243

Table 6-1

Sertraline Dissolution Rate (mg/ml- min) 3.5 20.9 O t— 9.3 14.5 4.3 8.0 6.4 9.5 4.3 SertralineSait FormConc. (wt%) lactate 100 lactate 14 0) C0 x}·73 T-_tp lactate 14 I ra JD Xj-O_TO lactate 24 lactate 13.1 ra S O ra lactate 14 lactate 14 lactate 19 OtherExcipientConc. (wt%) 1 I ! LO 1 1 1 1 1 r- "T KV O 1 1 1 1 1 1 Other Excipient none none Γ5 O O ra O none none 1 none ra C*5 O E Ο ΌCD UO CDO <s O CD O none none none OsmagentConc. (wt%) 1 t 20 12.5 uo T" T"* « 1 N- 12.5 12.5 LO 74.2 Osmagent none lactose lactose lactose lactose none lactose lactose lactose lactose lactose OrganicAcid Conc.(wt%) 1 1 51.0 49.5 51.0 ! 51.0 I 71.0 none 49.5 49.5 51.0 none Organic Acid none ascorbic ascorbic ! J ascorbic ascorbic ascorbic none ascorbic ascorbic ascorbic none Candidate Excipient Concen-tration (wt%) t 1 I 5.0 5.0 OS OS 4.7 o cri OS 5.0 6.8 Name None None (N X— CO Ό ? E Lecithin PEG 3550 2 O 2 s> 3 E CL CD O S O 2 3 E CL CD O - y— σ» T- L 2 5 E 1 OO & O ι- Ε > o> 2 CD O CD CD CL ω Ascorbyl palmitate 22 011243

11.5 5.3 _O> a> CO ro en O o ce en 1 1 1 ω CD c C O O c C LO b-' I ω ω ω ο c ο _ço no ο CM ό O ’çf ιη r-~ ο o XI ’ c ο _ÇB ο a. W ω (0 CB ο V LO 00 Ο CO ΙΟ Ο raben/ aben/ ate CM v» thyl paipyl parpyl gall co < o 5 <P O O Σ a ex JE 23 011243

Example 7

This examples illustrâtes a method for making osmotic tablets comprisinga tablet core containing sertraiine with and without solubilizing agents surroundedby a semipermeable asymmetric membrane coating. In this example the benefitof incorporating solubilizers into a controlled-reiease formulation containingsertraiine is demonstrated. Sertraline-hydrochloride was triturated by hand for 10minutes with citric acid and microcrystalline cellulose (Avicel PH 102, FMC) usinga 6 1/2 inch diameter mortar and pestle. Magnésium stéarate was then blended inas a lubricant by stirring with a spatula for 60 seconds. The weight ratio ofsertraline-hydrochloride to citric acid to microcrystalline cellulose to magnésiumstéarate was 8.5:63.8:23.7:4; with a total weight of 10 grams. The blendedmixture was pressed into 470 mg tablets in a modifîed hydraulic jack(manufactured by Dayton) fitted with a pressure gauge and 3/8 inch concavepunch under 2500 PSI pressure for 2 seconds. The dimensions of the resultingtablets were 3/8 inch in diameter and 1/4 inch thick. A semipermeable membranecoating (as described in U.S. Patent 5,612,059 was applied to these tablets usinga LDCS-20 pan coater (Vector Corp.) at a spray rate of 20 grams per minute, aninlet température of 40°C and air flow of 40 cfm. The coating solution contained byweight 10% Cellulose acetate, (Eastman Chemical, CA398-10), 2.5%polyethylene glycol (BASF, PEG 3350), 15% water and 72.5% acetone. Thecoated tablets were dried 1 hour at 50°C before testing. After drying, the weight ofapplied coating material was 15.4% of the total weight. Additional osmotic deitverytablets were prepared by using essentially the same procedure for making thetablet cores and applying the asymmetric membrane coating to the coresdescribed above. The composition of the cores and coating solution varied asshown in Table 7-1. Significant core compositional changes shown include: thesertraiine sait form, the type and amount of solubilizer, and the type and amount ofosmagent The amount of binder (Avicel®) lubricant (magnésium stéarate), andsolubilizer were varied as necessary to obtain good tabieting and wettingproperties. These tablets ail contained a sertraiine dose of 50 mgA/tablet. 24 011243

Table L-l

Coating Solution Coating Weight (dry wt %) V in T* T— *r~ v- Ô r· 10.3 O LO 20 o ω s? IO CO in T” O V IO T“ io v- IO lO T* O UJ O- 5 v> CM Xf 2.5 2.5 in 04 2.5 2.5 Polymer wt% O T— CO O CO O o T— O T— O v- Polymer Type | CA O LU CA _ EC < O < O CA CA Olher I none I none Ca Acetate Ca | lactate, Myrj Ca acetate none 1 Ca acetate Ca acetate CD .J 5« ξ 04 CO CO 2.5 j none _ ; 2.5 LO CM 2.5 2.5 Core Composition Avicelwt % | 20 CO o> 29.5 O r— 27 <O CM 27 29.5 Osmogenl ? CO CO X in CO 38 O m CO eo 28.5 36 38 Type I lactose | lactose fructose sucrose fructose fructose | fructose fructose Solubilizer tn LO LO LO Type I none auou J none j O 2 E E E none Solubilizer Acid •s© œ* ▼· O T— T· iO 04 r~ *T“ Type | none | none aspartic glutamic i aspartic glycine | aspartic aspartic en 3 Q ? 04 r* M- "’T •r— sf T“ ’M* T“ T-“ Sali Form | chloride [ lactate lactate I lactate I lactate lactate | <D <5 O JS lactate ® E ~ £ D> O) O O b- 470 470 470 O b* V o b· ’T O v © Û. . Œ X tu b- l 94 O r- Ό b* <D b- b^ en -b- JZ b. 25 011243 IM = Imwitor312 CA = cellulose acetate 398-10 EC = Ethocel S-100 ω ra U.

CB ω w

E ’w c

CD

CB

E

II w O) ç Q.

CB

O

O c

O

E

II

O

S

O in co

CO "ô

CJ >.

O ω c _φ >> £ ω _>» ο Q-

II Ο tu ο. ΙΩ 26 01 1 η 4 ο

The rates of release of sertraiine from these formulations were determinedtesting the tablets in a USP Apparatus #2 with paddle stirring speed set at 100 rpm.The receptor solution used in the dissolution apparatus was 0.13M acetate buffer atpH 4.0 with 0.075M sodium chloride kept at 37°C. Samples of the receptor solution 5 were taken at the fîmes shown in Table 7-2. Analysis of sertraiine released wasdetermined by reverse-phase high-performance liquid chromatography (RP HPLC).

The results of release-rate tests performed using these procedures are listedin Table 7-2. The first two formulations listed, 7a and 7b show low release rates andare included as comparison examples. Both these formulations contain a sertraiine 10 sait (hydrochloride or lactate) and only lactose as the osmagent and no solubifizingexcipients. The remaining formulations (7c-7h) listed in Table 7-2 ail contain one ormore solubilizing excipients and ail demonstrate significantly higher release rates ofsertraiine compared with the formulations that do not contain solubiiizers.

Table 7-2 15

Tablets ofExample No Fraction of Drug Released (%) At Specified Time OHr 1 Hr 2 Hr 4 Hr 8Hr 12 Hr 20 Hr 7a 0 0 0 0 0 0 0 7b 0 0 1 2 — 10 (17 hr) 12 7c 0 6 15 35 62 76 78 7d 0 0 0 4 19 28 44 7e 0 8 19 37 60 73 83 7f 0 0.7 6 17 37 54 78 7g 0 0.4 4 13 31 41 53 7h· 0 8 18 38 56 64 66

Claims

-27- 011243 CLAIMS

1. A composition of matter comprising sertraline or a pharmaceuticaiiyacceptable sait thereof and an amount of a solubilizing agent sufficient to produce aconcentration of dissolved sertraline in a use environment containing chloride ionswhich is 1.5 times higherthan the concentration effected by a comparativecomposition of matter identical thereto but for the inclusion of said solubilizing agent,provided said solubilizing agent is not alginic acid, sodium citrate, calcium carbonate,or a polyethylene glycol having a molecuiar weight greater than 3350.
2. A composition of matter as defined in claim 1, wherein said useenvironment is the Gl tract.
3. A composition of matter as defined in claim 1, wherein said useenvironment is an aqueous chloride ion-containing test medium.
4. A composition of matter as defined in claim 3, wherein said useenvironment is 0.075 M sodium chloride.
5. A composition of matter as defined in claim 1, which is an immédiaterelease dosage form. Γ
6. A composition of matter as defined in claim 1, which is a controlledrelease dosage form.
7. A composition of matter as defined in claim 1, wherein saidsolubilizing agent is selected from: 1) organic acids and organic acid salts; 2) partial glycerides; 3) glycerides; 4) glyceride dérivatives; 5) polyethylene glycol esters; 6) polypropylene glycol esters; 7) polyhydric alcohol esters; 3) polyoxyethylene ethers; -28- 01 1 2 4 ό 9) sorbitan esters; 10) polyoxyethytene sorbitan esters; and 11) carbonate saits.
8. A composition of matter as defined in claim 4, wherein the amount ofsaid solubiiizing agent is sufficient to maintain, for at least 2 hours, the concentrationof dissolved sertraline at a level which is at least 1.5 times higher than theconcentration of sertraline produced by a comparative composition of matter identicalthereto but for the inclusion of said solubiiizing agent
9. A composition as defined in claim 1, wherein said solubiiizing agent isselected from aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calciumacetate, ascorbic acid, citric acid, and glutamic acid.
10. A composition of matter comprising sertraline or a pharmaceuticallyacceptable sait thereof and an amount of a solubiiizing agent sufficient to produceand to maintain, for at least 2 hours in 0.075M sodium chloride, a concentration ofdissolved sertraline which is at least 1.5 times higher than the concentration effectedby a comparative composition of matter identical thereto but for the inclusion of saidsolubiiizing agent, provided said solubiiizing agent is not alginic acid, sodium citrate,calcium carbonate, or a polyethylene glycol having a molecular weight greater than3350.
11. A composition of matter as defined in claim 10, which is an immédiaterelease dosage form.
12. A composition of matter as defined in claim 10, which is a controlledrelease dosage form.
13. A composition of matter as defined in claim 10, wherein saidsolubiiizing agent is selected from: 1) organic acids and organic acid salts; 2) partial glycerides; 3) glycerides; -29- 011243 4) glyceride dérivatives; 5) polyethylene glycol esters; 6) polypropylene glycol esters; 7) polyhydric alcohol esters; 8) polyoxyethylene ethers; 9) sorbitan esters; 10) polyoxyethylene sorbitan esters; and 11) carbonate salts.
14. A composition as defined in claim 10, wherein said solubiiizing agentis selected from aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calciumacetate, ascorbic acid, citric acid, and glutamic acid.
15. A composition of matter comprising sertraline or a pharmaceuticallyacceptable sait thereof and an amount of a solubiiizing agent sufficient to effect, invivo, a Cmax and/or an AUC which is greater by at least 10% than the Cmax and/orAUC effected by a comparative composition of matter identical thereto but for theinclusion of said solubiiizing agent, provided said solubiiizing agent is not alginic acid,sodium citrate, calcium carbonate, or a polyethylene glycol having a molecularweightgreater than 3350.
16. A composition as defined in claim 15, wherein said Cmax and/or AUCeffected by said solubiiizing agent-containing composition is at least 15% higherthanthe corresponding Cmax and/or AUC effected by said comparative composition.
17. A composition as defined in claim 16, wherein said Cmax and/or AUCeffected by said solubiiizing agent-containing composition is at least 20% higher thanthe corresponding Cmax and/or AUC effected by said comparative composition.
18. A composition of matter as defined in claim 15, which is an immédiaterelease dosage form.
19. A composition of matter as defined in claim 15, which is a controlledrelease dosage form. -30- 011243
20 . A composition of matter as definedin claim 15, wherein said soiubilizing agent is selected from: 1) organic acids and organic acid salts; 2) partial glycerides; 3) glycerides; 4) glyceride dérivatives; 5) polyethylene glycol esters; 6) polypropylene glycol esters; 7) polyhydric alcohol esters; 8) polyoxyethylene ethers; 9) sorbitan esters; 10) polyoxyethylene sorbitan esters; 11 ) carbonate salts.
21. A composition of matter as defined in claim 15, wherein saidsoiubilizing agent is selected from aspartic acid, glyceryl monocaprylate, glycerylmonolaurate, calcium acetate, ascorbic acid, citric acid, and glutamic acid.
22. A method of increasing the solubility of sertraiine in an aqueouschloride ion-containing use environment, comprising administering said sertraiine to said use environment in a composition of matter additionally comprising a soiubilizing f agent, provided said soiubilizing agent is not alginic acid, sodium citrate, calciumcarbonate, or a polyethylene glycol having a molecular weight greater than 3350.
23. A method as defined in claim 22, wherein the concentration ofdissolved sertraiine in said use environment also containing said solubilizer is at least 1,5-fold higher than the concentration of sertraiine effected by a comparativecomposition identical to said soiubilizing agent-containing composition except for theinclusion of said soiubilizing agent.
24. A method as defined in claim 22, wherein said use environment is the Gl tract. -31- 011240
25. A method as defined in claim 22, wherein said use environment is anaqueous chloride ion-containing test medium.
26. A method as defined in claim 25, wherein said medium is 0.075 Msodium chloride.
27. A method as defined in claim 22, wherein said composition of matteris in the form of an immédiate release dosage form.
28. A method as defined in claim 22, wherein said composition of matteris in the form of a controlled release dosage form.
29. A method as defined in claim 22, wherein said solubilizing agent isselected from: 1) organic acids and organic acid salts; 2) partial glycerides; 3) glycerides; 4) glyceride dérivatives; 5) polyethylene glycol esters; 6) polypropylene glycol esters; 7) polyhydric alcohol esters; 8) polyoxyethylene ethers; 9) sorbitan esters; and 10) polyoxyethylene sorbitan esters. 11 ) carbonate salts