CA2290974C - Solubilized sertraline compositions - Google Patents

Abstract

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

Description

SnmhiIi~Pd Sertraline Compositions Field of the Invention This invention relates to a composition comprising sertraline or a phamlaceu-tically acceptable salt thereof and a solubilizing agent which prevents gel formation or otherwise maintains the solubility of sertraline in a use environment containing chloride ions. The invention further relates to a method of treating a psychiatric or other illness comprising administering sertraline in such a solubilized composition to a mammal, including a human patient, in need of such treatment.
Backgro nd of the Invention Sertraiine is a selective serotonin reuptake inhibitor (SSRI), which is useful as an antidepressant and anorectic agent, and in the treatment of obsessive-compulsive disorder, premenstrual dysphoric disorder, post-traumatic stress disorder, chemical dependencies, anxiety-related disorders, panic and premature ejaculation.
Sertraline is most commonly prescribed for therapy of depressive illness, in the general dose range 50-200 mglday. Sertraline has an elimination half life of 23 hr and is dosed once daily. Commercially, sertraline is available as the hydrochloride salt which is undeniably therapeutically effective, many patients having availed themselves of the benefits of this drug.
Some forms of sertraline, particularly salts which exhibit high solubility, can be problematic, however. Such salts, generally those having an aqueous solubility in excess of 10 mglmL, can exhibit a tendency to form a gel andlor exhibit reduced solubility (e.g., precipitate as a salt or as the free base having a lower solubility in the environment of use than the salt form originally administered) when exposed to a use environment containing chloride ions such as the gastrointestinal tract. The gel itself tends to dissolve slowly and otherwise releases sertrafine at a slow rate, thereby affecting absorption. It is not known whether gelation is the only mechanism which impacts the solubility of sertraline in a use environment. However, therapeutic difficulties can accordingly arise from administering an immediate-release dosage form in vivo if solubility is affected, regardless of mechanism. Problems can similarly arise in the case of controlled-release dosage forms since the controlled release profile of the dosage form can be altered ut vivo by factor's affe~ng sotuf~ty_ The unanticipated phenomenon of gelation of sertraiine 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 gelation is not well understood, and can be all the more problematic therapeutically since the release characteristics of a gei formed in situ may not be anticipated.
In particular, gelling of sertraline in sustained-release dosage forms can be detrimental in those sustained release systems known as non-eroding matrix systems, reservoir systems, and osmotic systems. In each of these types of sustained release formulations release of the drug is dependent on transport of the drug across a distance within the device (matrix or coating layer) to the surrounding fluid. This drug transport can occur by diffusive or convective mechanisms. In both mechanisms, formation of a gel can reduce transport by an order of magnitude or more and in some cases can result in devices that exhibit incomplete drug release (e.g., less than 70% of the total drug in the formulation).
Summary Of The Invention This invention provides a composition of matter, suitable for administration to a mammal, including a human, comprising sertraline or a pharmaceutically acceptable salt thereof and an amount of an excipient, herein termed a °solubilizing agent" sufficient to effect a concentration of dissolved sertraline in a use environment containing chloride ions which is at least 1.5 times higher, preferably 2 times higher, more preferably 3 times higher than the concentration effected by a comparative composition of matter (i.e., a control) identical thereto but for the inclusion of said solubilizing agent. The use environments mainly intended are the aqueous in vivo digestive fluids of the gastrointestinal (GI) tract including the stomach, small intestine and large intestine, and aqueous in vitro chloride ion-containing test media, as further described below. The compositions are suitable for formulating into oral dosage forms including tablets, capsules, multiparticulates, powders for oral suspension, and unit dose packets (sometimes referred to in the art as a "sachet°). In addition the compositions can be used in liquid dosage forms such as oral solutions or suspensions and injectable formutations. For making the compositions of this invention into oral dosage forms, conventional techniques known to the art can be employed. The composition can additionally comprise other conventional pharmaceutical ingredients andlor a pharmaceutically acceptable carrier.
By this invention, it has been determined that in cases of dosage forms containing sertraline salts which form gels or which otherwise exhibit reduced solubility in a use environment, solubility may advantageously be increased, and in some cases solution viscosity may be advantageously decreased, by employing the sertraline salt together with a solubilizing agent which increases the sertrafine's solubility. The solubilizing agent preferably also maintains solubility, meaning that the level of dissolved sertraline in a use environment, regardless of the salt employed, is head at a concentration greater than or equal to 1.5 times the concentration of sertraline in a like formulation without solubilizing excipient, for at feast 2 hours. For many dosage fomls it may be advantageous to maintain the sertraline concentration greater than or equal to 1.5 times the concentration of sertraline in tike formulations without solubilizing excipient for longer periods of time such as 4 hours, 8 hours, 16 hours, or 20 hours, and this can be effected by the choice and amount of solubilizing agent. It has otherwise been determined that in a chloride ion-containing use environment without a solubilizing agent, for example a test environment such as 0.075M sodium chloride solution, sertraline solubility is generally less than 10 mgAImL, usually less than 5 mgA/mL, regardless of the salt employed, and despite the fact that many of the salts themselves exhibit solubilities in pure water (i.e., no chloride ions) well in excess of 10 mgAImL. Solubiiizing agents thus could also be construed to be compounds that maintain sertraline concentrations of lOmgA/ml or greater in chloride-ion-containing environments of use.
Reference herein to "a solubilizing agent" herein, including the claims, shall be understood as also including the use of more than one solubizing agent in a composition, added separately or as a mixture.
As mentioned above, the term "use environment" can refer to the aqueous in vivo chloride ion-containing digestive fluids of the stomach, or to an in vitro chloride ion-containing aqueous environment used to test a dosage form for its sertraline release characteristics. A useful in vitro test environment for purposes of this invention is 0.075M sodium chloride. 0.075M sodium chloride is prefer-ed as a test medium because of its ready availability and similar chloride ion concentration to the lower levels of chloride ions found in the fluids in the GI tract. Blood 8~
Other Bodv Fluids, Dorothy S. Dittmer, ed., Federation of American Societies for Experimental Biology, Washington, D.C., 1961, pp. 404-419. Thus, as an additional feature, this invention provides an in vitro test to determine whether a dosage form is within the scope of the invention. That is, the invention provides a composition of matter comprising sertraline or a pharmaceutically acceptable salt thereof and an amount of a solubilizing agent sufficient to produce and to maintain, for at least 2 hours in 0.075M sodium chloride, a concentration of dissolved sertraline which is at least 1.5 times higher than the concentration effected by a comparative composition of matter 70 identical thereto but for the inclusion of said solubiiizing agent.
Agitation should be employed during the test although, as explained below, the degree or type of agitation is not critical. Salt solution temperature is not believed to be particularly critical so long as it is about 37°C, plus or minus 3°C, throughout the test. Excipients, including the solubilizing agents) should be at the desired concentration in the aqueous test solution prior to adding sertraline and sodium chloride.
Sertraline is then added to a concentration ranging between 80% to 100% of ifs saturation concentration in the test solution. This solution should be decanted off or filtered away from any solids. To this solution a 3M NaCI solution is slowly added with stirring until the NaCI concentration in the test solution is 0.075M. The sertraline concentration in this test solution after 2 hours is compared with a control solution made in the same manner and consisting of the same components except the solubilizing agent.
Alternatively, a solubilizing excipient can be identified in an in vivo test such as a crossover study. !n an in vivo crossover study a solubilized sertraline-containing dosage form is dosed to half a group of 12 or more humans and, after an appropriate washout period (e.g., one week) the same subjects are dosed with a dosage form otherwise identical but for inclusion of the solubif~zing agent.
The other half of the group is dosed with the non-soiubilized dosage fomz first, followed by the soiubilized dosage form. Maximum concentration in the blood (Cm~ and/or bioavailability, measured as the area under the curve (AUC) for a plot of the concentration of sertraline in blood versus time, is detemzined for each group. By comparison, assessment of the solubilized dosage form can be made. If the average Cm~ or AUC for the formulation containing the solubilizing agent is greater by 10% or more than the formulation without the solubilizing agent, then the sofubi('~zing excipient is an embodiment of this invention. It is preferred that the C~"~
and/or AUC
be greater by at least 15%, and mare preferred either or both be greater by at least .5 20%. The determination of AUC's is a well known procedure and is described, for example, in "Pharmacokinetics; Processes and Mathematics," by Peter Welling (ACS
Monograph 185, Amer. Chem. Soc., Wash. D. C., 196). Thus, as an additional feature of the invention, the invention provides a composition of matter comprising sertraline or a phamlaceutically acceptable salt thereofand an amount of a 117 solubifizing agent sufficient to effect, in vivo, a C",~ and/or an AUC
which is greater by at least 10% than the Cm~ and/or AUC effected by a comarison composition of matter (i.e., a control) identical thereto but for the inclusion of said solubilizing agent.
The invention further provides a method of increasing the solubility of sertratine in an aqueous chloride ion-containing environment, comprising 1!5 administering said sertraline in a composition of matter comprising sertraline and a sofubifrzing agent.
The invention is surprising in that, prior to the invention, it was not known that (1 ) the phenomenon of reduced sertraline solubility in chloride ion-containing environments existed, nor that (2) any chemical agent existed which would reduce or 20 prevent sertraline gelation or reduced sertraline solubility in chloride ion-containing use environments or otherwise operate to increase sertraline's solubility in such use environments. The term "solubilized sertraline~ is used herein to refer to a composition comprising sertraline or a sertraline salt plus an excipient (i.e.
the solubilizing agent) which prevents gelation or otherwise increases, and preferably 25 maintains, the solubility of the sertraline salt in an in vivo or in vitro chloride ion-containing use environment. t.ib;ewise, the term "solubil'~ze" is used to denote that the solubility of a sertraline salt is being increased by at least 1.5 times in a use environment over what it would be in the absence of a solubilizing agent.
The invention is preferred for use with !he aspartate, acetate, and lactate salts 30 which are salts that exhibit high solubilities in water relative to the free base. These salts are disclosed in commonly assigned co-pending Canadian Patent application No. 2,290,966.

For convenience and consistency, reference to "sertraline" in terms of thera-peutic amounts herein, including the claims, is to active sertraline, abbreviated herein as "mgA", i.e., the non-salt, non-hydrated free base having a molecular weight of 306.2. Amounts in mgA can corweniently be converted to equivalent weights for whatever salt fom~ is desired.
Many soiubiiizing agents useful herein can be grouped into several broad categories:
'I 0 1. Organic acids and organic acid salts;
2. Partial Glycerides, i.e., less than fully esterified derivatives of glycerin, including monoglycerides and diglycerides;
3. Glycerides;
4. Glyceride derivatives;

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 Qgtailed Description The amount of solubilizing agent employed in a composition according to the invention depends on the particular solubiI'~zing agent employed.
In the case of solubilizing agents which are organic acids the preferred amount of solubifizer can be calculated as a ratio multiplied by the quantity of sertraline to be used, wherein the ratio is of organic acid solubility to solubility of sertraline salt:
(organic acid or salt solubilitylsertraline or sertraline salt solubility) x quantity of sertraline where the solubilities referred to are in mg/ml. The above expression is approximate, and some adjustment may be advantageous for optimization. Generally the above expression will give a quantity 'which is plus or minus 25% of the final value employed, although higher quantities of solubifizing agent can be incorporated without any particular additional advantage. In addition, organic acid salts can be added to modify the pH andlor solubility of the organic acid, effectively optimizing the solubilization effect of the agents.
For other types of solubilizing agents listed, typically the amount of solubilizing 110 agent employed in the dosage form will be 1 to '150% by weight of the amount of sertraline employed therein, preferably 1 to 100%, mare preferably 3 to 75%.
Amounts of solubilizing agent higher than 150% may be employed, although it is believed that in most cases no particular advantage would be provided.
Salts of sertraline or excipients that in combination with sertraline aid in solubilizing sertraline can be beneficial to virtually any type of sertraline dosage forms intended for oral administration, including immediate release as well as controlled release systems, including (1) sustained-release dosage forms which meter out sertraline as they progress through the gastrointestinal system and (2) delayed release systems which release sertrafine after an initial delay period following ingestion. Immediate-release systems are well known and commercially available in both solid and liquid formulations. Controlled release dosage forms of sertraline are discussed and disclosed in commonly assigned co-pending Canadian Patent applications Nos. 2,290,966 and 2,290,969, Solubilized sertraline can enhance release from the dosage form by increasing the concentration gradient for diffusive based systems such as matrix dosage forms and reservoir dosage forms. Solubii'~zed sertraline can also enhance delivery from osmotic dosage farms in that a more soluble sertraline can increase the osmotic pressure in the care and increase the sertraline concentration in the fluid that is :10 pumped or extruded out of the dosage form. In addition, solubifized sertraline can benefit sustained-release formulations by aiding absorption of drug from the G.I.

WO 99/01120 $ PCT/IB98/00933 tract. For example, higher concentrations of drug in the colon can increase absorption due to a higher concentration gradient across the intestinal wail.
It is noted that currently available commercial dosage forms of sertraline are immediate-release dosage forms containing sertraline hydrochloride. Even though the hydrochloride has proven to be very effective, it is possible that dosage forms containing the hydrochloride can also benefit by the addition of a solubilizing agent.
Examples of organic acids useful in the invention include matic, citric, erythorbic, adipic, glutamic, aspartic, maieic, aconitic, and ascorbic acid.
Preferred acids are citric, erythorbic, ascorbic, gfutamic, and aspartic. Salts of organic acids such as alkalkine earth metal (magnesium, calcium) salts and alkali metal (lithium, potassium, sodium) salts are also effective as well as mixtures of organic acids and their salts. Calcium salts such as calcium carbonate, calcium acetate, calcium ascorbate, calcium citrate, calcium gluconate monohydrate, calcium lactobionate, calcium gluceptate, calcium levulinate, calcium pantothenate, calcium proprionate, 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.
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WO 99/01120 o PCT/IB98/00933 Solubilizing Agents Class Examples, Chemical Examples; Trade Designation, Name (Vendor) Partial Glyceryl MonocapryiateMonocaprylin (Sigma, Capmul Glycerides MCM(Abitec), tmwitor 308 (Huts) C8-C10 Partial GiyceridesCapmuh' MCM (Abitec), lmwitor'~

(Hills), Imwitor~ 988 (Huts) Glyceryl Monooieate Myverol~' 18-99 (Eastman), Calgene~' GMO
(Calgene), Capmul~ GMO(Abitec) Glyceryl MonolinoleateMyverol 18-92 (Eastman) Glyceryl Monostearatelmwitor'~ 791 (Huts) Calgene~' GSO(Calgene}

Glycery Monolaurate Imwitor~' 312 (Huts) Calgene~' GLO

(Calgene) Glyceryl Dilaurate Capmul GDL (Abitec) Glycerides Triacetin Triacetin (Sigma) Gfyceride PEG-Derivitized GlyceridesCremophor~' RH40, Cremophor'~

Derivatives (BASS, Acconon CAS, CA-9, CA-15, W230, TGH (Abitec) Polyglycolized GlyceridesGelucire'~ 44114, 42112, 50113, 53!10, 35110, 48109, 46/07, 62/05, 50102;
Labrasol~ (Gattefosse); Capmul~
360;

36S, 6620, 662S, 10640, 106100 (Abitec) Polyethylene PEG 200 Monoiaurate, Calgene~' 20-L, Calgene'~
glycol EstersPEG 400 Monolaurate, 40-L, Calgene~ 60-L

PEG 600 Monolaurate PEG 200 Monostearate,Calgene~' 20-S, Calgene'~
PEG 400 Monostearate,40-S, Calgene~ 60-S

PEG 600 Monostearate PEG 200 Dilaurate, Calgene~' 22-L, Calgene~

400 Dilaurate, PEG Calgene~ 62-L

Dilaurate PolypropylenePropylene Glycol Captex'~ 200 (Abitec) Glycol EstersDicaprylate Polyhydric Diethylene Glycol Calgene~' DGL

Alcohol EstersMonolaurate WO 99/01120 1 ~ PCT/IB98/00933 Propylene Glycol Calgene PGML
Monolaurate Ascorbyl Palmitate Ascorbyl Palmitate (Sigma) PolyoxyethylenePEG Lauryl Ether Nonionic L-4 (Calgene) Ethers PEG Stearyl Ether Nonionic S-20 (Calgene), Myrj 45, 52, 53, 59 (Sigma) Sorbitan EstersSorbitan MonolaurateCalgene SML, Span 20 (Sigma) Sorbitan Monooleate Calgene~ SMO, Span 80 (Sigma) PolyoxyethylenePOE-20 Sorbitan Calgene~' PSML-20, Span 20(Sigma}, Sorbitan EstersMonolaurate Tween 20 (Sigma), Capmul~
POE-L
(Abitec) POE-20 Monooleate Tween 80, PSMO-20 Saccharide Sucrose Monolaurate Ryoto LW 1540 CChem Service) Esters PhospholipidsPhosphatidyl cholineLecithin (Sigma) Mixed phospholipids Emphos D70-30C Witco) Block Co- PEO-PPO Block Pluronic' F-68, F127, L-fit polymers Copolymers (BASF) Polyethylene PEG 3350 Various sources Glycols In addition other compounds useful as solubilizing agents in the invention are ethyl propionate, methyl paraben, propyl paraben, propyl gallate, niacinarnide, ethyl vanillin, paraaminobenzoic acid, butylated hydroxyanisole, imidurea, and glycine. It is also noted that preferred compositions include mixtures of an organic acid with or without a corresponding organic acid salt, and one or more of the non-organic solubilizers listed above or in Table 1. It is also noted that it has generally been observed that in order to be most effective the solubilizer should have a solubility in the aqueous chtoride-ion containing use environment of at least 1 mglml, and preferably greater than 5mglml.
A preferred group of solubilizing agents, in addition to the prefer-ed organic acids previously mentioned, includes those in Table 2.

Table 22 Prefer-ed Solubilizing Agents Class Examples, ChemicalExamples, Trade Names (source) Name Partial Glyceryl monocapryiateMonocaprylin (sigma), Capmui Glycerides MCM(Abitec), Imwitor~ 308 (Huts) C8-C10 Partial Capmul~' MCM (Abitec), Imwitor~' Glycerides 742 (Huls), Imwitor~ 988 (Hills) Gfyceryl MonostearateImwitor~' 191 (Hills) Calgene'~
GSO(Calgene) Glyceryl MonolaurateImwitor~' 312 (Huts} Calgene~' GLO
(Calgene) Glycerides Triacetin Triacetin'~ (Sigma) Sorbitan EstersSorbitan MonolaurateCalgene~' SML, Span'' 20 (Sigma) Sorbitan MonoofeateCalgene SMO, Span 80 (Sigma) PhosphoiipidsPhosphatidyl cholineLecithin' (Sigma) Mixed phospholipidsEmphos D70-30C Witco) Block Co- PEO-PPO Block Pfuronic'~ F-68, F127, L-62 polymers Copolymers (BASF) Polyethylene PEG 3350 Various sources Glycols Note: Commercial vendors shown above 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

Prefer-ed combinations of sotubilizing agents include (1) an organic acid plus a salt of the same or a different organic acid, (2) an organic acid plus a non-ionic sotubilizing agent such as any of those listed in Table 1, and (3) an organic acid plus a salt of the same or a different organic acid plus a non-ionic sotubilizing agent.
Particularly preferred individual solubilizing agents include aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calcium acetate, ascorbic acid, citric acid, glutamic acid, and calcium carbonate. Aspartic acid, glyceryl monocaprylate, glyceryl monolaurate and calcium acetate are most preferred.
As previously discussed, a dosage fomz can be tested in vitro to determine whether an excipient has a solubilizing effect on sertraline in a chloride-ion containing use environment and thus is useful as a solubilizing agent. A 0.075M NaCI
solution is preferred for use as a test medium although other chloride-ion containing solutions with equivalent or higher chloride ion concentration than 0.075M (e.g., 0.1 N
HCI or isotonic saline) may be used to determine the solubilizing effect of a test excipient. In some cases reduced solubility is evident simply by adding a dosage form such as a powder to the test medium because gelation is visible. Similar problems may be evident in a dosage form such as a tablet if the tablet is, for example, cut open and gelation is visible on its open face. A recommended procedure is to initially make a solution containing the desired excipients, including solubilizing agent(s).
The excipients can be at any concentration relevant to the intended dosage form, but are typically for organic acids and soluble salts or sugars 80-100% of saturation.
For other surfactant-like compounds, concentrations typically range from 1 to 150%
of the sertraline concentration in the test solution. Sertraline is added to this excipient-containing solution at a concentration typically 80-100% of saturation. The solution is filtered or decanted to remove any solids and then a 3M solution of sodium chloride is added until the sodium chloride concentration is 0.075M. The concentrated sodium chloride solution should be added dropwise with stirring. This test medium should be kept at a temperature on the order of 37°C for at least 2 hours at which time the sertraline concentration in solution is determined. It is preferred that the sertraline concentration be maintained for 4 hours, more preferably for 8 hours, still more preferably for 16 hours, and most preferably for at least 20 hours. The amount of agitation is not critical. When sampling the test medium, filtration or centrifugation WO 99/01120 ~3 PCTIIB98100933 can be employed to obtain solution that is free of any solids or gel material, and also to avoid inclusion of particulates (which may contain sertraline) in the sample.
Analysis of the samples to determine sertraline concentration can be accomplished via several conventional analytical methods, such as by high performance liquid chromatography (HPLC). For example, sertraline concentrations can be determined using reverse phase HPLC with a ULTRACAR6~ 5 ODS 4.6 x 250 mm column (Phenomonex, Tomance, CA), and a mixture of acetic acid, triethylamine, acetonitrile, and water as mobile phase, with UV detection at 230 nm. For example, the mobile phase can be prepared by combining, with stirring, 2.86 ml of glacial acetic acid, 3.48 ml of triethylamine, diluting to a liter with water, and filtering and degassing. Flow rates are typically on the order of 1.5 mllmin, and retention times about 4 minutes.
Dosage forms with solubif~zing agent can be formulated by conventional tech-piques. Immediate release dosage forms can be capsules, tablets, multipartic-ulates, liquid solutions or suspensions. Capsule formulations can be either soft geEatin capsules where the sertraline is either dissolved or suspended within the capsule core or hard gelatin capsules filled with multiparticufates, tablets or a liquid (solution or suspension) fill. Immediate release tablets can be by techniques standard in the industry by simply including the solubilizing agent as one or more of the tablet excipients. Likewise immediate-release multiparticulates can be made that include solubilizing agents by techniques such as extension spheronization, rotary granulation, coating seed cores or other methods common in the pharmaceutical industry. Liquid formulations consisting of a solution or suspension or both can be made by methods common in the pharmaceutical industry.
Controlled-release dosage forms can also be made that include solubilizing agents by methods common in the pharmaceutical industry. Controlled release dosage forms include a wide variety of dosage forms that impart control over the dissolution rate or rate of release of sertraline from the dosage form. Such dosage forms include but are not limited to sustained release, delayed and then immediate release, delayed and-then sustained release and a dosage form with a small portion of sertraline released immediately and then followed by the majority of the sertraline in the dosage release at a sustained rate. Other algorithms of release can also be attained such as pulsitile release. Many such formulations are described in aforementioned c;o-pending Canadian Patent applications Nos. 2,290,966 and 2,290,969.
Standard techniques can be used to make controlled release dosage forms.
For example, tablets can be made by comrnoniy used direct compression methods that contain sertraline 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 C;arp.). The pH sensitive coating is resistant to low pH
environments such as typically in the stomach and then dissolves, releasing sertraline, in neutral pH environment such as typically in the small intestine. Such 11 l7 coating materials (e.g., cellulose acetate phthalate or methacrykic acid copolymer) are common in the pharmaceuticak industry. Aftematively, the tablets can be coated with a porous or semipermeable membrane coating to pravide sustained release of the tablet cores, A particutariy usefuk process for applying a membrane coating comprises dissolving the coating polymer in a mixture of solvents chosen such that 7 5 as the coating dries, a phase inversion takes place in the applied coating solution, resulting in a membrane with a porous structure. Numerous examples of this type of coating system are given in European Patent Specification 0 357 369 B1, published March 7, 1990. Many other types of controlled release dosage forms can also be made that benefit from the inclusion of solubilizing 20 agents such as matrix systems which include but are not limited to 1 ) non-eroding matrices, tablets, multiparticulates and hydrogel-based systems; 2) hydrophilic eroding, dispersible or dissolvable matrix systems, tablets and multiparticuiates; and 3) coated matrix systems. Another class of controlled-release dosage forms consists of reservoir systems where release of the drug is modulated by a membrane, such as 25 capsules and coated tablets or multiparticulates. A third class consists of osmotic-based systems such as 1 ) coated bilayer tablets; 2) coated homogeneous tablet cores; 3) coated multiparticulates; and 4) osmotic capsules_ A fourth class consists of swellable systems where drug is release by a swelling and then extrusion of the core components out through a passageway in a coating or surrounding shell or 317 outer layer.
The invention is further illustrated by the following examples, which are not to be taken as limiting.

Example 1 This example illustrates that organic acids have the ability to raise the solubility of the hydrochloride salt of sertraline. The acids were tested by dissolving the candidate acid in water and then stirring excess sertraline hydrochloride in the acid solution for at least 8 hours. The concentration of sertrafine in the supernatant was then measured by HPLC analysis. The results of this test are shown in Table 1-1, below. Most of the acids listed in the table successfully raised the solubility of sertraline hydrochloride (normal solubility 2.5 mglml).
Table 1-1 Approximate Excipient Excipient Concentration (mglml)Sertraline Solubility (mg/ml) D,L-malic acid 900 21 Citric acid 600 20 Erythorbic acid 400 19 Adipic acid 14 12 Malefic acid 700 6.4 L-aspartic acid 10 5.5 Tartaric acid 1400 5.5 L-giutamic acid 12 5.4 Fumaric acid 11 3.1 Tannic acid 2000 2.8 O, L-tyrosine 600 2.2 Preferred acids, based on the above-described test, are malic, citric, erythorbic, and adipic acids. Maieic, L-aspartic, tartaric, and L-glutamic acids also signifcantly improved sertraline hydrochloride solubility. Some controlled-release dosage forms with such acids in the core will perfoml better than those without such acids.
This is particularity true for osmotic-based formulations that deliver a solution of drug.
example 2 This example illustrates that organic acids have the ability to raise the solubility of the acetate salt of sertraline by a test method similar to that used for the hydrochloride salt described in Example 1. The soiubilizing agent, its concentration, and resulting sertraline solubility are shown in Table 2-1 below. Based on these results, preferred acids to include in a dosage form where increased sertraiine acetate solubility is desired are ascorbic, erythorbic, citric, lactic, aspartic, glutamic, and aconitic acids.
Table 2 1 Excipient ConcentrationSertraiine Solubility Excipient (mglml) {mglml) 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 This example illustrates that organic acids and three calcium salts have the ability to raise the aqueous solubility of the lactate salt of sertraline using a method similar to that used for the hydrochloride salt described in Example 1. The solubiiizing agent, its concentration in the aqueous test solution, and the sertraline lactate solubility in the test solution are fisted in Table 3-1 below.
Solubility of sertraline lactate in water is approximately 125 mglml. The data below show that eight organic acids effected sertraline lactate solubilities about the same as or higher than 125 mglml; adipic, erythorbic, itaconic, citric, aspart'c, giutamic, histidine, and ascorbic. 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 salt solutions, either alone (calcium citrate) or mixed with ascorbic acid.
. .. ~ .u._ _~ .~...._.....m....~_. r , .

Excipient ConcentrationSertraline Lactate Excipient (mglml) Solubility (mglml) 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 AscorbiclAspartic400/7 116 Ascorbic 400 102 Glycine 250 66 Aconitic acid 200 <59 Tartaric acid 1400 12 Fumaric acid 11 <9 Sorbic acid 3 <9 Calcium lactate)501400 160 Ascorbic acid Calcium citrate 10 165 Calcium carbonate)50/400 176 Ascorbic acid None - 125 The lower solubility of the sertraline chloride salt and of all sertraline lactate and sertraline acetate salts in the presence of high chloride concentrations suggest that core formulations are prefer-ed for which sertraline stays in solution that is, it does not precipitate or form a gel-like material when chloride is present.
Certain organic acids and salts were found to inhibit precipitation or gelation of sertafine when chloride is present via the following screening test. Sertraline lactate was dissolved in water either alone (as a control) or with a candidate solubifizing agent.
Sodium chloride was then added (as a concentrated solution) and the result observed.
An exapient was considered beneficial if the solution remained clear and fluid.
The more chloride that could be added to an excipient solution with the solution remaining clear, the more beneficial was the excipient. Table 4-1 below shows the results of this screening test, indicating that all the excipients tested increased sertraline concentration in the chloride solutions.

WO 99101120 1$ PCT/1B98I00933 Table 4-1 Final Sertraline Excipient ConcentrationObservation After 1=xcipient ConcentrationConcentration(mglml) NaCI Addition (mglml) NaCI (mM) None - 38 22 gellprecipitate Ascorbic) 40017 152 162 solution Aspartic acids Aspartic 7 114 162 solution acid 7 152 100 gel Ascorbic 400 100 102 precipitate acid Ascorbic 400/50 150 165 solution acid) calcium lactate Ascorbic 400150 150 170 slightly turbid acid) calcium carbonate Citric acid)600150 150 162 solution calcium lactate Histidine 42 150 110 slight precipitate Organic compounds (solubilizers) were screened for their ability to enhance the solubility of sertraiine lactate in aqueous solutions with or without the presence of chloride. Excess sertraline lactate was added to an aqueous soiution of the candidate sofubilizer and, in most cases an organic acid. The organic acids were saturated in these solutions and the additional solubilizing agents were at the concentration shown in Table 5-1. The equilibrium sertraline solubility was measured. Then, sodium chloride was added to the saturated solution and the final sertraline concentration was measured. The results of these screening tests are summarized in Table 5-1.

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r r r r r r r WO 99/01120 2~ PCT/IB98I00933 Examlhe 66 This example illustrates that solubilizers for sertratine also can increase the rate of dissolution of sertraline. The effect of a candidate excipient on sertraline dissolution rate was determined by adding solid drug, the candidate solubilizing excipient, and, in some cases, other excipients such as an organic acid and an osmagent (such as a sugar) to a 1.8 ml centrifuge tube. The sample tubes were spun at 14K G for 5 minutes in a microcentrifuge to pack the powder. 150 p.i gastric buffer was added to the packed powder and the samples were gently agitated, then spun at 14K G in a microcentrifuge for 2 minutes. The samples were then removed from the microcentrifuge and allowed to stand undisturbed until the solution was removed. The solution was removed from the samples after a total of 10 minutes after gastric buffer was added to the powder pack, and analyzed by HPLC to determine the sertraline concentration.
The dissolution rate (mg sertralinelmi-min) was calculated from the measured concentration of dissolved sertraiine in the supernatant as a function of time over the first 10 minutes of dissolution. These dissolution rates and the excipient mixtures far which they were measured are summarized in Table 6-1 below. As shown, several excipient mixtures containing solubilizers significantly (about 3X or greater) increased the dissolution rate of sertraline, compared with sertraline alone and compared with sertra(ine and ascorbic acid.
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Exam Ip a 7 This examples illustrates a method far making osmotic tablets comprising a tablet core containing sertrafine with and without solubilizing agents surrounded by a semipermeable asymmetric membrane coating. In this example the beneft of incorporating sofubilizers into a controlled-release fomlulation containing sertraline is demonstrated. Sertraline-hydrochloride was triturated by hand for 10 minutes with citric acid and microcrystalline cellulose (Avicel PH 102, FMC) using a 6 112 inch diameter mortar and pestle. Magnesium stearate was then blended in as a lubricant by stirring with a spatula for 60 seconds. The weight ratio of sertraline-hydrochloride to citric acid to microcrystalline cellulose to magnesium stearate was 8.5:63.8:23.7:4; with a total weight of 10 grams. The blended mixture was pressed into 470 mg tablets in a modified hydraulic jack (manufactured by Dayton) fitted with a pressure gauge and 318 inch concave punch under 2500 PSi pressure for 2 seconds. The dimensions of the resulting tablets were 3/8 inch in diameter and 1l4 inch thick. A semipermeable membrane coating (as described in U.S. Patent 5,612,059 was applied to these tablets using a LDCS-20 pan coater (Vector Corp.) at a spray rate of 20 grams per minute, an inlet temperature of 40°C and air flow of 40 cfm. The coating solution contained by weight 10% Cellulose acetate, (Eastman Chemical, CA398-10), 2.5%
polyethylene glycol (BASF, PEG 3350), 15% water and 72.5% acetone. The coated tablets were dried 1 hour at 50°C before testing. After drying, the weight of applied coating material was 15.4% of the total weight. Additional osmotic delivery tablets were prepared by using essentially the same procedure for making the tablet cores and applying the asymmetric membrane coating to the cores described above..The composition of the cores and coating solution varied as shown in Table 7-1. Significant core compositional changes shown include: the sertraiine salt form, the type and amount of solubiiizer, and the type and amount of osmagent. The amount of binder (Avicel~ lubricant (magnesium stearate), and solubilizer were varied as necessary to obtain good tableting and wetting properties. These tablets all contained a sertraline dose of 50 mgAltablet.

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a The rates of release of sertraline from these formulations were determined testing 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 at pH 4.0 with 0.075M sodium chloride kept at 37°C. Samples of the receptor solution were taken at the times shown in Table 7-2. Analysis of sertraline released was determined by reverse-phase high-performance liquid chromatography (RP HPLC).
The results of release-rate tests performed using these procedures are listed in Table 7-2. The first two fomZUlations listed, 7a and 7b show low release rates and are included as comparison examples. Both these formulations contain a sertraline salt (hydrochloride or lactate) and only lactose as the osmagent and no solubilizing excipients. The remaining formulations (7c-7h) listed in Table 7-2 all contain one or more solubilizing excipients and al( demonstrate significantly higher release rates of sertraiine compared with the formulations that do not contain solubilizers.
a Ie 7-2 Fraction of Drug Released (%) At Specified Time Tablets of 0 1 2 4 Hr 8 12 Hr 20 Example Hr Hr Hr Hr Hr No 7a 0 0 0 0 0 0 0 7b 0 0 1 2 - 10 12 (17 hr) 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 __ 0 8 18 38 56 64 66 7h-

Claims (30)

-27-

1. A composition of matter comprising sertraline or a pharmaceutically acceptable salt thereof and an amount of a solubilizing agent sufficient to produce a concentration of dissolved sertraline in a use environment containing chloride ions which is 1.5 times higher than the concentration effected by a comparative composition 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 molecular weight greater than 3350.

2. A composition of matter as defined in claim 1, wherein said use environment is the GI tract.

3. A composition of matter as defined in claim 1, wherein said use environment is an aqueous chloride ion-containing test medium.

4. A composition of matter as defined in claim 3, wherein said use environment is 0.075 M sodium chloride.

5. A composition of matter as defined in claim 1, which is an immediate release dosage form.

6. A composition of matter as defined in claim 1, which is a controlled release dosage form.

7. A composition of matter as defined in claim 1, wherein said solubilizing agent is selected from:

1) organic acids and organic acid salts;

2) partial glycerides;

3) glycerides;

4) glyceride derivatives;

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.

8. A composition of matter as defined in claim 4, wherein the amount of said solubilizing agent is sufficient to maintain, for at least 2 hours, the concentration of dissolved sertraline at a level which is at least 1.5 times higher than the concentration of sertraline produced by a comparative composition of matter identical thereto but for the inclusion of said solubilizing agent.

9. A composition as defined in claim 1, wherein said solubilizing agent is selected from aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calcium acetate, ascorbic acid, citric acid, and glutamic acid.

10. A composition of matter comprising sertraline or a pharmaceutically acceptable salt thereof and an amount of a solubilizing agent sufficient to produce and to maintain, for at least 2 hours in 0.075M sodium chloride, a concentration of dissolved sertraline which is at least 1.5 times higher than the concentration effected by a comparative composition 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 molecular weight greater than 3350.

11. A composition of matter as defined in claim 10, which is an immediate release dosage form.

12. A composition of matter as defined in claim 10, which is a controlled release dosage form.

13. A composition of matter as defined in claim 10, wherein said solubilizing agent is selected from:

1) organic acids and organic acid salts;

2) partial glycerides;

3) glycerides;

4) glyceride derivatives;

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 solubilizing agent is selected from aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calcium acetate, ascorbic acid, citric acid, and glutamic acid.

15. A composition of matter comprising sertraline or a pharmaceutically acceptable salt thereof and an amount of a solubilizing agent sufficient to effect, in vivo, a C max and/or an AUC which is greater by at least 10% than the C max and/or AUC effected by a comparative composition 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 molecular weight greater than 3350.

16. A composition as defined in claim 15, wherein said C max and/or AUC
effected by said solubilizing agent-containing composition is at least 15%
higher than the corresponding C max and/or AUC effected by said comparative composition.

17. A composition as defined in claim 16, wherein said C max and/or AUC
effected by said solubilizing agent-containing composition is at least 20%
higher than the corresponding C max and/or AUC effected by said comparative composition.

18. A composition of matter as defined in claim 15, which is an immediate release dosage form.

19. A composition of matter as defined in claim 15, which is a controlled release dosage form.

20. The composition of matter as defined in any one of claims 15 to 19, wherein the solubilizing agent is selected from:

1) organic acids and organic; acid salts;

2) partial glycerides;

3) glycerides;

4) glyceride derivative;

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.

21. The composition of matter as defined in any one of claims 15 to 20, wherein the solubilizing agent is selected from aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calcium acetate, ascorbic acid, citric acid, and glutamic acid.

22. A use of a composition of matter for increasing the solubility of sertraline in an aqueous chloride ion-containing use environment, wherein the composition of matter comprises sertraline or a pharmaceutically acceptable salt thereof and a solubilizing agent, provided the solubilizing agent is not alginic acid, sodium citrate, calcium carbonate, or a polyethylene glycol having a molecular weight greater than 3350.

23. The use as defined in claim 22, wherein the concentration of dissolved sertraline in the use environment also containing the solubilizer is at least 1.5-fold higher than the concentration of sertraline effected by a comparative composition identical to the solubilizing agent-containing composition except for the inclusion of the solubilizing agent.

24. The use as defined in claim 22 or 23, wherein the use environment is the GI tract.

25. The use as defined in any one of claims 22 to 24, wherein the composition of matter is in the form of an immediate release dosage form.

26. The use as defined in any one of claims 22 to 24, wherein the composition of matter is in the form of a controlled release dosage form.

27. The use as defined in any one of claims 22 to 26, wherein the solubilizing agent is selected from:
1) organic acids and organic acid salts;

2) partial glycerides;

3) glycerides;

4) glyceride derivatives;

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.

28. A method of determining whether a first composition of matter comprising sertraline or a pharmaceutically acceptable salt thereof and a solubilizing agent has a concentration of dissolved sertraline increased by a factor of 1.5 in relation to a comparative composition of matter identical thereto but for the inclusion of the solubilizing agent in an aqueous chloride ion-containing in vitro use environment, comprising:

a) administering the first composition of matter to the use environment and measuring the concentration of dissolved sertraline in the use environment;
b) administering the comparative composition of matter to the use environment and measuring the concentration of dissolved sertraline in the use environment; and c) comparing the results of (a) and (b) to determine whether the concentration of dissolved sertraline in (a) is 1.5 times higher than the concentration of dissolved sertraline in (b).

29. The method according to claim 28, wherein the in vitro use environment is 0.075 M sodium chloride.

30. The method according to claim 28 or 29, further comprising in step (c) comparing whether the concentration of dissolved sertraline in (a) is maintained for at least 2 hours at a concentration that is 1.5 times higher than the concentration of dissolved sertraline in (b).