SK181099A3 - 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

Solubilized sertraline compositions

Technical field

The invention relates to a composition comprising sertraline or a pharmaceutically acceptable salt thereof and a solubilizing agent which prevents the formation of gel or otherwise maintains the solubility of sertraline in an environment containing chloride ions. The invention further relates to a method of treating psychiatric or other diseases, comprising administering sertraline in such a solubilized composition to a mammal, including a human patient, in need of such treatment.

BACKGROUND OF THE INVENTION

Sertraline 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 dependence, anxiety related disorders, panic and premature disorder.

Sertraline is most commonly prescribed for the treatment of depressive disease at a general dosage range of 50 to 200 mg / day. Sertraline has an elimination half-life of 23 hours and is dosed once a day. Commercially, sertraline is available as the hydrochloride salt, which is undeniably therapeutically effective when many patients themselves have taken advantage of the drug.

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However, certain forms of sertraline, particularly salts, that exhibit high solubility may be problematic. Such salts, generally those having a water solubility in excess of 10 mg / ml, may show a tendency to gel formation and / or exhibit reduced solubility (e.g., precipitate as a salt or as a free base having lower solubility in the environment of use than the salt form originally administered) when exposed to an environment containing chloride ions such as the gastrointestinal tract.

The gel itself tends to dissolve slowly and otherwise releases sertraline at a slow rate, thereby affecting absorption. It is not known whether gelling is the only mechanism that affects the solubility of sertraline in the environment of use. However, therapeutic problems may accordingly arise from administration of an immediate release dosage form in vivo when solubility is affected, regardless of mechanism. Similarly, problems may arise in the case of controlled release dosage forms, since the controlled release profile of the dosage form may be varied in vivo by factors affecting solubility. The unexpected phenomenon of sertraline salt gelling in a chloride ion environment can thus create therapeutic difficulties by unexpectedly altering the release profile of the dosage form, upon immediate release or controlled release. The mechanism of sertraline gellation is not well known. However, it can be generally more problematic therapeutically since the release characteristics of the gel formed in situ cannot be predicted.

In particular, gelling of sertraline in sustained release dosage forms can be detrimental to these sustained release systems known as non-eroding matrix systems, reservoir systems and osmotic systems. In each of these types of sustained release formulations, drug release is dependent on drug delivery across the distance in the device (matrix or coating) into the surrounding fluid. This drug transport can be accomplished by diffusion or convection mechanisms. In both mechanisms, gel formation may reduce transport by an order of magnitude or more, and in some cases may lead to devices that exhibit incomplete drug release (e.g., less than 70% of the total drug content in the formulation).

SUMMARY OF THE INVENTION

The present invention provides a composition of a substance suitable for administration to a mammal, including a human, comprising sertraline or a pharmaceutically acceptable salt of sertraline and an amount of an excipient herein designated solubilizing agent sufficient to induce a dissolved sertraline concentration in the use environment containing chloride ions , preferably 2 times higher, more preferably 3 times higher than the concentration induced by the comparative composition of the substance (i.e., a control identical to that composition but without incorporating the solubilizing agent). Areas of use that are mainly considered are aqueous in vivo digestive fluids of the gastrointestinal (GI) tract, including the stomach, small intestine and colon, and aqueous in vitro test media containing chloride ions as described below.

These compositions are suitable for formulation into oral dosage forms including tablets, capsules, multiparticulates, powders for oral suspension and unit dosage packages (sometimes referred to in the art as "pouches"). In addition, these compositions can be used in liquid dosage forms such as oral solutions or suspensions and injectable formulations. Conventional techniques known in the art may be utilized to form the compositions of this invention into oral dosage forms. The composition may additionally comprise other conventional pharmaceutical ingredients and / or a pharmaceutically acceptable carrier.

In the present invention, it has been determined that in the case of dosage forms containing sertraline salts which form gels or which otherwise exhibit reduced solubility in the environment after use, solubility may be advantageously increased and in some cases the viscosity of the solution may be advantageously reduced by utilizing the sertraline salt together with solubilizing. an agent which increases the solubility of sertraline.

Preferably, the solubilizing agent also maintains solubility, which means that the level of dissolved sertraline in the environment of use, regardless of the salt used, is maintained at a concentration greater than or equal to 1.5 times the concentration of sertraline in such a solubilizing agent-free formulation for at least 2 hours.

For many dosage forms, it may be advantageous to maintain a sertraline concentration greater than or equal to 1.5 times the sertraline concentration in similar formulations without a solubilizing excipient for a longer period of time such as 4 hours, 8 hours, 16 hours or 20 hours and this may be affected by choice. and an amount of solubilizing agent.

Otherwise, it has been determined that in an environment of use containing chloride ions without solubilizing agent, for example in a test environment such as a 0.075M sodium chloride solution, the solubility of sertraline is generally less than 10 mgA / ml, usually less than 5 mgA / ml, regardless of the salt used. and in contrast to the fact that many of the salts themselves exhibit solubilities in pure water (i.e. without chloride ions), well in excess of 10 mgA / ml. Solubilizers should also be formulated to be compounds that maintain sertraline concentrations of 10 mgA / ml or greater in environments of use containing chloride ions.

The reference to the solubilizing agent used herein, including the claims, is also to be understood to include the use of more than one solubilizing agent in the composition, added separately or in a mixture.

As mentioned above, the term environment of use may refer to aqueous in vivo gastric fluids containing chloride ions or to the in vitro aqueous environment containing chloride ions used to test the dosage form for its sertraline release characteristics.

A suitable in vitro assay environment for the purposes of this invention is 0.075M sodium chloride. 0.075M sodium chloride is preferred as a test medium because it is readily available and a similar concentration of chloride ions at lower chloride ion levels was found in fluids in the GI tract.

Blood and Other Body Fluids, Dorothy S. Dittmer, Ed., Federation of American Societies for Experimental Biology, Washington, D.C., 1961, p. 404-419. As a further feature, the invention provides an in vitro assay to determine whether a dosage form is within the scope of the invention.

That is, the invention provides a composition of a sertraline-containing substance or a pharmaceutically acceptable salt thereof and an amount of a solubilizing agent sufficient to form and maintain, for at least 2 hours in 0.075M sodium chloride, a dissolved sertraline concentration of at least 1.5 times the concentration caused by a comparative composition of a substance that is identical thereto, but without incorporating said solubilizing agent. It should. mixing during the test should be used although, as explained below, the degree or type of mixing is not critical. The temperature of the saline solution is not particularly critical if it is about 37 ° C ± 3 ° C during the test.

Excipients, including the solubilizing agent (s), should be at the desired concentration in the aqueous test solution prior to the addition of sertraline or sodium chloride. Sertraline is then added to a concentration range between 80% to 100% of its saturation concentration in the test solution. This solution should be decanted or filtered from any solids.

To this solution was slowly added a 3M NaCl solution with stirring until the NaCl concentration in the test solution was 0.075M. The concentration of sertraline in this test solution after 2 hours is compared with a control solution made in the same way and consisting of the same components except for the solubilizing agent.

Alternatively, the solubilizing excipient may be identified in an in vivo assay such as a cross-study. In an in vivo cross-study, a solubilized sertraline-containing dosage form is dosed in half of a group of 12 or more people, and after an appropriate irrigation period (e.g., 1 week), a dosage form otherwise identical but without incorporation of the solubilizing agent is dosed. The other half of the group is dosed first with an unsolubilized dosage form, followed by a solubilized dosage form. The maximum blood concentration (C _may ) and / or bioavailability measured as area under the curve (AUC) in the blood sertraline concentration versus time graph is determined for each group. By comparison, an evaluation of the solubilized dosage form can be made.

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When the mean C _max or AUC for the formulation containing the solubilizing agent is greater than 10% or more than the formulation without the solubilizing agent, then the solubilizing excipient is within the scope of the invention. It is preferred that C _max and / or AUC be greater by at least 15% and more, preferably each or both are greater by at least 20%. Determination of AUC is a well known procedure and is described, for example, in Farmacokinetics, Processes and

Mathematics by Peter Welling (ACS Monograph 185, Amer. Chem. Soc. Wash. D.C., 1986).

As a further feature of the present invention, the invention provides a composition comprising a sertraline or a pharmaceutically acceptable salt thereof, certain amounts of a solubilizing agent sufficient to induce in vivo C _max and / or AUC greater than at least 10% than C _max and / or AUC caused by a comparative (i.e., control) composition of a substance identical to the former, but without incorporating said solubilizing agent.

The invention further provides a method of increasing the solubility of sertraline in an aqueous medium containing chloride ions, comprising administering said sertraline in a composition of a sertraline-containing substance and a solubilizing agent.

The invention is surprising in that it has not been known that (1) there is a phenomenon of decreased solubility of sertraline in environments containing chloride ions, or (2) there is any chemical agent that would reduce or prevent gelling of sertraline or reduced solubility of sertraline containing chloride ions, or otherwise act to increase the solubility of sertraline in such environments of use.

The term solubilized sertraline is used herein to refer to compositions comprising sertraline or a sertraline salt plus an excipient (i.e., a solubilizing agent) that prevents gelling or otherwise increases and preferably maintains the solubility of the sertraline salt in vivo or in vitro in an environment containing chloride ions.

Similarly, the term solubilizes is used to indicate that the solubility of the sertraline salt is increased at least 1.5-fold in the environment of use beyond that which would be in the absence of the solubilizing agent.

The invention is advantageous when used with aspartate, acetate, and lactate, which are salts that exhibit high water solubilities over the free base. These salts are described in PCT application PC9337JTJ, PCT application designating the United States and incorporated herein by reference.

For convenience and consistency, reference to sertraline in the terms of the therapeutic amounts set forth herein, including the claims, refers to active sertraline, abbreviated as mgA, i. a non-salt, unhydrated free base having a molecular weight of 306.2. The amount of mgA can be suitably changed to equivalent weights for any salt form, if necessary.

Many solubilizing agents that are suitable can be categorized into several broad categories:

1. organic acids and organic acid salts,

2. partial glycerides, i. 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. polyhydroxy alcohol esters;

8. polyoxyethylene ethers;

9. sorbitan esters,

10. Polyoxyethylene sorbitan esters; and

11. carbonate salts.

Detailed description

The amount of solubilizing agent used in the composition of the invention is dependent on the particular solubilizing agent used.

In the case of solubilizers which are organic acids, the preferred amount of solubilizer may be calculated as a ratio multiplied by the amount of sertraline to be used, the ratio being the solubility of the organic acid to the solubility of the sertraline salt:

(solubility of organic salt or acid - amount of sertraline) solubility of sertraline or sertraline salt wherein said solubilities are reported in mg / ml.

The above expression is approximate and certain settings may be advantageous for optimization. Generally, the above statement will provide an amount that is ± 25% of the final value used, although higher amounts of the solubilizing agent may be used without any particular additional benefit. In addition, organic acid salts may be added to modify the pH and / or solubility of organic acids, thereby effectively optimizing the solubilizing effect of the compositions.

For other types of solubilizing agents typically, the amount of solubilizing agent used in the dosage form is 1 to 150% by weight of the amount of sertraline used, preferably 1 to 100%, more preferably 3 to 75 I. Higher amounts of solubilizing agent than 150% may be used, although assumes that in most cases no particular advantage will be created.

Sertraline salts or excipients which, in combination with sertraline, assist in the solubilization of sertraline may be of benefit to virtually any type of sertraline dosage form intended for oral administration, including immediate release as well as controlled release systems including (1) maintaining release dosage forms that measure. sertraline as they pass through the gastrointestinal system; and (2) delayed release systems that release sertraline after an initial delay period upon ingestion.

Immediate release systems are well known and commercially available in both solid and liquid formulations. Sertraline controlled release dosage forms are described and discussed in commonly assigned Pfizer copending applications Serial Nos. PC9337JTJ and PC9824JTJ, each of which is a PCT application designating the United States and each of which is incorporated herein by reference in its entirety.

Solubilized sertraline can increase release from the dosage form by increasing the concentration gradient for diffusively based systems such as matrix dosage forms and reservoir dosage forms. Solubilized sertraline may also increase delivery from osmotic dosage forms in which more soluble sertraline can increase the osmotic pressure in the core and increase the concentration of sertraline in the fluid that is pumped or extruded from the dosage form. In addition, solubilized sertraline can enhance sustained release formulations by absorption of the drug from the GI tract. For example, higher drug concentrations in the colon may increase absorption due to a higher concentration gradient across the intestinal wall.

It is noted that commercially available commercial dosage forms of sertraline are immediate release dosage forms containing sertraline hydrochloride. Although the hydrochloride has been shown to be very effective, it is possible that these hydrochloride containing dosage forms can be improved by the addition of a solubilizing agent.

Examples of organic acids useful in the present invention include malic, citric, erytorbic, adipic, glutamic, aspartic, maleic, aconitic and ascorbic acid. Preferred acids are citric, erytorbic, ascorbic, glutamic and aspartic acids.

Salts of organic acids such as salts of alkaline earth metals (magnesium, calcium) and alkali metals (lithium, potassium, sodium) are also effective as well as mixtures of organic acids and their salts. Calcium salts such as calcium carbonate, calcium acetate, calciumascorbate, calcium citrate, calciumgluconate monohydrate, calcium lactobionate, calciumgluceptate, calcium levulinate, calcium pumotothenate, calcium propionate, dibasic calcium phosphate and calcium succinate are preferred organic salts.

Examples of compounds of the other categories listed above are summarized in Table 1 below.

and

Table 1

Solubilizing agents

The class Examples 1 chemical name Examples, Commercial designation (Trade) partial glycerides glyceryl Monocaprylin ^w (Sigma), Capmul® MCM (Ab'rtec), Imwitor® 308 (Hils) -C ^ io L ^arc IALN glycerides Capmur * MCM (Abitec), Imwitor ' ⁰ ' 742 (HQls) Imwitor® 988 (HQls) glyceryl Myverof ⁴¹ 18-99 (Eastman), Calgene ⁶ GMO (Calgene), Capmul GMO (Abitec) glyceryl monolinoleate Myverof 18-92 glyceryl Imwitor ' ⁴ ' 191 (HQls) Calgene ' ⁶ ' GSO (Calgene) - glyceryl Imwitor ' ⁴ ' 312 (HQls) Calgene ⁶ 'GLO (Calgene) g1yrà> ry1Hi ranr-af- Capmur GDL glycerides triacetin Triacetin (Sigma) glyceride derivatives PEG derivatized glycerides Cremophor® ⁰ 'RH40, Cremophor ^"01 RH60 (BASF), Acconon CA5, CA-9, CA-15, W230, TGH (Abitec) polyglycolized glycerides Gelucire ^'4' 44 / 14,42 / 12,50 / 13,53 / 10, 35 / 10.48 / 09.46 / 07.62 / 05.50 / 02 ; Labrasol® (Gattefosse); Capmul® 3GO; 3GS, 6G2O, 6G2S, 10G40.10G10O (Abitec) polyethylene glycol PEG 200 monolaurate PEG 400 monolaurate PEG 600 monolaurate Calgene ' ⁴ ' 20-L, Calgene ** 4Q-L, Calgene (R) 60-L PEG 200 monostearate PEG 400 monostearate PEG 600 monostearate Calgene ' ⁴ ' 20-S, Calgene ** 40-S, Calgene (R) 60-S PEG 200 dilaurate PEG 400 dilaurate PEG 600 dilaurate Calgene ' ⁴ ' 22-L, Calgene ** 42-L Calgene® 62-L polypropyléhglykolestery prqpylénglykoldikaprylát Captex 200 (Abitec) polyhydroxy alcohol esters 'diethylene glycol' monolaurate Calgene ⁴ DGL

propyléhglykolmonolaurát Calgene PGMĽ ascorbyl Ascorbyl Palmitate Sigma polyoxyethylene PEG lauryl ether Non-L-4 (Calgene) : PEG stearyl ether Nonionic S-20 (Calgene), Myrj 45,52,57,59 (Sigma) sorbitan esters sorbitan Calgene SML Span 20 (Sigma) sorbitan Calgene SMO Span 80 (Sigma) polyoxethylene POE-20 sorbitan monolaurate Calgene PSML-20 Span 20 (Sigma), Tween 20 (Sigma), Capmul® POE-L (Abitec) POE-20 ironooleate Tween 80, PSMO-20 carbohydrate esters sucrose molaurate Ryoto LW-1540 phospholipids fofatidylcholín Lecithin Sigma . mixed phospholipids Emphos D70-30 (Witco) vene copolymers PEO-PPO? Block copolymers Pluronic F-68, BAS12 polyethylene glycols PEG 3350 different sources

In addition, other compounds useful as solubilizing agents in this invention are ethyl propionate, methylparaben, propylparaben, propylgalaniacamide, ethylvanillin, paraaminobenzoic acid, butylated hydroxyanisole, imiduurea and glycine. It is also noted that preferred compositions include mixtures of an organic acid with or without the corresponding organic acid salt and one or more of the inorganic solubilizers listed above or in Table 1.

It is also noted that, in general, it has been found that, to be more effective, the solubilizer should have a solubility in the aqueous environment of use containing chloride ions of at least mg / ml and preferably greater than 5 mg / ml.

A preferred group of solubilizing agents in addition to the preferred organic acids mentioned above include those listed in Table 2.

Table 2

Preferred solubilizing agents

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The class Examples chemical name Examples, Commercial designation (source) partial glycerides glyceryl Monocaprylin * ¹ (sigma), Capmul ¹ 'MCM (Abitec),. Imwitor® 308 (Huls) Partial glycerides Capmule MCM (Abitec), Imwitor ' ¹¹ ' 742 (HQis) Imwitor® 988 (Huls) glyceryl ** Imwitor 191 (Holst) Calgene * ¹ GSO (Calgene) glyceryl ** Imwitor 312 (Hüls) Calgene GLO * ¹ (Calgene) glycerides triacetin Triacetin * ¹ (Sigma) • sorbitan esters sorbitan Calgene SML * ^1, * ¹ Span 20 (Sigma) soroitanmonooxeat Calgene SMO * ^1, * ¹ Span 80 (Sigma) phospholipids phosphatidylcholine Lecithin * ¹ (Sigma) mixed phospholipids Emphos D70-30C (Witco) ' moC copolymers PEO-PPO block lrnpr> l ym & -y .... * ¹ Pluronic F-68, F127, L-62 (BASF) polyethylene glycols PEG 3350 different sources

Note: the names of the retailers listed above are as follows:

Abitec Corp. Janesville, WI

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BASF, Parsippany, N.J. Calgene Chemical Inc. Skokie, IL Chem Service, Inc., West Chester, PA Huls America, Piscataway St. Louis, MO Witco, Houston, TX

Preferred combinations of solubilizers include (1) an organic acid plus a salt of the same or a different organic acid, (2) an organic acid plus a non-ionic solubilizer, 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 nonionic solubilizing 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.

T 1 _t

As previously discussed, the dosage form may be tested in vitro to determine whether the excipient has a solubilizing effect on sertraline in an environment of use containing chloride ions and thus is useful as a solubilizing agent. A 0.075M NaCl solution is preferred for use as a test medium, although other solutions containing chloride ions with an equivalent or higher chloride ion concentration than 0.075M (e.g., 0.1N HCl or isotonic saline) can be used to determine the solubilizing effect of the test excipient.

In some cases, the reduced solubility is due to the apparent addition of a dosage form such as a powder to the test medium since gelling is visible.

Similar problems may be evident in a dosage form such as a tablet, as the tablet is, for example, opened by incision and gelling is visible on its open area. The recommended procedure is to initially form a solution containing the desired excipients including the solubilizing agent or agents. These excipients may be in any concentration appropriate to the dosage form contemplated, but are typically 80-100% saturated for organic acids and soluble salts or sugars. For other surfactant compounds, concentrations are typically in the range of 1 to 150% of the concentration of sertraline in the test solution.

Sertraline is added to this excipient-containing solution at a concentration of usually 80 to 100% saturation. The solution is filtered or decanted to remove any solids and then a 3M sodium chloride solution is added to a sodium chloride concentration of 0.075M. The concentrated sodium chloride solution should be added dropwise with stirring. This test medium should be maintained at a temperature of the order of 37 ° C for at least 2 hours, at which time the concentration of sertraline in the solution is determined. Preferably, the concentric _(water sertraline was maintained for 4 hours, preferably 8 hours, more preferably for 16 hours and most preferably for at least 20 hours. Size of mixing is not critical. If the sample is the test medium, filtration or centrifugation may be used to obtain a solution that is free of any solids or gels and also to prevent the inclusion of particles (which may contain sertraline) in the sample.

The analysis of the samples to determine the sertraline concentration can be performed using conventional analytical methods such as high performance liquid chromatography (HPLC). For example, sertraline concentrations can be determined by reverse phase HPLC with a ULTRACARB1.5 ODS 4.6.250 mm column (Phenomonex, Torrance, CA) and a mixture of acetic acid, triethylamine, acetonitrile and water as the 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 1 liter with water and filtering and degassing. Flow rates are typically of an order of 1.5 ml / min and a residence time of about 4 minutes. I i

Dosage forms with a solubilizing agent may be combined by conventional techniques. The immediate release dosage forms may be capsules, tablets, multiparticulates, liquid solutions or suspensions. Capsule formulations may be either soft gelatin capsules, wherein sertraline is either dissolved or suspended in the capsule core or hard gelatin capsules filled with multiparticulates, tablets or liquid (solution or suspension) filling. Immediate release tablets may be formed by standard techniques in the industry, by simply incorporating the solubilizing agent as one or more tablet excipients. Similarly, immediate release multiparticulates can be made to include solubilizing agents using techniques such as extensive spheronization, rotary granulation, seed coatings ₍ or other methods common in the pharmaceutical industry. Liquid formulations containing a solution or suspension, or both, can be made by methods known in the art. pharmaceutical industry.

Controlled release dosage forms can also be made to include solubilizing agents, using methods conventional in the pharmaceutical industry. Controlled release dosage forms include a wide variety of dosage forms that exert control over the dissolution rate or the 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 dosage forms with a small proportion of sertraline released immediately, followed by a major proportion of sertraline in the sustained-release dosage. Release algorithms other than pulsatile release can also be achieved. Many such formulations are described in co-pending PC9337JTJ and PC9824JTJ above.

Standard techniques can be used to produce controlled release dosage forms. For example, tablets may be made by commonly used direct compression methods for tablets containing sertraline and a solubilizing agent. To create sustained release, a pH-sensitive coating may be applied to these tablets using perforated pan coaters (e.g., HCT-60 tablet coating, Vector Corp.). The pH sensitive coating is resistant to low pH environments such as typically in the stomach, and then dissolves to release sertraline in a neutral pH environment, as is typical in the small intestine. Such coating materials (e.g. cellulose acetate phthalate or methacrylic acid copolymer) are common in the pharmaceutical industry.

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Alternatively, the tablets may be coated with a porous or semi-permeable membrane coating to provide sustained release of the tablet cores. A particularly preferred process for applying the membrane coating comprises dissolving the coating polymer in a mixture of solvents selected such that when the coating dries, a phase inversion is performed in the applied coating solution, resulting in a membrane with a porous structure.

Numerous examples of this type of coating system are disclosed in European Patent Application 0 357 369 B1, published March 7, 1990, which is incorporated herein by reference.

Many other types of controlled release dosage forms can also be made to benefit from inclusion of solubilizing agents, such as, but not limited to, matrix systems.

(1) non-eroding matrices, tablets, multiparticulates and hydrogel-based systems;

Hydrophilic eroding, dispersible or dissolvable matrix systems, tablets and multiparticulates; and

3) coating matrix systems.

Another class of controlled release dosage forms includes reservoir systems wherein drug release is modulated by the membrane, such as capsules and coated tablets or multiparticulates.

The third class includes osmotically based systems such as

1) coated bilayer tablets,

2) coated homogeneous tablet cores; and

(3) coated multiparticulates; and

4) osmotic capsules.

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The fourth class includes swellable systems where the drug is released by swelling and then pushing the core components out through the passage in the coating or surrounding shell or outer layer.

The invention is further illustrated by the following examples which should not be construed as limiting the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

This example shows that organic acids have the ability to increase the solubility of sertraline hydrochloride. 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 sertraline in the supernatant was then measured by HPLC analysis. The results of this test are shown in Table 1-1 below. Most of the listed acids successfully increased the solubility of sertraline hydrochloride (normal solubility 2.5 mg / ml).

Table 1-1

excipient approximate excipient concentration (mg / ml) solubility of sertraline (mg / ml) D, L-malic acid 900 21 citric acid 600 20 erytorbic acid 400 19 adipic acid 14 12 maleic acid 700 6.4 L-aspartic acid i '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 assay are malic, citric, erytorbic and adipic acid. Maleic acid, L-aspartic acid, tartaric acid and L-glutamic acid also significantly increased the solubility of sertraline hydrochloride. Some controlled release dosage forms with such acids in the core will perform better than such forms without these acids. This is particularly true for osmotic formulations that deliver a drug solution.

Example 2

This example demonstrates that organic acids have the ability to increase the solubility of sertraline acetate salt by a test method similar to that used for the hydrochloride salt described in Example 1. The solubilizing agent, its concentration, and the resulting solubility of sertraline are shown in Table 2-1 below. Based on these results, preferred acids for inclusion in a dosage form where increased solubility of sertraline acetate is desired are ascorbic, erytorbic, citric, lactic, aspartic, glutamic and aconitic.

Table 2-1

excipient excipient concentration (mg / ml) and solubility of sertraline (mg / ml) ascorbic acid 400 > 425 erytorbic acid 400 > 330 citric acid 600 146

Table 2-1 (continued)

excipient excipient concentration (mg / ml) solubility of sertraline (mg / ml) lactic acid 213 > 294 aspartic acid 7 110 glutamic acid 12 108 aconitic acid 500 > 92 itaconic acid 150 72 succinic acid 77 28 no - 64

Example 3

This example illustrates that organic salts and three calcium salts have the ability to increase the water solubility of sertraline lactate by a method similar to the method used for the hydrochloride salt and described in Example 1. Solubilizing agent, its concentration in aqueous test solution and solubility of sertraline lactate in the test solution are summarized in Table 3-1 below.

The water solubility of sertraline lactate is approximately 125 mg / ml.

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The data presented below show that 8 organic acids affected the solubilities of sertraline lactate, about equal to or greater than 125 mg / ml, adipic, erytorbic, itaconic, citric, aspartic, glutamic, histidine and ascorbic acid. Also, the solution of the mixture of the two acids has equally high solubility, ascorbic acid and aspartic acid.

The solubility of sertraline lactate was also high in calcium salt solutions either alone (calcium citrate) or as a mixture with ascorbic acid.

Table 3-1

excipient excipient concentration (mg / ml) solubility of sertraline lactate (mg / ml) adipic acid 14 360 erytorbic acid 400 > 217 itaconic acid 150 > 202 citric acid 600 162 aspartic acid 7 > 155 glutamic acid 12 > 125 histidine 42 > 116 acid. ascorbic / aspartic 400/7 116 ascorbic acid 400 102 glycine 250 66 aconitic acid 200 <59 tartaric acid 1400 12 fumaric acid 11 <9 sorbic acid 3 <9 kalciumlaktát / acid. ascorbic acid, 50/40 ° 160 calcium citrate 10 165 calcium carbonate / Ascorbic Acid 50/400 176 no - 125

Example 4

The lower solubility of sertraline chloride salt and all sertraline lactate and sertraline acetate salts in the presence of high concentrations of chloride ions suggests that the core formulations are advantageous because sertraline remains in solution, i. it does not precipitate or form a gel-like material when chlorides are present. Certain organic acids and salts have been shown to inhibit the precipitation or gelling of sertraline when chlorides are present by subsequent screening.

Sertraline lactate was dissolved in water either alone (as a control) or with a candidate solubilizing agent. Sodium chloride (as a concentrated solution) was then added and the result was found. The excipient was considered to be preferred when the solution remained clear and fluid, the greater the amount of chloride could be added to the excipient solution while the solution remained clear, the more preferred the excipient. The following Table 4-1 shows the results of this screening and shows that all excipients that were tested increased the concentration of sertraline in chloride solutions.

and

Table 4-1

excipient concentration of the excipient (mg / ml) NaCl concentration (mM) final sertraline concentration (mg / ml) detection after addition of NaCl no - 38 22 gel / precipitate acid. ascorbic / aspartic 400/7 152 162 solution acid. aspartic 7 114 162 solution 7 152 100 gel acid. ascorbic 400 100 102 clot acid. ascorbic / calcium lactate 400/50 150 165 solution acid. ascorbic / calcium carbonate 400/50 150 170 slight turbidity acid. citric / calcium lactate 600/50 150 162 solution histidine 42 150 110 slight precipitate

Example 5

The organic compounds (solubilizers) were sorted for their ability to increase the solubility of sertraline lactate in aqueous solutions in the absence or presence of chlorides. Excess sertraline lactate was added to the aqueous solution of the candidate solubilizer and in most cases organic acid. The organic acids were saturated in these solutions and the other solubilizers were at the concentration given in Table 5-1. The equilibrium solubility of sertraline was measured, then sodium chloride was added to the saturated solution and the final sertraline concentration was measured. The results of these screenings are summarized in Table 5-1.

Table 5-1

solubilizer solubilizer concentration (mg / ml) organic acid solubility of sertraline (mg / ml) NaCl concentration (mM) sertraline concentration with NaCl (mg / ml) Ί none (control) - no 125 150 5 2 monocapryline 10 ascorbic 160 150 160 3 triacetin 100 ascorbic 170 150 170 4 monobutyrin 50 no 120 150 120 5 diacetin 50 ascorbic 120 150 120 6 Imwitor ^ 312 10 ascorbic 120 150 120 7 Inwitor ¹¹³⁷⁵ 10 ascorbic 120 150 120 8 Imwitor ¹¹⁷⁴² 50 no 120 150 120 9 Imwitor ¹ * 988 50 no 140 100 140 10 triethylcitrate 50 ascorbic 160 150 160 11 Pluronic ^R L31 50 no 120 100 120 11 Cremophore ^R EL 50 ascorbic 120 150 120 13 isobutyrate acetate sucrose 50 ascorbic 120 ^x 150 120 Sodium caprylactate 50 ascorbic 120 150 120 15 monolaurate sucrose 50 no 150 150 150 16 ¹ sodium lauryl 50 * 1 ascorbic 120 150 120 17 Span 50 ascorbic 120 150 120

Example 6

This example illustrates that sertraline solubilizers can also increase the sertraline dissolution rate. The effect of the candidate excipient on the dissolution rate of sertraline was determined by adding solid drug, candidate solubilizing excipient and, in some cases, other excipients such as organic acid and osmagent (such as sugar) to a 1.8 ml centrifuge tube. The sample tubes were centrifuged at 14,000 g for 5 minutes in a microcentrifuge to compact the powder. 150 μΐ of gastric buffer was added to the dense powder and the samples were gently mixed and then centrifuged at 14,000 g in a microcentrifuge for 2 minutes.

Samples were then taken from the microcentrifuge and allowed to stand intact until the solution was removed. The solution was removed from the samples after a total of 10 minutes after the gastric buffer was added to the powder fill and analyzed by HPLC to determine the sertraline concentration.

The dissolution rate (mg sertraline / ml / min) was calculated from the measured concentration of dissolved sertraline in the supernatant as a function of time after the first 10 minutes of dissolution. These dissolution rates and excipient mixtures for which they were measured are summarized in Table 6-1 below.

As shown, some excipient mixtures containing solubilizers significantly (about 3 or more) increased the dissolution rate of sertraline compared to sertraline alone and compared to sertraline and ascorbic acid.

Table 6-1

candidate excipient organic acid concentration of org. acids (% wt.) 1 osmagent title concentration (% wt.) no - no - no no - ascorbic 51.0 lactose Imwitor ^R 312 5.0 ascorbic 49.5 lactose lecithin 5.0 ascorbic 51.0 lactose PEG 3550 5.0 ascorbic 51.0 lactose Capmul ^R MCM 5.0 ascorbic 71.0 no Capmul ^R MCM 4.7 no no lactose Imwitor ^R 191 5.0 ascorbic 49.5 lactose Myvrerol ^R (18-99) 5.0 ascorbic 49.5 lactose Sparn ^R 60 5.0 ascorbic 51.0 lactose askorbol- 6.8 no no lactose palmitate methylparaben / propyl / 0.5 / 0.5 / 1.0 ascorbic 50.0 lactose propyl gallate Imwitor ^R 312 6.8 aspartic 74.2 no

Table 6-1 (continued)

osmagent concentration (wt.%) other excipient other excipient concentration (wt%) salt form of sertraline concentration (% by weight) sertraline dissolution rate (mg / ml / min) - no - lactate - 100 20 no - lactate, 14 3.5 12.5 CaCOj 5 lactate, 14 20.9 15 no - lactate, 14 10 15 define any - lactate, 14 9.3 - no - lactate, 24 14.5 17 Caco-j . 4.7 lactate, 13, i 4.3 Ca citrate 47 12.5 CaCO ₃ 1.0 lactate, 14 8.0 12.5 no - lactate, 14 6.4 15 no - lactate, 14 9.5 74.2 no - lactate, 19 4.3 17.5 no - lactate, 14 11.5 - no - lactate, 19 5.3

Example 7

This example illustrates a process for preparing osmotic tablets comprising a tablet core comprising seratralin with and without solubilizing agents surrounded by a semipermeable asymmetric membrane coating. In this example, the incorporation of a solubilizer into a controlled release formulation containing sertraline is demonstrated.

Sertraline hydrochloride was manually triturated for 10 minutes with citric acid and microcrystalline cellulose (Avicel PH 102, FMC) using a 16.5 cm diameter mortar and a pistil. Magnesium stearate was then admixed as a lubricant by stirring with a lance 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 g. The blended mixture was compressed into 470 mg tablets in a modified hydraulic lift (manufactured by Dayton), provided with a pressure measurement and a 0.95 cm concave press, under a pressure of 17.2 MPa for 2 seconds. The dimensions of the resulting tablets were 0.95 cm in diameter and 0.64 cm in thickness.

These tablets were coated with a semipermeable membrane coating (as described in US Patent 5,612,059 using an LDCS-20 pan coat (Vector Corp.) at a spray rate of 20 g / min, an inlet temperature of 40 ° C and an air flow of 40 CFM. the solution contained 10% by weight cellulose acetate (Eastman Chemical ', CA398-10), 2.5% polyethylene glycol (BASF, PEG 3350), 15% water and 72.5% acetone The coated tablets were dried for 1 hour at 50 ° C before After drying, the weight of the coating material applied was 15.4% of the total weight.

Other osmotically dosed tablets were prepared using essentially the same procedure for preparing tablet cores and using an asymmetric membrane coating over these cores as described above.

The composition of the cores and coating solution was varied as shown in Table 7-1 below.

Significant changes in core composition as shown include: sertraline salt form, type and amount of solubilizer, and type and amount of osmagent. The amounts of binder (Avicel ^R , lubricant (calcium stearate) and solubilizer) were different than necessary to obtain good tabletting and wetting properties, all containing a dose of sertraline 50 mg / tablet.

Notes on the following table:

IM = Im 312 ^R 312

CA = cellulose acetate 398-10

EC = Ethocel S-100

MC = mococapryline

Mg St. - magnesium stearate

PEG = polyethylene glycol 3350

Myrj = Myrj 52 ^R

Table 7-1

Pr. no. core composition solubilizer core weight (mg) drug solubilizing acid salt hm. Type wt.% Type wt.% form % 7a 470 chloride 12 no no 7b 470 lactate 14 no no 7c 470 lactate 14 aspartic 11 no 7d 470 lactate 14 glutamic 10 MC 5 7e 470 lactate 14 aspartic 11 them 5, 7f 470 lactate 14 glycine 25 them 5 7 g 470 lactate 14 aspartic 11 them 5 7h 470 lactate 14 aspartic 11 no

and

Table 7-1 (continued)

Pr. core composition coating solution no. (cont.) osmogent Avicel mg t t me Type polymer PEG Water coating type him. T hm.t st. polymer hm. and hm. T hm.t dry hm.t hm.t 7a lactose 66 20 2 no CA 10 2.5 15 15.4 7b lactose 65.4 19.3 1.33 no DE 6 4 8 1 7c fructose 38 29.5 2.5 ca CA 10 2.5 15 11 acetate 7d sucrose róza 50 15 Appl. ca lactate EC 6 4 10 10.1 Myrj 7e fructose 36 27 2.5 ca CA 10 2.5 15 10.3 acetate 7f fructose 28.5 25 2.5 no CA 10 2.5 15 15.9 fructose 36 27 2.5 ca CA 10 2.5 15 20 acetate 7h fructose 38 29.5 2.5 ca CA 10 2.5 15 10 acetate

The release rates of sertraline from these formulations were determined by testing the tablets in USP device # 2 with a paddle speed device 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, maintained at 37 ° C. Receptor solution samples were taken at the times shown in Table 7-2. Analysis of the released sertraline was determined by reverse phase high performance liquid chromatography (RP HPLC). The results of the release rate tests performed using these procedures are summarized in Table 7-2. The first two formulations that are shown, 7a and 7b, show low release rates and are included as comparative examples. Both of these formulations contain a sertraline salt (hydrochloride or lactate) and only lactose as osmagent and no solubilizing excipient. The remaining formulations (7c to 7h) listed in Table 7-2 all contain one or more solubilizing excipients and all demonstrate significantly higher sertraline release rates compared to formulations that do not contain solubilizers.

Table 7-2 Tablets Proportions of Drug Released (%) at a Specified Time from Ex.

number oh lh 2h 4h 8h 12h 20h 7a 0 0 0 0 0 0 0 7b 0 0 1 2 1 - 10 12 (17h) 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 7 g 0 0.4 4 13 31 41 53 7h 0 8 18 38 56 64 66

Claims (11)

PATENT CLAIMS (1) organic acids and organic acid salts; (1) organic acids or organic acid salts; (1) organic acids and organic acid salts; (1) organic acids and organic acid salts; A composition of matter comprising sertraline or a pharmaceutically acceptable salt thereof and an amount of solubilizing agent sufficient to produce a concentration of dissolved sertraline in an environment of use containing chloride ions which is 1.5 times the concentration elicited by a comparative substance composition identical thereto, but without incorporating said solubilizing agent. 2) partial glycerides, 2) partial glycerides, 2) partial glycerides, 2) partial glycerides, Compound composition according to claim 1, characterized in that the environment of use is the gastrointestinal tract. 3) carbohydrates, 3) glycerides, 3) glycerides, 3) glycerides, Compound composition according to claim 1, characterized in that the environment of use is a test medium containing chloride ions. 4) glyceride derivatives, (4) glyceride derivatives; 4) glyceride derivatives, 4) glyceride derivatives, Compound composition according to claim 3, characterized in that the environment of use is 0.075M sodium chloride. 5) polyethylene glycol esters, 5) polyethylene glycol esters, 5) polyethylene glycoesters, 5) polyethylene glycoesters, A composition according to claim 1, characterized in that it is an immediate release dosage form. • I t 'I 6) polypropylene glycol esters, 6) polypropylene glycol esters, 6) polypropylene glycol esters, 6) polypropylene glycol esters, The composition of matter of claim 1, which is a controlled release dosage form. 7) esters of polyhydroxy alcohols, 7) esters of polyhydroxy alcohols, 7) esters of polyhydroxy alcohols, 7) polyhydroxy alcohol esters, The composition of matter of claim 1, wherein the solubilizing agent is selected from: 8) polyoxyethylene ethers, 8) polyoxyethylene ethers, 8) polyoxyethylene ethers, The composition of matter of claim 4, wherein the amount of solubilizing agent is sufficient to maintain, for at least 2 hours, the dissolved sertraline concentration at a level that is at least 1.5 times the concentration of sertraline produced by the comparative substance composition that is identical but without incorporating the solubilizing agent. 8) polyoxyethylene ethers, 9) sorbitan esters, 9) sorbitan esters, * 10) polyoxyethylene sorbitan esters,> 11) carbonate salts. * t. 21. The composition of claim 15, wherein the solubilizing agent is selected from the group consisting of aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calcium acetate, ascorbic acid, citric acid, glutamic acid, and calcium carbonate. A method for increasing the solubility of sertraline in an aqueous medium of use comprising chloride ions, characterized in that sertraline is administered to said medium of use in a fabric composition additionally containing a solubilizing agent. The method of claim 22, wherein the concentration of dissolved sertraline in said environment of use also comprising the solubilizer is at least 1.5x higher than the concentration of sertraline elicited by the comparative composition identical to the substance composition containing the solubilizing agent except for the inclusion of the sol. bilizačného means. r '’ The method of claim 22, wherein the environment of use is the gastrointestinal tract. The method of claim 22, wherein the environment of use is an aqueous test medium containing chloride ions. 26. The process of claim 25 wherein said medium is 0.075M sodium chloride. The method of claim 22, wherein the fabric composition is in the form of an immediate release dosage form. The method of claim 22, wherein the fabric composition is in the form of a controlled release dosage form. The method of claim 22, wherein the solubilizing agent is selected from the group consisting of 9) sorbitan esters, The composition of matter of claim 1, wherein the solubilizing agent is selected from the group consisting of aspartic acid, glyceryl monocaprylate, glyceryl monolaurate, calcium acetate, ascorbic acid, citric acid, glutamic acid, and calcium carbonate. 9) sorbitan esters, 10) polyoxyethylene sorbitan esters; and 10) polyoxyethylene sorbitan esters; and 11) carbonate salts. . . I 14. A composition according to claim 10, wherein the solubilizing agent is selected from the group consisting of aspartic acid, glyceryl monocarpylate, glyceryl monolaurate, calcium acetate, ascorbic acid, citric acid, glutamic acid and calcium carbonate. A composition of matter comprising sertraline or a pharmaceutically acceptable salt thereof and an amount of solubilizing agent sufficient to induce in vivo C _max and / or AUC greater than at least 10% than the C _max and / or AUC induced by the reference substance. a composition which is identical thereto but without incorporating said solubilizing agent. The composition of matter according to claim 15, characterized in that the C 6 and / or AUC induced by the composition comprising the solubilizing agent is at least 15% higher than the corresponding C _max and / or AUC induced by said comparative composition. The composition of matter according to claim 16, characterized in that the C _max and / or AUC induced by said solubilizing agent composition is at least 20% higher than the corresponding C α and / or AUC induced by the comparative composition. 18. The composition of matter of claim 15, which is an immediate release dosage form. The composition of matter of claim 15, which is a controlled release dosage form. I. '' I, The composition of matter of claim 15, wherein the solubilizing agent is selected from the group consisting of: 10. A composition of matter comprising sertraline or a pharmaceutically acceptable salt thereof and an amount of solubilizing agent sufficient to form and maintain, for at least 2 hours in 0.075M sodium chloride, a dissolved sertraline concentration of at least 1.5 times greater than the concentration induced by the reference substance composition, which is identical but without the inclusion of said solubilizing agent. 11. A composition according to claim 10, wherein the composition is an immediate release dosage form. A composition according to claim 10, characterized in that it is a controlled release dosage form. 13. A composition according to claim 10, wherein the solubilizing agent is selected from the group consisting of: 10) polyoxyethylene sorbitan esters; and 11) carbonate salts. 11) carbonate salts.