MXPA00011153A - Novel formulation containing paroxetine - Google Patents

Abstract

Paroxetine hydrochloride, in a form other than the hemihydrate, which is formulated into capsules under conditions such there is no detectable conversion to hemihydrate during the manufacturing process.

Description

NEW FORMULATION CONTAINING PARQXETINE DESCRIPTIVE MEMORY This invention relates to new formulations and to the use of the formulations in the treatment and / or prevention of certain disorders. The patent of E.U.A. 4,007,196 describes certain compounds that possess antidepressant activity. A specific compound mentioned in this patent is known as paroxetine and has the following formula: This compound has been approved for use in humans and is marketed, in the form of its hydrochloride salt, in many countries as an antidepressant agent. All paroxetine hydrochloride sold to date has been in the form of oral swallowable tablets containing the hemihydrate, which is described in European patent EP-0 223 403. It has been reported that paroxetine hydrochloride also exists as anhydrate. The WO document 96/24595 describes the preparation and physical properties of four different polymorphic forms (forms A, B, C and D) of the anhydrate. WO 95/16448 discloses that it is possible for paroxetine to develop a pink color, unless it is formulated into tablets using a formulation procedure in which water is absent, such as dry direct paroxetine compression or dry paroxetine granulation followed by compression in tablets. The term 'dry' was used to denote substantially dry as opposed to the addition of wholesale water that had previously been employed in the wet granulation process. Surprisingly, it has now been discovered that, even under these relatively dry conditions, the paroxetine anhydrate hydrochloride has a tendency to become, at least partially, the hemihydrate during the tabletting process. Although not dangerous, this creates difficulties in establishing and maintaining a reference standard for regulatory and quality control purposes. Accordingly, this invention provides paroxetine hydrochloride in a form other than the hemihydrate, which is formulated into capsules under conditions such that there is no detectable conversion to hemihydrate during the manufacturing process. The paroxetine hydrochloride may be present, for example, in amorphous form or as a crystalline anhydrate. This can be achieved, for example, by the use of either excipients that are essentially anhydrous for capsules that are filled with powder (ie, they contain less than 2%, especially less than 1.5%, preferably less than 1% water) or excipients that are essentially hydrophobic for capsules that are filled with solids or liquids. It has been found, for example, that anhydrous dibasic calcium phosphate and polyglycolized glycerides can be used to form oral swallowable capsules with anhydrous paroxetine hydrochloride without undesirable conversion to hemihydrate during the manufacturing process. The capsules are then packed with a desiccant to prevent the conversion of anhydrate to hemihydrate during storage. Accordingly, this invention also provides a process for the preparation of paroxetine anhydrate hydrochloride capsules free of detectable hemihydrate, which is characterized by the use of conditions such that there is no detectable conversion of the anhydrate to hemihydrate during the manufacturing process. Said conditions can be achieved by the use of essentially anhydrous / hydrophobic excipients under conditions of low relative humidity. Examples of excipients with the required low moisture content include materials such as anhydrous dibasic calcium phosphate, anhydrous direct compression lactose, monosaccharides (such as mannitol), disaccharides (such as lactitol), powdered cellulose, pregelatinized starch and similar materials. These materials can also be of an appropriate degree for direct compression, since this can assist in the filling of powder in the capsule filling machine and also gives appropriate characteristics of compression in the mixture for certain types of capsule filling machines Dibasic anhydrous calcium phosphate is commercially available to a pharmaceutically acceptable degree, for example, A- (Rhone Poulenc) as the main excipient in a formulation of capsules that are filled with powder In a particular method of the invention, paroxetine anhydrate hydrochloride is mixed with anhydrous dibasic calcium phosphate and other pharmaceutically acceptable excipients, such as a lubricant (magnesium stearate), and mixed in an appropriate mixer before filling the wrappers of cellulose from intrinsically low moisture content capsules (eg, Shionogí Qualicaps, <3%) In addition, some of the low moisture sugars are available in direct compression grades, for example, mannitol and lactitol, lactitol Direct compression is commercially available at a pharmaceutically acceptable level, for example, Finlac DC (Xyro end) In a particular process of the invention, paroxetine hydrochloride anhydrate is mixed with direct compression lactitol and other pharmaceutically acceptable excipients, such as a lubricant (magnesium stearate), and mixed in an appropriate mixer before filling the wrappers of cellulose from intrinsically low moisture content capsules (eg, Shionogy Qualicaps < 3%) Examples of excipients with the necessary hydrophobic character include materials such as polyglycolized glycends (such as Gelucire 44/14), complex fatty materials of vegetable origin (such as cocoa oil, carnauba), vegetable oils (such as peanuts, olive, palm kernels, cotton, corn, soybeans), hydrogenated vegetable oils (such as peanuts, palm kernels, cotton, soybeans, castor oil, coconut), natural fatty materials animal origin (such as beeswax, lanolin, fatty alcohols such as cetyl, stearyl, lauric, myristic, palmitic, stearic), esters (such as glycerol stearate, glycol stearate, ethyl oleate, isopropyl myristate), interesterified semi-synthetic solid glycerides (as Suppocire, Witepsol), interesterified semisynthetic liquid glycerides (such as Miglyol 810/812, Labrafil), fatty acid or amide alcolamides (such as stearamidoethanol, coconut fatty acid diethanolamine, polyoxyethylene glycols (such as PEG 400, PEG 600, PEG 4000) An appropriate vegetable oil, such as peanut oil (Arachis oil), is commercially available to a pharmaceutically acceptable degree, for example, Lipex 101 (Karlsham ns) In a particular process of the invention, the paroxetine anhydrate hydrochloride is mixed with hot Lipex 101 in an appropriate mixer (to form a suspension) before filling the gelatin shells of the capsules. A hydrogenated vegetable oil is commercially available to a commercially acceptable degree; for example, Lubritab (Edward Mendell). In a particular process of the invention, paroxetine anhydrate hydrochloride is mixed with molten Lubritab in a suitable mixer, a hydrophilic excipient; for example, anhydrous lactose (to form a suspension) is added before filling the gelatin shells of the capsules.

An appropriate fatty alcohol, such as cetyl alcohol, is commercially available to a pharmaceutically acceptable degree; for example, Crodacol C95 (Croda). In a particular process of the invention, the paroxetine anhydrate hydrochloride is mixed with molten Crodacol C95 in an appropriate mixer (to form a suspension) before filling the gelatin shell of the capsules. A polyglycolized glyceride is commercially available to a pharmaceutically acceptable degree; for example, Gelucire 44/14 (Gattfosse). In a particular process of the invention, paroxetine anhydrate hydrochloride is mixed with melted Gelucire 44/14 in an appropriate mixer (to form a solid suspension) before filling the gelatin shells of the capsules. An interesterified semisynthetic liquid glyceride is commercially available to a pharmaceutically acceptable degree; for example, Labrafil M 2125CS (Gattfosse) or Migiyol 810/812 (Hull). In a particular process of the invention, the paroxetine anhydrate hydrochloride is mixed with Labrafil M 2125CS (Gatfosse) to produce a suspension in a soft or hard gelatin capsule formulation. Alternatively, the paroxetine anhydrate hydrochloride is mixed with Migiyol 810 (HOls AG) in an appropriate mixer to produce a suspension in a soft or hard gelatin capsule formulation. An interesterified semisynthetic solid glyceride is commercially available to a pharmaceutically acceptable degree; by example, Suppocire AM - DM (Gattfosse). In a particular process of the invention, (example 4) paroxetine hydrochloride anhydrate is mixed with molten Suppocire DM in an appropriate mixer (to form a suspension) before filling the gelatin shells of the capsules. The capsule formulation is packaged in standard package / cap pharmaceutical presentations, optionally with a desiccant. The amount of paroxetine used is adjusted in such a way that in a single unit dose there is a therapeutically effective amount of paroxetine. Preferably, the dose of one unit contains from 10 to 100 mg of paroxetine (measured in terms of free base). More preferably, the amount of paroxetine in a dose of one unit is 10 mg, 20 mg, 30 mg, 40 mg or 50 mg. The amount of paroxetine that is most preferred at a dose of one unit is 20 mg. The paroxetine used in the formulation is in the form of the anhydrated hydrochloride, which can be prepared according to the procedures described in WO 96/24595. Appropriate procedures for preparing paroxetine include those mentioned in the U.S. Patents. 4,009,196, 4,902,801, 4,861, 893 and 5,039,803 and PCT / GB 93/00721. It has been mentioned that paroxetine has a particular utility in the treatment of depression; Paroxetine can also be used in the treatment of mixed anxiety and depression, obsessive-compulsive disorders, panic, pain, obesity, senile dementia, migraine, bulimia, anorexia, social phobia and depression arising from premenstrual tension and adolescence.

Therefore, this invention also provides a method for treating or preventing any of the above disorders, which is to administer an effective or prophylactic amount of the swallowable oral capsules prepared in accordance with this invention. The following examples illustrate this invention: EXAMPLE 1 m9 Paroxetine hydrochloride t 22.22 Dibasic calcium phosphate anhydrous 225.28 Magnesium stearate 2.50 Capsule weight 250.00 EXAMPLE 2 mg paroxetine hydrochloride t 22.22 Direct compression lactitol 225.28 Magnesium stearate 2.50 Weight of the capsule 250.00 EXAMPLE 3 mg Paroxetine hydrochloride t 22.22 Anhydrous lactose 225.28 Magnesium stearate 2.50 Weight of the capsule 250.00 EXAMPLE 4 g Paroxetine hydrochloride t 22.22 Anhydrous lactose 175.78 Magnesium stearate 2.00 Weight of the capsule 200.00 EXAMPLE 5 g Paroxetine hydrochloride t 22.22 Anhydrous lactose 126.28 Magnesium stearate 1.50 Weight of the capsule 150.00 Paroxetine hydrochloride t EXAMPLE 6 22 22 Lipex 101 227.78 Weight of the capsule 250.00 EXAMPLE 7 mg Paroxetine hydrochloride t 22.22 Lactose anhydrous 50.0 Lubritab 177.78 Weight of the capsule 250.00 EXAMPLE 8 mg Paroxetine hydrochloride t 22.22 Crodacol C95 227.78 Weight of the capsule 250.00 EXAMPLE 9 mg Paroxetine hydrochloride t 22.22 Gelucire 44/14 227.78 Weight of the capsule 250.00 mg Paroxetine hydrochloride t EXAMPLE 10 22 22 Labrafil M 2125CS 227.78 Weight of the capsule 250.00 EXAMPLE 11 mg Paroxethane hydrochloride t 22.22 Migiyol 810 227.78 Capsule weight 250.00 EXAMPLE 12 mg paroxetine hydrochloride t 22.22 Suppocire DM 227.78 • JO Weight of the capsule 250.00 t Equivalent to 20 mg of paroxetine in an anhydrous free base base

Claims (8)

NOVELTY OF THE INVENTION CLAIMS

1. - Paroxetine hydrochloride in a form other than hemihydrate, which is formulated in capsules under conditions such that there is no detectable conversion to hemihydrate during the manufacturing process.

2. - Paroxetine hydrochloride according to claim 1, further characterized in that it is amorphous or in the form of a crystalline anhydrate.

3. A process for the preparation of free paroxetine hydrochloride capsules of the detectable hemihydrate, further characterized by the use of conditions such that there is no detectable conversion to hemihydrates during the tabletting process.

4. The process according to claim 3, further characterized in that it is carried out using essentially anhydrous and / or hydrophobic excipients.

5. The process according to claim 4, further characterized in that the excipients are chosen from the groups consisting of anhydrous dibasic calcium phosphate, anhydrous direct compression lactose, monosaccharides, disaccharides, powdered cellulose and pregelatinized starch.

6. - The method according to claim 4, further characterized in that the excipients are selected from the group consisting of polyglycolized glycerides, complex fatty materials of vegetable origin, vegetable oils, hydrogenated vegetable oils, natural fatty materials of animal origin, fatty alcohols, esters, interesterified semi-synthetic solid glycerides, interesirified semi-synthetic liquid glycerides, fatty acid or amide alcolamides and polyoxyethylene glycols.

7. - The method according to any of claims 3 to 6, further characterized in that it is carried out under conditions of low relative humidity.

8. A set of parts consisting of capsules according to claim 1 or 2, or obtainable by the method of any of claims 3 to 7, together with a desiccant.