SK6942003A3 - Oral extended release formulation of gepirone - Google Patents

Abstract

This invention makes a pharmaceutical formulation for oral administration with extended release properties available comprising an amount of gepirone hydrochloride, an amount of a cellulosic polymer matrix and an amount of microcrystalline cellulose characterised in that the amount the pharmaceutically acceptable cellulosic polymer matrix is from 70 to 85 wt%, the amount of carbohydrate binder is from 7 to 10 wt% and the amount of gepirone hydrochloride is from 13 to 21 wt%. The formulation is useful for a treatment for depression or a related central nervous system disorder with gepirone administered in a once-a-day oral formulation for extended release of gepirone.

Description

The invention relates to a pharmaceutical composition for oral administration with sustained release properties comprising a certain amount of gepirone hydrochloride, a certain amount of cellulose polymer matrix and a certain amount of microcrystalline cellulose.

BACKGROUND OF THE INVENTION

Such pharmaceutical compositions are described in EP 700 680 for use in the treatment of CNS disorders such as fear, depression and panic disorders. Gepiron is a drug that induces side effects when reaching high peak levels. It is desirable that an even distribution of drug levels in the blood have a suitably tolerated therapeutic dose level. It has been reported that optimal treatment of major depressive disorders was achieved with daily doses of up to 100 mg gepirone hydrochloride (Wilcox et al., Psychopharmacology Bulletin). Administration of the total daily amount of gepirone was extended to the administration of 20 mg gepirone hydrochloride prolonged-release tablets at intervals throughout the day. This has been done not only because it has been noted previously (EP 700 680) that sustained release formulations can be reliably manufactured and have slow release properties when the proportion of gepirone hydrochloride is at most 12% of the total content, preferably at most 11% by weight. and the proportion of microcrystalline cellulose is at least 10%, with a preferred minimum of 11% by weight, but also because high doses once a day could be expected to be poorly tolerated, even if the sustained release formulation is administered.

Contrary to what was expected, it has been found that appropriate higher strength prolonged-release tablets can be made and are well tolerated in a once-daily dosage form in those patients who have already become accustomed to lower dosages.

It is clear that it is more convenient for such patients to receive the once-daily formulation.

2. Summary of the Invention

The present invention provides a pharmaceutical composition for oral administration with sustained release properties comprising an amount of gepirone hydrochloride, an amount of cellulose polymer matrix, and an amount of microcrystalline cellulose in which the amount of pharmaceutically acceptable cellulose polymer matrix is from 70 to 85% by weight. % is from 7 to 10 wt. and the amount of gepirone hydrochloride is from 13 to 21 wt.

The pharmaceutical composition may optionally contain other pharmaceutically acceptable excipients such as glidants, lubricants and coloring agents.

The invention also provides once-daily gepirone hydrochloride drug therapy in a pharmaceutical composition for oral administration having a composition as described above. This treatment is appropriate and well tolerated in those patients treated for depression or related central nervous system disorders who have started on a treatment regimen starting with approximately 20 mg gepirone hydrochloride per day and who gradually increased to 60 to 100 mg gepirone hydrochloride per day.

The pharmaceutical composition for oral administration is usually in the form of a tablet and a capsule. In contrast to the weight of an 80 mg tablet according to EP 700 680, the tablets according to the invention may have a total weight of at most 450 mg. Despite the relatively high amount of gepirone hydrochloride relative to the cellulosic polymer matrix and also to the carbohydrate binding agent, oral compositions, especially tablets, could produce tablets with acceptable gepirone dissolution properties and sufficient stability during manufacture and handling.

The pharmaceutically acceptable cellulosic polymer matrix has the task of retaining gepirone hydrochloride so as to obtain a sustained release effect. Suitable matrices include hydroxyalkyl substituted alkylcelluloses having a viscosity of 15,000 cps to 100,000 cps. Hydroxymethylpropylcellulose (HPMC) grades K15M and K100M is preferred, and grade K100M, Premium (Methocel) is particularly preferred. The amounts of the ingredients in the pharmaceutical composition of the invention are expressed in weight percent (% by weight) based on the total weight of the composition, which is usually a tablet. The term alkyl as used herein,

-3 means a branched or linear saturated unsubstituted carbon chain.

In view of the desired viscosities, the alkyl groups belonging to this paragraph contain no more than 6 carbon atoms.

The term "pharmaceutically acceptable" for suitable excipients for use in the practice of the invention corresponds to the requirements set forth for pharmaceutical excipients in general. These requirements with respect to safety and non-interference with the active ingredient in pharmaceutical compositions are well known to those skilled in the art. Standard compositions of pharmaceutically acceptable carriers and excipients can be found in the Handbook of Pharmaceutical excipients (2nd ed., Ed. A. Wade and P.J. Weller, edited by the American Pharmaceutical Company, Washington and The Pharmaceutical Press, London 1994). The ingredients in the pharmaceutical composition, such as e.g. carriers, binders, glidants, lubricants and colorants are used, e.g. to obtain some consistency, coloring and flowability in the tablets. In a preferred embodiment of the present invention magnesium stearate, colloidal silicon dioxide and iron oxide dyes are used.

Glidants and lubricants are agents that reduce the adherence of the powder mixture or tablets during manufacture. Methods of using such additives are known in the art of pharmaceutical compositions, such as e.g. described in Chapter 19 of Remington's Pharmaceutical Sciences (18 Ed., ed. A.R. Gennaro; Mack Publishing Comp; Easton, Pennsylvania).

Binders are substances used to induce the cohesive properties of a pharmaceutical composition, resulting in minimal loss from the pharmaceutical composition during manufacture and handling. Carbohydrate binding agents are e.g. cellulose, methylcellulose, ethylcellulose, hydroxypropylcellulose, sugars, starches, amylopectin, dextrin, maltodextrin, resins and alginates. Microcrystalline cellulose, particularly Avicel pH 101, is a preferred binding agent for use in the invention.

The term pharmaceutical composition for oral administration with sustained release properties is used herein to refer to the sustained release properties of gepirone, as described in EP 700 680. Specifically, the composition of the invention has a rate of release of gepirone from the composition

Approximately such that 18 to hours are required to achieve 90-95% gepirone absorption.

The oral pharmaceutical compositions of the present invention may be prepared by methods known in the art, e.g. such as those described in the standard Gennaro et al., Remington's Pharmaceutical Sciences (18th ed., Mack Publishing Company, 1990, see in particular section 8: Pharmaceutical compositions and their manufacture). Care should be taken when handling the high strength compressed compositions of the present invention to prevent tablet disintegration and breakage.

Gepirone can be produced by any of the methods known in the art. Conveniently, the compound is produced by the methods described in US Patent No. 5,201,549. 4,423,049. Gepirone sustained release pharmaceutical compositions are described in EP 700 680. The contents of these documents are incorporated herein by reference.

The following examples serve to illustrate embodiments of the invention.

DETAILED DESCRIPTION OF THE INVENTION

Example 1

Production of 160 000 tablets

Tablet composition (numbers in the table refer to mg)

ingredients 40 mg 60 mg 80 mg feature gepiron HCl 40.0 60.0 80.0 active substance hydroxypropyl (Metocel K100M Premium) 290.0 290.0 290.0 drug release controlling polymer Microcrystalline cellulose (Avicel pH 101) 52.12 31.0 33.7 thinner Euroxide yellow or red (E7055, E7056, or E7016) 0.08 1.2 3.5 coloring colloidal silicon dioxide (cab-o-sil 1.6 1.6 1.6 glidant

M5) magnesium stearate N F 1.2 1.2 1.2 lubricant

Effective premix

Transfer colloidal silicon dioxide, NF, dye (40 mg yellow E 7056; 60 mg yellow 7055; 80 mg yellow E 7055 and red Eur 701 E 7016), powdered gepirone hydrochloride and 20% hydroxypropylmethylcellulose USP up to 0.60 m ³ ( 2 cu. Ft.) Planetary mixer (Hobart mixer). Mix the ingredients for 15 min in a planetary mixer (Hobart mixer). Mark as "Active pre-mix.

Pressing mixture

Grind the effective pre-blend in a Fitzmill grinding machine using perforated plate no. 0020 at high speed to crush any lumps.

Mix the active pre-blend in a 3.048 m ³ (10 cu. Ft.) "V" blender without a high speed blender, passage through a # 12 mesh screen and transfer a mixture of 80% HPMC, microcrystalline cellulose, NF and 50% magnesium stearate, NF to V-mixer without high speed mixing blade. Mix the ingredients in the V-mixer without the high-speed stirring blade for 24 minutes and mark it as "pressing mixture".

pressing

Compress the mixture into moldings using a 7/8 round flat (60.80) inclined edge die (40) using a Kikusui-Hercules compression machine.

During the process:

mass 2250 mg hardness 7 kp target thickness 0.255 (0.64 cm)

-6Final mixture

Grind the extrusions in the SS Fitz grinder with screw filler using perforated plate no. 0093 at medium speed, with the blades forward and the screw filler set to 3.5 ± 0.5. Transfer ground material to 3,048 m ³ (10 cu. Ft.) Of SS V mixer without high speed mixing blade. Sieve a mixture of 50% magnesium stearate, NF through a # 18 mesh and transfer to a V-blender. Stir for 6 minutes.

Compress the tablets in a rotary Kukusui-Libra compression press using 0.338 x 0.405 (0.858 cm x 1.028 cm) Ovoid rectangular punches.

During the process:

strength, mg 40 & 60 80 weight, mg 385 ± 27 410 ± 29 hardness, kp 18 ± 4 20 ± 8 thickness, in inches (cm) 0.230 to 0.260 (0.584 to 0.660) 0.235 to 0.265 (0.596 to 0.673)

Store in sealed containers until further use or testing.

The drug release profile of the tablets produced is as shown in this example. Another 20 mg tablets were made according to the method described in EP 700 680 to compare the drug release profile of the 60 and 80 mg tablets of the invention.

Characterization of gepirone release from tablets (the numbers in the table indicate the percentage dissolution of the theoretical content in the tablets)

Release after: 1 h 5h 12 h 20 h "Recovery" 20 mg tablets 19 49 77 93 102 40 mg tablets 21 50 77 93 100 60 mg tablets 21 51 81 97 102 80 mg tablets 22 52 80 96 101

-7Example 2

To make production for batches of 800,000 tablets, some adjustments were used:

The procedures are according to the methods of Example 1, but the effective premix is mixed in 321.6 L (340 qt.) AZMF Glen mixer for 28 min, the size of the V-mixer is 9.144 m ³ (30 cu. Ft) and the final mixing takes 7 minutes. The tablets had similar properties to those found in Example 1. Particular attention was paid to the problem of friability of the 80 mg strength tablets. It is preferred to compress 80 mg tablets at a speed of 20 rpm, i.e. generally less than 30 rpm, which is set in the compression device to reduce the friability of the tablets.

Claims (4)

A pharmaceutical composition for oral administration with sustained release properties comprising an amount of gepirone hydrochloride, an amount of cellulose polymer matrix, and an amount of microcrystalline cellulose, wherein the amount of pharmaceutically acceptable polymer matrix is in the range of 70 to 85% by weight. the amount of carbohydrate binding agent is from 7 to 10 wt. and the amount of gepirone hydrochloride is from 13 to 21 wt. Pharmaceutical composition according to claim 1, characterized in that the cellulosic polymer matrix is hydroxymethylpropylcellulose with a viscosity of 15,000 cps to 100,000 cps. Pharmaceutical composition according to claim 1, characterized in that the microcrystalline cellulose is Avicel pH 101. The sustained release oral gepirone pharmaceutical composition of claim 1 for use in the treatment of depression and related disorders of the central nervous system by administration once a day.