Title of Invention


Abstract The present invention relates to mirtazapine formulation process containing anhydrous mirtazapine as the active with a specific particle size distribution (PSD), having satisfactory handling properties and which formulation with suitable adjuvants results in compliance with the desired pharmaceutical parameters.
Full Text

This invention is in the general field of pharmaceuticals and relates in particular to the formulation of Mirtazapine or any of its pharmaceutically acceptable salts. More specifically, the present invention relates to a pharmaceutical formulation process, which comprises anhydrous Mirtazapine or any of its pharmaceutically acceptable salts as an active ingredient with other suitable excipients.
Mirtazapine, 1,2,3,4,10,14b-hexahydro-2-methyl-pyrazino [2,1 -a]pyrido[2,3-c][2] benzazepine, is approved, under the trademark Remeron.RTM., by the U.S. Food and Drug Administration, for the treatment of depression. Mirtazapine has a tetracyclic chemical structure unrelated to other classes of antidepressants such as selective serotonin reuptake inhibitors, tricyclics or monoamine oxidase inhibitors. Conventional therapeutics for treating depression include selective serotonin reuptake inhibitors (e.g., fluoxetine), monoamine oxidase inhibitors (e.g. phenelzine), and tricyclic antidepressant agents (e.g. doxepin).
Mirtazapine has a low affinity for muscarinic cholinergic receptors, noradrenaline uptake carrier and α1 adrenergic receptors. Further to having the ability to enhance serotonin release, mirtazapine does not inhibit the neuronal uptake pump for serotonin. The most significant adverse effect of mirtazapine treatment is somnolence.
Evidence suggests that mirtazapine acts as an antagonist at central presynaptic α1 -adrenergic autoreceptors and heteroreceptors, thereby possibly resulting in increased central noradrenergic and serotonergic neurotransmission. Mirtazapine is a potent

antagonist of serotonin type 2 (5-HT2) and type 3 (5-HT3) receptors, but the drug does not exhibit any significant affinity for serotonin type 1A (5-HTIA) or type IB (5-HTIB) receptors. Mirtazapine is a potent antagonist of histamine (Hi) receptors, is a moderate antagonist at muscarinic receptors, and exhibits moderate peripheral α2-adrenergic blocking activity. Because of its unique pharmacodynamic properties, mirtazapine is an effective, safe and well-tolerated antidepressant agent that has demonstrated important anxiolytic and sleep-improving effects.
U.S. Pat. No. 4,062,848, claims a class of tetracyclic compounds in which Mirtazapine is a member and discloses a process for making Mirtazapine. US Patent No. 6552189 claims a method of preparation of low-hygroscopic anhydrous Mirtazapine crystals from the hydrate form of Mirtazapine by the methods of pulverization and drying. US Patent application no 20030130504 claims anhydrous Mirtazapine crystals having a water-content of not more than 0.5% by weight. But nowhere in any of the above prior art formulation processes and the compositions of anhydrous Mirtazapine are disclosed or claimed.
In accordance with the present invention, anhydrous Mirtazapine is prepared as pharmaceutical compositions by a suitable formulation process which are particularly useful for the treatment of depression. Such compositions comprise a therapeutically effective amount of anhydrous Mirtazapine with pharmaceutically acceptable carriers and/or excipients known to one of skill in the art.
Objective of this invention is to formulate water insoluble drug anhydrous Mirtazapine by a suitable formulation process in such a way that it will comply with the reference product [usually innovator's REMERON] in terms of in vivo parameters

like bioequivalence and in vitro parameters like dissolution, disintegration and etc. This invention also aims to address particular difficulties associated with dealing with Mirtazapine hemihydrate and provides a simple, cost effective and efficient formulation process of anhydrous Mirtazapine on a commercial scale by employing a specific particle size distribution (PSD) of Mirtazapine for deriving the advantage in terms of the improved surface area availability.
This invention discloses a simple, cost effective and efficient process for preparing the solid dosage forms of a preferred particle size distribution (PSD) of anhydrous mirtazapine on a commercial scale with adequate hardness and good reproducibility.
Owing to certain handling advantages that anhydrous Mirtazapine has over the other forms of Mirtazapine, formulation process of the same with some suitable adjuvants is contemplated and achieved in our lab with satisfactory results in terms of the formulation parameters which constitute both invitro as well as invivo aspects. The different kinds of excipients that can be used for the above formulation are selected from binders, lubricants, disintegrants, fillers and etc.
In the present specification, the term "anhydrous" of the anhydrous Mirtazapine crystals means that the Mirtazapine crystals do not substantially contain moisture. Those skilled in the art will recognize, or be able to ascertain using simple routine experimentation, many equivalents to the specific embodiments of the invention described in the present specification. Such equivalents are intended to be encompassed in the scope of the present invention as recited in the following claims.

Mirtazapine is essentially insoluble in water. The Particle Size Distribution (PSD) of mirtazapine crystals may be used to determine the available surface area for the drug dissolution thus effecting the solubility. Often, it is observed that the available surface area for drug dissolution correlates to the rate of dissolution and solubility where a greater surface area enhances the solubility of a drug and enhances the rate of dissolution of a drug. Further, the velocity of dissolution of a drug often effects the drug's bioavailability. Thus the PSD of mirtazapine and, in particular, the mean particle diameter are important parameters to characterize and predict the bioavailability of the drug. It is desireable to have mirtazapine with a particle size in which the mean particle size enhances the reproducibility of the rate of dissolution and the reproducibility of the dissolution. It is desirable to have mirtazapine in which the mean particle size imparts an improved and stable dissolution profile.
In one preferable embodiment, the invention relates to the formulation process of mirtazapine containing a particle size distribution(PSD) of 90% particles less than 800 Microns, more preferably the particle size distribution(PSD) for the above formulation process of mirtazapine is 90% particles less than 600 Microns and most preferable the particle size distribution(PSD) for the Mirtazapine formulation process is 90% particles less than 400 Microns.
The present formulation process for preparing the solid dosage forms of mirtazapine led to unexpected results of possessing a more stable and reproducible dissolution profile. When compared to mirtazapine made by conventional methods, the present formulation process of mirtazapine unexpectedly demonstrated a more reproducible dissolution curve and a smaller standard of deviations. This valuable improvement provides for more accurate dosing of mirtazapine.

The different formulation process steps that are involved in making the solid dosage forms of mirtazapine as disclosed above are given below: -
1) Sift Mirtazapine through 425µ sieve, Hydroxy Propyl cellulose and Lactose monohydrate through 850µ sieve separately;
2) Resift Mirtazapine and Hydroxy Propyl cellulose together through 850µ, sieve;
3) Mill the material of step 2;
4) Rinse the mill with sufficient quantity of sifted Lactose;
5) Mix material of step 3 and Lactose monohydrate in a Rapid Mixer Granulator and granulate with purified water;
6) Dry the granules in a fluid Bed Dryer;
7) Sift the dried granules through 850µsieve. Collect the retentions separately;
8) Mill the retentions in a Multi mill;
9) Sift the milled granules of through 850µ sieve;
10) Sift extra granular Low substituted Hydroxy Propyl Cellulose through 850µ sieve. Sift starch and silica colloidal anhydrous together through 850µ. Sift Magnesium Stearate through 425µ and collect separately;

11) Mix sifted Low substituted Hydroxy Propyl cellulose, starch and Colloidal silicon dioxide from step 10 with the material of step 7;
12) Lubricate material of step (11) with sifted Magnesium Stearate of step (10);
13) Compress the lubricated blend into tablets using the approved tooling. Dedust the tablets and collect in in-process containers;
14) Prepare Opadry coating suspension in water;
15) Coat the tablets with coating suspension of step 14 till the desired weight build-up is achieved;
16) Dry the coated tablets. Allow to cool and unload;
17) Packing the coated tablets in suitable containers;
The present invention will now be further explained in the following example. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.
It should be understood that some modification, alteration and substitution is anticipated and expected from those skilled in the art without departing from the teachings of the invention. Accordingly, it is appropriate that the following claims be construed broadly and in a manner consistent with the scope and spirit of the invention.


The different formulation processes that can be employed for making the disclosed formulation are by dry granulation, wet granulation, slugging, compaction, direct compression and etc. But preferably the above tablets are prepared by the wet granulation formulation process. The different process steps that are involved in this method are sifting, mixing, granulating, drying, sizing the granules, lubricating and finally compressing the granulates into the tablets and optionally film coating the core.
For making the solid dosage form units like tablets or capsule, the use of conventional additives such as fillers, colorants, polymeric binders and the like is contemplated. In general any pharmaceutically acceptable additive, which does not interfere with the function of the active compounds, can be used.

With regard to the invention disclosed here, it will be obvious that the same may be varied in many ways. Such variations are not to be regarded as a departure from the spirit and scope of the invention and all such modifications are intended to be included within the scope of the claims.

We claim:
[1] A process for preparing a pharmaceutical composition comprising anhydrous Mirtazapine or any of its pharmaceutically acceptable salts as an active and along with other pharmaceutically acceptable excipients provided that the Mirtazapine used has 90% particles less than 400 Microns.
[2] The formulation process as claimed in claim [1] is by any granulation or Direct Compression method.
[3] The formulation process as claimed in claim [1] is by wet granulation process.
[4] The formulation process as claimed in claim [1] is for the dosage form for a tablet,
[5] The formulation process as claimed in claim [1] is for the Orally dissolving tablet.
Dated this the 22nd day of November 2003
For Aurobindo Pharma Limited



964-che-2003-claims duplicate.pdf

964-che-2003-claims original.pdf

964-che-2003-correspondence others.pdf

964-che-2003-correspondence po.pdf

964-che-2003-description complete duplicate.pdf

964-che-2003-description complete original.pdf

964-che-2003-form 1.pdf

964-che-2003-form 19.pdf

964-che-2003-form 26.pdf

964-che-2003-form 3.pdf

Patent Number 203491
Indian Patent Application Number 964/CHE/2003
PG Journal Number 05/2007
Publication Date 02-Feb-2007
Grant Date 27-Nov-2006
Date of Filing 25-Nov-2003
# Inventor's Name Inventor's Address
PCT International Classification Number A61K 31/65
PCT International Application Number N/A
PCT International Filing date
PCT Conventions:
# PCT Application Number Date of Convention Priority Country
1 NA