Claims:We Claim
Claim 1: A process for preparing a pharmaceutical formulation of a low dose drug, wherein the process comprises a single step mixing of the drug and one or more pharmaceutically acceptable excipients.
Claim 2: A process for preparing a pharmaceutical formulation of a low dose drug, wherein the process comprises a single step mixing of the drug and one or more pharmaceutically acceptable excipients, and wherein the mixing is performed while supplying nitrogen gas into the mixing instrument.
Claim 3: A process for preparing a pharmaceutical formulation of a low dose drug wherein the process comprises mixing of the drug and one or more pharmaceutically acceptable excipients, wherein the mixing is performed while supplying nitrogen gas into the mixing instrument.
Claim 4: The process according to any of the above claims comprises the steps of:
(vi) weighing drug,
(vii) weighing and sifting one or more pharmaceutically acceptable excipients,
(viii) transferring the materials of step (i) and (ii) into a rapid mixer granulator,
(ix) mixing the materials of step (iii), and
(x) processing the material of step (iv) either by compressing to form a tablet or filling into a capsule.
, Description:The following specification particularly describes the invention and the manner in which it is to be performed:

BACKGROUND
Many low dose drugs have been formulated in prior art. The problems associated with the low dose drug formulations are (i) content uniformity due to their low dose and (ii) their degradation possibility.
The practice generally followed in the art to overcome the issue of content uniformity is to use dual or multiple step mixing.
SUMMARY
The present inventors have prepared a pharmaceutical formulation comprising low dose drug by using a single step mixing. The formulation has shown better content uniformity and assay as compared to the formulations prepared according to the process disclosed in the art.

DETAILED DESCREPTION
A first aspect of the present invention relates to a process for preparing a pharmaceutical formulation of a low dose drug, wherein the process comprises a single step mixing of the drug and one or more pharmaceutically acceptable excipients.
A second aspect of the present invention relates to a process for preparing a pharmaceutical formulation of a low dose drug, wherein the process comprises a single step mixing of the drug and one or more pharmaceutically acceptable excipients, and wherein the mixing is performed while supplying nitrogen gas into the mixing instrument.
A third aspect of the present invention relates to a process for preparing a pharmaceutical formulation of a low dose drug wherein the process comprises mixing of the drug and one or more pharmaceutically acceptable excipients, wherein the mixing is performed while supplying nitrogen gas into the mixing instrument.
According to a first embodiment of above aspects, the process comprises the steps of:
(i) weighing drug,
(ii) weighing and sifting one or more pharmaceutically acceptable excipients,
(iii) transferring the materials of step (i) and (ii) into a rapid mixer granulator,
(iv) mixing the materials of step (iii), and
(v) processing the material of step (iv) either by compressing to form a tablet or filling into a capsule.
According to a second embodiment of above aspects, the pharmaceutically acceptable excipients are selected from diluent, binder, glidant and lubricant.
According to a third embodiment of above aspects, the pharmaceutical formulation is a tablet.
The term “pharmaceutical formulation” as disclosed herein, may include solid dosage forms suitable for oral administration such as tablets, capsules, pills, caplets and the like. In particular the pharmaceutical formulation is a tablet. Tablet may be an immediate release tablet, a delayed release tablet, a modified release tablet, a chewable tablet, a confectionary tablet, an oral disintegrating tablet. Tablet may be coated with sugar coating or film coating with the aim of, for example, preventing abrasion wear, masking bitterness, improving stability, and the like.
The term “low dose drug” as disclosed herein refers to any drug which is administered in an oral dose of 10 mcg to 500 mcg, in particular 25 mcg to 300 mcg.
The term “single step mixing” as disclosed herein refers to a process of mixing drug and pharmaceutically acceptable excipients in a single mixing instrument. If required the blend of the drug and the excipients can be further mixed numerous times when a new excipients added to the blend.
The mixing can be performed by using various blenders e.g., "V"-blender, double cone blender, octagonal blender, oblicone blender, bin blender, container blender, horizontal/vertical drum blender, ribbon blender, planetary blenders, horizontal high intensity blender, vertical high intensity blender, fluid bed blender, tumbling blender, agitated powder blender, rapid mixer granulator and high shear mixing blender. In particular the blender is rapid mixer granulator.
The term “pharmaceutically acceptable excipients,” as disclosed herein, includes any physiologically inert additives that are routinely used in pharmaceutical dosage forms. Pharmaceutically acceptable excipients are selected from the group comprising diluents, binders, colorants, disintegrants, lubricants, and glidants.
Suitable diluents are selected from the group comprising lactose, e.g., lactose monohydrate, directly compressible lactose, lactose anhydrous, and spray dried lactose; sugars, e.g., sucrose which is available in different particle sizes like granular (table sugar), fine granular, fine, superfine and confectioner’s sugar (very fine sugar in which 80% should pass through #325 mesh and starch, e.g., pregelatinized starch; microcrystalline cellulose, e.g., microcrystalline cellulose PH 112, microcrystalline cellulose PH 101, and microcrystalline cellulose PH 102; sugar alcohols, e.g., sorbitol, erythritol, xylitol, and mannitol. In particular the diluents are lactose monohydrate, directly compressible lactose, confectioner’s sugar, microcrystalline cellulose, sorbitol, pregelatinized starch, and combinations thereof.
Suitable binders are selected from the group comprising povidone; acacia; xanthan gum; sodium alginate; copovidone; celluloses, e.g., hydroxypropyl methylcellulose, hydroxy ethylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose; starch, e.g., pregelatinized starch and low density starch; microcrystalline cellulose; propylene glycol; polyvinyl alcohol; corn syrup; methacrylates; carboxyvinyl polymers, e.g., carbomers; and combinations thereof.
Suitable colorants are selected from the group comprising FD&C (Federal Food, Drug and Cosmetic Act) approved coloring agents; natural coloring agents; pigments, e.g., FD&C Yellow # 6 Aluminium Lake, iron oxide, titanium dioxide, zinc oxide and combinations thereof.
Suitable disintegrants are selected from the group comprising croscarmellose sodium, hydroxypropyl cellulose, crospovidone, carboxymethyl cellulose sodium, carboxymethyl cellulose calcium, sodium starch glycolate, gums, alginic acid or alginates, pregelatinized starch, corn starch, modified starch, carboxymethyl starch, polyacrylates, and combinations thereof
Suitable glidants are selected from the group comprising talc, magnesium stearate, stearic acid, calcium stearate, colloidal silicon dioxide, starch, and combinations thereof.
Suitable lubricants are selected from the group comprising magnesium stearate, talc, and silica.
EXAMPLES
Example 1: Tablet formulations prepared by single step mixing in rapid mixer granulator
Unit composition
Ingredients
Drug
Acacia
Lactose monohydrate
Confectioner’s sugar
Povidone
FD&C yellow#6 Aluminium Lake
Talc
Magnesium stearate
Procedure:
1. Acacia, povidone, and a part of lactose monohydrate were weighed and sifted through mesh #40 and mixed in a rapid mixer granulator for 5 minutes.
2. Confectioner’s sugar, FD&C Yellow #6 Aluminium Lake were weighed and sifted through mesh #60.
3. A part of confectioner’s sugar was added to the material of step 1.
4. Drug was added to the material of step 3 along with the remaining part of confectioner’s sugar, and FD&C Yellow #6 Aluminium Lake and mixed in the rapid mixer granulator for 10 minutes at impeller speed of 34 RPM followed by for 50 minutes at impeller speed of 68 RPM.
5. Another part of lactose monohydrate was weighed and sifted through mesh #40, added to the material of step 4 and mixed in the rapid mixer granulator for 60 minutes.
6. Talc was weighed and sifted through mesh #60, added to the material of step 5 and mixed in the rapid mixer granulator for 5 minutes.
7. Magnesium stearate was weighed and sifted through mesh #60, added to the material of step 6 and mixed in the rapid mixer granulator for 20 minutes.
8. The material of step 7 was compressed into tablets.
The mixing in above procedure was performed while supplying nitrogen gas into the rapid mixer granulator.