Claims:We claim:
1. A pharmaceutical composition comprising microspheres of Guaifenesin and at least one additive, wherein the said composition is compressed into tablet.
2. A pharmaceutical composition comprising microspheres of Guaifenesin and at least one additive, wherein the said composition is compressed into single layer tablet.
3. A pharmaceutical composition according to claim 1, where in the Guaifenesin microspheres have average particle diameter of less than 400µm.
4. A pharmaceutical composition comprising microspheres of Guaifenesin and at least one additive, wherein the said composition is compressed into single layer tablet and the said composition comprise two portions of guaifenesin in the form of immediate release portion and extended release portion.
5. A compressed tablet according to claim 1, is in the form of bilayer tablet comprising two portions of guaifenesin in the form of immediate release portion and extended release portion in two different compartments.
6. A pharmaceutical composition according to claim 4 where the ratio of immediate release portion to extended release portion is in the range of 20-30% to 70-80%.
7. A pharmaceutical composition according to claim 4, where in the extended release portion comprise Guaifenesin microspheres coated with one or more gelling polymers.
8. A Pharmaceutical composition according to claim 8, where in the gelling polymers are selected from cellulose polymers like ethylcellulose, hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) and hydroxypropylmethyl cellulose (HPMC), or mixtures thereof .
9. A guaifenesin composition in the form of single layer tablet according to claim 4 is bioequivalent to the marketed dosage form.
10. A guaifenesin composition in the form of single layer tablet according to claim 4 resulted in increased output in yield compared to marketed dosage form.
, Description:FIELD OF THE INVENTION
The present invention relates to stable pharmaceutical compositions of Guaifenesin and process for its preparation. The present invention also relates to Guaifenesin microspheres compressed into a single layer dosage forms. The present invention provides Guaifenesin microspheres of at-least 50 µm in size and further microspheres compressed into tablets with at least one acceptable pharmaceutical excipient.

BACKGROUND OF THE INVENTION
Guaifenesin is an expectorant medication chemically termed as 3-(2-methoxyphenoxy)-1,2-propanediol and structurally represented by the following structure:

Guaifenesin is a highly water-soluble classified as a BCS class I drug. It is available as over-the-counter medicine for cough and cold in the form of tablets, solution and extended release tablet. It is a drug which helps to loosen phlegm (mucus) and thin bronchial secretions to rid the bronchial passageways of bothersome mucus and make coughs more productive.
Guaifenesin is readily absorbed from the intestinal tract and is rapidly metabolized and excreted in urine. It has a typical plasma half-life of approximately one hour. Because of the rapid metabolism and excretion, typical immediate release dosage forms of guaifenesin are generally administered three times within 12 hours to maintain adequate bioavailability and to achieve therapeutic effect, which ultimately reduce the patient compliance.
To overcome the above disadvantages, extended release formulations were developed which can permit once in 12 hour dosing by maintaining a stable drug plasma concentration for an extended period of time. The extended release formulation reduces the side effects associated with the frequent administrations, which ultimately enhance the patient compliance.
In the United States Guaifenesin is approved as 600, 1200 mg oral extended release tablets under the brand name MUCINEX® to Reckitt Benckiser. These extended release tablets of Mucinex are available as bilayered tablets with both immediate and modified release layers and contain carbomer, Hydroxypropylmethyl cellulose, magnesium stearate, microcrystalline cellulose, sodium starch glycolate and dyes as inactive ingredients.
U.S. Patent No’s. 6,372,252 and 6,955,821 discloses the technology and composition of Mucinex® extended release tablets. These patents disclose modified release tablets having two portions, wherein a first portion comprises a first quantity of guaifenesin in an immediate release form and a second portion comprises a second quantity of guaifenesin and a release-delaying matrix comprising a hydrophilic polymer and a water-insoluble polymer. It endures challenges to deliver a robust formulation.
US Patent application No. 20030012820 disclose method for making a guaifenesin dosage form by compressing a guaifenesin composition comprising guaifenesin and a binder, being in the form of particles with specific particle sizes.
US Patent application No. 20060257473 disclose the use of a water-insoluble, non-swellable channeling agent and a hydrophilic polymer in a granulation containing a pharmaceutically active compound to allow compression of the granulation into a single tablet layer or portion.
The production of microspheres containing active agent(s) is described in U.S. Pat. No.5,683,720. This patent discloses the use of liquiflash processing to spheronize compositions containing one or more active agents. U.S. Pat. No. 5,849,223 describes liquiflash particles.
Owing to its typical plasma half-life with rapid metabolism and excretion, formulating a stable composition especially a high-dose one with a simple process which can maintain a stable drug plasma concentration for an extended period of time may be a challenge.
It has been surprisingly found by the inventors that pharmaceutical compositions of Guaifenesin according to present invention were found to be simple, cost effective, and stable and exhibited desired bioavailability which was also found to be comparable with to the marketed formulation.
The inventors of the present invention also found surprisingly that the single layer tablets has resulted in increased output in yield compared to existing bilayer tablets and also the same single layer tablets is bioequivalent to marketed dosage form.

SUMMARY OF INVENTION
Particular aspect of the present invention relates to stable pharmaceutical composition comprising microspheres of Guaifenesin and manufacturing methods thereof.
One aspect of the present invention relates to pharmaceutical compositions comprising microspheres of Guaifenesin having an average particle diameter of less than 400µm.
In another aspect the present invention relates to pharmaceutical composition comprising two portions of guaifenesin, in the form of immediate release portion and extended release portion present in a single compartment or two different compartments.
More particularly the present invention relates to pharmaceutical composition comprising Guaifenesin microspheres and at least one additive, where in the composition is in the form of single layer tablets comprising two portions of Guaifenesin in the form of immediate release portion and extended release portion.
In one aspect of the present invention provides single layer pharmaceutical composition of Guaifenesin where in the composition is in the form of tablets, capsules and tablets filled in capsules.
In another aspect of the present invention provides more than single layer pharmaceutical composition of Guaifenesin where in the composition is in the form of tablets, capsules and tablets filled in capsules.
In yet another aspect the present invention relates process for preparing pharmaceutical composition of Guaifenesin.
In another aspect of the present invention provides single layer pharmaceutical composition of Guaifenesin. The compositions specially comprise of at-least one active agent and at-least one polymer.
In another aspect of the present invention the polymer is selected from gelling agents selected from ethylcellulose, hydroxypropylcellulose (HPC), carboxymethylcellulose (CMC) and hydroxypropylmethyl cellulose (HPMC), or mixtures thereof.
Further particular aspects of the invention are detailed in the description part of the specification, wherever appropriate.

BRIEF DESCRIPTION OF FIGURES:
Fig.1: Represents Particle size distribution analysis data of Guaifenesin microspheres.

DETAILED DESCRIPTION
As set forth herein, embodiments of the present invention provide stable pharmaceutical compositions of Guaifenesin with microspheres and at least one additive.
In one embodiment the present invention provides stable pharmaceutical compositions of Guaifenesin comprising microspheres, where in the microspheres are spherical in shape with average particle diameter of less than 400µm.
In another embodiment according to present invention provides Guaifenesin microspheres having average particle diameter of at-least 50 µm in size.
Preferably average particle diameter of the microspheres is between 100-300µm, more preferably average particle diameter of microspheres is between 150-300µm.
Accordingly "average particle diameter" means volume based distribution median diameter (median diameter: 50% particle diameter from cumulative distribution), unless otherwise specified.
In another embodiment according to present invention the microspheres are prepared using Guaifenesin alone (or) combined with one or more pharmaceutically acceptable excipients.
In another embodiment the pharmaceutically acceptable excipients are lubricants selected from stearic acid, magnesium stearate and sodium stearyl fumarate.
In yet another embodiment according to present invention the microspheres are prepared by combining Guaifenesin with lubricants and processed by Ceform™ Microsphere technology.
Accordingly, this technology involves the processing of the microspheres in a continuous fashion, whereby a pre-blend of drug and excipient(s) are fed into a spinning “microsphere head”, also termed as a “spheronizing head”. The microsphere head, which is a multi-aperture production unit, spins on its axis and is heated by electrical power. The drug and excipients pre-blend are fed into the center of the head with an automated feeder. The material is moved, via centrifugal force, to the outer rim where the heaters, located in the rim of the head, heat the material. Microspheres are formed when the molten material exits the head, which are then cooled by convection as they fall to the bottom of the chamber. The obtained microspheres are collected in a collector.
In another embodiment the microspheres may further coated with extended release coating comprising gelling polymers and one or more solvents to form extended release microspheres.
Accordingly gelling polymers are selected from carbopols, carboxymethyl cellulose, ethylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, hydroxypropylmethyl cellulose and methylcellulose or mixtures thereof
Preferably ethylcellulose, hydroxypropylcellulose, carboxymethylcellulose and hydroxypropylmethyl cellulose, or mixtures thereof.
Accordingly solvents are selected from water, ethanol or isopropyl alcohol and the like.
In yet another embodiment, the present invention relates to pharmaceutical composition comprising microspheres of Guaifenesin and at least one additive, wherein the said composition is compressed into tablet
Accordingly the additives are selected from diluents, disintegrants, polymers, glidants, lubricants and the like.
Suitable "diluents" include, but are not limited to, either individually or in combination, microcrystalline cellulose, lactose, starch, corn starch, pregelatinized starch, maize starch, potato starch, powdered celluloses, sorbitol, xylitol, dibasic calcium phosphate, calcium phosphate, calcium carbonate, magnesium carbonate and the like.
Suitable "disintegrants" include, but are not limited to, either individually or in combination, sodium starch glycolate, croscarmellose sodium, polacrilin potassium, crospovidone, pregelatinized starch and the like.
Suitable "polymers" include, but are not limited to, Carbopol and Sodium polyacrylate.
Suitable "glidants" include, but are not limited to, either individually or in combination, colloidal silicon dioxide, talc, magnesium silicate, magnesium trisilicate, and other forms of silicon dioxide, such as aggregated silicates, hydrated silica and the like.
Suitable "lubricants" include, but are not limited to, either individually or in combination, glyceryl distearate, talc, magnesium stearate, stearic acid, fumaric acid, palmitic acid, sodium stearyl fumarate, carnauba wax, hydrogenated vegetable oils, mineral oil, polyethylene glycols and the like.
In another embodiment the present invention relates to pharmaceutical composition comprising two portions of guaifenesin, in the form of immediate release portion and extended release portion, where in the ratio of immediate release portion to extended release portion is in the range of 20-30% to 70-80%.
In one embodiment the immediate release portion comprise Guaifenesin microspheres and one or more pharmaceutically acceptable excipients or additives selected from diluents, disintegrants, glidants, lubricants and the like.
In one another embodiment the extended release portion comprise extended release Guaifenesin microspheres and one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, polymers, glidants, lubricants and the like.
In another embodiment, the present invention provides Guaifenesin compositions where in the immediate release and extended release portions are present in a single compartment or as two separate compartments in a single dosage form.
Accordingly the dosage form containing single compartment is a single layer tablet and the dosage form containing two separate compartments is a bilayer tablet.
In one embodiment according to present invention relates single layer tablet dosage form comprising two portions, where in first portion of Guaifenesin is present as immediate release microspheres, second portion of guaifenesin is present as extended release coated microspheres and one or more additives selected from diluent, disintegrants, polymers, glidants and lubricants, where the ratio of first quantity of Guaifenesin to second quantity is in the range of 20-30% to 70-80%.
In another embodiment according to present invention a bilayer tablet comprise
a) A first layer comprising first portion of Guaifenesin in the form of immediate release microspheres and one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, glidants and lubricants
b) A second layer comprising second portion of guaifenesin in the form of extended release coated microspheres and one or more pharmaceutically acceptable excipients selected from diluents, disintegrants, polymers, glidants and lubricants where ratio of first portion of Guaifenesin to second portion of Guaifenesin is in the range of 20-30% to 70-80%.
In yet another embodiment the present invention provides process for preparing compositions of Guaifenesin where in the process comprise direct compression involving blending guaifenesin microspheres with one or more pharmaceutically acceptable excipients and compressing accordingly to form a single layer or bilayer tablets.
In one particular embodiment the present invention provides a process for preparing compressed dosage form of Guaifenesin in the form of a single layer tablet comprising the steps of:
(a) Preparing microspheres of Guaifenesin with one or more pharmaceutically acceptable excipient to form immediate release microspheres
(b) coating a portion of the microspheres with extended release coating to form microspheres in the ratio of immediate release microspheres to extended release microspheres in the range of 20-30% to 70-80%.
(c) blending both the immediate and extended release microspheres with one or more pharmaceutically acceptable excipients
(d) lubricating the blend with one or more lubricant(s) and finally
(e) compressing the blend in the punching machine to obtain single layer guaifenesin tablets.
In another particular embodiment the present invention provides a process for preparing compressed dosage form of Guaifenesin in the form of bilayer tablets comprising the steps of:
(a) Preparing microspheres of Guaifenesin with one or more pharmaceutically acceptable excipient to form immediate release microspheres
(b) coating a portion of the microspheres with extended release coating to form the ratio of immediate release microspheres to extended release microspheres in the range of 20-30% to 70-80%.
(c) blending both the first and second portions separately with one or more pharmaceutically acceptable excipients to form two different blends
(d) lubricating both the blends separately with one or more lubricants and finally compressing both the blends in bilayer compression machine to form bilayer guaifenesin tablets.

The invention is further exemplified with following examples which are not intended to limit the scope of the invention.

EXAMPLES:
The following examples further describe and demonstrate particular embodiments within the scope of the present invention. It will be apparent to those skilled in the art that many modifications, both to materials and methods, may be practiced without departing from the scope of the invention.

Table 1: Examples 1-8: Guaifenesin bilayer tablets with immediate release (IR) layer and extended release (ER) layers.
S. No Name of the Material IR Layer : ER Layer - 20:80 IR Layer : ER Layer - 30:70
Ex-1 Ex-2 Ex-3 Ex-4 Ex-5 Ex-6 Ex-7 Ex-8
Mg/ tab Mg/ tab Mg/ tab Mg/ tab Mg/ tab Mg/ tab Mg/ tab Mg/ tab
Microspheres
1 Guaifenesin API 1200 1200 1200 1200 1200 1200 1200 1200
2 Stearic Acid 48 48 48 48 48 48 48 48
ER Coating
3 Hydroxypropyl methyl cellulose (HPMC) 35 35 60 60 35 35 60 60
4 Isopropyl Alcohol q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
5 Water q.s. q.s. q.s. q.s. q.s. q.s. q.s. q.s.
Extra-granular – IR Layer
6 Guaifenesin Uncoated Microspheres 250 250 250 250 374 374 374 374
7 Microcrystalline Cellulose 107.5 103.5 87 83 111.5 107.5 93.5 89.5
8 Sodium starch glycolate 20 20 20 20 20 20 20 20
9 Magnesium stearate 0.5 0.5 0.5 0.5 0.5 0.5 0.5 0.5
Extra-granular – ER Layer
10 Guaifenesin ER Coated Microspheres 1026 1026 1046.5 1046.5 898 898 916 916
11 Carbopol 974P 18 22 18 22 18 22 18 22
12 Magnesium stearate 8 8 8 8 8 8 8 8
Total Tablet Weight 1430 1430 1430 1430 1430 1430 1430 1430
q.s.: quantity sufficient

Manufacturing process:
Step 1: Preparation of microspheres:
a) Guaifenesin and stearic acid were sifted separately and blended to form a pre-mix.
b) The pre-mix was then charged for microspheres using Ceform™ Microsphere technology.
c) The microspheres were screened to obtain microspheres of uniform size.
d) The obtained microspheres are used further to prepare dosage forms.

Step 2: Extended release coating:
Preparation of coating solution:
a) Hydroxypropylmethyl cellulose was sifted and added slowly to Isopropyl alcohol under continuous stirring. The stirring was continued till a uniform dispersion was obtained.
b) To this dispersion water was added slowly under stirring to obtain a clear solution.
Extended release Coating by Top spray/ Bottom spray:
a) Uncoated microspheres were sifted and loaded in to top spray coater and further coated with hydroxypropylmethyl cellulose coating solution to obtain extended release microspheres.
b) The obtained extended release microspheres are used further to prepare dosage forms.

Step 3: Blending, Lubrication & Compression:
Preparation of Blend for Immediate release layer:
a) Guaifenesin microspheres obtained according to step 1, microcrystalline cellulose and sodium starch glycolate were sifted and blended.
b) The obtained blend was lubricated with magnesium stearate to form a compression blend for immediate release layer.
Preparation of Blend for Extended release layer:
a) Guaifenesin microspheres obtained according to step 1, Carbopol & magnesium stearate were sifted separately and blended.
b) The obtained blend was lubricated with magnesium stearate to form a compression blend for extended release layer.
Compression:
The lubricated blends of immediate release & extended release layers are compressed using capsule shaped punches to form bilayered tablets

Dissolution data
The dissolution data of the compositions made according to example -3 were tested by using the following method were represented in Table 2
Apparatus: USP Type I (Basket)
Media: 0.1N HCl (OGD Media)
Rpm: 75; Temperature: 37 ± 0.5°C
Volume: 900ml
Time points: 30 minutes, 1, 2, 4, 6, and 12 hours

Table 2: Dissolution Profile
Multimedia Dissolution Profile
Time in hrs 0.1N HCl (OGD Media) pH 4.5 Acetate Buffer pH 6.8 Phosphate Buffer
Reference (BS164) Test Reference (BS164) Test Reference (BS164) Test
1 36 43 35 37 35 34
2 47 53 45 47 44 43
4 61 64 58 61 57 58
6 71 76 70 70 67 71
12 88 95 88 89 85 99

Table 3: Example 9: Guaifenesin Single layer tablets with immediate release and extended release microspheres of Guaifenesin

S. No Name of the Material Mg/tab
Microspheres
1. Guaifenesin 1200.0
2. Stearic Acid 48.0
ER Coating
3. Hydroxypropyl methyl cellulose (HPMC) 60.0
4. Isopropyl Alcohol q.s.
5. Water q.s.
Extra-granular
6. Guaifenesin Uncoated Microspheres 250.0
7. Guaifenesin ER Coated Microspheres 1046.5
8. Microcrystalline Cellulose 87.0
9. Sodium starch glycolate 20.0
10. Carbopol 18.0
Lubrication
11. Magnesium stearate 8.5
Total Tablet Weight 1430.0
q.s.: quantity sufficient

Manufacturing process:
Step 1: Preparation of microspheres:
a) Guaifenesin and stearic acid were sifted separately and blended to form a pre-mix.
b) The pre-mix was then charged for microspheres using Ceform™ Microsphere technology.
c) The microspheres were screened to obtain microspheres of uniform size.
d) The obtained microspheres are used further to prepare dosage forms.

Step 2: Extended release coating:
Preparation of coating solution:
c) Hydroxypropylmethyl cellulose was sifted and added slowly to Isopropyl alcohol under continuous stirring. The stirring was continued till a uniform dispersion was obtained.
d) To this dispersion water was added slowly under stirring to obtain a clear solution.
Extended release Coating by Top spray/ Bottom spray:
c) Uncoated microspheres were sifted and loaded in to top spray coater and further coated with hydroxypropylmethyl cellulose coating solution to obtain extended release microspheres.
d) The obtained extended release microspheres are used further to prepare dosage forms.

Step 3: Blending, Lubrication & Compression:
a) Guaifenesin microspheres obtained according to step 1, microcrystalline cellulose and sodium starch glycolate were sifted and blended to form a blend.
b) Guaifenesin Extended release microspheres obtained according to step 2 and carbopol were sifted separately, added to the above blend (a) and blended to form a common blend (b).
c) The obtained common blend (b) was lubricated with sifted magnesium stearate and compressed using capsule shaped punches to form single layer Guaifenesin tablets.
Dissolution data
The dissolution data of the compositions made according to example -9 were tested by using the following method were represented in Table 4
Apparatus: USP Type I (Basket)
Media: 0.1N HCl (OGD Media)
Rpm: 75; Temperature: 37 ± 0.5°C
Volume: 900ml
Time points: 30 minutes, 1, 2, 4, 6, and 12 hours

Table 4: Dissolution Profile
Multimedia Dissolution Profile
Time in hrs 0.1N HCl (OGD Media) pH 4.5 Acetate Buffer pH 6.8 Phosphate Buffer
Reference (BS164) Test Reference (BS164) Test Reference (BS164) Test
1 36 41 35 39 35 32
2 47 52 45 48 44 41
4 61 65 58 64 57 58
6 71 78 70 72 67 71
12 88 95 88 90 85 98

Bioequivalence Study:
A bioequivalence study was carried out using the Test comprising Bilayer tablets of Guaifenesin as prepared in example 3 and Single layer tablet prepared in example 9 against the commercially available MUCINEX® 1200 mg oral extended release tablets under Fed conditions.

The bioequivalence data for this study is shown below in table 5 and 6. The study was monitored in terms of the AUC and Cmax achieved with the test product and reference product. Values between 80 and 125% for the 90% Confidence Intervals of these ratios indicate bioequivalence as recommended by the USFDA.

Table: 5
Comparative bioequivalence study data of guaifenesin bilayer tablets against the commercially available MUCINEX® extended release tablets using eighteen human volunteers.

Guaifenesin Extended Release Bi-Tablet 1200mg (FED Bio study data), Number of subjects : 18
Bio parameters T/R ratio 90% C.I, Lower Limit 90% C.I, Upper Limit
Cmax 100.6 83.0 121.9
AUC 0-T 100.0 93.0 107.5
AUC 0-Inf 99.9 93.0 107.5

Table: 6
Comparative bioequivalence study data of guaifenesin Single layer tablets against the commercially available MUCINEX® extended release tablets using ten human volunteers.

Guaifenesin Extended Release Monolayer-Tablet 1200mg (FED Bio study data), Number of subjects : 10
Bio parameters T/R ratio 90% C.I, Lower Limit 90% C.I, Upper Limit
Cmax 112.1 93.7 123.9
AUC 0-T 98.5 91.3 106.3
AUC 0-Inf 98.5 91.2 106.3

From the results of this study we can conclude that both the Bilayer tablets and Single layer tablet prepared according to current invention exhibits bioequivalence to that of the currently marketed extended release tablet formulation “MUCINEX®”1200 mg.
The invention having been disclosed in connection with the foregoing embodiments, additional variations will now be apparent to persons skilled in the art. Various modifications and variations to the above described formulation compositions can be made without departing from the scope of the invention.
From the foregoing it will be understood that the embodiments of the present invention described above are well suited to provide the advantages set forth, and since many possible embodiments may be made of the various features of this invention and as the formulation herein described may be varied in various compositions, all without departing from the scope of the invention, it is to be understood that all matter hereinbefore set forth or shown in the accompanying examples is to be interpreted as illustrative and that in certain instances some of the features may be used without a corresponding use of other features, all without departing from the scope of the invention.
Further, the present invention has been illustrated in the examples. The following specific and non-limiting composition for functioning need to be construed as merely illustrative, and do not limit the present disclosure in any way whatsoever.