DESC:The following specification particularly describes the invention and the manner in which it is to be performed:

FIXED DOSE PHARMACEUTICAL FORMULATIONS OF ANALGESIC AND ANTI-SPASMODIC DRUGS

BACKGROUND OF THE INVENTION
Dysmenorrhea (dysmenorrhea or painful periods) is a medical condition of pain during menstruation that interferes with daily activities. Menstrual pain is often used synonymously with menstrual cramps, but the latter may also refer to menstrual uterine contractions, which are generally of higher strength, duration and frequency than in the rest of the menstrual cycle.
Dysmenorrhea can feature different kinds of pain, including sharp, throbbing, dull, nauseating, burning, or shooting pain. Dysmenorrhea may precede menstruation by several days or may accompany it, and it usually subsides as menstruation tapers off. Dysmenorrhea may coexist with excessively heavy blood loss, known as menorrhagia.
Dysmenorrhea can be classified as primary and secondary type. Secondary dysmenorrhea is diagnosed when symptoms are attributable to an underlying disease, disorder, or structural abnormality either within or outside the uterus. Primary dysmenorrhea is diagnosed when none of these are detected.
Molecular compounds called prostaglandins are released during menstruation, due to the destruction of the endometrial cells, and the resultant release of their contents. Release of prostaglandins and other inflammatory mediators in the uterus cause the uterus to contract. When the uterine muscles contract, they constrict the blood supply to the tissue of the endometrium, which, in turn, breaks down and dies. These contractions, and the resulting temporary oxygen deprivation to nearby tissues, are responsible for the pain or "cramps" experienced during menstruation.
The prevalence of dysmenorrhea is estimated to be found in approximately 25% of women. Reports of dysmenorrhea are greatest among individuals in their late teens and twenties, with reports usually declining with age.
There are several ways to manage menstrual pain. Strong menstrual pain can be effectively treated with an antispasmodic (to relieve painful cramps of the surrounding abdominal organs) in combination with an analgesic (to relieve the pain. The first line of management of this pain is by the use of NSAIDs.
Some of the commonly used NSAIDs are Ibuprofen, acetaminophen, mefenamic acid etc. Ibuprofen is a non-steroidal anti-inflammatory drug (NSAID) derivative of propionic acid used for relieving pain, helping with fever and reducing inflammation. It is an optically active compound with both S and R-isomers, of which the S (dextrorotatory) isomer is the more biologically active, this isomer has also been isolated and used medically.
Non-steroidal anti-inflammatory drugs such as ibuprofen work by inhibiting the enzyme cyclooxygenase (COX), which converts arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is converted by other enzymes to several other prostaglandins (which are mediators of pain, inflammation, and fever) and to thromboxane A2.
Drotaverine is an antispasmodic drug, structurally related to papaverine. Drotaverine is a selective inhibitor of phosphodiesterase 4, and has no anticholinergic effects. Drotaverine has been shown to possess dose-dependent analgesic effects in animal models. Drotaverine has powerful antispasmodic action on smooth muscle by inhibiting the enzyme phosphodiesterase (PDE). Drotaverine is absorbed well from the gastrointestinal tract. It undergoes first pass metabolism and Cmax is achieved within 45-60minutes.
Drotaverine (or 1-[(3,4-diethoxyphenyl)methylene]-6,7-diethoxy-1 ,2,3,4-tetrahydro-isoquinoline) is a known antispasmodic drug and is commercialized under the trademark No-spa® mainly in some countries of Eastern and Central Europe, and Sub Saharan Africa.
A combination of an analgesic and an anti-spasmodic agent such as ibuprofen and drotaverine for treating menstrual and abdominal cramps provides a unique combination of active agents which alleviates the pain associated with menstruation and relieve abdominal cramps at the same time.
One such commercially available product is Algoflex-M® from Sanofi-Aventis which contains 400mg of ibuprofen and 80mg of Drotaverine hydrochloride as a combination pack comprising 6 tablets each. This product is available in some European countries such as Hungary. The combination pack contains Ibuprofen 400 mg tablets which are round, biconvex, pink, film-coated tablet, debossed with "S59" on one side. Drotaverine 80 mg tablets are available as yellow-green to orange hues on each side, biconvex, scored on one side of the tablet.
Very few combination products of analgesics and anti-spasmodic agents are available for treatment of menstrual pains and cramps. Moreover, these are available as two different tablets in a single pack. Hence to provide a compact formulation for patient compliance, there is still a need to prepare a fixed dose combination of ibuprofen and drotaverine available in an easy to administer single tablet dosage form.
SUMMARY OF THE INVENTION
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising analgesic agent and anti-spasmodic agent and one or more pharmaceutically acceptable excipients.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation of ibuprofen and drotaverine and one or more pharmaceutically acceptable excipients wherein the pharmaceutical formulation is a monolithic tablet or a bilayer tablet used for relief of menstrual and abdominal cramps commonly seen in dysmenorrhea.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients wherein the pharmaceutical formulation is a monolithic tablet.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients wherein the pharmaceutical formulation is a bilayer tablet.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients which includes an acidifier.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients which includes an antioxidant.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients which includes an acidifier which is selected from the group consisting of citric acid, fumaric acid, lactic acid, maleic acid, malic acid and tartaric acid.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients which includes an antioxidant selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid and cysteine.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients wherein the pharmaceutical formulation is prepared by direct compression.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients wherein the pharmaceutical formulation is prepared by wet granulation.
The process of preparing a pharmaceutical formulation wherein the pharmaceutical formulation is a monolithic tablet by direct compression involves blending ibuprofen, drotaverine and other pharmaceutically acceptable excipients and compressing the blend into tablets.
The process of preparing a pharmaceutical formulation wherein the pharmaceutical formulation is a monolithic tablet by wet granulation, the process involves preparing an intragranular portion comprising ibuprofen and pharmaceutically acceptable excipients and an extragranular portion comprising drotaverine and pharmaceutically acceptable excipients which are then blended and compressed into tablets.
Alternatively, both ibuprofen and drotaverine may be included in the intragranular portion which is then blended with extragranular excipients and compressed into tablets.
The process of preparing a pharmaceutical formulation wherein the pharmaceutical formulation is a monolithic tablet by wet granulation, the process involves preparing a first granulation portion comprising ibuprofen and pharmaceutically acceptable excipients, a second granulation process comprising drotaverine and pharmaceutically acceptable excipients which are then blended together to form an intragranular portion. The intragranular portion is blended with extragranular excipients and compressed into tablets.
In these embodiments, the granulation liquid may comprise water along with other excipients such as binders, surfactants, antioxidants or acidifiers.
The process of preparing a pharmaceutical formulation wherein the pharmaceutical formulation is a bilayer tablet which is prepared by wet granulation, the process of preparing the pharmaceutical formulation involves preparing individual layers comprising ibuprofen and pharmaceutically acceptable excipients and drotaverine and pharmaceutically acceptable excipients. Both these layers are then compressed to form bilayer tablets.
In these embodiments, the granulation fluid may be water or non-aqueous solvent.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients wherein the pharmaceutical formulation comprises not more than 0.2% of varaldine when stored for 6 months at accelerated stability conditions of 40°C and 75% relative humidity and throughout the shelf life of the product.

DETAILED DESCRIPTION
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising analgesic agent and anti-spasmodic agent and one or more pharmaceutically acceptable excipients.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients wherein the pharmaceutical formulation is a monolithic tablet.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients wherein the pharmaceutical formulation is a bilayer tablet.
The term “monolithic tablet” refers to a tablet dosage form in which the active agents and the pharmaceutically acceptable excipients are intimately mixed and compressed into a single unit dosage form and does not contain any distinguishable portions.
The term “bilayer tablet” refers to a tablet dosage form in which the active ingredients and the pharmaceutically acceptable excipients are granulated separately and lubricated to form two different blends which are then compressed to form a bilayer tablet as two distinguishable portions.
In embodiments of the present invention, ibuprofen used in the present invention is a propionic acid derivative which is recommended for reducing fever and treat pain or inflammation caused by many conditions such as headache, toothache, back pain, arthritis, menstrual cramps, or minor injury. The recommended dose of ibuprofen for relieving abdominal cramps is from about 200mg to about 800mg.
Ibuprofen may be present in the form of its pharmaceutically acceptable salts, solvates, isomers, esters and derivatives thereof. It may be present in crystalline or amorphous forms or mixtures thereof.
In embodiments of the present invention, drotaverine is a papaverine derivative which is recommended for control and prevention of pain & dysfunction caused by smooth muscle spasm, smooth muscle cramps and painful menstruation.
Drotaverine may be present in the form of any of its pharmaceutically acceptable salts, solvates, esters and derivatives thereof. Drotaverine is present as amorphous form, crystalline form, or mixtures thereof. In a preferred embodiment drotaverine is present as drotaverine hydrochloride. The recommended dose of drotaverine for relief from abdominal cramps is from about 20 mg to about 100 mg.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising about 200mg to about 800mg of ibuprofen and 20mg to about 100mg of drotaverine hydrochloride and pharmaceutically acceptable excipients.
In embodiments of the present invention, the pharmaceutically acceptable excipients comprise acidifiers, antioxidants, diluents, disintegrants, binders, surfactants, glidants and lubricants.
Drotaverine as an active agent is highly prone to oxidative degradation especially under basic, peroxide and heat stress conditions to form a major impurity called varaldine or drotaveraldine (VRLDN). The presence of this impurity beyond permissible limits in pharmaceutical formulations comprising drotaverine renders them unfit for human consumption. Hence to keep this impurity within permissible limits, pharmaceutically acceptable excipients such as acidifiers and antioxidants are added to pharmaceutical formulations comprising drotaverine.
Permissible limits refers to the presence of not more than 0.2% of varaldine in the pharmaceutical formulation when stored for 6 months at accelerated stability conditions of 40°C and 75% relative humidity and throughout the shelf life of the product i.e., 24 months.
Acidifiers are compounds which are added to pharmaceutical formulations to maintain a microenvironment pH usually below 5 so as to aid in solubility or enhance stability of formulations.
Antioxidants are agents which are added to pharmaceutical formulations to protect active ingredients from oxidative degradation and therefore enhance stability of the formulations.
Hence, embodiments of the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients which include acidifiers and antioxidants to control the formation of oxidative impurities.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and pharmaceutical acceptable excipients which includes acidifiers selected from the group consisting of citric acid, fumaric acid, lactic acid, maleic acid, malic acid and tartaric acid.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen and drotaverine and pharmaceutical acceptable excipients which includes antioxidants selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid and cysteine.
Auxiliary pharmaceutically acceptable excipients according to the present invention include, for example, one or more of diluents, disintegrants, binders, lubricants and glidants that are useful in preparation of pharmaceutical formulations.
Diluents that are used in embodiments of the present invention include but are not limited to, sugars such as lactose monohydrate, lactose anhydrous, mannitol, starches maize starch, corn starch, pregelatinized starches such as PCS PC10 from Signet Chemical Corporation and starch 1500 and cellulose derivatives such as crystalline cellulose and powdered cellulose. Examples of crystalline cellulose products include but are not limited to Ceolus™ KG801, Avicel™ PH101, PH102, PH301, PH302 and PH-F20, PH-112, microcrystalline cellulose 114, and microcrystalline cellulose 112. Other diluents include, but are not limited to, sorbitol and xylitol, calcium carbonate, magnesium carbonate, dibasic calcium phosphate, and tribasic calcium phosphate.
Disintegrants that are used in embodiments of the present invention include but are not limited to crospovidone, croscarmellose sodium, L-HPC and alginic acid.
Binders that are used in embodiments of the present invention include but are not limited to, hydroxypropylcellulose, also called HPC (e.g., Klucel™ LF and Klucel™ EXF), various grades of hydroxypropyl methylcellulose, also called hypromellose or HPMC (e.g., Methocel™ products), various grades, polyvinylpyrrolidone or povidone (such as grades K25, K29, K30, and K90), copovidone (e.g., Plasdone™ S 630), powdered acacia, gelatin, guar gum, carbomers (e.g., Carbopol® products), methylcellulose, polymethacrylates, and starches.
Surfactants that are used in embodiments of the present invention include but are not limited to polyoxyethylene-polyoxypropylene block copolymers (poloxamers), alkyl sulfates (e.g. sodium lauryl sulfate sodium stearyl sulfate sodium oleyl sulfate and sodium cetyl sulfate), alkyl aryl sulfonate (e.g. sodium dodecyl benzene sulfonate and dialkyl sodium sulfosuccinate), polyethylene glycol and polysorbates.
Lubricants that are used in embodiments of the present invention include but are not limited to magnesium stearate, glyceryl monostearate, palmitic acid, talc, carnauba wax, calcium stearate, sodium stearate, sodium lauryl sulfate, magnesium lauryl sulfate, zinc stearate, polyoxyethylene monostearate, calcium silicate, silicon dioxide, hydrogenated vegetable oils and fats, stearic acid, and mixtures thereof.
Glidants that are used in embodiments of the present invention include but are not limited to colloidal silicon dioxide, talc, and mixtures thereof.
In embodiments of the present invention, solvents may be used as granulating fluids in the preparation of pharmaceutical formulations by wet granulation. Solvents that may be used in the present invention, include but are not limited to, water, methanol, ethanol, acidified ethanol, acetone, diacetone, polyols, polyethers, esters, alkyl ketones, methylene chloride, isopropyl alcohol, butyl alcohol, methyl acetate, ethyl acetate, isopropyl acetate, ethylene glycol monoethyl ether, diethylene glycol monobutyl ether, diethylene glycol monoethyl ether and mixtures thereof.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients wherein the pharmaceutical formulation is a monolithic tablet which is prepared by direct compression.
In embodiments of the present invention where the pharmaceutical formulations are monolithic tablets prepared by direct compression, ibuprofen that is used is of the directly compressible grade to provide adequate flow properties to the powder blend.
In embodiments, where the monolithic tablets are prepared by direct compression, the process comprises the steps:
a) Blending Ibuprofen and drotaverine along with other excipients such as diluents, acidifier, antioxidant and disintegrants.
b) Blending the mixture of step (a) along with the lubricants to achieve content uniformity.
c) Compressing the lubricated blend using suitable punches.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen and drotaverine and pharmaceutically acceptable excipients wherein the pharmaceutical formulation is a monolithic tablet which is prepared by wet granulation.
In embodiments, where the monolithic tablets are prepared by wet granulation ibuprofen may be present in the intragranular portion and drotaverine in the extra granular portion and the process comprises the steps:
a) Blending Ibuprofen and other excipients such as diluents and disintegrants
b) Acidifiers and antioxidants are dissolved in water to prepare the granulation fluid
c) Granulating the intra granular premixed portion with the granulating fluid to form granules
d) Drying and milling the formed granules into suitable size
e) Blending drotaverine and excipients such as diluents and glidants to form the extra granular portion.
f) Blending the intragranular and the extragranular portions to form a pre lubricated blend
g) Blending the pre lubricated blend with the lubricant to form a final lubricated blend
h) Compressing the lubricated blend with suitable punches to form tablets.
In embodiments, where the monolithic tablets are prepared by wet granulation, ibuprofen and drotaverine may be granulated with pharmaceutically acceptable excipients to form two separate granulation portions. These two portions may then be blended together and mixed with extragranular excipients and compressed into tablets. This process comprises the following steps:
a) Blending ibuprofen and other excipients such as diluents, disintegrants and glidants
b) Dissolving surfactants in water to prepare the granulation fluid
c) Granulating the premixed portion with the granulating fluid to form first portion of granules
d) Drying and milling the formed granules into suitable size.
e) Blending Drotaverine, diluents, binders, disintegrant and antioxidants
f) Dissolving acidifiers in water to form a granulation fluid
g) Granulating the premixed portion with granulating fluid to form second portion of granules
h) Drying and milling the formed granules into suitable size
i) Blending disintegrants, diluents and glidants to form an extragranular blend
j) Blending the two portions of the granules with the extragranular material and lubricants to form a final blend
k) Compressing the lubricated blend using suitable punches to form tablets
In embodiments, where the monolithic tablets are prepared by wet granulation both ibuprofen and drotaverine may be present in the intragranular portion and the process comprises the steps:
a) Blending Ibuprofen, drotaverine and other excipients such as diluents and disintegrants
b) Acidifiers and antioxidants, they are dissolved in water to prepare the granulation fluid
c) Granulating the intra granular premixed portion with the granulating fluid to form granules
d) Drying and milling the formed granules into suitable size
e) Blending the diluents and glidants through to form the extra granular portion.
i) Blending the intragranular and the extra granular portions to form a pre lubricated blend
j) Blending the pre lubricated blend with the lubricant to form a final lubricated blend.
f) Compressing the lubricated blend with suitable punches to form tablet
In embodiments, the present invention relates to a fixed dose formulation comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients wherein the pharmaceutical formulations are bilayer tablets which are prepared by wet granulation.
In embodiments, the bilayer tablet are prepared by wet granulation, the process comprises the steps:
(i) Preparing the Ibuprofen Layer:
a) Blending Ibuprofen and excipients such as diluents and disintegrants
b) Granulating the intragranular premixed portion with water which acts as a granulating fluid to form granules
c) Drying and milling the formed granules into a suitable size.
d) Blending diluents and glidants to form the extragranular portion
e) Blending the intragranular and the extra granular portions to form a pre lubricated blend
f) Blending the pre lubricated blend with a lubricant to form a final lubricated blend.
(ii) Preparing the Drotaverine hydrochloride Layer:
a) Blending drotaverine and excipients such as diluents and disintegrants
b) Acidifiers and antioxidants may be dissolved in isopropyl alcohol to prepare the granulation fluid.
c) Granulating the intragranular premixed portion with granulation fluid to form granules
d) Drying and milling the formed granules
e) Blending excipients such diluents and glidants to form the extragranular portion
f) Blending the intragranular and the extra granular portions to form a pre lubricated blend
g) Blending the pre lubricated blend with the lubricant to form a final lubricated blend.
h) Compressing both the ibuprofen and drotaverine granules to form bi layer tablets
Compression is achieved on tableting machines to obtain compressed tablets of desired weight, size and hardness by the use of appropriate tooling and machine parameters.
In embodiments, the present invention relates to fixed dose pharmaceutical formulations comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients wherein the pharmaceutical formulations are monolithic or bilayer tablets which may be further coated with a non-functional coating. In embodiments of the present invention, coating solutions may be used to provide non-functional coatings to tablets. Commonly used coating solvents include but are not limited to Opadry® polymers available from Colorcon®, HPMC, HPC and others.
The coating can be carried out using conventional techniques known to the art such as spray coating, compression coating, powder coating.
In embodiments, the pharmaceutical formulations of the present invention are evaluated for flow properties of the powder blend by measuring Hausner’s ratio and Compressibility index.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen and drotaverine and one or more pharmaceutically acceptable excipients wherein the pharmaceutical composition is a monolithic tablet or bilayer tablet comprising a final lubricated blend which has Hausner’s ratio of less than 1.
In embodiments, the present invention relates to a fixed dose pharmaceutical formulation comprising ibuprofen, drotaverine and one or more pharmaceutically acceptable excipients wherein the pharmaceutical composition is a monolithic tablet or a bilayer tablet wherein the final blend has compressibility index between15 to 20.
The pharmaceutical formulations of the present invention are subjected to in-vitro dissolution testing in a dissolution media. Rate and content of actives that is released from the formulations were determined using techniques such as high performance liquid chromatography (HPLC).
The fixed dose pharmaceutical formulations comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients as per the present invention are cost-effective and also are easy to make on a commercial scale.
In embodiments, the present invention relates to fixed dose pharmaceutical formulations comprising ibuprofen, drotaverine and pharmaceutically acceptable excipients which are intended for oral administration to a subject in need thereof.
While this invention has been described with reference to specific embodiments, the scope of the invention is not limited to these embodiments alone.
Further some of the embodiments are illustrated as working examples below and are meant to be representative only. The invention may be construed in any other forms and embodiments which may be understood and applied by a person skilled in the art within the scope of the present invention

EXAMPLES
Example 1: Monolithic tablets prepared by direct compression
S. No. Ingredients Mg/tablet
1A 1B
1 Ibuprofen 400.00 400.00
2 Starch 1500 200.00 178.00
3 Lactose monohydrate(200) ** **
4 Crospovidone XL10 12.00 12.00
5 Citric acid ** 15,00
6 Ascorbic acid ** 7.00
7 Microcrystalline Cellulose PH 102 ** **
8 Aerosil 200 ** **
9 Stearic acid ** **
10 Drotaverine Hydrochloride 80.00 80.00
11 Stearic acid 8.00 8.00
Total Weight 700.00 700.00

Brief Manufacturing Process for tablets of Example 1A:
1) Ibuprofen DC90 was sifted from #18 mesh, Drotaverine HCl, Starch 1500 & Crospovidone XL10 were sifted from #40 mesh.
2) Step 1 mixture was mixed in a double cone blender thoroughly to form Step 2 blend.
3) Stearic acid was sifted from #40 mesh.
4) Step 3 powder was added to blend from step 2 and lubricated thoroughly in a double cone blender.
6) The lubricated blend was then compressed into a monolithic tablet.

Brief Manufacturing Process for tablets of Example 1B:
1) Ibuprofen DC90 was sifted from #18 mesh
2) Drotaverine HCl, Starch 1500, ascorbic acid & Crospovidone XL10 were geometrically sifted from #40 mesh.
3) Citric acid was sifted from #60 mesh which was then geometrically sifted from #40 mesh with Step 2 blend
4) Step 1 powder was added to Step 3 blend and it was blended in a double cone blender.
5) Stearic acid was sifted from #40 mesh.
6) Step 4 blend was added to step 2 blend and lubricated thoroughly in Double Cone Blender.
7) The lubricated blend was then collected and compressed into a monolithic tablet.

Example 2: Monolithic tablets prepared by wet granulation.
S.No Ingredients Mg/tab
2A 2B
1 Ibuprofen 400.00 400.00
2 Starch 1500 100.00 100.00
3 Lactose monohydrate(200) 90.00 90.00
4 Crospovidone XL10 10.00 10.00
5 Citric acid 15.00 15.00
6 Ascorbic acid 9.00 9.00
7 Water Q.S Q.S
8 Drotaverine HCl 80.00 80.00
9 Flowlac 100 86.00 86.00
10 Starch 1500 52.00 52.00
11 Aerosil 200 8.00 8.00
12 Stearic acid 16.00 16.00
Core Tablet Weight 866.00 866.00mg
13 Opadry II Yellow 26.00mg 26.00mg
14 Water qs qs

Brief Manufacturing Process for tablets of Example 2A:

1) Ibuprofen, Starch1500, Lactose Monohydrate 200M, Crospovidone XL 10 were sifted through #40 mesh.
2) Citric acid and Ascorbic acid were dissolved in required amount of water.
3) The mixture of step1 was added in a Rapid Mixer Granulator and granulated with step 2 solution.
4) The granules of step 3 were dried in Fluid bed drier and the milled through Co-mill.
5) Drotaverine HCl, starch 1500, Flowlac100, Aerosil 200 were sifted through #40 mesh.
6) The mixture of step 5 was added to step 4 granules and blended in a Double cone Blender to form a pre lubricated blend.
7) Stearic acid was sifted through #40 mesh.
8) Stearic acid of step 7 was added to step 6 pre lubricated blend and lubricated to form the final blend.
9) The final blend of step 8 was compressed in to tablets.
10) The tablets of step 9 were loaded in Coating machine and Coated with Opadry II yellow.

Brief Manufacturing Process for tablets of Example 2B:

1) Ibuprofen, Drotaverine HCl, Starch1500, Lactose Monohydrate 200M, Crospovidone XL 10, were sifted through #40 mesh.
2) Citric acid and Ascorbic acid were dissolved in required amount of water.
3) The mixture of step1 was added in a Rapid Mixer Granulator and granulated with step 2 solution.
4) The granules of step 3 were dried in Fluid bed drier and the milled through Co-mill.
5) The required quantity of starch 1500, Flowlac100, Aerosil 200 were sifted through #40 mesh.
6) The mixture of step 5 was added to step 4 and blended in Double cone Blender to form the pre lubricated blend.
7) Stearic acid was sifted through #40 mesh.
8) Stearic acid of step 7 was added to step 6 pre lubricated blend and lubricated to form the final blend.
9) The final blend of step 8 was compressed in to tablets.
10) The tablets of step 9 were loaded in coating machine and coated with Opadry II yellow.

Example 3: Monolithic tablets prepared by blending two portions of granules
S. No Ingredients Mg/tab
1st granulation 3A 3B
1 Ibuprofen 400.00 400.00
2 Starch 1500 114.42 106.00
3 Microcrystalline Cellulose PH 101 70.00 87.46
4 Colloidal silicon dioxide 6.00 6.00
5 Crospovidone XL10 33.72 32.00
6 Sodium Lauryl Sulfate 2.80 2.54
7 Water Q.S Q.S
Weight of granules 626.94 mg 634.00 mg
7 Drotaverine Hydrochloride 80.00 80.00
8 Flowlac 100 100.00 98.19
9 Starch 1500 20.00 20.00
10 Povidone K30 10.00 10.00
11 Ascorbic acid 4.18 4.20
12 Citric acid 3.68 3.61
13 Isopropyl alcohol Q.S Q.S
Weight of granules 218.88 mg 216.00 mg
14 Crospovidone XL10 10.00 10.00
15 MCC PH102 28.00 28.00
16 Aerosil 200 4.00 4.00
17 Stearic acid 8.00 8.00
Core Total Weight 895.82 mg 900.00 mg
18 Opadry II 32K540017 24.18 27.00
19 Water QS QS
Total Weight 920.00 mg 927.00 mg

Brief Manufacturing Process for tablets of Example 3A
Preparation of Ibuprofen granules
1) Ibuprofen, Starch1500, Microcrystalline Cellulose PH101, Crospovidone XL10 and colloidal silicon dioxide were sifted through #40 mesh.
2) Sodium Lauryl Sulfate was dissolved in required amount of water.
3) The mixture of step 1 was added in a Rapid Mixer Granulator and granulated with step 2 solution.
4) The granules of step 3 were dried in a fluid bed drier and milled through 50G screen.
Preparation of Drotaverine granules
1) Drotaverine HCl, Flowlac 100 (Lactose monohydrate), Starch 1500, Povidone K30 and ascorbic acid were sifted through #40 mesh.
2) Citric acid was dissolved in isopropyl alcohol.
3) The mixture of step 1 was added in a Rapid Mixer Granulator and granulated with step 2 solution.
4) The granules of step 3 were dried in a fluid bed drier and milled through 40G screen.
Preparation of Extragranular material
1) Microcrystalline cellulose PH102, Crospovidone XL 10 and Aerosil 200 (Colloidal silicon dioxide) was sifted through #40 mesh.
2) The Ibuprofen and Drotaverine HCl granules were blended together in a double cone blender.
3) The granules of step 2 were added to the mixture of step 1 and blended together.
4) Stearic acid was sifted through #40 mesh.
5) Stearic acid of step 5 was added to step 3 blend and lubricated to form the final blend.
6) The final lubricated blend of step 5 was compressed into tablets.
7) The tablets of step 6 were loaded into coating machine and coated with Opadry II 32K540017.

Brief Manufacturing Process for tablets of Example 3B
Preparation of Ibuprofen granules
1) Ibuprofen, Starch1500, Microcrystalline Cellulose PH101, Crospovidone XL10 and colloidal silicon dioxide were sifted through #40 mesh.
2) Sodium Lauryl Sulfate was dissolved in required amount of water.
3) The mixture of step 1 was added in a Rapid Mixer Granulator and granulated with step 2 solution.
4) The granules of step 3 were dried in a fluid bed drier and milled through 50G screen.
Preparation of Drotaverine granules
1) Drotaverine HCl, Flowlac 100 (Lactose monohydrate), Starch 1500, Povidone K30 and ascorbic acid were sifted through #40 mesh.
2) Citric acid was dissolved in isopropyl alcohol.
3) The mixture of step 1 was added in a Rapid Mixer Granulator and granulated with step 2 solution.
4) The granules of step 3 were dried in a fluid bed drier and milled through 40G screen.
Preparation of Extragranular material
1) Microcrystalline cellulose PH102, Crospovidone XL 10 and Aerosil 200 (Colloidal silicon dioxide) was sifted through #40 mesh.
2) The Ibuprofen and Drotaverine HCl granules were blended together in a double cone blender.
3) The granules of step 2 were added to the mixture of step 1 and blended together.
4) Stearic acid was sifted through #40 mesh.
5) Stearic acid of step 5 was added to step 3 blend and lubricated to form the final blend.
6) The final lubricated blend of step 5 was compressed into tablets.
7) The tablets of step 6 were loaded into coating machine and coated with Opadry II 32K540017.
Example 4: Bilayer tablets prepared by granulation.
S.No Ingredients Mg/tab
1st granulation 4A 4B
1 Ibuprofen 400.00 400.00
2 Starch 1500 90.00 90.00
3 Lactose monohydrate(200) 100.00 88.00
6 Crospovidone XL10 10.00 10.00
7 Citric acid ** 9.00
8 Ascorbic acid ** 3.00
Granulation
9 Water Q.S Q.S
Extragranular
10 MCC PH 102 26.00 26.00
11 Aerosil 200 6.00 6.00
12 Stearic acid 8.00 8.00
Weight of 1st layer 640.00mg 640.00mg
2nd Granulation
13 Drotaverine Hydrochloride 80.00 80.00
14 Lactose(Flowlac 100) 108.00 98.00
15 Starch 1500 26.00 26.00
16 Crospovidone XL10 10.00 10.00
17 Ascorbic acid ** 4.00
18 Citric acid ** 6.00
19 IPA Q.S Q.S
20 Stearic acid 2.00 2.00
Weight of 2nd layer 226.00mg 226.00mg
Total Weight 866.00mg 866.00mg

Brief Manufacturing Process for Preparing Tablets of Examples 4A:

Ibuprofen Layer
1) Ibuprofen, Starch1500, Lactose monohydrate 200M, Crospovidone XL10 were sifted through #40 mesh.
2) The blend of step1 was added to a Rapid Mixer Granulator and granulated with water.
3) The granulated material of step 2 was dried in fluid bed drier and milled through 50 G screen.
4) Microcrystalline cellulose and Aerosil 200 were sifted through #40 mesh,
5) The material of step 4 was added to step 3 and was blended in a Double Cone Blender to form a pre lubricated blend.
6) Stearic acid was weighed and sifted through #40 mesh.
7) The powder of step 6 was added to step 5 blend and lubricated.
Drotaverine Layer:
1) Drotaverine HCl, Lactose (Flowlac 100), Starch 1500, Crospovidone XL 10 were sifted through #40 mesh.
2) The blend of step1 was added to a Rapid Mixer Granulator and granulated with IPA.
3) The blend of step 2 was dried in fluid bed drier and milled through 40G screen.
4) Stearic acid was sifted through #40 mesh.
5) Stearic acid of step 4 was added to the blend of step 3 and was lubricated.
Compression: Both Ibuprofen granules and drotaverine granules were then compressed into a bilayer tablet.

Brief Manufacturing Process for Preparing Tablets of Examples 4B:
Ibuprofen Layer
1) Ibuprofen, Starch1500, Lactose monohydrate 200M, Crospovidone XL10 were sifted through #40 mesh.
2) Citric acid and ascorbic acid were dissolved in required amount of water
3) The blend of step 1 was added in a Rapid Mixer Granulator and granulated with solution of step 2.
4) The granulated material of step 3 was dried in a Fluid Bed Drier and milled through 50 G screen.
5) Microcrystalline cellulose and Aerosil 200 were sifted through #40 mesh,
6) The material of step 5 was added to the granulated material of step 4 and blended in a Double cone blender to form a pre lubricated blend.
7) Stearic acid was sifted through #40 mesh.
8) Stearic acid of step 7 was added to the pre lubricated blend of step 6 and lubricated to form the final blend.
Drotaverine Layer:
1) Drotaverine HCl, Lactose (Flowlac 100), Starch 1500, Crospovidone XL 10 and ascorbic acid were sifted through #40 mesh.
2) Citric acid was dissolved in IPA.
3) The mixture of step 1 was added to a Rapid Mixer Granulator and granulated with IPA.
4) The blend of step 3 was dried in a Fluid bed drier and milled through 40G screen.
5) Stearic acid was sifted through #40 mesh.
6) The material of step 5 was added to blend of step 3 in a Double cone Blender to form a final lubricated blend.
Compression: Both Ibuprofen Granules and drotaverine Granules are compressed in to a Bilayer tablet.
All the tablets which were described in the above examples were tested for related substances (RS) at the initial stage of formulation and under stability conditions of 40°C and 75%Relative Humidity.

The data obtained from the study is shown below:
*VRLDN – Drotaveraldine/ Varaldine (oxidative impurity)
*Unk – Unknown
ND – Not detected

Table 1
RRT (min)
Impurity 1A
1B
Initial 1M Initial 1M
Amine ND ND ND ND
Acid 0.03 ND 0.03 0.03
Amide ND ND ND ND
VRLDN 0.14 0.37 0.08 0.14
Unk - 0.06 - 0.01
Unk 0.01 0.08 0.03 -
Unk - 0.30 - -
Unk - 0.16 - 0.03
Unk - 0.24 - 0.02
Unk 0.12 0.32 - 0.01
Total 0.68 1.85 0.49 0.51

Table 2
RRT (min)
Impurity 2A 2B
Initial Initial
Amine ND 0.03
Acid 0.03 0.04
Amide 0.03 0.02
VRLDN 0.04 0.13
Unk 0.05 -
Unk 0.04 0.02
Unk - 0.01
Unk 0.02 0.03
Unk - -
Unk - -
Total 0.31 0.55

Table 3
RRT (min)
Impurity 3A
Initial 1M 3M
Amine ND ND ND
Acid ND ND ND
Amide ND ND ND
VRLDN 0.02 0.03 0.04
Unk 0.04 0.03 0.05
Unk 0.06 0.05 0.05
Unk 0.09 0.08 0.10
Unk 0.03 0.06 0.20
Unk 0.04 0.04 0.07
Unk 0.04 0.03 0.06
Total 0.32 0.32 0.57

Table 4
RRT (min)

Impurity 4A 4B
Initial 1M Initial 1M
Amine 0.02 0.03 0.02 0.02
Acid 0.03 0.03 0.04 0.04
Amide ND 0.04 0.02 0.02
VRLDN 0.08 0.20 0.10 0.05
Unk - 0.02 0.05 0.04
Unk 0.02 0.05 0.02 0.02
Unk - 0.09 - 0.02
Unk - 0.04 0.03 0.03
Unk - 0.09 - -
Unk 0.15 0.10 - -
Total 0.56 0.89 0.51 0.50

From the above data depicted in tables 1, 2, 3 and 4, it appears that fixed dose pharmaceutical formulations comprising ibuprofen and drotaverine and pharmaceutically acceptable excipients which include acidifiers and antioxidants are more stable and contain varaldine impurities within permissible limits which is desirable.
,CLAIMS:We Claim
1. A fixed dose pharmaceutical formulation comprising analgesic agent, anti-spasmodic agent and one or more pharmaceutically acceptable excipients.

2. The fixed dose pharmaceutical formulation of claim 1 wherein the analgesic agent is ibuprofen and anti-spasmodic agent is drotaverine.

3. The pharmaceutical formulation of claim 1 wherein the pharmaceutical formulation is used for relief of menstrual and abdominal cramps associated with dysmenorrhea.

4. The pharmaceutical formulation of claim 1, wherein the pharmaceutically acceptable excipients are selected from the group consisting of acidifiers, antioxidants, diluents, disintegrants, binders, surfactants, glidants and lubricants.

5. The pharmaceutical formulation of claim 4 wherein the acidifier is selected from the group consisting of citric acid, fumaric acid, lactic acid, maleic acid, malic acid and tartaric acid.

6. The pharmaceutical formulation of claim 4 wherein the antioxidant is selected from the group consisting of butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), sodium metabisulfite, sodium thiosulfate, propyl gallate, ascorbic acid and cysteine.

7. The pharmaceutical formulation of claim 1 wherein the pharmaceutical formulation is a monolithic tablet or a bilayer tablet.

8. The pharmaceutical formulation of claim 7 wherein the pharmaceutical formulation is prepared by direct compression or wet granulation.
9. The pharmaceutical formulation of claim 1 wherein the pharmaceutical formulation comprises not more than 0.2% of varaldine when stored for 6 months at accelerated stability conditions of 40°C and 75% relative humidity and throughout the shelf life of the product.

10. A fixed dose pharmaceutical formulation comprising ibuprofen and drotaverine as described and illustrated in the examples herein.