Technical Field of the Invention
The present invention relates to a solid oral pharmaceutical composition containing two therapeutically active agents to be used as a spasmolytic and analgesic composition.
Background of the invention
It is well known that several compounds containing an isoquinoline ring possess spasmolytic properties. One such important isoquinoline derivative is drotaverine, which is a phosphodiesterase (PDE4) inhibitor and a non-anticholinergic antispasmodic. Chemically, it is, 1-[(3,4-Diethoxyphenyl) Methylene]-6,7-diethoxy 1,2,3,4-tetrahydroisoquinoline and is a subject of the patent GB 1,011,554. Further, GB 1,011,554 also discloses pharmaceutical compositions of drotaverine.
Non-steroidal anti-inflammatory drugs (NSAIDs) are well known anti-inflammatory, analgesic, antipyretic agents and smooth muscle relaxants. One particularly useful NSAID in pain management is Ketorolac tromethamine, which is available as oral, ophthalmic and parenteral formulations and is a subject of US Patent, US 4,089,969. Furthermore, there are numerous patents and applications, which disclose pharmaceutical compositions, particularly oral pharmaceutical compositions of ketorolac or a pharmaceutically acceptable salt thereof.
Besides, EP 1253919 discloses a pharmaceutical composition containing a PDE4 inhibitor and an NSAID in separate or combined form. However, a combination of ketorolac or its pharmaceutically acceptable salt and drotaverine or its pharmaceutically acceptable salt thereof is nowhere a subject of discussion in the prior art.
Furthermore, physicians often prescribe the spasmolytic drugs such as drotaverine along with the anti-inflammatory drugs, whenever inflammation is an inalienable component of muscle spasms. Taking this as the bottom-line, it would be very valuable to combine the two drugs in a single composition in order to ameliorate patient compliance.
We hereby disclose, stable solid oral pharmaceutical compositions comprising ketorolac or a pharmaceutically acceptable salt thereof and drotaverine or a pharmaceutically acceptable salt thereof.
Summary of the Invention
In one general aspect, the present invention relates to a solid oral pharmaceutical composition comprising ketorolac, drotaverine and a pharmaceutically acceptable carrier.
In another general aspect, it relates to a solid oral pharmaceutical composition comprising:
(a) a first discrete portion made with ketorolac and a pharmaceutically acceptable
carrier; and
(b) a second discrete portion made with drotaverine and a pharmaceutically
acceptable carrier.
In another general aspect, it relates to a solid oral pharmaceutical composition comprising ketorolac and drotaverine having two discrete portions as granules, wherein granules of both the drugs are formulated as a bilayer tablet.
In another general aspect, it relates to a solid oral pharmaceutical composition comprising ketorolac and drotaverine having two discrete portions as granules, wherein granules of both the drugs are filled in a capsule.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a capsule comprising ketorolac and drotaverine having two discrete portions, wherein the capsule contains separate pellets of both the drugs.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a capsule comprising ketorolac and drotaverine having two discrete portions, wherein the first portion comprises granules of one drug and the second portion comprises a powder blend of the other drug with a pharmaceutically acceptable carrier.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a tablet comprising ketorolac and drotaverine having two discrete portions, wherein the first portion comprises granules of one drug and the second portion comprises a powder blend of the other drug with a pharmaceutically acceptable carrier.

In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a capsule comprising ketorolac and drotaverine having two discrete portions, wherein the first portion comprises pellets of one drug and second portion comprises granules of the other drug.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a capsule comprising ketorolac and drotaverine having two discrete portions, wherein the first portion comprises pellets of one drug and second portion comprises a powder blend of the other drug with a pharmaceutically acceptable carrier.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a tablet comprising ketorolac and drotaverine having two discrete portions as pellets, wherein pellets of both the drugs are formulated as a bilayer tablet.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a tablet comprising ketorolac and drotaverine having two discrete portions, wherein the first portion comprises pellets of one drug and second portion comprises granules of the other drug.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a tablet comprising ketorolac and drotaverine having two discrete portions, wherein the first portion comprises pellets of one drug and second portion comprises a powder blend of the other drug with a pharmaceutically acceptable carrier.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a capsule comprising ketorolac and drotaverine having two discrete portions, wherein one of the drugs is formulated as a tablet and the other as a powder blend with a pharmaceutically acceptable carrier.
In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a capsule comprising ketorolac and drotaverine having two discrete portions, wherein one of the drugs is formulated as a tablet and the other as granules with a pharmaceutically acceptable carrier.

In another general aspect, it relates to a solid oral pharmaceutical composition in the form of a capsule comprising ketorolac and drotaverine having two discrete portions, wherein both the drugs are separately formulated as individual tablets with a pharmaceutically acceptable carrier.
In another general aspect, it relates to a method of preparation of a solid oral pharmaceutical composition comprising ketorolac and drotaverine having two discrete portions, wherein the method comprises the conventional processes of wet granulation, dry granulation or direct compression.
In another general aspect, it relates to a method of preparation of a solid oral pharmaceutical composition comprising ketorolac and drotaverine having two discrete portions, wherein the method comprises subjecting at least one of the drugs to the step of extrusion and spheronization.
In yet another general aspect, it relates to a method of treatment of spasmodic conditions, wherein the method comprises oral administration of a solid oral pharmaceutical composition comprising ketorolac and drotaverine.
Detailed Description of the Invention
"Ketorolac", as recited in the present invention, means ketorolac or a pharmaceutically acceptable salt thereof. Similarly, "Drotaverine" means drotaverine or a pharmaceutically acceptable salt thereof. Preferably, the solid oral pharmaceutical composition comprises a combination of ketorolac tromethamine and drotaverine hydrochloride.
Pharmaceutical compositions of ketorolac or a pharmaceutically acceptable salt thereof and drotaverine or a pharmaceutically acceptable salt thereof individually are given an extensive coverage in the literature. Also, combination of PDE4 inhibitors and NSAIDs are known from the prior patent data. However, a combination of both the aforementioned drugs is nowhere explicitely disclosed in the prior art. Drotaverine is well known for its spasmolytic activity, and ketorolac for its anti-inflammatory, analgesic and spasmolytic activities. It would therefore be of immense advantage to incorporate

these drugs in a single pharmaceutical composition for combined administration for the treatment of a spasmodic condition associated with an inflammatory component.
The spasmolytic drugs such as drotaverine are often prescribed with the anti-inflammatory agents, whenever there is an inflammatory condition associated with the muscle spasms To this perspective, a combined pharmaceutical composition would be an advantage in order to improve patient compliance. The present invention therefore, relates to solid oral dosage forms comprising a combination of ketorolac or a pharmaceutically acceptable salt thereof and drotaverine or a pharmaceutically acceptable salt thereof.
In the present invention, we have found that the two drugs i.e. ketorolac tromethamine and drotaverine hydrochloride when formulated into a dosage form as intimate mixture; undergo a certain amount of degradation. This is evident from the impurity profile of the tablets prepared by mixing the two drugs together and formulating into a dosage form by conventional tabletting procedures such as wet granulation, dry granulation or direct compression (Table 1). Degradation product of Ketorolac includes 1-keto analog of Ketorolac and that for drotaverine is drotaveralidine, the respective amounts of which would give an idea about the stability of a pharmaceutical composition comprising these two drugs. In contrast, the total amount of related substances as reflected by the impurity profile of the dosage forms where the two drugs are separated is minimal. This evidence underscores the incompatibility between the two drug components and a need to overcome the same by suitable formulation techniques.
The incompatibility may be circumvented by any such technique, which can help avoid contact between ketorolac and drotaverine. One such formulation technique is incorporating the two drugs in a bilayer tablet. The tablets may be prepared by conventional tabletting procedures such as wet granulation, dry granulation or direct compression. Two different blends of the drugs are prepared along with other pharmaceutically acceptable excipients by any of the aforementioned tabletting procedures and the blends are then compressed by using conventional tooling and a bilayer tabletting press. Alternatively, the separate granules of these two drugs may be filled into capsules.

Further, one of the drugs may be formulated as granules while preparing a simple powder blend of the other drug with a pharmaceutically acceptable carrier followed by either compressing the two into a bilayer tablet or filling in a capsule.
Furthermore, there is a formulation technique known as multiple unit pellet system (MUPS), which comprises of small pellets of a drug filled in a capsule. Such Multiple Unit Pellets are prepared by a particularly distinctive wet granulation process i.e. extrusion and spheronization. The pellet contains the drug, a fine particle diluent which also aids in the formation of the pellets (examples are lactose and mannitol) and a spheronization aid such as microcrystalline cellulose. Furthermore, the pellets may be coated with hydroxypropyl methylcellulose and polyethylene glycol 6000 mixture in purified water. The pellets may instead be compressed into a tablet dosage form.
A defined ratio of the two therapeutic agents is required in order to obtain an optimum therapeutic effect. An optimum therapeutic ratio of drotaverine or a pharmaceutically acceptable salt thereof to ketorolac or a pharmaceutically acceptable salt thereof is about 4:1, for example 40 mg of drotaverine hydrochloride with 10 mg of ketorolac tromethamine in a single dosage unit.
Besides, the solid dosage form further comprises a pharmaceutically acceptable carrier, which comprises one or more of diluent(s), binder(s), disintegrant(s), glidant(s) and lubricant(s).
Diluent(s) may be selected from mannitol, sorbitol, xylitol, lactose, microcrystalline cellulose, magnesium carbonate, calcium carbonate, dicalcium phosphate, tribasic calcium phosphate, calcium sulphate, and the like. The diluent may comprise from about 10% to about 80% by weight of the solid dosage form.
Binder(s) may be selected from starch, polyvinylpyrrolidone; hydroxypropyl cellulose, hydroxypropyl methylcellulose and other such materials routinely used in the art of solid dosage forms. The binder may be present in an amount varying from about 1% to about 10% by weight of the solid dosage form.
Disintegrant(s) may be selected from cross-linked carboxymethylcellulose and its sodium salt, crospovidone, starch, sodium starch glycolate, sodium carboxymethyl

cellulose, calcium carboxymethyl cellulose, low-substituted hydroxypropyl cellulose and sodium alginate or any other such material routinely used in the art of solid dosage forms. The disintegrant may be added intragranulary or extragranularly or both The concentration erf the disintegrant may vary from 1% to 15 % by weight of the solid dosage form.
Glidant(s) and lubricant(s) may be selected from the group consisting of talc, magnesium stearate, zinc stearate, calcium stearate, sodium stearyl fumarate, stearic acid, and the like. The lubricant may be used in a concentration varying from 0.5% to 2.5 % by weight of the tablet.
Preferred pharmaceutical compositions of the present invention may take form of several different embodiments.
In one embodiment of the present invention, the bilayer tablets are prepared by granulating ketorolac tromethamine with the aid of a pharmaceutically acceptable carrier, granulating similarly drotaverine hydrochloride with a pharmaceutically acceptable carrier, lubricating the respective granules and compressing with suitable punches and dies. The tablets may further be optionally coated with opadry aqueous dispersion.
In another embodiment, the bilayer tablets are prepared by granulating ketorolac tromethamine with the aid of a pharmaceutically acceptable carrier, preparing a powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier, lubricating the above granules and powder blend and compressing with suitable punches and dies. The tablets may be further be optionally coated with opadry aqueous dispersion.
In another embodiment, the bilayer tablets are prepared by blending ketorolac tromethamine with a pharmaceutically acceptable carrier, preparing a powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier in a similar way, lubricating the respective powder blends and compressing into a bilayer tablet with suitable punches and dies. The tablets may be further optionally coated with opadry aqueous dispersion.

In another embodiment, the bilayer tablets are prepared by granulating drotaverine hydrochloride with a pharmaceutically acceptable carrier, preparing a powder blend of ketorolac tromethamine with a pharmaceutically acceptable carrier, lubricating the above granules and powder blend and compressing with suitable punches and dies. The tablets may be further be optionally coated with opadry aqueous dispersion.
In another embodiment, the tablets are prepared by formulating ketorolac tromethamine as pellets by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, similarly preparing pellets of drotaverine hydrochloride, lubricating the above pellets and compressing with suitable punches and dies. Alternatively, the pellets may be compressed as bilayer tablets. The tablets may be further be optionally coated with opadry aqueous dispersion.
In another embodiment, the tablets are prepared by formulating ketorolac tromethamine as pellets by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, formulating drotaverine hydrochloride as granules by any of wet granulation or dry granulation, lubricating the above pellets and granules and compressing with suitable punches and dies. Alternatively, the above mass may be compressed as bilayer tablets. The tablets may further be optionally coated with opadry aqueous dispersion.
In another embodiment, the tablets are prepared by formulating drotaverine hydrochloride as pellets by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, formulating ketorolac tromethamine as granules by any of wet granulation or dry granulation, lubricating the above pellets and granules and compressing with suitable punches and dies. Alternatively, the above mass may be compressed as bilayer tablets. The tablets may further be optionally coated with opadry aqueous dispersion.
In another embodiment, the tablets are prepared by formulating ketorolac tromethamine as pellets by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline

cellulose followed by sub-coating of the pellets, preparing a powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier, lubricating the above pellets and powder blend and compressing with suitable punches and dies. Alternatively, the above mass may be compressed as bilayer tablets. The tablets may further be optionally coated with opadry aqueous dispersion.
In another embodiment, the tablets are prepared by formulating drotaverine hydrochloride a$ pellets by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, preparing a powder blend of ketorolac tromethamine with a pharmaceutically acceptable carrier, lubricating the above pellets and powder blend and compressing with suitable punches and dies. Alternatively, the above mass may be compressed as bilayer tablets. The tablets may further be optionally coated with opadry aqueous dispersion.
In another embodiment, the separate granules of ketorolac tromethamine and drotaverine hydrochloride with a pharmaceutically acceptable carrier are lubricated and filled into a capsule.
In another embodiment, granules of ketorolac tromethamine with a pharmaceutically acceptable carrier and a powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier are lubricated and filled into a capsule.
In another embodiment, granules of drotaverine hydrochloride with a pharmaceutically acceptable carrier and a powder blend of ketorolac tromethamine with a pharmaceutically acceptable carrier are lubricated and filled into a capsule.
In another embodiment, a lubricated powder blend of ketorolac tromethamine with a pharmaceutically acceptable carrier compressed into a tablet and a lubricated powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier are filled into a capsule.
In another embodiment, a lubricated powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier compressed into a tablet and a lubricated blend of
ketorolac tromethamine with a pharmaceutically acceptable carrier are filled into a capsule.
In another embodiment, a lubricated blend of ketorolac tromethamine with a pharmaceutically acceptable carrier compressed into a tablet and similarly a lubricated blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier compressed into a tablet are filled into a capsule.
In another embodiment, a lubricated blend of ketorolac tromethamine with a pharmaceutically acceptable carrier compressed into a tablet and a powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier formulated as granules are filled into a capsule.
In another embodiment, a lubricated blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier compressed into a tablet and a powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier formulated as granules are filled into a capsule.
In another embodiment, pellets of ketorolac tromethamine are prepared by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, similarly preparing pellets of drotaverine hydrochloride, lubricating the above pellets and filling into a capsule.
In another embodiment, pellets of ketorolac tromethamine are prepared by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, formulating drotaverine hydrochloride as granules by any of the wet granulation or dry granulation processes, lubricating the above pellets and granules and filling into a capsule.
In another embodiment, pellets of drotaverine hydrochloride are prepared by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, formulating ketorolac tromethamine as granules by any of
the wet granulation or dry granulation processes, lubricating the above pellets and granules and filling into a capsule.
In another embodiment, pellets of ketorolac tromethamine are prepared by the process of extrusion and: spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, preparing a powder blend of drotaverine hydrochloride with a pharmaceutically acceptable carrier, lubricating the pellets and the powder blend and filling into a capsule.
In another embodiment, pellets of drotaverine hydrochloride are prepared by the process of extrusion and spheronization with the help of a fine particle diluent such as lactose or mannitol and a spheronizing aid such as microcrystalline cellulose followed by sub-coating of the pellets, preparing a powder blend of ketorolac tromethamine with a pharmaceutically acceptable carrier, lubricating the pellets and the powder blend and filling into a capsule.
The following examples are illustrative of the invention, and are not intended to be construed as limiting the invention.
Comparative Example:-
mg/tablet
Ketorolac Tromethamine 10.00
Drotaverine Hydrochloride 40.00
Lactose monohydrate 75.00
MCC 120.00
Sodium carboxymethylcellulose 13.00
Magnesium Stearate 2.00
Opadry white 6.00
Purified Water q.s.
Process:- Ketorolac tromethamine, drotaverine hydrochloride, lactose, microcrystalline
cellulose and sodium carboxymethylcellulose are sifted through a suitable sieve
followed by lubricating the blend with magnesium stearate. The blend is then compressed into tablets with suitable punches and dies.
Example 1:- Bilayer tablet prepared by direct compression
ln«redients mgteblet
Layer 1
Ketorolac tromethamine 10.00
Lactose monohydrate 73.00
MCC 19.89
Sodium carboxymethylcellulose 6.00
Magnesium Stearate 1.10
Layer 2
Drotaverine Hydrochloride 40.00
Lactose monohydrate 75.00
MCC 26.80
Sodium carboxymethylceilulose 7.00
Magnesium Stearate 1.20
Film Coating
Opadry White 6.00
Purified Water* q.s.
Process:- Ketorolac tromethamine, lactose, microcrystalline cellulose and sodium carboxymethylcellulose are sifted through a suitable sieve followed by lubricating the blend with magnesium stearate. Similarly, drotaverine hydrochloride, lactose, microcrystalline cellulose and sodium carboxymethylcellulose are sifted through suitable sieve and the blend lubricated with magnesium stearate. The respective blends of the two drugs are then compressed into a bilayered tablet with suitable punches and dies followed by coating using opadry aqueous dispersion.
Example 2:- Tablets with Multiple Unit Pellet System (MUPS)
Ingredients mgftablet
Ketordlac Tromethamine Pellets
Ketorolac tromethamine 10.00
MCC 118.00
Povidone 2.00
Purified Water q.s.
Sub coating of Ketorolac Tromethamine Pellets
Ketorolac Tromethamine Pellets 120.00
Hydroxypropyl methylcellulose 2.25
PEG 6000 0.75
Purified Water q.s.
Granulation of Drotaverine Hydrochloride
Drotaverine Hydrochloride 40.00
Lactose monohydrate 105.00
Corn Starch 55.80
Microcrystalline cellulose 165.00
Povidone 2.20
Purified Water q.s.
Sodium starch glycolate 12.00
Magnesium Stearate 2.00
Process:-
Formulation of Ketorolac tromethamine pellets
1). Ketorolac tromethamine, microcrystalline cellulose and povidone are sifted through
a suitable sieve.
2). The mixture of step 1 is granulated with purified water.
3). The granulate is passed through extruder and spheronized at specified rpm.
4). Ketorolac spheres are dried at 50°C.
5). The Ketorolac tromethamine pellets are sub-coated by using HPMC/PEG 6000
mixture.
Formulation of Drotaverine blend
6). Drotaverine hydrochloride, lactose, microcrystalline cellulose, corn starch, sodium
starch glycolate and povidone are sifted through a suitable sieve.
7). The mixture of step 6 is granulated with purified water.
Lubrication and Compression
8). Ketorolac Tromethamine pellets equivalent to 10 mg are weighed and mixed with
dried drotaverine granules.
9). The above mixture is compressed using a suitable tooling.
Example 3:- Capsules with Ketorolac tromethamine tablet and drotaverine HCI blend
Qtv
ln«rediente mg/tablet
Ketorolac Tromethamine tablet
Ketorolac tromethamine 10.00
MCC112 10.00
Lactose (DCL 21) 40.40
Sodium carboxymethylcellulose 4.40
Colloidal silicon dioxide 0.60
Magnesium Stearate 0.60
Film Coating
Opadry white 2.00
Purified Water q.s.
Drotaverine Hydrochloride blend
Drotaverine Hydrochloride 40.00
Lactose monohydrate 252.00
Magnesium stearate 2.00
Talc 6.00
Process:-
Formulation of Ketorolac Tromethamine tablet
Ketorolac tromethamine, lactose, microcrystalline cellulose, and sodium carboxymethylcellulose are sifted through a suitable sieve and the blend is lubricated
with magnesium stearate and colloidal silicon dioxide. The blend is then compressed into a tablet using a suitable tooling.
Formulation of Drotaverine blend
Accurately weighed drotaverine, lactose, talc and magnesium stearate are sifted through a suitable sieve and formed into a blend.
Capsule filling
Ketorolac Tromethamine tablets and drotaverine hydrochloride blend are filled in the required size of capsule.
Table 1:- Impurity Profile of Ketorolac Tromethamine and Drotaverine Hydrochloride tablets

(Table Removed)
* Not Detectable
The total related substances in examples 1, 2 and 3 are much less in contrast to those in the comparative example. This draws attention to the incompatibility between the two drugs and a need to separate the two in the final formulation in order to produce stable dosage forms.

WE CLAIM:-
1). A solid oral pharmaceutical composition comprising ketorolac, drotaverine and a pharmaceutically acceptable carrier.
2). The solid pharmaceutical composition of claim 1, wherein the composition comprises:
(c) a first discrete portion made with ketorolac and a pharmaceutically acceptable
carrier; and
(d) a second discrete portion made with drotaverine and a pharmaceutically
acceptable carrier.
3). The solid pharmaceutical composition of claim 2, wherein the discrete portions are in the form of granules, pellets, powder blend or tablet.
4). The solid pharmaceutical composition of claim 3, wherein one of the discrete portions comprises granules and the other comprises a powder blend.
5). The solid pharmaceutical composition of claim 3, wherein one of the discrete portions comprises pellets and the other comprises granules.
6). The solid pharmaceutical composition of claim 3, wherein one of the discrete portions comprises pellets and the other comprises a powder blend.
7). The solid pharmaceutical composition of claims 1-6, wherein the composition is a tablet or a capsule.
8). The solid pharmaceutical composition of claim 7, wherein the tablet is a bilayer tablet.
9). The solid pharmaceutical composition of claim 7, wherein the composition is a capsule containing at least one of the discrete portions compressed as a tablet.
10). The pharmaceutical composition of claim 1 or 2, wherein the pharmaceutically acceptable carrier is selected from one or more of diluents, binders, disintegrants, glidants and lubricants as herein described.
11). A method of preparation of the solid pharmaceutical composition of preceding claims, wherein the method comprises the conventional processes of wet granulation, dry granulation or direct compression.
12). A method of preparation of the solid pharmaceutical composition of claim 11, wherein the wet granulation is executed by the process of extrusion and spheronization.