Claims:1. A modified release pharmaceutical composition of methocarbamol or its pharmaceutically acceptable salts.
2. A modified release pharmaceutical composition of claim 1, where in composition is in the form of granules or tablet.
3. A modified release pharmaceutical composition of claim 1, where in composition comprises methocarbamol in the range of 500mg to 1500mg.
4. A modified release pharmaceutical composition of claim 1, where in composition comprises methocarbamol is released from the composition over a period of 6 hours to 18 hours.
5. A modified release pharmaceutical composition of claim 1, where in composition comprises methocarbamol in a compacted tablet form.
6. A modified release pharmaceutical composition of claim 1, where in composition comprises methocarbamol to be administered twice or thrice a day.
7. A modified release pharmaceutical composition of claim1, where in composition comprises methocarbamol and release controlling excipient.
8. A process to prepare modified release methocarbamol composition, where in methocarbamol and binder are melt extruded, extrudes are milled to desired size, milled and sized granules are blended with release controlling excipient and lubricant, lubricated blend is compressed using rotary compression machine. , Description:Field of invention
The present invention provides modified release compositions of methocarbamol or its pharmaceutically acceptable salts thereof, in a dosage form that is compact and provides ease to swallow and reduce pill burden.

Background of invention
The chemical name of methocarbamol is 3-(2-methoxyphenoxy)-l,2-propanediol 1-carbamate and has the empirical formula C11H15NO5. Its molecular weight is 241.24. The structural formula is shown below.

Methocarbamol is a white powder, sparingly soluble in water and chloroform, soluble in alcohol (only with heating) and propylene glycol, and insoluble in benzene and n-hexane.

Robaxin is the brand name of methocarbamol tablets available in United States of American market. These are immediate release film coated tablets available in 2 strengths 500mg and 750mg. These are indicated as an adjunct to rest, physical therapy, and other measures for the relief of discomfort associated with acute painful musculoskeletal conditions. 6 grams a day are recommended for first 48 to 72 hours of treatment, for severe conditions 8 grams a day may be administered. Thereafter, the can be usually reduced to approximately 4 grams a day.

4 to 8 grams of dose per day requires about 8 to 16 tablets of 500mg strength or about 5 to 10 tablets of 750mg strength resulting into high pill burden to the patient in need thereof.
Naresh Gorantla et al., have published an article titled “Fabrication & characterization of bilayer sustained release tablets using ibuprofen and methocarbamol as model drugs” in Int. J. Chem. and Life sciences, accepted on 13th January, 2013. As the title clearly says authors have taken said drugs as model drugs only and their focus was mainly on fabrication and characterization of bilayer tablets. More over this article has not discussed or disclosed any modified release tablets that reduces pill burden or reduce frequency of administration or compositions having methocarbamol more than 500mg per dosage form.

Remya PN et al., have published an article titled “Formulation & evaluation of bilayered tablets of ibuprofen and methocarbamol” in International journal of pharm tech research, Vol 2, No 2, PP 1250-1255, Apr-Jun 2010. This article has not discussed or disclosed any modified compositions of methocarbamol.

Hence there is a strong need to develop improved dosage forms that reduces pill burden, reduce frequency of dosing and provide minimum Cmax – Cmin fluctuations.

Detailed description

In an embodiment of the present invention, a modified release pharmaceutical composition comprises of methocarbamol or its pharmaceutically acceptable salts.

In another embodiment of present invention, a modified release pharmaceutical composition, where in composition is in the form of granules or tablet.

In another embodiment of present invention, a modified release pharmaceutical composition, where in composition comprises methocarbamol in the range of 500mg to 1500mg.

In yet another embodiment of present invention, a modified release pharmaceutical composition, where in composition comprises methocarbamol is released from the composition over a period of 6 hours to 18 hours or 8 to 16 hours or 8 to 12 hours.

In another embodiment of present invention, a modified release pharmaceutical composition, where in composition comprises methocarbamol in a compacted tablet form.

In an embodiment of present invention, a modified release pharmaceutical composition, where in composition comprises methocarbamol to be administered twice or thrice a day or once or twice a day.

In another embodiment of present invention, a modified release pharmaceutical composition, where in composition comprises methocarbamol and release controlling excipient.

In another embodiment of present invention, a process to prepare modified release methocarbamol composition, where in methocarbamol and binder are melt extruded, extrudes are milled to desired size, milled and sized granules are blended with release controlling excipient and lubricant, lubricated blend is compressed using rotary compression machine.

In the present invention, to prepare granules or tablets of modified release methocarbamol, excipients such as but not limited to diluents, disintegrants, binders, release controlling excipients, lubricants, glidants, colors, coating agents, plasticizers, opacifying agents and the like are used in various proportions that result in compact tablets or granules providing desired release profiles.

Diluents selection should be made carefully as physical-chemical changes might render the product unstable and might cause problems in manufacturing. Binders are added to tablet formulations to add cohesiveness to powders thereby providing the necessary bonding to form granules which under compaction form a compact mass as tablet. In other words, binders are essential to achieve the “hardness” of the tablet.
Binders are usually selected on basis of previous experience, particular product needs, literature or vendor data or the preference of individual scientists or manufacturing unit. The primary criterion when choosing a binder is its compatibility with other tablet components.

It must add sufficient cohesion to the powders to allow for normal processing yet allow the tablet to disintegrate and the drug to dissolve upon ingestion, releasing the active ingredients for absorption. Disintegrants facilitate the breakup of a tablet after oral administration.

They can be added prior to granulation or during the lubrication step prior to compression or at both processing steps. The effectiveness of many disintegrants is affected by their position within the tablet. Since disintegration is the opposite operation to granulation (agglomeration) and the subsequent formation of strong compacts, one must carefully weigh these two phenomena when designing a tablet. Lubricants prevent sticking of the tablets to the tablet punches during the compression phase of the tablet manufacturing process.

When lubricants are added to a powder mass, they form a coat around individual particles which remains more or less intact during compression. Lubricants are mostly hydrophobic. The presence of lubricant coating may cause an increase in the disintegration time and a decrease in drug dissolution rate. The choice of a lubricant may depend upon the type of tablet being manufactured, dissolution, flow characteristics and requirements of the formulation in terms of hardness, friability and compatibility. Glidants are the materials that have good flow properties and poor lubrication properties.

Glidants improve the flow of powder into the tableting machines for compaction. They act to minimize the tendency of a granulation to separate or segregate due to excessive vibration. High speed tablet machine require smooth even flow of material to die cavities (tablet mold). The uniformity of tablet weights directly depends on how uniformly the die cavity is filled. In general many materials commonly referred to as lubricants possess only a minimal lubricating activity and are better glidants or anti-adherents.

Release controlling excipients of the present invention includes but not limited to gums such as acacia, xanthane gum, gum Arabica and the like; cellulose derivatives such as but not limited to hydroxypropyl cellulose, hydroxypropylmethyl cellulose, cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate phthalate, hydroxypropylmethyl cellulose acetate succinate and the like; eudragits such as but not limited to Eudragit L, Eudragit S, Eudragit R, Eudragit RS, Eudragit E, Eudragit RSPO and the like or combinations of gums or celluloses or Eudragits.

Thus a blend of two or more materials may be necessary to obtain these properties.
Exemplary list of excipients and its role in solid oral preparation is listed in Table 1.

Table 1
No: Excipient Number of times excipients used in tablets out of 200 Use
1 Acacia 2 Emulsifying agent; stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent
2 Alginate 1 Binder
3 Alginic Acid 1 Stabilizing agent; suspending agent; tablet binder,
tablet disintegrant; viscosity-increasing agent.
4 Aluminum Acetate 1 Antiseptic
5 Benzyl Alcohol 2 Antimicrobial preservative; disinfectant; solvent
6 Butyl Paraben 1 Antimicrobial preservative
7 Butylated Hydroxy Toluene 1 Antioxidant.
8 Citric acid 1 Disintegrant
9 Calcium carbonate 1 Tablet and capsule diluent; therapeutic agent
10 Candelilla wax 4 Binder
11 Croscarmellose sodium 22 Tablet and capsule disintegrant
12 Confectioner sugar 1 Sugar coating adjunct; sweetening agent; tablet and capsule diluents
13 Colloidal silicone dioxide 22 Adsorbent; anticaking agent; emulsion stabilizer; glidant;
suspending agent; tablet disintegrant; thermal stabilizer;
viscosity-increasing agent.
14 Cellulose 19 Adsorbent; suspending agent; tablet and capsule diluent;
tablet disintegrant.(cellulose microcrystaline) Adsorbent; glidant; suspending agent;
tablet and capsule diluent; tablet disintegrant (cellulose powdered) Tablet and capsule diluent.(cellulose Silicified)
15 Plain or anhydrous calcium phosphate 3 Diluent
16 Carnuba wax 12 Binder
17 Corn starch 17 Binder
18 Carboxymethylcellulose calcium 3 Stabilizing agent; suspending agent;
tablet and capsule disintegrant;
viscosity-increasing agent; water-absorbing agent
19 Calcium stearate 5 Tablet and capsule lubricant
20 Calcium disodium EDTA 1 Chelation
21 Copolyvidone 1 Film-former; granulating agent; tablet binder
22 Castor oil hydrogenated 4 Extended release agent; stiffening agent; tablet and
capsule lubricant
23 Calcium hydrogen phosphate dihydrate 1 Diluent
24 Cetylpyridine chloride 1 Antimicrobial preservative; antiseptic;
cationic surfactant; disinfectant;
solubilizing agent; wetting agent
25 Cysteine HCL 1 Reducing Agent
26 Crosspovidone 20 Tablet disintegrant.
27 calcium phosphate di or tri basic 7 Tablet and capsule diluent Anticaking agent; buffer, nutrient; dietary supplement;
glidant; tabletand capsule diluent and
clouding agent (for calium phosphage tribasic)
28 Dibasic Calcium Phosphate 9 Diluent
29 Disodium hydrogen phosphate 1 Buffering agent
30 Dimethicone 1 Antifoaming agent;
emollient
31 Erythrosine Sodium 2 Color
32 Ethyl Cellulose 3 Coating agent;flavoring fixative;tablet binder;tablet filler;viscosity-increasing agent.
33 Gelatin 14 Coating agent;film-former;gelling agent;suspending agent;tablet binder;viscosity-increasing agent
34 Glyceryl monooleate 2 Nonionic surfactant
35 Glycerin 3 Antimicrobial preservative;emollient;humectant;
plasticizer;solvent;sweetening agent;tonicity agent
36 Glycine 1 Tonicity
37 Glyceryl monostearate 1 Emollient; emulsifying agent;solubilizing agent;
stabilizing agent;sustained-release ingredient;
tablet and capsule lubricant
38 Glyceryl behenate 1 Coating agent; tablet binder; tablet and capsule lubricant
39 Hydroxy propyl cellulose 25 Coating agent; emulsifying agent;stabilizing agent; suspending agent;tablet binder; thickening agent;
viscosity-increasing agent.
40 Hydroxyl propyl methyl cellulose 45 Coating agent; film-former;rate-controlling polymer for sustained release;stabilizing agent; suspending agent; tablet binder; viscosity-increasing agent.
41 Hypromellose 7 Coating agent; film-former;rate-controlling polymer for sustained release; stabilizing agent;suspending agent; tablet binder; viscosity-increasing agent.
42 HPMC Pthalate 1 Coating agent.
43
Iron oxides or ferric oxide 15 Color
44 Iron oxide yellow 5 Color
45 Iron oxide red or ferric oxide 6 Color
46 Lactose hydrous or anhydrous or monohydrate or spray dried 77 Binding agent; diluent for dry-powder inhalers; lyophilization aid;tablet binder; tablet and capsule diluent.( lactose anhydrous) Binding agent; diluent for dry-powder inhalers; tablet binder;tablet and capsule diluent(lactose monhydrate) Binding agent; diluent for dry-powder inhalations; tablet and capsule diluent;
tablet and capsule filler.(lactose spray dried)
47 Magnesium stearate 108 Tablet and capsule lubricant
48 Microcrystalline cellulose 61 Adsorbent; suspending agent; tablet and capsule diluent; tablet disintegrant
49 Mannitol 4 Sweetening agent; tablet and capsule diluent; tonicity agent;vehicle (bulking agent) for lyophilized preparations
50 Methyl cellulose 3 Coating agent; emulsifying agent; suspending agent;
tablet and capsule disintegrant; tablet binder; viscosity-increasing agent
51 Magnesium carbonate 2 Tablet and capsule diluent
52 Mineral oil 3 Emollient; lubricant; oleaginous vehicle; solvent
53 Methacrylic acid copolymer 5 Coating
54 Magnesium oxide 2 Tablet and capsule diluent
55 Methyl paraben 5 Antimicrobial preservative
56 Povidone or PVP 36 Disintegrant; dissolution aid; suspending agent; tablet binder.
57 PEG 40 Ointment base; plasticizer; solvent; suppository base;
tablet and capsule lubricant
58 Polysorbate 80 19 Solubilizer
59 Propylene glycol 10 Antimicrobial preservative; disinfectant; humectant; plasticizer;solvent; stabilizer for vitamins; water-miscible cosolvent.
60 Polyethylene oxide 3 Mucoadhesive; tablet binder; thickening agent.
61 Propylene paraben 4 Antimicrobial preservative
62 Polaxamer 407 or 188 or plain 3 Dispersing agent; emulsifying and coemulsifying agent;
solubilizing agent; tablet lubricant; wetting agent.
63 Potassium bicarbonate 1 Alkalizing agent; therapeutic agent
64 Potassium sorbate 1 Antimicrobial preservative
65 Potato starch 1 Binder
66 Phosphoric acid 1 Acidifying agent
67 Polyoxy140 stearate 1 Emulsifying agent; solubilizing agent; wetting agent
68 Sodium starch glycolate 20 Tablet and capsule disintegrant
69 Starch pregelatinized 21 Tablet and capsule diluent; tablet and capsule disintegrant;tablet binder (starch pregelatinized Glidant; tablet and capsule diluent; tablet and capsule disintegrant;tablet binder.( starch , potato, corn , wheat, rice) so check the above and make the changes
70 Sodium crossmellose 1 Disintegrant
71 Sodium lauryl sulfate 13 Anionic surfactant; detergent; emulsifying agent;
skin penetrant; tablet and capsule lubricant; wetting agent
72 Starch 19 Glidant; tablet and capsule diluent; tablet and capsule disintegrant;tablet binder.( starch , potato, corn , wheat, rice) combine all the starches
73 Silicon dioxide 14 Same as colloidal silicon dioxide
74 Sodium benzoate 2 Antimicrobial preservative; tablet and capsule lubricant
75 Stearic acid 12 Emulsifying agent; solubilizing agent; tablet and capsule lubricant.
76 Sucrose 9 Base for medicated confectionery; granulating agent;
sugar coating adjunct; suspending agent; sweetening agent;tablet and capsule diluent; viscosity-increasing agent.
77 Sorbic acid 3 Antimicrobial preservative
78 Sodium carbonate 1 Carbonating agent
79 Saccharin sodium 1 Sweetening agent
80 Sodium alginate 1 Stabilizing agent; suspending agent; tablet and capsule disintegrant;tablet binder; viscosity-increasing agent.
81 Silica gel 1 Adsorbant
82 Sorbiton monooleate 1 Solubilizer
83 Sodium stearyl fumarate 4 Tablet and capsule lubricant.
84 Sodium chloride 3 Tablet and capsule diluent; tonicity agent
85
Sodium metabisulfite 1 Antioxidant.
86 Sodium citrate dihydrate 1 Alkalizing agent; buffering agent; emulsifier; sequestering agent.
87 Sodium starch 1 Binder
88 Sodium carboxy methyl cellulose 1 Coating agent; tablet and capsule disintegrant;
tablet binder; stabilizing agent; suspending agent;
viscosity-increasing agent; water-absorbing agent.
89 Succinic acid 1 Acidity
90 Sodium propionate 1 Antimicrobial preservative
91 Titanium dioxide 49 Coating agent; opacifier; pigment
92 Talc 20 Anticaking agent; glidant; tablet and capsule diluent; tablet and capsule lubricant.
93 Triacetin 6 Humectant; plasticizer; solvent
94 Triethyl citrate 3 Plasticizer

Examples
Example 1
S.No. Material mg per unit
1. Methocarbamol 1000
2. HPC-ELF 250
3. HPMC 100 LV 50
4. Magnesium stearate 13
Total 1313

Manufacturing process
Step-1: Methocarbamol and HPC-ELF were processed through hot melt extruder to get hard flakes.
Step-2: Flakes were milled using multimill and sifted through #18 mesh.
Step-3: SiftedHPMC 100 LV and Magnesium Stearate through #60 mesh.
Step-4: The abovesifted material of step-3 added into step-2 and mixed for 25rotations.
Step-5: The tablets were compressed by using rotary compression machine by using caplet shaped punches.
Bulk density of granules was observed to be 0.65.
Up to four hours, about 25% of tablet mass was observed in disintegration test apparatus.

Example 2
S.No. Material mg per unit
1. Methocarbamol 1000
2. Plasdone S560 300
3. HPMC 100 LV 50
4. Magnesium stearate 13
Total 1363

Manufacturing process
Step-1: Methocarbamol and plasdone were processed through hot melt extruder to get hard flakes.
Step-2: Flakes were milled using multimill and sifted through #18 mesh.
Step-3: SiftedHPMC 100 LV and Magnesium Stearate through #60 mesh.
Step-4: The above sifted material of step-3 added into step-2 and mixed for 25 rotations.
Step-5: The tablets were compressed by using rotary compression machine by using caplet shaped punches.
Bulk density of granules was observed to be 0.63.
Up to four hours, about 25% of tablet mass was observed in disintegration test apparatus.

Example 3
S.No. Material mg per unit
1. Methocarbamol 1000
2. HPC-ELF 100
3. HPMC 100 LV 100
4. Magnesium stearate 12
Total 1212

Manufacturing process
Step-1: Methocarbamol and HPC-ELF were processed through hot melt extruder to get hard flakes.
Step-2: Flakes were milled using multimill and sifted through #18 mesh.
Step-3: SiftedHPMC 100 LV and Magnesium Stearate through #60 mesh.
Step-4: The above sifted material of step-3 added into step-2 and mixed for 25 rotations.
Step-5: The tablets were compressed by using rotary compression machine by using caplet shaped punches.
Bulk density of granules was observed to be 0.64.
Up to four hours, about 25% of tablet mass was observed in disintegration test apparatus.

Example 4
S.No. Material mg per unit
1. Methocarbamol 1000
2. Plasdone S560 100
3. HPMC 100 LV 100
4. Magnesium stearate 12
Total 1212

Manufacturing process
Step-1: Methocarbamol and plasdone were processed through hot melt extruder to get hard flakes.
Step-2: Flakes were milled using multimill and sifted through #18 mesh.
Step-3: SiftedHPMC 100 LV and Magnesium Stearate through #60 mesh.
Step-4: The above sifted material of step-3 added into step-2 and mixed for 25 rotations.
Step-5: The tablets were compressed by using rotary compression machine by using caplet shaped punches.
Bulk density of granules was observed to be 0.62.
Up to four hours, about 25% of tablet mass was observed in disintegration test apparatus.

Example 5-9
S.No. Material Example 5 Example 6 Example 7 Example 8 Example 9
1. Methocarbamol 1000 1000 1000 1000 1000
2. Plasdone S560 50 NA NA 50 NA
3. HPC – ELF NA 50 NA NA 50
4. HPMC 100 LV 100 100 NA NA NA
5. Eudragit RSPO NA NA 100 NA NA
6. Magnesium stearate 10 10 10 10 10
Total 1160 1160 1110 1060 1060
Bulk density 0.61 0.6 0.58 0.61 0.6

Manufacturing process
Step-1: Except HPMC and magnesium stearate, other materials were processes through hot melt extruder to form hard flakes.
Step-2: Flakes were milled using multi mill and milled material was sifted through #18 sieve.
Step-3: HPMC and magnesium stearate were sifted through #60 sieve.
Step 4- Sifted materials from steps 2 & 3 were blended for specified time.
Step-5: Blended material was compressed on rotary compression machine using caplet shaped punches.
Tablets from examples 5, 6 & 7 were subjected to dissolution testing using USP apparatus 2, RPM 50 and 900ml of purified water as dissolution media and the results are tabulated below.
Time in hours Example 5 Example 6 Example 7
% Drug dissolved RSD % Drug dissolved RSD % Drug dissolved RSD
2 40 8.8 39 14.5 17 0
4 63 4.5 63 14.6 28 7.6
8 90 2.4 87 9.8 42 9.4
12 100 0 98 3.6 65 10.1

Example 10-12
S.No. Material Example 10 Example 11 Example 12
1. Methocarbamol 1000 1000 1000
2. HPC – ELF 100 NA NA
3. HPMC 100 LV 100 NA NA
4. Eudragit RSPO NA 50 75
5. Magnesium stearate 10 10 10
Total 1160 1060 1085
Bulk density 0.59 0.59 0.58

Manufacturing process
Step-1: Except HPMC and magnesium stearate, other materials were processes through hot melt extruder to form hard flakes.
Step-2: Flakes were milled using multi mill and milled material was sifted through #18 sieve.
Step-3: HPMC and magnesium stearate were sifted through #60 sieve.
Step 4- Sifted materials from steps 2 & 3 were blended for specified time.
Step-5: Blended material was compressed on rotary compression machine using caplet shaped punches.