Form 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE 2003
PROVISIONAL SPECIFICATION
[See section 10 and rule 13]
L TITLE OF THE INVENTION
"Extended release pharmaceutical compositions of Cyclobenzaprine"
2. APPLICANT
(a)NAME: USV LIMITED
(b)NATIONALITY: Indian Company incorporated under the
Companies ACT 1956
(c)ADDRESS: B.S.D. Marg, Govandi, Mumbai 400 088, Maharashtra, India
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention.

Technical field of the invention:
The present invention relates to extended release pharmaceutical compositions comprising a plurality of coated mini tablets, each comprising the active ingredient Cyclobenzaprine hydrochloride and pharmaceutically acceptable excipients and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each coated mini tablet comprises :(a) an inner core comprising the active ingredient; (b) optionally, a seal coat applied to the inner core; and (c) an extended release coat thereon.
More specifically, the present invention relates to extended release capsule dosage forms of Cyclobenzaprine hydrochloride.
Further, the invention relates to a process for preparation of extended release pharmaceutical compositions of Cyclobenzaprine hydrochloride.
Background and Prior art:
Cyclobenzaprine hydrochloride is a skeletal muscle relaxant, which relieves muscle spasm of local origin without interfering with muscle function. Cyclobenzaprine hydrochloride is chemically 3-(5H-dibenzo[a,d] cyclohepten-5-ylidene)-N,N-dimethyl-1 -propanamine hydrochloride.
Cyclobenzaprine hydrochloride is a white, crystalline tricyclic amine salt with the empirical formula C20H21N.HC1 and a molecular weight of 311.9. It has a melting point of 217°C, and a pKa of 8.47 at 25°C. It is freely soluble in water and alcohol, sparingly soluble in isopropanol, and insoluble in hydrocarbon solvents. If aqueous solutions are made alkaline, the free base separates.
Cyclobenzaprine extended release capsules are marketed in United states under the Brand AMRIX® and are available in 15 and 30 mg strengths. AMRIX® capsules contain the following inactive ingredients: diethyl phthalate NF,
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ethylcellulose NF (Ethocel Standard 10 Premium), gelatin, Opadry® Clear YS-1-7006, sugar spheres NF (20-25 mesh), and titanium dioxide. AMRIX® 15mg capsules also contain red ferric oxide and yellow ferric oxide. AMRIX® 30mg capsules also contain FD&C blue #1, FD&C blue #2, FD&C red #40, and FD&C yellow #6.
US3882246 discloses pharmaceutical compositions of Cyclobenzaprine and salts thereof used as a skeletal muscle relaxant. Further disclosed is a method of treating muscular spasm and other similar muscular disorders associated with or caused by injury or arising spontaneously with no known cause by the administration of a pharmaceutical composition containing Cyclobenzaprine or a salt thereof as one of the active ingredients.
WO2005048996 discloses an extended release capsule dosage form of Cyclobenzaprine hydrochloride which contains one or more populations of drug containing particles such as beads, pellets, granules where at least one bead population exhibits a pre-designed sustained release profile. The drug delivery system is designed for once-daily oral administration to maintain an adequate plasma concentration- time profile, thereby providing relief of muscle spasm associated with painful musculoskeletal conditions over a 24 hour period.
GB1337068 discloses pharmaceutical dosage units having skeletal muscle relaxant activity containing 1-25 mg of Cyclobenzaprine or an acid addition salt thereof and a carrier.
US20060246134 discloses a pharmaceutical multi-particulate dosage form comprising a mixture of IR beads and timed, pulsatile release (TPR) beads and a method for the preparation of a multi-particulate dosage.
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Although there are various Cyclobenzaprine compositions known in the art, many of them are provided in the form of pellets filled into hard gelatin capsule. However, there are several drawbacks associated with the pellet formulation, such as high temperature and fluidization is required for pellets formation and the process of preparation is time consuming and tedious and requires special skills. Though pellets can be obtained by various processes such as by extrusion, spheronisation or loading of the drug on sugar spheres or microcrystalline cellulose spheres; the optimization process involves a substantial loss in the yield of the product. Further, disadvantage is that pellets require high amount of coating in comparison to mini tablets. Agglomeration and fracturing of pellets occur during drug loading as well as coating, which may lead to difficulty in achieving reproducible dissolution profile.
In view of the aforementioned drawbacks associated with prior art compositions it is apparent that there still exists a need for developing compositions which would ameliorate the aforementioned drawbacks. The inventors of the present invention have developed compositions, which overcome the above drawbacks.
Object of the Invention:
The main object of the invention is to provide extended release pharmaceutical compositions comprising a plurality of coated mini tablets, each comprising the active ingredient Cyclobenzaprine hydrochloride and pharmaceutically acceptable excipients and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each coated mini tablet comprises :(a) an inner core comprising the active ingredient; (b) optionally, a seal coat applied to the inner core; and (c) an extended release coat thereon.
Another object of the invention is to provide a process for preparation of extended release pharmaceutical compositions of Cyclobenzaprine hydrochloride.
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Another object of the invention is to provide a process, which is easy, and less time consuming and which allows incorporation of high amount of active ingredient in the mini tablets in comparison to pellets.
Another object of the invention is to provide compositions, which have better patient compliance as the frequency of dosing, can be reduced.
Yet another object of the invention is to provide Cyclobenzaprine extended release compositions useful as skeletal muscle relaxants and method of treating skeletal muscle spasm comprising administering a safe and therapeutically effective amount of the compositions of the present invention to a patient in need thereof.
Summary of the invention:
The present invention provides extended release pharmaceutical compositions comprising a plurality of coated mini tablets, each comprising the active ingredient Cyclobenzaprine hydrochloride and pharmaceutically acceptable excipients and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each coated mini tablet comprises :(a) an inner core comprising the active ingredient; (b) optionally, a seal coat applied to the inner core; and (c) an extended release coat thereon.
Further, the present invention provides a process for preparation of said extended release pharmaceutical compositions comprising a plurality of coated mini tablets each comprising the active ingredient Cyclobenzaprine hydrochloride and pharmaceutically acceptable excipients and capable of being quantitatively filled into an empty hard gelatin capsule shell, the said process comprising the steps of:
(a) preparing the coated mini tablets; and
(b) filling the coated mini tablets equivalent to the desired weight of active
ingredient in to hard gelatin capsule, wherein the coated mini tablets are prepared
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by the process comprising,
(i) providing an inner core comprising the active ingredient;
(ii) optionally, coating the inner core with a seal coat;
(iii) coating the inner core of step (i) or (ii) with an extended release layer.
Brief description of the drawings:
Figure 1 shows comparative invitro-dissolution profile of Amrix® and capsule composition prepared according to Example 1 of the present invention.
Detailed Description:
The present invention describes extended release compositions of Cyclobenzaprine hydrochloride. Particularly, the said compositions are in the form of capsule dosage form comprising a plurality of coated mini tablets.
Extended release pharmaceutical compositions of the present invention comprises of a plurality of coated mini tablets, each comprising the active ingredient Cyclobenzaprine hydrochloride and pharmaceutically acceptable excipients and capable of being quantitatively filled into an empty hard gelatin capsule shell, wherein each coated mini tablet comprises :(a) an inner core comprising the active ingredient; (b) optionally, a seal coat applied to the inner core; and (c) an extended release coat thereon.
The invention also encompasses method of treating skeletal muscle spasm comprising administering a safe and therapeutically effective amount of the compositions of the present invention to a patient in need thereof.
Extended release compositions are advantageous in administration as the frequency of dosing can be reduced and a constant plasma concentration of the drug over an extended period of time can be ensured. The advantage of the present invention is in providing a composition and process
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of preparation, which allows incorporation of high amount of active ingredient in the mini tablets in comparison with the pellets. Further, the process as provided by the present invention is easy and less time consuming.
According to one embodiment of the present invention, the extended release pharmaceutical compositions are provided in the form of hard gelatin capsules which comprises of coated mini tablets.
Cyclobenzaprine hydrochloride may be present in an amount from about 10.0% to about 40.0% by weight, preferably from about 20.0% to about 30.0% of the total weight of the extended release composition.
According to the present invention, Cyclobenzaprine hydrochloride is present in an amount from about lOmg to about 30mg, preferably from about 15mg to 30mg and more preferably in strengths of 15mg and 30mg.
According to one embodiment, the extended release composition comprises of 10.0% to 40.% by weight of Cyclobenzaprine hydrochloride, 30.0% to 40.0% by weight of diluents, 2.0% to 10.0% by weight of binders, 0.1% to 2.5% by weight of lubricants, 0.1% to 2.5% by weight of glidants, 10.0% to 30.0% by weight of plasticizers and 10.0% to 50.0% by weight of rate controlling polymer.
According to a preferred embodiment, the extended release composition comprises of 20.0% to 30.0% by weight of Cyclobenzaprine hydrochloride, 30.0% to 40.0% by weight of lactose monohydrate, 30.0% to 40.0% by weight of microcrystalline cellulose, 2.0% to 10.0% by weight of pregelatinised starch, 0.1% to 2.5% by weight of colloidal silicon dioxide and 0.1% to 2.5% by weight of magnesium stearate.
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According to one embodiment, the present invention provides a process for preparation of said extended release pharmaceutical compositions comprising a plurality of coated mini tablets each comprising the active ingredient Cyclobenzaprine hydrochloride and pharmaceutically acceptable excipients and capable of being quantitatively filled into an empty hard gelatin capsule shell, the said process comprising the steps of:
(a) preparing the coated mini tablets; and
(b) filling the coated mini tablets equivalent to the desired weight of active
ingredient in to hard gelatin capsule, wherein the coated mini tablets are prepared
by the process consisting of
(i) providing an inner core comprising the active ingredient;
(ii) optionally, coating the inner core with a seal coat;
(iii)coating the inner core of step (i) or (ii) with an extended release layer.
In the practice of the present invention, the inner core comprising the active
ingredient is prepared by the following steps:
(i)blending Cyclobenzaprine hydrochloride with one or more diluents and binders;
(ii)granulating the blended mixture using water to form a cohesive mass and
drying the granulated mass;
(iii) milling the dried granules;
(iii)lubricating the dried granules using lubricants and glidants; and
(iv)compressing the lubricated granules into tablets using suitable compression
machine fitted with punches of 2mm diameter.
Mixing and granulation can be carried out in a conventional rapid mixer granulator and the wet granules can be further dried using fluid bed drier. However, in a conventional fluid bed processor both the steps of granulation and drying can be carried out in the same equipment thereby simplifying the process and saving the processing time.
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Suitable pharmaceutically acceptable excipients that can be used according to the present invention include, but are not limited to diluents/fillers, binders, glidants, lubricants, solvents, rate controlling polymers, pore formers, plasticizers and the like.
Diluents which may be employed for preparation of Cyclobenzaprine mini tablets as per the invention, include, but are not limited to maize starch, microcrystalline cellulose, lactose anhydrous, mannitol or mixtures thereof. Diluents may be used in the range of about 10.0% to 50.0% by weight of the total composition. Preferred diluent being lactose and microcrystalline cellulose each in an amount from 30% to 40% by weight of the total extended release composition.
Binders which may be employed as per the invention, include, but are not limited to maize starch, povidone, gelatin, polyvinyl acetate, pregelatinised starch or mixtures thereof. Binders may be used in the range of about 2% to 10% by weight of the total composition.
Lubricants which may be employed as per the invention, include, but are not limited to magnesium stearate, calcium stearate, stearic acid, silicon dioxide, purified talc, sodium stearyl fumarate., hydrogenated vegetable oil, hydrogenated castor oil, glyceryl palmito distearate, glyceryl behenate, or mixtures thereof. Lubricants may be used in the range of about 0.1 % to 2.5%) by weight of the total composition.
Glidants which may be employed as per the invention, include, but are not limited to colloidal silicon dioxide, purified talc and the like. Glidants may be used in the range of about 0.1 %> to 2.5% by weight of the total composition.
Seal coating may be performed using Opadry, a ready mix coating material. Solvents that may be employed for the coating include isopropyl alcohol,
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methylene chloride or mixtures thereof. Isopropyl alcohol and methylene chloride may be employed in ratio of 10 : 90 to 50: 50.
Rate controlling polymers which may be employed for the manufacture of extended release compositions include, but are not limited to ethyl cellulose, methacrylic acid copolymers (Type A), methacrylic acid copolymers (Type B) and the like. Ethyl cellulose having viscosity in the range of 4cps to 45 cps is used; preferred viscosity being 4 to 10 cps that provides functional coating may be employed for the extended release coating.
Pore formers that may be employed in the manufacture of extended release compositions include hydroxypropyl methyl cellulose, polyethylene glycols, and the like and may be present in an amount from 10% to 70% by weight of the total extended release composition.
Plasticizers that may be employed in the manufacture of extended release compositions include hydrophilic or hydrophobic. Hydrophilic plasticizers that may be employed include, but are not limited to triethyl citrate, triacetin, polyethylene glycols and the like and may be present in an amount from 10.0% to 30.0%) by weight of the total extended release composition.
Hydrophobic plasticizers that may be employed include, but are not limited to dibutyl sebacate, diethyl phthalate and the like and may be present in an amount from 10.0% to 30.0% by weight of the total extended release composition.
In the practice of the present invention, coated mini tablets equivalent to the desired weight of active ingredient is filled into the hard gelatin capsule or hard cellulose capsule. Empty hard gelatin capsule or empty hard cellulose capsules of size ranging from '4' to '0' may be used; preferred being size '3' and '4' based on the desired weight of the active ingredient to be incorporated into the capsule
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dosage form.
The present invention is further defined by reference to the following examples, which does not limit the scope of the invention in any way. It will be apparent to those skilled in the art that many modifications, both to the materials and methods, may be practiced without departing from the purpose and scope of the invention.
Examples
Example 1 Preparation of core
Cyclobenzaprine (750.Og), lactose monohydrate (1200.Og), microcrystalline cellulose (1180.Og), starch 1500 (75.Og) were mixed in a suitable blender to form a blend. This blend was granulated with water to form a cohesive wet mass and the wet mass was dried in a fluid bed drier/Glatt drier at inlet temperature 60°C for sufficient time till loss on drying value of not more than 3.0% is achieved. Sized the dried granules and lubricated with colloidal silicon dioxide (12.5g) and magnesium stearate (32.5g). Lubricated granules were further compressed using conventional compression machine fitted with multi-tip punches of size 2mm to provide mini tablets of size 2 mm in diameter.
Preparation of Extended release composition
Compressed mini tablets ( 300g) were seal coated using Opadry (23g) and a mixture of isopropyl alcohol (218g) and methylene chloride (219g), in Fluid Bed processor. Seal coated tablets (280g) were further coated with ethylcellulose (19.Og) and hydroxypropyl methyl cellulose (12.6g) and dibutyl sebacate (4.4g) dissolved in isopropyl alcohol and methylene chloride mixture and finally overcoated using Opadry ( 12g ) in a mixture of isopropyl alcohol and methylene chloride.
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Coated mini tablets equivalent to the desired weight of active ingredient (20 nos. and 10 nos. for 30mg and 15mg strengths respectively) were filled into hard gelatin capsules of suitable size using a capsule-filling machine.
Table 1 summarizes the invitro-dissolution profile for the extended release capsule prepared according to Example 1 of the present invention versus Amrix® (Cyclobenzaprine hydrochloride capsules 30mg) (ref. Figure 1). Dissolution of Cyclobenzaprine Hydrochloride ER capsules 30mg was carried out in 0.1N HCL using USP Type I (basket), at 50 rpm, 900ml.
Table 1

Time (in Hours) % released

Amrix® Example 1
0 0.0 0
0.5 2.2 2.4
1 4.2 9.2
2 31.0 27.7
4 57.3 53.3
6 69.0 68.2
8 76.3 77.2
10 82.7 84
12 86.1 89.6
Example 2
Preparation of core
Cyclobenzaprine (750g), Lactose monohydrate (1200g), microcrystalline cellulose
(1180g), starch 1500 (75g) were mixed in a suitable blender to form a blend. This
blend was granulated with water form a cohesive wet mass and the wet mass was
dried in a fluid bed drier/Glatt drier at inlet temperature 60°C for sufficient time
till loss on drying value of not more than 3% is achieved. Sized the dried granules
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and lubricated with colloidal silicon dioxide (12.5g) and magnesium stearate (32.5g). Lubricated granules were further compressed using conventional compression machine fitted with multi-tip punches of size 2mm to provide mini tablets of size 2 mm in diameter.
Preparation of Extended release composition
Compressed mini tablets ( 300 g) were loaded into a fluid bed processor and were
seal coated using Opadry (23 g) and a mixture of isopropyl alcohol (218g) and
methylene chloride (219g). Seal coated tablets (280g) were further coated with
ethylcellulose (16.0g) and hydroxypropyl methyl cellulose (8.6g) and dibutyl
sebacate (3.4g) and finally overcoated using Opadry (12g) in a mixture of
isopropyl alcohol and methylene chloride.
Coated mini tablets equivalent to the desired weight of active ingredient (20 nos.
and 10 nos. for 30mg and 15mg strengths respectively) were filled into hard
gelatin capsules of suitable size using a capsule-filling machine.
While the present invention is described above in connection with preferred or illustrative embodiments, these embodiments are not intended to be exhaustive or limiting of the invention. Rather, the invention is intended to cover all alternatives, modifications and equivalents included within its spirit and scope, as defined by the appended claims.
Dated this the 08th day of May 2008
DrKG RafeWran Head-K lowledge Cell USV Liiktted
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