DESC:

FORM 2
THE PATENTS ACT 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)

1. TITLE OF THE INVENTION:
“A carbamazepine dual release tablet”

2. APPLICANT:

1. (A) Bharat Parenterals Limited
(B) Indian
(C) Jarod Samlaya Road, Vill. Haripura,
Ta. Savli, Dist. Vadodara-391520
Gujarat, India.

3. PREMABLE TO THE DESCRIPTION:
PROVISIONAL
SPECIFICATION
(See section 10 and rule 13)
The following specification describes the invention.
þ COMPLETE
SPECIFICATION
The following specification particularly describes the invention and the manner in which it is to be performed.

FIELD OF INVENTION

The present invention relates to a carbamazepine dual release tablet for the treatment of partial and clonic seizure disorder. More particularly, the present invention relates to composition in the form of dual release tablet for immediate drug release of carbamazepine followed by extended release having dissolution profile upto 24 hours.

BACKGROUND OF THE INVENTION

Seizures caused by epilepsy require long-term therapy and most anti-epileptic medications must be administered several times a day. Carbamazepine is used as an anticonvulsant medication in the treatment of epilepsy. Carbamazepine is reported to be quite erratic in its absorption. Possible reasons for irregular or inconsistent absorption are (a) low water solubility and physico-chemical properties of the molecule leading to very slow dissolution rate in the gastrointestinal fluid, (b) anticholinergic properties of the drug which may become more evident during prolonged treatment and thus modify its gastrointestinal transit time.

Carbamazepine (CMZ) has an initial half-life of 20-40 hours, the half life becomes shorter through autoinduction during repetitive administration. Carbamazepine half life is decreased to 12 hrs with a single dose and 8 hrs upon multiple doses. Due to its increased metabolism, pronounced daily fluctuations in the serum concentration of carbamazepine are observed. Usual adult therapeutic levels of carbamazepine in plasma are between 4-12 mcg/ml.

US 5326570 determine an advanced drug delivery system and method of treating psychiatric, neurological and other disorders with carbamazepine in which there are three units such as immediate release unit, sustained release unit and enteric coating unit. The problem associated in this method is high in cost and time consuming.
US 20090143362 determine carbamazepine formulations. It particularly discloses a process for preparing a pharmaceutical composition comprising carbamazepine for constant release profile. The limitation of this invention is it discloses a pharmaceutical composition of carbamazepine not determines a dual release tablet and the process for preparation of this pharmaceutical composition includes coating.
Hence, to overcome the above mention problems (i.e. high in cost, early dissolution of drug and fluctuation in plasma drug concentration) it is desperately needed to invent a dual release tablet of carbamazepine which is not subjected to above mention problems so that the finally obtained carbamazepine tablet has desired properties, lower in cost and yet which is suitable for treatment.

OBJECT OF THE INVENTION
The principle object of the present invention is to provide a carbamazepine dual release tablet.
Further object of the present invention is to provide a carbamazepine dual release tablet with improved and more economical, stable and convenient treatment of epilepsy.
Another object of the present invention is to provide a carbamazepine dual release tablet with steady state plasma concentration up to 24 hrs.
Yet another object of the present invention is to provide a carbamazepine dual release tablet that can deliver substantially dual release tablet of carbamazepine at a controlled and beneficial rate over time.

SUMMARY OF THE INVENTION

The present invention relates to a carbamazepine dual release tablet for the treatment of partial and clonic seizure disorder. It particularly determines carbamazepine dual release tablet having an immediate release first layer comprising an effective amount of carbamazepine and pharmaceutically acceptable excipients and an extended release second layer comprising an effective amount of carbamazepine and pharmaceutically acceptable excipients. A process for preparation of dual release tablet comprises a step that includes a preparation of immediate release layer, a preparation of extended release layer and compression of both immediate and extended release layer. A carbamazepine dual release tablet which has dissolution profile upto 24 hours and maintain therapeutically effective plasma concentration of carbamazepine for 24 hours if taken once in a day.

BRIEF DESCRIPTION OF DRAWING

Fig. 1 illustrates release pattern of dosage form containing loading dose and maintenance dose.
Fig. 2 illustrates release pattern of Carbamazepine dual release tablet.

DETAIL DESCRIPTION

The nature of invention and the manner in which it is performed is clearly described in the specification. The invention has various components and they are clearly described in the following pages of the complete specification.

Carbamazepine has the chemical name 5H-dibenzo[b,f]azepine-5-carboxamide is a well established anti-epileptic compound. It is regarded as a first-line drug in the treatment of patients suffering from partial seizures, with and without second generalization, and in patients with generalized tonic-clonic seizures. Besides being an antiepileptic compound, carbamazepine has also proved effective in the treatment of pain associated with trigeminal neuralgia and in patients suffering from manic-depressive illness, post therapeutic neuralgia, or phantom limb pain.

The present invention determines a carbamazepine dual release tablet comprising immediate release and extended release of the carbamazepine and pharmaceutically acceptable excipient. Dual release can be defined as a release which involves initial prompt release of the carbamazepine for achieving early onset of action which is then followed by its extended release for longer duration of action.

The present invention provides dual release carbamazepine tablet for oral administration containing two layers comprising a first or immediate release layer containing carbamazepine, disintegrant, surface active agent, diluent, glidant, binder, solvent and coloring agent intended for immediate delivery and a second or extended release layer that includes carbamazepine for extended delivery, a matrix forming agent, flow enhancer, glidant, lubricant and surface active agent.

Binders of the present invention is selected but not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), low subsituted hydroxy propyl cellulose (L-HPC), ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, liquid glucose, dextrin, polyethylene oxide, polyvinyl pyrrolidone K 30 (PVP k30), poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol and sucrose. More preferably low subsituted hydroxy propyl cellulose (L-HPC) and polyvinyl pyrollidone K30 are used as binder.

Fillers or diluents of the present invention include, but is not limited to confectioner's sugar, compressible sugar, microcrystalline cellulose powder, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, cellulose derivatives, calcium carbonate and dibasic calcium phosphate or tribasic calcium sulphate. More preferably microcrystalline cellulose powder is used as filler or diluent.

Lubricants of the present invention is selected from, but not limited to, magnesium stearate, aluminum stearate or calcium stearate polyethylene glycol (PEG), mineral oil, sodium stearyl fumarate, stearic acid salt, stearic acid derivatives, hydrogenated vegetable oil and talcum. More preferably magnesium stearate is used as lubricant.

Glidants includes, but are not limited to, silicon dioxide, powdered cellulose, starch, talcum, tribasic calcium phosphate, calcium, silicate, magnesium silicate, colloidal silicon dioxide, silicon hydro gel, corn starch and aerosil. More preferably talcum and aerosil are used as glidant.

The carbamazepine dual release according to present invention also comprise a disintegrant which includes the oral dosage form to ensure rapid disintegration of the dosage form or part of the dosage form (for example, one of the layers in a dual release tablet) after administration.

Disintegrants of the present invention includes, but not limited to carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, magnesium aluminum silicate, sodium alginate, sodium starch glycolate, pregelatinised starch and polacrillin potassium. More preferably crospovidone is used as disintegrant.

The present invention provides the carbamazepine dual release tablet where the second extended release layer contains one or more matrix forming agents selected from group consisting of Eudragit S 100, hydroxy propyl methyl cellulose (HPMC) and its grades (HPMC K4M, HPMC K15M, HPMC K100M), methyl cellulose, hydroxyl ethyl cellulose, hydroxy propyl cellulose, Elegence SR base II, carboxy methyl cellulose, mannitol, dextrates, lactose, dibasic calcium phosphate and microcrystalline cellulose. More preferably Eudragit S 100 and Elegence SR base II are used as matrix forming agent.

Carbamazepine is practically insoluble in water. A surfactant is added to improve solubility of carbamazepine. Anionic, cationic or non ionic surfactants are preferred surfactant. It is selected from sodium, potassium, or magnesium n-dodecylsuphate, n-tetradecylsulphate, n-hexadecylsulphate or n-octadecylsulphate, sodium lauryl sulphate, sodium, potassium or magnesium n-dodecyloxyethyl sulfate, n-tetradecyloxyethyl sulfate, n-hexadecyloxyethyl sulfate or n-octadecyloxyethyl sulfate; sodium, potassium or magnesium n-dodecanesulphonate, sorbitan monolaurate and sorbitan tristerate or triolate. More preferably sodium lauryl sulphate is used as surfactant.

The present invention contains a coloring agent. Any water soluble or insoluble coloring agent is used in pharmaceuticals which are approved by the FDA. More preferably lake indigo carmine is used as coloring agent.

It should be appreciated that there is considerable overlap between the above-listed additives in common usage, since a given additive is often classified differently by different practitioners in the field, or is commonly used for any of several different functions. Thus, the above-listed additives should be taken as merely exemplary, and not limiting, of the types of additives that can be included in compositions of the present invention. One or more of these additives can be selected and used by the skilled artisan having regard to the particular desired properties of the dosage form by routine experimentation without any undue burden.

The present invention includes an immediate release layer comprises 11.11 % w/v carbamazepine, 0.5 to 3 % w/v disintegrant, 0.05 to 0.15 % w/v surfactant, 0.1 to 2 % w/v glidant, 0.15 to 0.3 % w/v coloring agent, 0.15 to 0.3 % w/v binder, diluent QS and solvent QS.

The present invention includes an extended release layer comprises 33.33 % w/v carbamazepine, 14 to 20 % w/v binder, at least two matrix forming agents, at least two glidants, 0.4 to 0.8 % w/v lubricant, 0.8 to 1.5 % w/v surfactant and solvent QS.

The 1st matrix forming agent is range of 18 to 22 % w/v, and 2nd matrix forming agent is range of 3.5 to 5.5 % w/v. The 1st glidant of the present invention is range of 0.05 to 0.15 % w/v and 2nd glidant is range of 0.4 to 0.8 % w/v.

The present invention also relates to a process for the preparation of carbamazepine dual release tablet comprising the following steps:

A) Preparation of Immediate release layer:
i) Accurately weighted carbamazepine, disintegrant, surfactant, glidant and diluent are taken and passed through sieve to achieve uniform particle size,
ii) Properly dissolved binder into solvent and coloring agent are added into it,
iii) Prepared solution are added to the above prepared bulk (step (ii)) to form wet mass,
iv) Above prepared wet mass are passed through sieve and air dried to form granules,

B) Preparation of Extended release layer:

iv) Accurately weighted carbamazepine and binding agent are passed through sieve to achieve uniform particle size,
v) Binding procedure are done by using solvent and prepared wet mass are passed through sieve to form granules,
vi) Prepared granules are air dried and passed through sieve,
vii) Accurately weighted matrix forming agent, surfactant, glidant and lubricant are passed through sieve and then added to above prepared dried granules to prepared extended release layer,

Compression:
A first immediate release layer (A) and second extended release layer (B) are compressed to form carbamazepine dual release tablet.

The invention is illustrated more in detail in the following examples. The examples describe and demonstrate embodiments within the scope of the present invention. These examples are given solely for the purpose of illustration and are not to be construed as limitations of the present invention, as many variations thereof are possible without departing from the spirit and scope.

Example 1

One accomplishment of the present invention may be illustrated by preparation of a carbamazepine dual release tablet and its preferred excipients ratios are described in Table 1 and Table 2 below:

Composition of the carbamazepine dual release tablet
Table 1
Immediate release layer:
Sr No Ingredients Qty/tab (%w/v)
1 Carbamazepine 11.11
2 Croscarmellose Sodium 1
3 Sodium Lauryl Sulphate 0.11
4 Talcum 0.56
5 Microcrystalline Cellulose 102 9
Binding
6 Lake Indigo Carmine 0.22
7 PVP K-30 0.22
8 Isopropyl Alcohol QS
Total 22.22 % w/v

Table 2
Extended release layer:
Sr No Ingredients Qty/tab (%w/v)
1 Carbamazepine 33.33
2 Low substituted Hydroxypropyl Cellulose 16.91
3 Isopropyl Alcohol QS
4 Elegance SR Base II 20
5 Eudragit S 100 4.98
6 Aerosil 0.11
7 Talcum 0.66
8 Magnesium Stearate 0.66
9 Sodium Lauryl Sulphate 1.11
Total 77.77 % w/v

A process for preparation of carbamazepine dual release tablet

A) Preparation of Immediate release layer:
i) Freshly prepared 11.11 % w/v carbamazepine, 1 % w/v croscarmellose sodium, 0.11 % w/v sodium lauryl sulphate, 0.56 % w/v talcum and 9 % w/v microcrystalline cellulose 102 were taken and passed through 40 # sieve to achieve uniform particle size,
ii) 0.22 % w/v polyvinyl pyrollidone K30 was dissolved into sufficient quantity of isopropyl alcohol and 0.22 % w/v lake indigo carmine was added into it,
iii) Prepared solution are added to the above prepared bulk (step (i)) to form wet mass,
iv) Above prepared wet mass was passed through 40 # sieve and then air dried to form granules,

B) Preparation of Extended release layer:
v) Freshly prepared 33.33 % w/v carbamazepine and 16.91 % w/v low substituted hydroxypropyl cellulose was taken and passed through 40 # sieve to achieve uniform particle size,
vi) Binding procedure was done by using isopropyl alcohol and prepared wet mass was passed through 22 # sieve to form granules,
vii) Prepared granules were then air dried and passed through 22 # sieve,
viii) Freshly prepared 20 % w/v Elegance SR base II, 4.98 % w/v Eudragit S 100, 0.11 % w/v aerosil, 0.66 % w/v talcum, 0.66 % w/v magnesium stearate and 1.11 % w/v sodium lauryl sulphate were taken and passed through 40 # sieve and after that the mixture was added into above prepared dried granules to prepare extended release layer,

C) Compression:
(200) mg weight for first immediate release layer (A) and (700) mg weight for second extended release layer (B) were compressed to form carbamazepine dual release tablet at 6.01 mm thickness.

Results:

Time (Hrs) Specification Results
0.5 NLT 20% 21.4%
3 20% - 50% 40.27%
6 40% - 70% 53.34%
12 60% - 90% 68.704%
24 NLT 75% 84.43%

Observation:
About 20% of the total carbamazepine is released within 30 minutes. About 20 % to 50 % of the total carbamazepine release within 3 hours. 40 to 70 % of the total carbamazepine release within 6 hours. The remaining amount is released slowly up to a period of 24 hours and thus facilitates once a day administration of carbamazepine.

Although the example as well as the process of preparation and use has been specifically described, it should be understood that variations in the preferred embodiment could be achieved by a person skilled in the art without departing from the spirit of the invention. It is also to be understood that the present invention is given with the understanding that this invention is intended only to be illustrations without serving as a limitation on the scope of the invention as defined in the claims.

,CLAIMS:We claim:

1. A carbamazepine dual release tablet comprises an immediate release layer and an extended release layer;
wherein an immediate release layer comprises 11.11 % w/v carbamazepine, 0.5 to 3 % w/v disintegrant, 0.05 to 0.15 % w/v surfactant, 0.1 to 2 % w/v glidant, 0.15 to 0.3 % w/v coloring agent, 0.15 to 0.3 % w/v binder, diluent QS and solvent QS;

wherein an extended release layer comprises 33.33 % w/v carbamazepine, 14 to 20 % w/v binder, at least two matrix forming agents, at least two glidants, 0.4 to 0.8 % w/v lubricant, 0.8 to 1.5 % w/v surfactant and solvent QS.

2. The carbamazepine dual release tablet as claimed in claim 1, wherein the 1st matrix forming agent is range of 18 to 22 % w/v and the 2nd matrix forming agent is range of 3.5 to 5.5 % w/v.

3. The carbamazepine dual release tablet as claimed in claim 1, wherein the 1st glidant is range of 0.05 to 0.15 % and the 2nd glidant is range of 0.4 to 0.8 % w/v.

4. The carbamazepine dual release tablet as claimed in claim 1, wherein the disintegrant is selected from carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, magnesium aluminum silicate, sodium alginate, sodium starch glycolate, pregelatinised starch and polacrillin potassium.

5. The carbamazepine dual release tablet as claimed in claim 1, wherein surfactant is selected from sodium, potassium, or magnesium n-dodecylsuphate, n-tetradecylsulphate, n-hexadecylsulphate or n-octadecylsulphate, sodium lauryl sulphate, sodium, potassium or magnesium n-dodecyloxyethyl sulfate, n-tetradecyloxyethyl sulfate, n-hexadecyloxyethyl sulfate or n-octadecyloxyethyl sulfate; sodium, potassium or magnesium n-dodecanesulphonate, sorbitan monolaurate and sorbitan tristerate or triolate.

6. The carbamazepine dual release tablet as claimed in claim 1, wherein glidant is selected from silicon dioxide, powdered cellulose, starch, talcum, tribasic calcium phosphate, calcium, silicate, magnesium silicate, colloidal silicon dioxide, silicon hydro gel, corn starch and aerosil.

7. The carbamazepine dual release tablet as claimed in claim 1, wherein binder is selected from starches, potato starch, wheat starch, corn starch; microcrystalline cellulose such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), low subsituted hydroxy propyl cellulose (L-HPC), ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, liquid glucose, dextrin, polyethylene oxide, polyvinyl pyrrolidone K 30 (PVP k30), poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol and sucrose.

8. The carbamazepine dual release tablet as claimed in claim 1, wherein lubricant is selected from magnesium stearate, aluminum stearate or calcium stearate polyethylene glycol (PEG), mineral oil, sodium stearyl fumarate, stearic acid salt, stearic acid derivatives, hydrogenated vegetable oil and talcum.

9. The carbamazepine dual release tablet as claimed in claim 1, wherein matrix forming agents selected from group consisting of Eudragit S 100, hydroxy propyl methyl cellulose (HPMC) and its grades (HPMC K4M, HPMC K15M, HPMC K100M), methyl cellulose, hydroxyl ethyl cellulose, hydroxy propyl cellulose, Elegence SR base II, carboxy methyl cellulose, mannitol, dextrates, lactose, dibasic calcium phosphate and microcrystalline cellulose.

10. The carbamazepine dual release tablet as claimed in claim 1, wherein coloring agent is selected from water soluble or insoluble coloring agent approved by FDA.

11. A process for preparation of carbamazepine dual release tablet comprises:

A) preparing an immediate release layer:
i) mixing carbamazepine, disintegrant, surfactant, glidant and diluent and passing through sieve;
ii) dissolving the binder into solvent and adding coloring agent into it;
iii) adding above prepared solution of step (ii) into step (i) to form wet mass;
iii) passing the above prepared wet mass through sieve and air drying to form granules;

B) preparing of extended release layer:
v) mixing carbamazepine and binding agent and passing through sieve;
vi) adding solvent into above prepared mixture to execute the binding procedure and prepared wet mass is passing through sieve to form granules;
vii) air drying the above prepared granules and passing through another sieve;
viii) mixing matrix forming agent, surfactant, glidant and lubricant after that passing through sieve and adding the mixture into above prepared dried granules;

C) compression:
compressing the first immediate release layer (A) and second extended release layer (B) to form carbamazepine dual release tablet.

Dated this on April 18, 2017.