F O R M 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
1. TITLE OF THE INVENTION: - “CARBAMAZEPINE EXTENDED-RELEASE
FORMULATIONS”

2. APPLICANT:
a) NAME
b) NATIONALITY
c) ADDRESS : INTELLISCEND NDDR PRIVATE LIMITED : Indian Company
: Plot #A111, Road #18, Wagle Industrial Estate, Thane (W), Maharashtra, India 400604.
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which
it is to be performed.

CARBAMAZEPINE EXTENDED-RELEASE FORMULATIONS
FIELD OF INVENTION
The invention covers wax based extended-release formulations of carbamazepine. The preferred wax is carnauba wax and employed in amounts from 5 – 25 % of the formulation. The formulations are prepared in such a way that carbamazepine either does not get exposed to water or gets exposed to water when in coated form or when layer of wax is at least partially covering its particle so as to get minimum exposure. The formulations are essentially coating free i.e. without having any functional coating viz. coating controlling release pattern.
BACKGROUND OF THE INVENTION
Carbamazepine is a well-established antiepileptic 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 (Porter, R. J., Penry, J. K., pp. 220-231, Advances in Epileptology, Meinardi, H., Rowan, A. J., Eds., Swets & Zeitlinger, Amsterdam (1977) and Acta Neurol. Scand., 64, Suppl. 88 (1981)). Besides being an antiepileptic compound, carbamazepine has also proved effective in the treatment of trigeminal neuralgia and in patients suffering from manic depressive episodes (Neurol. Neurosurg. Psychiat., 29:265-267 (1966); Arch. Neurol., 19:129-136 (1968); Excerpta Medica, 139-147 (1984); and Excerpta Medica, 93-115, (1984)).
Although the half-life of carbamazepine is relatively long, between 25 and 85 hours, after a single dose due to autoinduction, its effect is substantially reduced after repeated dosing (J. Clin. Pharmacol., 23:241-244 (1982); J. Ther. Drug Monit., 3:63-70 (1981); and Europ. J. Clin. Pharmacol., 8:91-96 (1975)). Due to its particular physical properties and due to its increased metabolism, pronounced daily fluctuations in the serum concentration of carbamazepine were observed and are of concern. Because there is a correlation between peak concentrations of carbamazepine and central nervous system (CNS) side effects, especially in patients

receiving polytherapy (Epilepsia, 28:507-514 (1987); Epileysia, 28:286-299 (1987); Epileysia, 21:341-350 (1980); Epilepsia, 25:476-481 (1984) and Arch. Neurol., 41:830-834 (1984)), it is of great clinical importance to assure a steady level of carbamazepine during a 24-hour carbamazepine delivery.
Using conventional carbamazepine formulations, however, this can only be achieved by dividing the total daily intake into several, typically 3-4 doses per day. This is very bothersome for ambulatory patients and laborious for medical personnel in institutions and may, therefore, result in compliance problems. The availability and introduction of slow or extended release carbamazepine formulations is therefore, regarded as a major clinical advantage.
A critical aspect to be considered in carbamazepine formulation is that in the presence of water, carbamazepine transforms rapidly to carbamazepine dihydrate. Carbamazepine dihydrate crystals grow by the whisker mechanism (Int. J. Pharm., 20:307-314 (1984)) and conversion has been shown by X-ray powder diffraction to be 95% complete after 1 hour (J. Pharm. Sci., 80:496-500 (1991)).The inhibition of formation of large crystals of carbamazepine dihydrate is of great importance for its pharmaceutical formulation since the large crystals of carbamazepine dissolve slowly and unpredictably thus causing bioavailability problems and may result in unpredictable and uncontrollable drug delivery.
Some attempts to overcome the above problems were made. For example, Khanna S. C., et al., U.S. Pat. No. 4,857,336, have described an oral dosage form for administration of carbamazepine wherein a core comprising a paste of a fine carbamazepine powder dissolved in a protective colloid, a hydrophilic swelling agent and, optionally, a water-soluble osmosis inducing-agent was encapsulated in a water-permeable shell impermeable to the components of the core. The water-permeable encapsulation shell permits a water passage through the cell for the transport of the water-soluble core components into the surrounding aqueous body fluid. However, in this arrangement the delivered amount is not strictly controllable

because it depends on the amount of water present in the surrounding environment, on the permeability of the shell to the water and on the overall kinetics of carbamazepine release from the colloid and its transport through the shell. Additionally, the manufacturing of the paste masses is inconvenient and laborious due to the need for encapsulation and additionally requires use of organic solvents which may affect the drug biological activity.
Another attempt to solve the above problems is described in U.S. Pat. No. 5,284,662, has improved the oral dosage form described above by reducing the usage of the organic solvents, particularly in core preparations, thus resulting in somehow easier processing, avoiding possible formation of unsuitable pasty masses in manufacture. However, similarly to above formulation, this formulation does not eliminate or inhibit crystallization and therefore also results in unpredictable drug delivery.
Another attempt is described in U.S. Pat. No. 5,284,662, which described the usage of minimum organic solvents over the U.S. Pat. No. 4,857,336, particularly in core preparations. Pat. No. 5,980,942 describes a zero-order sustained release matrix tablet formulation of carbamazepine. The matrix tablet formulation comprises a hydrophilic polymer gel that inhibits transformation of carbamazepine into carbamazepine dihydrate and effectively changes the anhydrous carbamazepine into an amorphous form that can be released from the matrix by zero-order release kinetics’. Pat. Nos. 5,326,570 and 5,912,013, assigned to Shire disclose drug delivery systems consisting of a single dosage form containing three types of units: immediate release unit, sustained release unit and enteric release unit, capable of releasing carbamazepine at varying times.
TEGRETOL XR Extended-Release Tablets available in 100 mg, 200 mg and 400 mg strengths utilizes osmotic pressure to deliver Carbamazepine at a controlled rate. It has a core of Carbamazepine, and hydroxypropylmethylcellulose, mannitol as an osmotic driving agent, two different grades of hydroxyethyl cellulose (in a 1:1 weight ratio) as the core matrix polymers, lubricant and wetting agent; and a

semipermeable wall with a bore connecting the core and the outer environment to release the Carbamazepine. Oral osmotic dosage forms of Carbamazepine disclosed in U.S. Pat. No. 6,534,090, US 2003/008006 covers dosage form which shows ascending rate of release over an extended period.
There are various disadvantages associated with osmotic drug-release technology; like requirement of highly sophisticated equipment’s for processes like compression, coating and laser drilling. Further osmotic drug-release technology requires special excipients like osmogene, homopolymer, polymer for semipermeable membrane, which ultimately increases cost of manufacturing. Also, while preparing osmotic dosage forms using laser drilling, the drilling may not be performed and such faulty dosage form may not able to release active at all. Although aqueous granulations have been utilized in extended-release formulations of carbamazepine performing these granulations in a high shear mixer or a fluid bed can cause dihydrate formation and the subsequent drying can cause desolvation. Carbamazepine is transformed from one anhydrate to another through a dihydrate intermediate during these processes.
In general, many of the available extended-release compositions for poorly water-soluble active ingredients like carbamazepine have the inherent drawbacks of being expensive and require time-consuming methods of production. Thus, there is still unmet need to develop a simple, stable, extended-release solid oral pharmaceutical composition of Carbamazepine, which are simple to manufacture, cost effective with stable compositions and acceptable dissolution profile.

OBJECTS OF THE INVENTION
An object of the invention is to provide high dosed extended-release formulation of carbamazepine using a simple, fast, easy and more practical manufacturing process than those in prior art.
One more object of the invention is to develop and provide a high dosed extended release formulation wherein the release is not controlled by any functional coating.
Another object of this invention is to provide an extended release carbamzepine tablet releasing not more than 35 – 40 % Carbamazepine in 3 hrs and / or not more than 65 – 70 % Carbamazepine in 6 hrs. when tested in 1800 ml of water using dissolution apparatus type II. This condition is laid down to match its dissolution as provided under United States Pharmacopeial Monograph for an extended release Carbamazepine tablets such that the peak plasma level of carbamazepine obtained in vivo occurs at least 15 hours after administration.
Yet another object of the invention is to provide a process for preparing a high dosed extended release formulation of carbamazepine that minimizes and preferably inhibits the transformation of anhydrous carbamazepine into crystallized dihydrate form and to provide a composition that has a desired release profile.
SUMMARY OF THE INVENTION
Under the first aspect, the present invention provides a high dosed extended-release formulation of carbamazepine comprising an extended release material, as well as a simple and easy method to prepare such an extended-release formulation that can be employed for a poorly water-soluble active ingredient. The formulation contains a wax-based extended-release material. The formulation may be prepared, for example, by simple granulation methods, e.g., hot melt granulation, wet granulation and combinations of both hot melt granulation and wet granulation. The formulations are essentially coating free i.e. without having any functional coating viz. coating controlling release pattern.

The present invention provides an extended release formulation comprising first granules made up of carbamazepine and a wax-based extended release material wherein first granules are further wet granulated to provide second granules thus providing double granulated mass which is further processed into an extended release formulation., wherein the extended release formulation has an in vitro dissolution profile, when measured using a USP apparatus II at 100 rpm in 1,800 mL water at 37° C. of not more than 35 – 40 % Carbamazepine in 3 hrs and / or not more than 65 – 70 % Carbamazepine in 6 hrs. and preferably of not less than 10% not more than 35% in 3hrs , not less than 35 % not more than 65% in 6 hours, not less than 65 % not more than 90% in 12 hours and not less than 75 % in 24 hours Preferably, the in vitro release profile is chosen such that the peak plasma level of carbamazepine obtained in vivo occurs at least 15 hours after administration.
In one embodiment, the wax-based extended-release material is carnauba wax. Preferably, the wax-based extended release material such as carnauba wax is present in an amount of from about 5 – 25 % and preferably from 5 to 15% and more preferably from 10 – 13 % of the formulation and from about 10 – 30 %, preferably from 12 – 25 % and more preferably from 14 – 22 % of weight of first granules. Yet more preferably, the wax-based extended-release material is present in an amount of from about 8% to about 16% by weight of total weight of the granules.
The formulation of the present invention may further comprise one or more inert additives selected from the group consisting of a wetting agent, a filler, a binder, and a surfactant.
Under yet another aspect, the present invention provides a high dosed extended-release formulation of carbamazepine wherein the release of Carbamazepine is not controlled by any functional coat. The formulation is a matrix formulation without coating. This saves several laborious steps of coating, drying, curing etc. Further, nonaqueous coatings pose more challenges and restrictions on the disposal of solvent. Thus, under this aspect, one is able to manufacture a high dosed extended

release formulation using simple equipments, avoiding spending additional time and resources on coating and without facing any challenge for solvent disposal. Further, the present invention provides a process or a method for preparing a high dosed extended-release formulation containing a poorly water-soluble active ingredient, the method comprising: i) preparing first granules by (a) melting a wax-based extended-release material; and (b) mixing the active ingredient with the melted wax-based extended-release material at a temperature higher than the melting temperature of the wax-based extended-release material to produce first granules ; and ii) preparing second granules by wet granulating first granules; and iii) preparing the extended-release formulation from second granules.
The method preferably comprises admixing one or more inert additives with the first granules before subjecting it to wet granulation to produce second granules and admixing second granules with one or more inert additives wherein tsuch inert additives comprise of one or more of glidant, lubricant etc..

DETAILED DESCRIPTION OF THE INVENTION
Preparing high dosed formulations is challenging and more so when an extended-release formulation accommodating such high dose is desired. The present invention provides extended-release formulations accommodating highest dose of carbamazepine which is 400 mg. An extended release tablet formulation according to the present invention contains 400 mg of carbamazepine which is at least 30 %, preferably at least 40 % and most preferably at least 50 % w/w of the final formulation in order to restrict total weight of the formulation. As a result, it leaves limited scope for presence of other essential ingredients mainly extended-release materials. The formulations are essentially coating free i.e. without having any functional coating viz. coating controlling release pattern.
The present invention relates to high dosed extended-release formulations containing a poorly water-soluble active ingredient namely carbamazepine and a wax-based extended-release material, namely carnauba wax.
The formulation may be prepared, for example, by simple granulation methods, e.g., hot melt granulation, wet granulation and combinations of both hot melt granulation and wet granulation. In a first type of preferred embodiment, only hot melt granulation is employed. In a most preferred second embodiment, hot melt granulation is adopted followed by wet granulation to produce double granulated product which is subsequently processed to produce final formulation.
Extended-release Carbamazepine tablet formulations of the present invention preferably should comply with carbamazepine monograph in United States Pharmacopoeia (USP 35) including in vitro dissolution profile provided therein. Dissolution should be performed in 1800 ml water, apparatus II using 100 rpm, to check compliance with the following dissolution specifications as per table I.

Table I: In Vitro Dissolution Specification of Carbamazepine ER tablet of United States Pharmacopoeia.

Sr. No. Time (hrs) % dissolved (cumulative) as per USP Specification
1 3 10 % -35 %
2 6 35 % - 65 %
3 12 65 % - 90 %
4 24 NLT 75%
Before arriving at the desired extended-release formulations accommodating highest dose of carbamazepine, several trial batches were executed. Some of the relevant trial batches which helped in arriving at the present formulations are presented as comparative examples 1, 2, 3 and 4 etc.
In a first type of embodiments, a single granulation is adopted such as hot melt granulation. In few embodiments, when carnauba wax is employed in amount of 30 – 40 % , such as 35.88 % (Comparative example 1 - Batch CAR 400-006), the in vitro release profile as provided in table 2 is obtained wherein release of Carbamazepine is 16.3 % at 3 hrs. 27.1 % at 6 hrs. 40.6 % at 12 hrs. and only 51.5 % at 24 hrs. This batch failed in in vitro release profile, however, it indicated need to employ carnauba wax in lower quantities. Accordingly, when carnauba wax is reduced from 35 % to 20 - 25 % w/w of the formulation, the release of such batches comply with that of USP limits provided table 1. Therefore, amount of Carnauba wax is preferably not more than 25 % w/w of the formulation.

TABLE 2

Sr. Time in hrs. Comparative Modified batches USP limits
No. example 1 -CAR400-006 with 20 – 25 % w/w of carnauba wax
1 3 16.3 >16.3 -<35 % 10 % -35 %
2 6 27.1 >35 -<65 % 35 % - 65 %
3 12 40.6 >65 -<90 % 65 % - 90 %
4 24 51.5 >75% NLT 75%
According to second type of preferred embodiments, both hot melt granulation followed by wet granulation are employed. When higher amounts of carnauba wax in excess of 30 % is employed such as 30.5 % w/w (Comparative example 2 - Batch CAR 400-005), the in vitro release profile as provided in table 3 is obtained wherein release of Carbamazepine is 1.6 % at 3 hrs. 2.5 % at 6 hrs. 3.2 % at 12 hrs. and only 4.4 % at 24 hrs. This batch miserably failed to release Carbamazepine. Thus, it was clear that in a double granulated product, much lower amount of carnauba wax is needed. Accordingly, when carnauba wax is reduced from 30 % to 10 - 20 % w/w of the formulation, the release of such batches complies with that of USP limits provided table 1.
Therefore, amount of Carnauba wax is preferably not more than 25 % w/w of the formulation. Also, for double granulated product, carnauba wax is preferably not more than 20 % and most preferably not more than 15 % w/w of the formulation.

TABLE 3

Sr. Time in hrs. Comparative Modified batches USP limits
No. example 2 -CAR400-005 of double granulated product with 10 – 20 % w/w of carnauba wax
1 3 1.6 >10 - <35 % 10 % -35 %
2 6 2.5 >35 -<65 % 35 % - 65 %
3 12 3.2 >65 -<90 % 65 % - 90 %
4 24 4.4 >75% NLT 75%
The suitable upper limit of carnauba wax is same as that in the first type of embodiment, viz. not more than 25 % preferably not more than 20 % and most preferably not more than 15 %.
While it is desired to produce an extended release formulation of Carbamazepine, it is also essential that the formulation should provide a specific in vitro release profile pattern so as to attain in vivo, peak plasma level of carbamazepine at least 15 hours after administration.
When an extended-release formulation of Carbamazepine is prepared without any waxy material such as carnauba wax by merely employing wet granulation process for preparing granules and tablets thereafter, release of carbamazepine from such tablets is faster than as specified in table 1. Particularly, more than 90 % is released in 8-12 hrs. A batch as provided under a comparative example 3 (under examples section) is without carnauba wax or any wax-based extended-release material and had released more than 65 % in 6 hrs and 100 % in 12 hrs (table 4).
In order to further control dissolution of such batches which release 100 % Carbamazepine in 8 – 12 hrs, generally, a functional coating is applied on the core

tablets. This adds another processing step and may further expose Carbamazepine to aqueous coating solution and possibly generating dihydrate of Carbamazepine. Non-aqueous coatings are environmentally hazardous and add several other requirements and restrictions to the overall process.
Aqueous or non-aqueous coating, drying, curing etc. add additional burden on the manufacturing with respect to resources and time.
In order to control dissolution of comparative example 3, a simple modification is possible. With a few modified batches similar to comparative example 3 but with 5 – 10 % Carnauba wax employing around at least 37 mg / 74 mg of carnauba wax per formulation weighing 740 mg, and with a process involving producing first granules by hot melt granulation followed by second granulation employing wet granulation, an in vitro release profile complying that of table 1 is achievable wherein release at 6 hrs is not more than 65 % and release at 12 hrs is not more than 90 %.
A comparative example 3 is tried without employing hot melt granulation. In this batch (comparative example 3 - CAR 400-003), Carbamazepine, polymers HEC (2 grades, 250L and 250HX), wetting agent sodium lauryl sulphate, diluent mannitol, binder dextrate hydrate are sifted and transferred in rapid mixer granulator and blended for 15 minutes at an impeller speed of 100. Aqueous binder solution of HPMC is employed to granulate mixture. Granulation is continued for 5 mins at an impeller speed of 100 RPM. The wet granulated mass is preferably transferred to fluidized bed dryer and dried at 60°C. Dried granules are milled using a screen of 1.5 mm. The milled granules are subjected to lubrication. In the lubrication step, # 60 ASTM sifted magnesium stearate ( 1 – 3 % w/w, preferably, 1.5 – 2 % w/w of the final formulation) is added to milled granules and lubricated for 5 min. at 15 RPM in a suitable blender such as double cone blender. The granules are now ready for compression and compressed using a suitable compression machine such as for example ELIZA PRESS 200L Tablet compression machine, using 12.00 mm round punch. The average weight of each tablet is from 730 mg to 750 mg.

The in vitro release profile of comparative example 3 without hot melt granulation and without carnauba wax as provided in table 4 is obtained wherein release of Carbamazepine is 32.6 % at 3 hrs. 68.3 % at 6 hrs. 100 % at 12 hrs. and 101.5 % at 24 hrs. This batch failed due to higher release than USP limits. An additional time point selected at 8 hrs. showed at least 90 % release (90 – 95%). Therefore, only wet granulation without hot melt granulation also failed in complying with set in vitro release pattern.
Few modified batches employing hot melt granulation using carnauba wax 5 – 10 % w/w of final formulation (around 37 – 74 mg / tablet) and followed by wet granulation as described in comparative example 3 - CAR 400-003 produced carbamazepine double granulated tablets that complied with in vitro release pattern of USP.
Table 4

Sr. Time in hrs. Comparative Modified batches USP limits
No. example 3 -CAR400-003 of double granulated product with 5 – 10 % w/w of carnauba wax
1 3 32.6 % >10 - <35 % 10 % -35 %
2 6 68.3 % >35 -<65 % 35 % - 65 %
3 12 100 % >65 -<90 % 65 % - 90 %
4 24 101.5 % >75% NLT 75%
Generally, due to very poor water solubility, it is preferable that wet granulation method employing binder solution and / or surfactant shall be adopted for preparing Carbamazepine formulations. However, such formulations exhibited faster release of carbamazepine than desired and are also prone to generation of a dihydrate crystal of carbamazepine which is undesired.

Therefore, wet granulation using binder solution and / or surfactant should be carried out on first granules of Carbamazepine prepared without such wet granulation but by using hot melt granulation. In this method, before subjecting carbamazepine to wet granulation, carbamazepine granules with wax material are produced. These granules have a coating or layer of waxy material deposited on the surface of catbamazepine. This coating or layer so deposited protects carbamazepine from generating a dihydrate crystals.
The first granules produced by using 5 – 25 %, preferably 5 – 15 % carnauba wax are subjected to wet granulation and are converted to second granules. The second granules are further processed into suitable extended-release formulation such as tablets. Such tablets are produced from double granulated product.
Therefore, the amount of waxy material such as carnauba wax employed is preferably from 5 % to 25 % of the weight of the formulation and more preferably, from 5 – 15 % w/w of the final formulation. When only hot melt granulation is employed (single granulated product), it can be kept preferably on the higher side of the range of 5 – 25 % w/w such as 20-25 % w/w whereas when both hot melt granulation followed by wet granulation is employed, it can be kept preferably on the lower side of the range viz. 5 – 15 % w/w.
In a double granulated product, two granulations enable incorporation of several inactives. Other inactive ingredients include one or more of diluent, binder, surfactant, glidant and lubricant. Preferably, the inactive ingredients are chosen which are similar to TEGRETOL XR Extended-Release Tablets available in 100 mg, 200 mg and 400 mg strengths. Thus, the extended release Carbamazepine formulations preferably comprise of hydroxypropyl methylcellulose, mannitol, two different grades of hydroxyethyl cellulose as the core matrix polymers, magnesium stearate as lubricant and sodium lauryl sulphate as a wetting agent in addition to a wax material carnauba wax.
The extended-release carbamazepine formulation of the present invention is preferably a double granulated product having first granules which are granulated further to produce second granules which are processed to arrive at high dosed

extended release formulations of Carbamazepine. Double granulated product enables incorporation of both waxy material in preparing first granules as well as water soluble materials such as polymers and water-soluble surfactant in preparing second granules.
The present invention provides a novel method of providing a double granulated product comprising: i) preparing first granules by (a) mixing carbamazepine and a wax-based extended-release material; and (b) subjecting mixture to a temperature higher than the melting temperature of the wax-based extended-release material to cause melting of wax-based extended-release material and c) further mixing to produce first granules; and ii) preparing second granules by wet granulating first granules; and iii) preparing the extended-release formulation from second granules.
The process further comprises preparing aqueous solution of binder polymer / and / or wetting agent sodium lauryl sulphate wherein one or more binder polymers is selected from hydroxy propyl methyl cellulose and hydroxy ethyl cellulose (2 grades, 250L and 250HX) to use during wet granulation.
Most preferred binder solution is aqueous solution of HPMC alone.
Preferably, both the granulations are carried out in the same equipment. A jacketed Rapid mixer granulator having a capacity to heat inside mixture at a temperature of at least 75°C and preferably from 80°C – 95°C is employed. Alternatively, wet granulation can be carried out in another equipment such as another rapid mixer granulator or fluid bed granulator etc.
In first type of embodiments employing only hot melt granulation, Carbamazepine and carnauba wax together comprise of at least 80 – 90 % of total mass of the final formulation. In a double granulated product, Carbamazepine and carnauba wax together comprise of at least 60 % of total mass of the final formulation. A suitable mixer having suitable speed can be selected for mixing carbamazepine and carnauba wax. In a rapid mixer granulator, both are mixed for at least 10 – 15 mins at low impeller speed. When temperature of 80°C is achieved, a further mixing for at least 10 – 15 mins at an impeller speed of around 100 RPM is desired. During

this mixing, carnauba wax starts melting causing formation of hot melt granulation. Once the granulation is complete, this mass is transferred to another vessel and cooled to room temperature. After cooling, the granulated mass is subjected to 2 – 3 millings. In a first milling, a 9 mm screen is used. Granules that are passed through a 9 mm screen are subjected to second and third milling using 1.5 mm screen and 1.2 mm screen respectively. Final milled granules are processed further to produce exatended release formulations of the present invention.
Either the milled granules are lubricated to produce granules ready for compression or the milled granules are subjected to a second granulation process i.e. wet granulation.
In the lubrication step, # 60 ASTM sifted magnesium stearate (1 – 3 % w/w, preferably, 1.5 – 2 % w/w of the final formulation) is added to milled granules and lubricated for 5 min. at 15 RPM in a suitable blender such as double cone blender. The granules are now ready for compression and compressed using a suitable compression machine such as for example ELIZA PRESS 200L Tablet compression machine, using 12.00 mm round punch. The average weight of each tablet is from 630 mg to 650 mg.
To prepare double granulated product, milled granules (hot melt granulated) are transferred to a suitable equipment for wet granulation employing water or aqueous solution of binder polymer HPMC or aqueous solution of binder polymer HPMC and wetting agent sodium lauryl sulphate are employed. First milled granules are blended with one or more inactive such as diluent, binder etc. and optionally wetting agent and one or more binder polymers and then subjected to wet granulation by adding either water or any one of the above- mentioned aqueous solutions.
Wetting agent can be added in dry form or an aqueous solution of wetting agent can be employed during granulation. Similarly, binder polymers are added in dry form or their aqueous solutions are used for granulation.

Preferably, wetting agent is added in dry form along with hydroxy ethyl cellulose polymers and aqueous solution of HPMC is prepared for granulation.
Preferably, aqueous binder solution of HPMC alone is prepared and all other ingredients are dry mixed in rapid mixer granulator at 100 RPM. The binder solution is added to dry mixture containing carbamazepine hot melt granules (first granules which are milled and sized), hydroxy ethyl cellulose (2 grades, 250L and 250HX), wetting agent sodium lauryl sulphate, diluent mannitol and dextrate hydrate binder. The granulation is continued for 5 minutes and at impeller speed of 100 RPM.
The wet granulated mass is preferably transferred to fluidized bed dryer and dried at 60°C. Dried granules are milled using a screen of 1.5 mm. The milled granules are subjected to lubrication. In the lubrication step, # 60 ASTM sifted magnesium stearate ( 1 – 3 % w/w, preferably, 1.5 – 2 % w/w of the final formulation) is added to milled granules and lubricated for 5 min. at 15 RPM in a suitable blender such as double cone blender. The granules are now ready for compression and compressed using a suitable compression machine such as for example ELIZA PRESS 200L Tablet compression machine, using 12.00 mm round punch. The average weight of each tablet is from 730 mg to 750 mg.
Finally, in most preferred embodiments which led to best mode batches, incorporation of around 9 – 14 % of carnauba wax, hydroxypropyl methyl cellulose ( 5 – 8 %), two grades of hydroxyethyl cellulose differing in molecular weights and viscosities such as one with molecular weight below 300,000 and preferably below 100,000 (of viscosity of around less than 250 mPa.s and preferably around less than 150 mPa.s) and the other with high molecular weight above 720,000 and preferably around 1000,000 (of viscosity of around more than 1000 mPa.s and preferably around more than 1500 mPa.s) employed in a ratio of from 1:4 to 4:1 and preferably in a weight ratio of 1:1 to 1:3 and most preferably in a weight ratio of 1:2 and in amount of 6 – 10 % provided desired in vitro release of Carbamazepine as shown in the table 5.

Table 5: In vitro release profile of best mode batch CAR400-008

Sr. No. Time in hrs. Comparative example 4 - CAR400-008 USP limits
1 3 26.3 % 10 % -35 %
2 6 46.6 % 35 % - 65 %
3 12 73.2 % 65 % - 90 %
4 24 85.2 % NLT 75%
To find out role of Carnauba wax during hot melt granulation in the present invention, the inventors decided to test its role by adding it in the same amounts but without conducting hot melt granulation.
A batch was taken (comparative example 4 – batch CAR 400-008) employing from 9 – 14 % of carnauba wax, 5 – 8 % of hydroxypropyl methyl cellulose and total of 6 – 10 % of hydroxyethyl cellulose of two grades in 1:2 weight ratio as provided in best mode batches but without any granulation step. In this batch, all ingredients are dry mixed, lubricated with lubricant magnesium stearate and compressed into tablets. This batch (table 6) in spite of having all desired ingredients in desired proportion fails to comply with in vitro release profile provided in table 1 and released faster at each time point.
Table 6

Sr. No. Time in hrs. Comparative example 4 - CAR400-008 USP limits
1 3 37.3 % 10 % -35 %
2 6 69.4 % 35 % - 65 %
3 12 100.7 % 65 % - 90 %
4 24 99.5 % NLT 75%

Therefore, process of preparation plays an important role. Double granulated product is most desired employing hot melt granulation followed by wet granulation. If single granulation is employed, hot melt granulation employing carnauba wax is desired.
The single and double granulated products preferably contain following: Table 7:

Sr. Ingredients Single granulated Double USP limits
No. product
Hot melt granulated granulated
product; hot
melt
granulated
followed by
wet
granulated
1 Carbamazepine 400 mg 400 mg 10 % -35 %
2 Carnauba wax 5 – 25 %; preferably 15 – 25 % 5 – 25 %; preferably, 5 – 15 % 35 % - 65 %
3 Hydroxypropyl
methyl
cellulose - 2 – 10 % 65 % - 90 %
4 Hydroxy ethyl cellulose (2 grades, 250 L and 250HX in 1:2 ratio) - 5 – 15 NLT 75%
5 Other ingredients such as mannitol, Q.S.

dextrate hydrate
6 Sodium lauryl sulphate Up to 2 % ( 0.01 – 1 %)
7 Magnesium stearate 1 – 3 % 1 – 3 %
The invention thus provides an extended release Carbamazepine tablet having at least 30 % w/w preferably at least 40 % w/w and most preferably at least 50 % w/w of Carbamazepine, hydrophobic component comprising from 5 – 25 % w/w carnauba wax and 1 – 3 % w/w lubricant and from 15 – 45 % hydrophilic component comprising diluent, binder, one or more binder polymers (HPMC and HEC) and a wetting agent wherein In Vitro Dissolution complies with following specification.
Table I: In Vitro Dissolution Specification of Carbamazepine ER tablet

Sr. No. Time (hrs) % dissolved (cumulative) as per USP Specification
1 3 10 % -35 %
2 6 35 % - 65 %
3 12 65 % - 90 %
4 24 NLT 75%
The advantages of the invention include
1. Double granulated or wax granulated high dosed extended release formulation complying with in vitro release profile provided by USP monograph;
2. high dosed extended release formulation of carbamazepine having coating of wax or layer of wax deposited on carbamazepine exposing it minimum to water during wet granulation to avoid dihydrate crystal formation;

3. Simple process which employs jacketed rapid mixer granulator and dryer.
No functional coating is required. Less burden on manufacturing process and resources. Usually, process of coating, drying, curing takes longer time and requires additional manufacturing facility and resources and prolongs manufacturing process. If functional coating is aqueous based, additionally it exposes risk of dihydrate formation. If non-aqueous based coatings are employed, such processes add several other restrictions and require proper disposal of solvents used.
Following examples describe invention without limiting scope of the invention. From the following examples, comparative examples 1, 2 and 3 do not belong to this invention. The Formulation composition and manufacturing process is as provided below:
Comparative example 1

Sr. No Ingredients CAR 400-006
1 Carbamazepine 400.00
2 Carnauba wax 230.00
3 Magnesium Stearate 11.00
Core Weight. 641.00
Process:
1. Sifted Carbamazepine and Carnauba wax through # 20 ASTM and transferred to RMG (Jacketed) for Hot Melt Granulation (RMG)
2. Ingredients of Step no. 1were dry mixed for 15 min without heating.
3. A temperature of 80°C was achieved in jacketed rapid mixer granulator and thereafter mixture of step 2 was mixed for 15min with Impeller at 100 RPM.

4. During mixing of step 3, Carnauba wax started melting and granulation formed and further the hot melt granulation was transferred to the vessel and cooled at room temperature.
5. Granulation of the step no.4 transferred to milling through 9.00 mm screen.
6. Granules milled again through 1.5mm screen at 1000 RPM.
7. The granules of step 6 were sifted through # 20 ASTM and retained granules again milled through 1.2mm screen.
8. The milled granules further added with extra granular # 60 ASTM Sifted Magnesium Stearate and mixed for 5 min to produce lubricated blend / granules ready for compression;
9. The lubricated blend compressed using 12.00mm round punch By ELIZA PRESS 200L Tablet compression machine.
Example 1 viz. Modified example of Comparative example 1 having 24.4 % carnauba wax

Sr. No Ingredients CAR 400-006
1 Carbamazepine 400.00
2 Carnauba wax 133.00
3 Magnesium Stearate 11.00
Core Weight. 544.00
Process: Same as comparative example 1.

Comparative example 2:

Sr. No Ingredients CAR 400-005
1 Carbamazepine 400.00
2 Carnauba wax 230.00
3 HPMC 3 CPS 47.00
4 Hydroxy Ethyl cellulose (Natrosol 250 L) 20.00
5 Hydroxy Ethyl cellulose (Natrosol 250HX) 40.00
6 SLS 5.00
7 Purified water q.s.
8 Magnesium Stearate 11.00
Core Weight. 753.00
Process:
1. Sifted Carbamazepine and Carnauba wax through # 20 ASTM and transferred
to RMG (Jacketed) for Hot Melt Granulation (RMG)
2. Ingredients of Step no. 1 were dry mixed for 15 min without heating.
3. A temperature of 80°C was achieved in jacketed rapid mixer granulator and thereafter mixture of step 2 was mixed for 15min with Impeller at 100 RPM.
4. During mixing of step 3, Carnauba wax started melting and granulation formed and further the hot melt granulation was transferred to the vessel and cooled at room temperature.
5. Granulation of the step no.4 transferred to milling through 9.00 mm screen.
6. Granules milled again through 1.5mm screen at 1000 RPM.

7. The granules of step 6 were sifted through # 20 ASTM and retained granules
again milled through 1.2mm screen.
8. The milled granules were dry mixed with Hydroxy Ethyl cellulose (Natrosol 250 L), Hydroxy Ethyl cellulose (Natrosol 250HX) and SLS and wet granulated using aqueous solution of hydroxypropyl methyl cellulose.
9. Wet granulation of step no. 8 was transferred to the Fluidized Bed Dryer and dried at a temperature of 60°C.
10. The dried granules of step no. 9 were milled through 1.5mm screen.and thereafter added # 60 ASTM sifted magnesium stearate to milled granules and lubricated for 5 min. at 15 RPM to produce lubricated blend / granules ready for compression.
11. The lubricated blend compressed using 12.00mm round punch By ELIZA PRESS 200L Tablet compression machine.
Example 2: Modified batch from comparative example 2 with 5 % w/w of carnauba wax of formulation weight

Sr. No Ingredients CAR 400-003
1 Carbamazepine 400.00
2. Carnauba wax 37.00
3 HPMC (3 cps) 47.00
4 Hydroxy Ethyl cellulose (Natrosol 250 L) 20.000
5 Hydroxy Ethyl cellulose (Natrosol 250HX) 40.000
6 Mannitol 35b(Perlitol 50C) 93.30
8 Dextrate Hydrate (Edmex Non-GMO) 85.20

9 Iron Oxide Yellow 0.1
10 Iron Oxide Red 0.1
11 TiO2 1.3
12 SLS 5.0
13 Purified water q.s.
14. Magnesium Stearate 11.00
Core Weight. 740.00
Process: Same as in example 3.
Comparative example 3: Without hot melt granulation with wet granulation only.

Sr. No Ingredients CAR 400-003
1 Carbamazepine 400.00
2 HPMC (3 cps) 47.00
3 Hydroxy Ethyl cellulose (Natrosol 250 L) 20.000
4 Hydroxy Ethyl cellulose (Natrosol 250HX) 40.000
5 Mannitol 35b(Perlitol 50C) 110.30
6 Dextrate Hydrate (Edmex Non-GMO) 105.20
8 Iron Oxide Yellow 0.1
9 Iron Oxide Red 0.1

10 TiO2 1.3
11 SLS 5.0
12 Purified water q.s.
13 Magnesium Stearate 11.00
Core Weight. 740.00
Process:
1. Sifted Carbamazepine, HPMC E5, Hydroxy ethyl cellulose (Natrosol 250L)
and Hydroxy ethyl cellulose 250 HX, Mannitol, Dextrate Hydrate (Edmex
Non-GMS SLS and titanium dioxide through #20 ASTM
2. Sifted iron oxide red through # 80 ASTM and added to above step no. 1.
3. All sifted material of step no. 1 and step no. 2 were transferred to RMG and dry mixed for 15 minutes at 100rpm
4. Binder solution prepared using water and HPMC E5 is used to granulate dry mix materials of step no. 3
5. Granulation was performed for 5 min at 100rpm
6. After processing of granulation, wet granules of the step no. 5 were transferred to the Fluidized Bed Dryer and dried at a temperature of 60°C.
7. The dried granules of step no. 6 were milled through 1.5mm screen.
8. sized granules of step no. 7 were lubricated for 5 min, and physical evaluation of lubricated blend was done and found to be satisfactory.
9. The lubricated blend was compressed using 12.00 mm round punch By ELIZA PRESS 200L Tablet compression machine.
Example 3: Best mode batches

Sr. No Ingredients CAR 400-007 (ranges of all best mode batches); most preferred range
1 Carbamazepine 400.00
2 Carnauba wax 85.00 (68 – 102 mg)
3 HPMC 3 CPS 47.00 (39 – 56 mg)
4 Hydroxy Ethyl cellulose (Natrosol 250 L) 20.00 (16 – 24 mg)
5 Hydroxy Ethyl cellulose (Natrosol 250HX) 40.00 (32 – 48 mg)
6 Mannitol 72.00 (Q.S 740 mg)
7 Dextrate Hydrate 62.00
6 SLS 5.00
7 Purified water q.s.
8 Magnesium Stearate 11.00
Core W eight. 740.00
Process:
1. Sifted Carbamazepine and Carnauba wax through # 20 ASTM and transferred to RMG (Jacketed) for Hot Melt Granulation (RMG)
2. Ingredients of Step no. 1 were dry mixed for 15 min without heating.
3. A temperature of 80°C was achieved in jacketed rapid mixer granulator and thereafter mixture of step 2 was mixed for 15 min with Impeller at 100 RPM.
4. During mixing of step 3, Carnauba wax started melting and granulation formed and further the hot melt granulation was transferred to the vessel and cooled at room temperature.

5. Granulation of the step no.4 transferred to milling through 9.00 mm screen.
6. Granules milled again through 1.5mm screen at 1000 RPM.
7. The granules of step 6 were sifted through # 20 ASTM and retained granules again milled through 1.2mm screen.
8. The milled granules were dry mixed with mannitol, dextrate hydrate, Hydroxy Ethyl cellulose (Natrosol 250 L), Hydroxy Ethyl cellulose (Natrosol 250HX) and SLS and wet granulated using aqueous solution of hydroxypropyl methyl cellulose.
9. After wet granulation, wet granules of the step no. 8 were transferred to the Fluidized Bed Dryer and dried at temperature 60°C.
10. The dried granules of step no. 9 were milled through 1.5mm screen.
11. Added # 60 ASTM Sifted magnesium stearate to milled granules and lubricated for 5 min. at 15 RPM to produce lubricated blend / granules ready for compression.
12. The lubricated blend compressed using 12.00mm round punch By ELIZA PRESS 200L Tablet compression machine.
Comparative Example 4 - CAR 400-008 – Carnauba wax not added during granulation

Sr. No Ingredients CAR 400-008
1 Carbamazepine 400.00
2 HPMC 3 CPS 47.00
3 Hydroxy Ethyl cellulose (Natrosol 250 L) 20.00
4 Hydroxy Ethyl cellulose (Natrosol 250HX) 40.00
5 Mannitol 72.00

6 Dextrate Hydrate 62.00
7 SLS 5.00
8 Carnauba wax 85.00
9 Magnesium Stearate 11.00
Core Weight. 740.00
Process
1. Sifted Carbamazepine, HPMC, Hydroxy Ethyl cellulose (Natrosol 250 L), Hydroxy Ethyl cellulose (Natrosol 250HX), Mannitol, Dextrate and Carnauba wax through # 20 ASTM and blend for 30min.
2. Added # 60 ASTM Sifted magnesium stearate to milled granules and lubricated for 5 min. at 15 RPM
3. The lubricated blend compressed using 12.00mm round punch By ELIZA PRESS 200L Tablet compression machine.
The wax-based extended-release material, and other optional inert additives, may be included in any amount effective to provide a final extended-release product having acceptable bioavailability. The formulation of the present invention may be prepared by generally all conventional processes, including, but not limited to, granulation, cooling / drying milling, compression, casting in a mold, tableting under pressure, and the like. Preferably, the extended-release formulation is prepared by hot melt granulation alone (first type) or by hot melt granulation followed by wet granulation (second type). The ingredients (both active and inert) can be added in any order during the granulation process. Granulation can take place in any conventional manner to produce a blend. For example, it can be prepared using a jacketed rapid mixer granulator or alternatively, jacketed bowl equipped with planetary mixer, or using a hot melt extruder or a fluid bed granulator coater, mixed in a shell blender, a V-shape blender, a double cone blender, a ribbon mixer, and the like.

In one embodiment, the process for production of the solid dosage form of the present invention is hot melt granulation using an oil or steam jacketed rapid mixer granulator or oil or steam jacketed double planetary motion mixer, or using a hot melt extruder or a fluid bed granulator coater.
The temperature for granulation according to the present invention is selected according to, among other factors, the types of wax and active ingredient, optional inert additives used, as well as the equipment used to prepare the extended-release formulation. Generally speaking, these temperatures can be set at levels same or higher than the melting point of the wax by about 5-30° C., preferably about 10-20° C. In one embodiment, the active ingredient, and optionally, other inert additives are added to the hot wax. Granules are formed when the wax-based extended-release material solidifies on the cold materials as they are added. The temperature may be kept slightly elevated (e.g., about 5-30° C., preferably about 10-20° C. higher than the melting point of the wax).
Carnauba wax melts at 80 - 82°C. a granulator should be able to provide a temperature of at least 80°C.
As used herein, the term “average granule size” (i.e., average particle size) is used interchangeably with the term “median granule size. “The desired average granule size may be achieved by any conventional means, for example, by passing the granules through a conventional sifter with a defined size screen.
For formulations where carbamazepine is the active ingredient, carbamazepine is typically formulated in amounts of about 0.001 to about 1.2 grams, preferably from about 0.2 to about 0.8 grams. The daily dose can be formulated in a single unit form or more than one unit, depending on the daily dose of carbamazepine and the number of times the formulation is to be administered. Carbamazepine, formulated according to the invention, may be delivered once or twice a day, depending on the release kinetics from the formulation.
Testing Method

The dissolution test was performed at 37° C. in a USP apparatus II (paddles) at 100 rpm in 1800 mL water. Samples were taken at 3, 6, 12 and 24 hours. Samples were withdrawn at the specified time for analysis.
Equivalents and alternatives
The invention may be embodied in other specific forms without departing from the scope of the invention. The foregoing embodiments are therefore to be considered in all respects illustrative rather than limiting on the invention described herein. Scope of the invention is thus indicated by the appended claims rather than by the foregoing description, and all changes that come within the meaning and range of equivalency of the claims are intended to be embraced therein.

Claims
1. Carbamazepine Extended-Release formulation comprising melt- or heat-
granulated Carbamazepine and carnauba wax in an amount of from 5 – 25 %.
2. Carbamazepine Extended-Release formulation as claimed in claim 1 wherein formulation is a tablet.
3. Carbamazepine Extended-Release tablet as claimed in claim 2 wherein the formulation is without having any functional coating.
4. Carbamazepine Extended-Release tablet as claimed in claim 2 comprising single
granules prepared by process involving hot melt granulation.
5. Carbamazepine Extended-Release tablet as claimed in claim 2 comprising
double granules prepared by process involving hot melt granulation followed by
wet granulation.
6. Carbamazepine Extended-Release tablet as claimed in claim 4 comprising from 15 – 25 % w/w of carnauba wax of total formulation weight.
7. Carbamazepine Extended-Release tablet as claimed in claim 5 comprising from 5 – 15 % w/w of carnauba wax of total formulation weight.
8. Carbamazepine Extended-Release tablet as claimed in claim 7 comprising i) carnauba wax from 5 – 15 %;
ii). hydroxy propyl methyl cellulose from 2 – 10 %;
iii) hydroxy ethyl cellulose combining a low viscosity grade and a high viscosity
grade from 5 – 15 % in a weight ratio of from 1:4 to 4:1 and preferably in a weight
ratio of 1:2 wherein low viscosity grade is having viscosity below 250 mPa.s and
high viscosity grade is having viscosity of more than 1000 mPa.s.;
iv) sodium lauryl sulphate from 0.01 to 2 %;
v) diluent mannitol and binder dextrate hydrate;
vi) magnesium stearate from 1 – 3 %.

9. Carbamazepine Extended-Release formulation according to any of the preceding claims is an extended release tablet providing following in vitro release profile as provided in table I
Table I: In Vitro Dissolution Profile of Carbamazepine ER tablet

Sr. No. Time (hrs) % dissolved (cumulative)
1 3 10 % -35 %
2 6 35 % - 65 %
3 12 65 % - 90 %
4 24 NLT 75%
10. A process to prepare carbamazepine extended release formulation comprising,
i) adding and mixing carbamazepine and carnauba wax in a mixer / granulator for
5 – 15 minutes and either transferring mixture to another granulator or keeping
mixture in the same granulator for granulation wherein granulator in which
granulation is done is equipped with a jacket or with any other mechanism enabling
increasing temperature of mixture to at least 80°C;
ii) increasing temperature of mixture to around 80°C and mixing at this temperature
for 10 – 15 minutes to allow formation of granulation mass due to melting of
carnauba wax;
iii) transferring the granulation to another vessel for cooling;
iv) sizing granules by milling 2 – 3 times employing a first screen for coarser
granules to obtain coarse granules followed by a second screen for finer granules to
obtain fine granules.
11. The process to prepare carbamazepine extended release formulation as
claimed in claim 10 comprising transferring fine granules of step iv) to a blender;
sifting and adding magnesium stearate to the blender and blending for 5 minutes to
obtain final granules.

12. The process to prepare carbamazepine extended release formulation as claimed
in claim 11 comprising compressing granules employing a suitable machine into
tablet or filling granules into a capsule.
13. The process to prepare carbamazepine extended release formulation as
claimed in claim 10 comprising
i) transferring fine granules to a granulator;
ii) adding one or more of diluent, binder, wetting agent and binder polymers to
the granulator and mixing;
iii) preparing aqueous solution of binder polymer and / or wetting agent;
iv) wet granulating the mixture of step ii with aqueous solution of step iii or
with plain water;
v) transferring granulation to a dryer and drying at 60°C to obtain dry granules;
vi) sizing granules by milling to obtain fine granules.
vii) transferring fine granules of step vi) to a blender; sifting and adding
magnesium stearate to the blender and blending to obtain final granules.
14. The process to prepare carbamazepine extended release formulation as claimed in claim 13 comprising compressing granules employing a suitable machine into tablet or filling granules into a capsule.
15. The process to prepare carbamazepine extended release formulation as claimed in any of the preceding claims wherein
i) a 9 mm screen is selected for milling coarser granules and 1.5 and / or 1.2
mm screen is selected for finer granules during milling;
ii) amount of magnesium stearate added is from 1 – 3 % w/w of the final
extended release formulation;
iii) binder polymer is hydroxypropyl methyl cellulose in an amount of from 2 –
8 % and hydroxy ethyl cellulose in an amount of from 5 – 15 % wherein two grades
of hydroxy ethyl cellulose one of low viscosity and other high viscosity are
employed in a weight ratio of from 1:4 to 4:1 and preferably in a weight ratio of 1:2

wherein low viscosity grade is having viscosity below 250 mPa.s and high viscosity grade is having viscosity of more than 1000 mPa.s.
16. An extended release Carbamazepine tablet having at least 30 % w/w preferably at least 40 % w/w and most preferably at least 50 % w/w of Carbamazepine, hydrophobic component comprising from 5 – 25 % w/w carnauba wax and 1 – 3 % w/w lubricant and from 15 – 45 % hydrophilic component comprising diluent, binder, one or more binder polymers and wetting agent.
17. The extended release Carbamazepine tablet as claimed in claim 16 providing following in vitro release profile as provided in table I Table I: In Vitro Dissolution Profile of Carbamazepine ER tablet

Sr. No. Time (hrs) % dissolved (cumulative)
1 3 10 % -35 %
2 6 35 % - 65 %
3 12 65 % - 90 %
4 24 NLT 75%
18. The extended release Carbamazepine tablet as claimed in claim 16 wherein
i) Diluent is mannitol and binder is dextrate hydrate;
ii) binder polymer is hydroxypropyl methyl cellulose in an amount of from 2 –
8 % and hydroxy ethyl cellulose in an amount of from 5 – 15 % wherein two grades of hydroxy ethyl cellulose one of low viscosity and other high viscosity are employed in a weight ratio of from 1:4 to 4:1 and preferably in a weight ratio of 1:2 wherein low viscosity grade is having viscosity below 250 mPa.s and high viscosity grade is having viscosity of more than 1000 mPa.s.; and iii) wetting agent is sodium lauryl sulphate.