DESC:F O R M 2

THE PATENTS ACT, 1970
(SECTION 39 of 1970)
&
THE PATENTS RULES, 2003

COMPLETE SPECIFICATION
(See section 10; rule 13)

“PHARMACEUTICAL COMPOSITION OF EXTENDED RELEASE POTASSIUM CITRATE TABLET”

ALEMBIC PHARMACEUTICALS LIMITED
An Indian Company
Alembic Campus, Alembic Road, Vadodara-390 003,
Gujarat, India.

The following specification describes the invention and the manner in which it is to be performed:
This application claims priority to Indian Provisional Patent Application No. 201821032046, filed on Aug 27, 2018. The contents of the foregoing applications are hereby incorporated in their entirety.

TECHNICAL FIELD:
The present invention relates to extended release potassium citrate tablet containing carnauba wax, prepared by roller compaction process, which does not involve melting or heating of carnauba wax. The extended release potassium citrate tablet of this invention has very low friability, improved dissolution, leads to enhanced manufacturing capacity and simplified process without any manufacturing complexities.

BACK GROUND:
Potassium citrate extended release tablet is developed and sold by Mission Pharmacal for treating renal tubular acidosis (RTA) with calcium stones, hypocitraturic calcium oxalate nephrolithiasis and uric acid lithiasis. Potassium Citrate is also known by the chemical name: tripotassium; 2-hydroxypropane-1, 2, 3-tricarboxylate and is reported to have the following chemical structure:

Potassium Citrate in the form of 5 mEq (540 mg), 10 mEq (1080 mg) and 15 mEq (1620 mg) oral wax-matrix extended release tablets is approved in US under the brand name Urocit®-K. Urocit®-K is administered in patients with severe hypocitraturia orally, initiated at a dosage of 60 mEq /day (30 mEq two times/day
or 20 mEq three times/day) with meals or within 30 minutes after meals or bedtime snack and in patients with mild to moderate hypocitraturia, administered orally, initiated at 30 mEq/day (15 mEq two times/day or 10 mEq three times/day) with meals or within 30 minutes after meals or bedtime snack.

Potassium citrate is used clinically to treat kidney stones by alkalizing the urinary pH and increasing urinary citrate concentration. However, its therapeutic efficacy is limited by its gastrointestinal complications such as irritation and ulcerations. Extended-release tablets of potassium citrate could minimize these side effects and have been shown to lead to sustained elevation of urinary pH and citrate concentration (Pak et al., 1984).

Solid oral dosage forms of water-soluble alkali metal and alkaline earth metal salts are preferably provided in large doses (typically greater than 1 g per dosage unit). Such large dosage units of these active pharmaceutical ingredients present problems. It is difficult to produce a suitable pharmaceutical product using these salts because they are all somewhat hygroscopic and because the ions are both irritating and somewhat erosive to the gastric mucosa, each must be given in a slow release form. Historically, wax matrix tablets or microencapsulated products have been used to avoid poor patient acceptance and poor dosage compliance.

An example of such active pharmaceutical ingredients is Potassium citrate, which is very soluble in water and the dosage required is very high. The only way to extend the release of potassium citrate tablet while keeping the tablet size acceptable for swallowing is to use a hydrophobic wax matrix, wherein the total amount of inactive ingredients is below 25% w/w.

U.S. Patent No. 4,904,478 teaches an extended-release wax matrix tablet of a highly water-soluble drug, sodium fluoride, wherein the carnauba wax, present at 35-70% w/w of the tablet weight, is dry mixed with the drug and other inactive ingredients prior to compression.

U.S. Application No. 20080131504 discloses use of carnauba wax at less than 25% w/w (Example 1), wherein the drug and carnauba wax were heated until drug and carnauba wax liquefies, to give an acceptable extended-release profile and abrasion. Abrasion is a measure of the durability of the tablet from the time it is compressed, to packaging, and to the time of use.

U.S. Application No. 20150231267 discloses a simpler process with reduced production time and manufacturing complexities in developing potassium citrate extended release tablet without melting the carnauba wax; but by heating the wax at a temperature below the temperature at which carnauba wax liquefies, i.e., preferably higher than or at least 55°C and not exceeding 80°C with good abrasion and dissolution profile similar to the tablets produced by prior art method (disclosed in US20080131504).

U.S. Patent No. 9,295,659 discloses an extended-release potassium citrate tablet produced by a first portion of melt- or heat- granulated potassium citrate and carnauba wax with a second portion of non-granulated potassium citrate, leading to good friability and robust dissolution and moreover increases production capacity and reduces production cost.

The process for making extended-release potassium citrate tablet containing carnauba wax is difficult. Heating until the carnauba wax liquefies requires a lot of time and then there is the problem of discharging the molten potassium citrate-carnauba wax mixture from the mixer. The cooled mass is extremely hard; therefore the molten mass must be poured into molds so that the cooled mixture is of appropriate size for feeding into a comminuting machine. There is a need for a significantly simpler process to make extended-release potassium citrate wax matrix tablet which does not involve either melting or heating of wax.

SUMMARY OF THE INVENTION:

It has been surprisingly found that extended release potassium citrate tablet can be produced using roller compaction and without heating or melting the carnauba wax. Contrary to exception, by producing tablet using roller compaction does not lead to tablets with poorer friability or dissolution. The tablet by this process has superior friability and consistently passes the USP dissolution. Further as melt- or heat- granulation is most difficult step of production process, eliminating it completely increase the productivity and also decreases production time and cost.

DETAILED DESCRIPTION OF THE INVENTION:

Accordingly, the present invention relates to a process for producing extended release potassium citrate tablet without heating or melting carnauba wax.

Accordingly, the present invention relates to a process for producing extended release potassium citrate tablet using roller compaction method.

Example 1

A 15 mEq tablet was prepared using the melt-granulation technique according to the prior art method. The formulation is given in Table 1.

Table 1
Ingredients mg/tablet % w/w
Potassium citrate monohydrate 1620 85
Carnauba wax 266 14
Magnesium stearate 19 1

The procedure is as follows:
1. Potassium citrate monohydrate and carnauba wax was screened using 16 mesh and mix for 10 min in blender
2. The said blend is then granulated in rapid mixture granulator at more than 80 °C, i.e., above the melting point of carnauba wax; heating until carnauba wax is fully melted and further for some time.
3. Then the prepared granules/liquefied mass are poured and allowed to cool at room temperature.
4. The granules are milled through 1.5 mm screen at medium speed and passed through 16 mesh.
5. The magnesium stearate was passed through 40 mesh and mixed with the milled and screened granules for 5 minutes.
6. The said granules were then compressed at rotary compression machine to form tablet.
The tablet hardness was in the range of 4.9 - 6.1 kp. Its friability was not acceptable as tablets broke down easily. Dissolution profile is given in Table 2.

Table 2
Dissolution Data
Time % Drug release
30 min 50 %
1 hr 68 %
4 hr 100 %

This example illustrates that tablet produced by prior art method, i.e., by fully melting carnauba wax, does not produce tablet of acceptable hardness and abrasion and also fails USP dissolution.

Example 2

A 15 mEq tablet was prepared by using the heat-granulation in US20150231267. The formulation is same as Example 1.
The procedure is as follows:
1. The potassium citrate was comminuted in a Fitzmill D6, knives forward, using perforated screen mesh 8.
2. The comminuted potassium citrate from step 1 was mixed with carnauba wax in a sigma mixer for 20 minutes.
3. The granule from step 2 was comminuted in a Fitzmill D6, knives forward, using perforated screen mesh 12.
4. The granule from step 3 was heated in a jacketed sigma mixer, with continued mixing. Heating was continued until the temperature reached 70°C., which is below the melting point of carnauba wax.
5. The granule from step 4 was discharged into plastic drums and allowed to cool to room temperature.
6. The cooled granule from step 5 was comminuted in a Fitzmill D6, knives forward, using perforated screen mesh 16.
7. Magnesium stearate was passed through mesh 30 and mixed with the comminuted granule of step 6 in a sigma mixer for 2 minutes.
8. The granule from step 7 was compressed into 18.9x8.6 mm elliptical tablet in a Stokes-Pennwalt rotary tablet press model 900.
The tablet hardness was in the range of 11-14 kp. The friability was less than 3% for all the three batches. Dissolution profile is given in Table 3.

Table 3
Dissolution Data
Time Lot 1 Lot 2 Lot 3
% Drug release
30 min 39.5 % 37.1 % 37.0 %
1 hr 54.5 % 50.2 % 51.2 %
3 hr 84.5 % 76.8 % 78.2 %

Two out of the three batches fail USP dissolution. This example illustrates that tablet produced by heat-granulation method, i.e., by heating carnauba wax below its melting point, does not produce tablet of acceptable dissolution and are not robust.

Example 3

Three formulations of 15 mEq tablets with varying concentrations of carnauba wax were prepared by using the heat-granulation in US20150231267. The formulations are given in Table 4.
Table 4
Ingredients Example 3A Example 3B Example 3C
Potassium citrate monohydrate 1620 1620 1620
Carnauba wax 223 (12%) 182 (10%) 133 (7.5%)
Magnesium stearate 19 18 18

The procedure for preparation is same as Example 2.
Dissolution profile is given in Table 5.
Table 5
Dissolution Data
Time Example 3A Example 3B Example 3C
% Drug release
30 min 40.2 % 48.5 % 54.8 %
1 hr 54.6 % 63.7 % 71.9 %
3 hr 86.7 % 96.9 % 98.1 %

Example 3A tablet had hardness of about 10 kp and friability was less than 3%. Note that reducing carnauba wax from 14 % (taken in Example 2) to 12 % did not change the dissolution significantly.
Example 3B tablet had hardness of 8.9 kp and passes USP dissolution but friability of 5.8 % was found to be not acceptable.
Example 3C tablet hardness was 7 kp and failed friability as to capping of tablets and also failed USP dissolution.
This example illustrates that tablet produced by heat-granulation method, even by varying concentration of carnauba wax, does not produce tablet of acceptable dissolution, hardness and friability. Also it is difficult to achieve a good balance of friability and robust dissolution for extended release potassium citrate tablet.

Example 4

Three formulations of 15 mEq tablets with varying ratios of non-granulated and heat-granulated potassium citrate were prepared in US 9295659. The heat granulated potassium citrate and non-granulated potassium citrate were combined according to Table 6.

Table 6
Ingredients Example 4A
85/15 Example 4B
80/20 Example 4C
75/25
Heat-granulated potassium citrate-carnauba wax 1603 mg 1509 mg 1414 mg
Non-granulated potassium citrate monohydrate 243 mg 324 mg 133 (7.5%)
Magnesium stearate 19 mg 19 mg 18 mg

The formulation of Table 6 in percent w/w is given in Table 7:

Table 7
Ingredients Example 4A Example 4B Example 4C
Potassium citrate monohydrate 1620 (86.9%) 1620 (87.5%) 1620 (88.2%)
Carnauba wax 226 (12.1%) 213 (11.5%) 199 (10.8%)
Magnesium stearate 19 (1%) 19 (1%) 18 (1%)

The procedure is as follows:
The heat-granulated potassium citrate was prepared according to step 1-6 of Example 2. This potassium citrate-carnauba wax heat granulate is 85.9% potassium citrate and 14.1% carnauba wax.
To prepare non-granulated potassium citrate for dry addition, potassium citrate was comminuted in a Fitzmill D6. Knives forward, medium speed using perforated screen mesh 14.
The heat-granulated potassium citrate and the non-granulated potassium citrate were mixed in a Sigma mixer for 20 minutes. Magnesium stearate (passed thru mesh 30) was then added, and mixed for 3 minutes. The final granule was compressed into 22.5.times.9.3 mm elliptical tablet in a Stokes-Pennwalt rotary tablet press model 900.
Dissolution profile is given in Table 7.
Table 7
Dissolution Data
Time Example 4A Example 4B Example 4C
% Drug release
30 min 43.6 % 44.3 % 46.2 %
1 hr 58.2 % 58.1 % 62.2 %
3 hr 90.4 % 90.9 % 98.2 %
Example 4A passes the USP dissolution. The tablet hardness was 10 kp and friability was 1.9%.
Example 4B passes the USP dissolution. The tablet hardness was 11 kp and friability was 1.4%.
Example 4C passes USP dissolution. The tablet hardness was 11.5 kp and friability was 1.8%.
This example illustrates that tablet produced by combination of heat granulated potassium citrate and non-granulated potassium citrate leads to acceptable dissolution and friability. However there is need for further improvement in process which gives superior dissolution profile, friability and hardness leading to robust extended release potassium citrate tablet.

Example 5

According to present invention, 15 mEq extended release potassium citrate tablet was prepared using roller compaction technique which does not involve heating or melting of carnauba wax.
The formulation is given in Table 8:
Table 8
Ingredients mg/tab % w/w
Potassium citrate monohydrate 1620 85
Carnauba wax 266 14
Magnesium stearate 19 1

The procedure is as follows:
1. Potassium citrate monohydrate and carnauba wax was screened using 20 mesh screen and mix for 10 min in blender.
2. The said blend is then compacted in roller compactor for 3 cycles.
3. The granules obtained from roller compactor are then passed through 1.0 mm screen.
4. The magnesium stearate was passed through 40 mesh and mixed with the screened granules for 5 minutes.
6. The said granules were then compressed using rotary compression machine using 21.8 X 10.9 mm oval shaped punches.
Dissolution profile is given in Table 9.
Table 9
Dissolution Data
Time Lot 1 Lot 2 Lot 3
% Drug release
30 min 37 % 38 % 41 %
1 hr 52 % 52 % 55 %
3 hr 81 % 81 % 84 %
4 hr 88 % 89 % 92 %
5 hr 94 % 94 % 100 %

Lot 1 passes the USP dissolution. The tablet hardness was 16.7-17.9 kp and friability was 0.1%.
Lot 2 passes the USP dissolution. The tablet hardness was 21.2-25.3 kp and friability was 0.1%.
Lot 3 passes USP dissolution. The tablet hardness was 16.8-18.2 kp and friability was 0.1%.
This example illustrates that tablet produced by using roller compaction without melting or heating carnauba wax surprisingly leads to superior dissolution, superior friability and robust hardness in all the three batches. Also shows robust batch-to batch dissolution, friability and hardness of extended release potassium citrate tablet prepared by present invention. This instant invention also significantly simplifies the production of tablet with reduced production time and reduced manufacturing difficulties.

Example 6

A 15 mEq extended release potassium citrate tablet was prepared using roller compaction technique without melting the carnauba wax.
The formulation is same as given in Example 5. The only exception is adding PVP K90 also in the formulation:
Table 10
Ingredients mg/tab % w/w
Potassium citrate monohydrate 1620 85
Carnauba wax 206 10.81
PVP K90 60 3.15
Magnesium stearate 19 1

The procedure for preparation of extended release tablet is similar to the process given in Example 5. The only difference in the process is adding PVP K30 with potassium citrate and carnauba wax in Step 1 of Example 5.
The tablet hardness was in the range of 16.7-17.9 kp. The friability was found to be 0.1 %. Dissolution profile is given in Table 11.

Table 11
Dissolution Data
Time % Drug release
30 min 41 %
1 hr 58 %
3 hr 97 %
4 hr 98 %
5 hr 100 %

This example illustrates that tablet produced by using roller compaction without melting or heating carnauba wax surprisingly leads to robust dissolution, friability and hardness of extended release potassium citrate tablet.
,CLAIMS:We claim:
1. An extended release pharmaceutical composition comprising a therapeutically effective amount of potassium citrate and at least one natural wax, wherein the said natural wax is not melted or heated.
2. The extended release pharmaceutical composition as claimed in claim 1, wherein the pharmaceutical composition is in the form of tablet.
3. The extended release pharmaceutical composition as claimed in claim 1, wherein the natural wax is carnauba wax.
4. The pharmaceutical composition as claimed in claim 1, wherein the extended release pharmaceutical composition comprises about 15 % w/w of the natural wax based on the total weight of composition.
5. The extended release pharmaceutical composition as claimed in claim 1, which further comprises lubricant in about 1 % w/w of the lubricant based on the total weight of composition.
6. The extended release pharmaceutical composition as claimed in claim 5, wherein the lubricant is magnesium stearate.
7. A method of producing an extended release tablet of potassium citrate and at least one natural wax, wherein the said natural wax is carnauba wax and wherein the said wax is not melted or heated.
8. The method as claimed in claim 7, wherein the potassium citrate and carnauba wax are mixed without melting or heating carnauba wax to form blend.
9. The method as claimed in claim 8, wherein the potassium citrate and carnauba wax blend further undergoes roller compaction process prior to tableting.
10. The method as claimed in claim 7, wherein the carnauba wax does not undergo either, melt-granulation or heat-granulation.