FIELD OF INVENTION

The invention relates to controlled release composition comprising potassium chloride.
The invention also relates to a process for preparing controlled release composition comprising potassium chloride.

BACKGROUND OF THE INVENTION AND RELATED PRIOR ART

Potassium chloride is widely used as a supplement for necessary element along with diet as well as a drug to maintain the proper balance of potassium in the human body and help in avoiding complications associated with the administration of diuretics or any such drug that leads to potassium depletion.

When potassium is taken along with a normal diet as a supplement, it is slowly absorbed from the intestinal tract. Following potassium distribution and uptake by the cells, the kidneys excrete an appropriate amount to maintain a proper balance. As a consequence of a large volume of distribution and a rapid response of the kidney, the extracellular and intracellular concentrations of potassium are normally maintained within relatively narrow limits.

Similarly, when potassium is administrated as a drug, the factors that govern the rate and extent of its distribution are of major importance. It is not possible to increase the total cellular content of potassium significantly above normal. However, it is very easy to raise the extracellular concentration which leads to life-threatening toxicity.

Moreover, it is known that large doses of potassium chloride taken orally can cause gastrointestinal irritation, purging, weakness and circulatory disturbances.

Hence, there was a need to develop a controlled or extended release formulation of potassium chloride that replenishes potassium in an acceptable manner without undesirable side effects.

In order to meet such requirement, various ccontrolled release dosage form of potassium chloride has been developed and approved by the United States Food & Drugs Administration. Potassium chloride is commercially available as extended release tablets, extended release capsules and injection. The extended release tablet of potassium chloride is marketed under the trade name Klor-Con®, K-Tab®etc.

Patents/ Patent applications, which disclose various controlled release compositions comprising potassium chloride, are disclosed below:

U.S. 4,832,955 discloses a composition comprising microencapsulated potassium salt which is encapsulated in a shell wall containing essentially of from about 85.0% to about 97.0% ethyl cellulose and from about 3.0% to about 15.0% of an amphiphile based on the weight of the shell wall; wherein the weight of said shell wall is from about 3% to about 15% of the total weight of said microencapsulated potassium salt which is filled into gelatin capsules.

U.S. 4,863,743 discloses a controlled release potassium chloride tablet which includes potassium chloride crystals coated with about 9.5 to 18% by weight of a polymeric mixture preferably comprising ethylcellulose and hydroxypropylcellulose, which further include a compression aid such as a disintegrant and a tableting lubricant.

U.S. 5,035,898 discloses potassium chloride crystals coated with a combination of high viscosity ethyl cellulose and at least one of hydroxypropylcellulose and polyethyleneglycol, which is further combined with immediate-release magnesium salt to provide the necessary physical and pharmacological characteristics for maximum efficacy.

U.S. 5,397,574 discloses oral dosage form of potassium chloride wherein potassium chloride crystals are coated with a coating composition consisting of low viscosity ethyl cellulose in combination with triacetin.

U.S. 5,422,122 discloses a method of preparing ethyl cellulose microencapsulated potassium chloride crystals with a coating of a hydrophilic polymer which allows compression into tablets of suitable hardness and friability at low compaction pressures when combined with a minimum amount of excipients and having controlled dissolution characteristics. This patent publication further discloses that ethyl cellulose may be applied by using coacervation using polyethylene as a phase separator.

U.S. 5,505,962 discloses a controlled release potassium chloride tablet comprising: a core of potassium chloride in association with other excipient and a permeable membrane surrounding the core containing a potassium chloride impermeable component and a potassium chloride permeable component which is water soluble and dissolves in water to generate pores in the membrane to permit the egress of the potassium chloride from the core in an aqueous environment.

U.S. 6,780,437 discloses potassium chloride granule that contains both crystals of potassium chloride and a thermoplastic cellulose ether that forms a coating on the crystals without any additional additives and further mixed with acceptable compression aids and disintegrants and compressed into tablets.

U.S. 6,974,591 discloses a controlled-release pharmaceutical preparation comprising a drug-containing solid core; and a coating on the solid core, said coating having a water insoluble polymer with a predetermined amount of particles of a pore-forming agent dispersed therein, said pore-forming agent having a balanced solubility in an aqueous dispersion of a film-forming, essentially water insoluble polymer wherein the mean particle size of the pore-forming agent is 0.5-100um; and wherein the amount of the pore-forming agent is 40-95% by weight of the total weight of the dry coating and wherein the coating provides good mechanical strength requiring a force of from 18N to 27N to
break, compared to a force below IN to break.

U.S. 7,632,521 discloses a process for preparing a controlled release tablet of potassium chloride comprising: (a) microencapsulating potassium chloride crystals with an inner membrane comprising ethylcellulose by coacervation or phase separation to form potassium chloride microcapsules (b) coating said potassium chloride microcapsules with an outer membrane comprising a plasticized polymer to form compressible coated microcapsules (c) preparing a blend comprising said compressible coated microcapsules, microcrystalline cellulose, and colloidal silicon dioxide and (d) compressing said blend into tablets.

U.S. 2005/0084531 discloses an aqueous-based sustained release coating for tablets containing potassium chloride, wherein the coating requires a short drying time.

WO 01/43725 discloses controlled release potassium chloride tablet wherein potassium chloride crystals are coated with a first coating of a water insoluble polymeric membrane and a second coating of a plasticized hydrophilic polymer, blending the coated potassium chloride crystals with one or more excipients, and compressing the blend into a tablet.

The above prior arts disclose various controlled release compositions of potassium chloride comprising various excipients such as various diluents, plasticizers and thermoplastic polymer etc., and prepared by means of coating, coacervation, MUPS and/or microencapsulation. However, the use of such technology is time consuming and costly for regular production. Hence, there is a need to develop controlled release compositions of potassium chloride, which is simple and cost effective.

The present inventors found that the granulates of potassium chloride prepared by wet granulation using a mixture of ethyl cellulose and at least one amphiphile, is effective to produce an improved controlled release composition which doesn't require any further additives or agents during compression into tablet and further said tablet being bioequivalent to the marketed dosage form.

SUMMARY AND OBJECTIVES OF THE INVENTION

The invention relates to controlled release composition comprising potassium chloride.
In particular, the invention relates to controlled release composition comprising potassium chloride, wherein the composition comprising potassium chloride granules are prepared by wet granulation method using a non-aqueous solvent.

More particularly, the invention relates to controlled release composition comprising potassium chloride, wherein the composition comprising potassium chloride granules comprising ethyl cellulose, at least one amphiphile and optionally other excipient are prepared by wet granulation method using a non aqueous solvent.

More particularly, the invention further relates to controlled release composition comprising potassium chloride, wherein said composition comprises potassium chloride granules comprising ethyl cellulose, at least one amphiphile and optionally other excipient are prepared by wet granulation method using a non-aqueous solvent, such that the composition is substantially free of any extra-granular additive or excipient.

More particularly, the invention further relates to process of preparing a controlled release composition comprising potassium chloride, wherein said composition comprises potassium chloride granules comprising ethyl cellulose, at least one amphiphile and optionally other excipient that are prepared by wet granulation method using a non-aqueous solvent, such that the composition is substantially free of any extra-granular additive or excipient.

The invention also relates to controlled release composition comprising potassium chloride, wherein said composition in the form of tablet has comparable in-vitro dissolution profile as well as in-vivo bioequivalence when compared with the commercially available Klor-Con®.

DETAILED DESCRIPTION OF THE EMBODIMENTS OF THE
INVENTION

In particular, the invention relates to controlled release composition comprising potassium chloride, wherein the composition comprising potassium chloride granules are prepared by wet granulation method using a non-aqueous solvent.

More particularly, the invention relates to controlled release composition comprising potassium chloride, wherein the composition comprising potassium chloride granules comprising ethyl cellulose, at least one amphiphile and optionally other excipient are prepared by wet granulation method using a non¬aqueous solvent.

More particularly, the invention further relates to controlled release composition comprising potassium chloride, wherein said composition comprises potassium chloride granules comprising ethyl cellulose, at least one amphiphile and optionally other excipient are prepared by wet granulation method using a non-aqueous solvent, such that the composition is substantially free of any extra-granular additive or excipient.

"Amphiphile" as used herein, refers to a water-insoluble material which possesses both hydrophilic and lipophilic part in the same molecule. Suitable amphiphile according to the invention include fatty acids and alcohols having a chain length of C12-C20 Suitable fatty acids include without any limitations, such as lauric acid, stearic acid, myristic acid, palmitic acid and arachidic acid and the like or combinations thereof. Suitable alcohols include without any limitations, such as cetyl alcohol, lauryl alcohol, myristyl alcohol, stearyl alcohol and the like or combinations thereof.

"Substantially free" as used herein, refers that the pharmaceutical composition contains
negligible amount of extra-granular excipient or additive. If present, then it is present in an amount of 5% or less by weight of final composition. More preferably, if present, then it is present in an amount of 1% or less by weight of final composition. More preferably, if present, then it is present in an amount of less than 0.5 % or less by weight of the final composition.

"Controlled release composition" used herein refers to controlled, modified, sustained, extended, prolonged-release pellets, beads, crystals, granules, tablets, mini-tablets or pellets, beads, crystals, granules, tablets, mini-tablets encapsulated in a capsule shell.

Binders according to the invention generally refer to polymers which provide binding as well as drug release- retarding effect. Suitable binders include both water-soluble as well as water-insoluble polymers. Examples of water- soluble polymers include polyvinylpyrrolidone, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose and polyethylene oxide or combinations thereof. Examples of water-insoluble polymers include ethyl cellulose, cellulose acetate, polymethacrylic acid esters copolymer such as Eudragit™ and glyceryl behenate, or combinations thereof.

Use of amphiphile in presence of ethyl cellulose enhances its binding properties, which results in granules having better compressibility without the need for any extra-granular excipient or additive. Further tablets compressed from granules prepared according to the invention, results in increased hardness and reduced friability.

Wet granulation process according to the invention, can be carried out either in conventional high shear mixer granulator or agitation fluid bed granulator or fluid bed or rotary processor. More preferably, the wet granulation process according to the invention is carried out in fluid bed processor wherein the potassium chloride crystal is loaded into the equipment and further non-aqueous solution comprising ethyl cellulose and at least one amphiphile is sprayed into it, wherein the equipment was preset to optimum processing parameters.

In an embodiment, the potassium chloride granules are prepared in a fluid bed processor having optimum processing parameters for granulation which provides controlled agglomeration and controlled growth of granules.

In an embodiment, the non-aqueous wet granulation process according to the invention may be carried out in a fluid bed processor either by top-spray, bottom-spray or tangential-spray of the granulating solution.

Various processing parameters of the fluid bed processor, such as inlet temperature, exhaust temperature, product temperature, spray rate, atomization and nozzle size are controlled and maintained in order to have controlled agglomeration and controlled growth of the granules, so that the final granules prepared have better compressibility, thus obviating the need for any extra-granular excipient or additive for the compression into tablets.

In a preferred embodiment, ethyl cellulose used is in the range of about 10-50%w/w and that of amphiphiles used is in the range of about 4-10%w/w of the tablet core. Ethyl cellulose used is generally of lower viscosity. Preferably, the viscosity of ethyl cellulose used is in the range of about 5-20cps, more preferably in the range of about 5 tolocps.

Suitable solvents used in the process described herein include any solvent which will dissolve both ethyl cellulose and the amphiphile. Suitable examples include cyclohexane, mixtures of cyclohexane and n-hexane, isopropyl alcohol, methylene chloride and the like or combinations thereof. More preferably, the solvent used according to the invention is isopropyl alcohol.

Suitable lubricants used according to the invention are selected from magnesium stearate, calcium stearate, sodium stearyl fumarate, stearic acid, fumaric acid and the like or combinations thereof. More preferably, the lubricant used is magnesium stearate present in an amount of less than 3% of the total weight of the tablet core.

The tablets prepared according to the invention exhibit a better hardness of not less than 20Kp and thereby possess a friability of less than 0.1%.

The particle size of potassium chloride is in the range of about 125-212 microns before milling and further particles size distribution (PSD) of potassium chloride after milling is in the range of about 75-100microns.

The invention further includes dosage unit having different strengths such as 8mEq or 10mEq potassium per unit.

The invention further relates to a process of preparing a controlled release composition comprising potassium chloride wherein potassium chloride granules are prepared by wet granulation using non-aqueous solution comprising ethyl cellulose, at least one amphiphile and optionally other excipient and a solvent and further the composition being substantially free of any extra-granular additive or excipients, wherein said process comprises the following steps:

1. Loading potassium chloride crystal in fluid bed processor.

2. Preparing binder solution by dissolving ethyl cellulose and at least one amphiphile in suitable solvents.

3. Granulating potassium chloride crystal of step 1 using binder solution of step 2 followed by drying.

4. Milling the dried granules of step 3 using Quadracomil fitted with 40G screen to provide the desired granules.

5. Lubricating the granules of step 4 using magnesium stearate.

6. Compressing the lubricated granules of step 5 to obtain tablets and

7. Finally coating the tablets of step 6 by Opadry™.

Various processing parameters of fluid bed processor used in the process for the preparation of potassium chloride granules were set at following values:

The tablets prepared according to the present invention, may be further coated with a film former such as commercially available Opadry™.

Further, it has been found that the controlled release KC1 tablets prepared according to the invention are bioequivalent to the commercially available Klor-
Con®

Bioequivalence studies were carried out according to the In-Vivo Bioequivalence Guidance for Potassium Chloride Modified-Release Tablets and Capsules as prescribed by The United States Food and Drug Administration, which can be accessed here: - http://www.fda.gov/cder/guidance/index.htm.

The recommended study design was a two-treatment, two-period, two-sequence crossover study. Each subject had received a single oral dose of potassium chloride of both the test and reference formulations. Extensive urine sampling for determination of urinary potassium excretion were be performed before and after each dose, with creatinine clearance determined to ensure that urine collection has been adequate.

Further, the results from the above study were determined by calculating least squares means and standard errors of the test and reference formulations and the standard error of difference between the test and reference least squares.

The following examples illustrate specific aspects and embodiments of the invention and demonstrate the practice and advantages thereof. It is to be understood that the examples are given by way of illustration only and are not intended to limit the scope of the invention in any manner.

Example 1

Brief Manufacturing Process:

1. Potassium Chloride having particle size between 125-212 microns were loaded into Fluid bed processor.

2. Stearic acid was dissolved in isopropyl alcohol under stirring to get a clear solution.

3. Ethyl cellulose was dissolved into the solution of step 2 under stirring to get clear solution.

4. Potassium chloride was granulated in fluid bed processor having the following parameters set using the binder solution of step 3.

Inlet Temp: 35-40 °C Exhaust Temp: 25-30 °C Product temperature: 25-30 °C Spray rate: 15-30g/min Automization: 0.8-1.2bar Nozzle size: 1mm

5. Wet granules obtained in step 4 were dried below 40 °C.

6. Granules of step 5 were milled using Quadracomil fitted with 40G screen.

7. Magnesium stearate was sifted though sieve #60 and lubricated the granules of step 6.

8. Lubricated blend of step 7 was compressed into tablets using suitable tooling.

9. Tablets of step 8 were further coated with Opadry™.

The compositions given in examples 2 to 6 were prepared by using similar procedure as described in example 1.

Example 2

Example 3

Example 4

Example 5

Example 6

Tablet Parameters:

The controlled release tablet prepared according to the invention was tested for various tablet parameters such as hardness and friability which is compiled in Table-1.

Table-1

Particle Size Distribution:

The particle size of milled granules was measured by sieve analysis method and the data is complied in Table-2.

Table-2

Dissolution Study:

The controlled release tablet prepared according to the invention were tested for drug release in 900ml of purified water for 16 hours using USP Dissolution Apparatus II with paddle speed set at 50 rpm. The samples were periodically withdrawn and analyzed for potassium chloride content. The drug release profile is compiled in Table 3.

Further, the drug release was tested for Example 2 using different medium with variable parameters. The drug release profile was analyzed and the results are compiled in Table 4, 5, 6, 7 and 8.

Table-3

Table-4

Table-5

Table-6

Table-7

Table-8

The tablet prepared according to Example-2 of the invention was subjected to stability studies at accelerated conditions [40°C/75% RH] for 12 weeks and parameters such as assay and drug dissolution were analyzed.

The results are summarized in Table 9 & 10.

Table-9

Table-10

Bio Study:

The results of the bioequivalence studies as disclosed above are compiled below in Table 11 in comparison with commercially available Klor-Con ®

Table-11

Amount Recovered - refers to cumulative amount of KC1 eliminated or excreted.

AURClast - refers to Area under the urinary excretion rate curve from time 0 to the last measured time.

Max_Rate - refers to maximum excretion rate.
Vo21UR - refers to sum of urinary volume.

RefGeoLSM - refers to geometric least squares mean for reference sample.
TestGeoLSM - refers to geometric least squares mean for test sample.

WE CLAIM:

1. A controlled release composition comprising potassium chloride, wherein said composition comprises potassium chloride granules that are prepared by wet granulation method using a non-aqueous solvent.

2. A controlled release composition comprising potassium chloride, wherein said composition comprising ethyl cellulose, at least one amphiphile and optionally other excipient is prepared by wet granulation method using a non-aqueous solvent

3. A controlled release composition comprising potassium chloride, wherein said composition comprises potassium chloride granules comprising ethyl cellulose, at least one amphiphile and optionally other excipient, wherein said granules are prepared by wet granulation method using a non-aqueous solvent, such that said composition is substantially free of any extra-granular additive or excipient.

4. A process of preparing a controlled release composition in the form of tablet comprising potassium chloride wherein said composition is prepared by a process involving the following steps:

(a) Preparing a non-aqueous solution of ethyl cellulose, atleast one amphiphile and optionally other excipient in suitable solvents;

(b) Granulating the potassium chloride using non-aqueous solution of step (a);

(c) Drying the granules of step (b);

(d) Milling the dried granules of step (c);

(e) Lubricating the granules of step (d);

(f) Compressing the lubricated granules of step (e) to get tablets; and

(g) Optionally coating the tablets of step (f) to get film-coated tablets.

5. The composition according to any of the claims 2-4, wherein said amphiphile is selected from a group comprising lauric acid, stearic acid, myristic acid, palmitic acid and arachidic acid, cetyl alcohol, lauryl alcohol, myristyl alcohol or stearyl alcohol or combinations thereof.

6. The non-aqueous solvent according to any of the claims 1-4, is selected from a group comprising cyclohexane, n-hexane, isopropyl alcohol, methylene chloride or combinations thereof.

7. The composition according to any of the preceding claims, wherein said
ethyl cellulose is present in the weight range of about 10-50%.

8. The composition according to any of the preceding claims, wherein said amphiphile is present in the weight range of about 4-10%.

9. A controlled release composition in the form of tablet comprising:
wherein said tablet is prepared by wet granulation method using a non aqueous solvent.

10. A controlled release composition in the form of tablet comprising:
wherein said tablet is prepared by wet granulation method using a non aqueous solvent.