FIELD OF INVENTION
The present invention relates to a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
A number of combination drugs comprising an angiotensin II receptor antagonist and a calcium channel blocker have been proposed in the prior art. The present invention discloses the composition and the manufacturing procedure for the Amlodipine besylate [referred to herein as only 'amlodipine'] and Olmesartan medoxomil [also referred to herein as only 'olmesartan'].
The below WO publications [all assigned to Sankyo] along with their family members form the relevant prior art for the present combination formulation. WO2004067003 discusses combinations of olmesartan medoxomil and amlodipine. However, the only working formulation example covers olmesartan medoxomil and Azelnidipine, not Amlodipine.
WO2007001065 discloses a wet granulated formulation comprising olmesartan medoxomil and amlodipine. The document states that dissolution properties of such a formulation are improved by inclusion of a wet granulation step. We believe that the process may not be suitable for moisture sensitive drugs like amlodipine besylate.
WO2007001066 discloses a formulation comprising olmesartan medoxomil and amlodipine and at least one substance selected from a hydrophilic polymer, an acidic substance and a fluidizing agent. The Applicants assert that their pharmaceutical preparation demonstrated improved dissolution properties.
Meanwhile, WO2007001067 discloses a formulation comprising olmesartan medoxomil and amlodipine wherein the active ingredients are formulated such that

they are not intimately mixed in said solid dosage form. The Applicants assert that 'the dissolution properties of a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker are improved by separately blending each active ingredient to form particles and then mixing the particles comprising each active ingredient such that they are not intimately mixed in the dosage form'. The Applicant, by means of example states that the formulation so prepared shows improved dissolution parameters for olmesartan medoxomil. However, this is a complicated process requiring individual production of two different drug granules/ drug layers and this will result in larger processing time.
It is interesting to note that while Daiichi has stated in the WO2007001067 that the drugs, when kept separate, in the final formulation, either in form of disparate granules of in the form of individualized layers, Olmesartan Medoxomil shows a higher dissolution; while the present Applicant has found that a direct compression solid dose and its process, wherein both the drugs are mixed intimately, result in higher dissolution for Olmesartan Medoxomil, in contrast to the teachings of the reference example in the '167 document.
WO2008032107 also from Daiichi-Sankyo discloses solid dosage forms comprising olmesartan medoxomil and amlodipine, free from reducing sugars. This formulation has low impurity formation [less than 5.1% concentration (w/w) of total impurities].
Daiichi, in the WO2008032107 document advise against use of reducing sugars so as to achieve a final formulation that has a low level of impurity, while the present Applicant has found that use of water soluble excipients, more specifically, water soluble carbohydrates, gives a robust solid dosage form with total impurities less than 1% at the end of a three month stability check.
Objects of the invention:

The object of the present invention is to provide a solid dosage form comprising
Olmesartan and Amlodipine with improved processing and dissolution properties,
using a simple process involving either direct compression or dry granulation
process.
Another object is to manufacture a solid dosage form comprising Olmesartan and
Amlodipine using simple direct compression method.
Yet another object is to manufacture a solid dosage form comprising Olmesartan
and Amlodipine having low level of impurities.
Summary of the Invention:
The present invention provides a solid dosage form comprising an angiotensin II receptor antagonist and a calcium channel blocker, wherein each active ingredient is in the form of particles and the particles comprising each active ingredient are intimately mixed in the dosage form using a simple process such as direct compression. Alternatively, even dry granulation of all the ingredients will be an option. The present composition is free of any hydrophilic polymer or acidic agent or a fluidizing agent. The solid dosage form has excellent dissolution characteristics and very low level of impurity formation.
The present invention provides a pharmaceutical composition comprising an angiotensin II receptor antagonist, a calcium channel blocker and at least one non-polymeric water soluble pharmaceutically acceptable excipients, preferably a carbohydrate.
Detailed description:
The invention, in its broad form comprises:
an angiotensin II receptor antagonist drug,
a calcium channel blocker drug,
a non-polymeric, water-soluble, pharmaceutically acceptable excipient

and
optionally other pharmaceutically acceptable excipients, such that the drugs are present in an intimately mixed state in said dosage form.
The invention also includes a process to make above solid dosage form comprising the following steps:
i) mixing the angiotensin II receptor antagonist drug, the calcium channel blocker drug, the non-polymeric water soluble pharmaceutically acceptable excipient, optionally in presence of other excipients,
ii) blending ingredients of step [i] in blender;
iii) optionally adding a lubricant;
iv) compressing the blend of step [iii] into tablets; and
v) optionally coating the tablets of step [iv] with a coating layer.
Angiotensin II receptor antagonist drug included in the present invention is selected from losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil and irbesartan and includes pharmaceutically acceptable salts or esters of the same. The preferred angiotensin II receptor antagonist drug is Olmesartan Medoxomil.
Calcium channel blocker drug included in the present invention is selected from nifedipine, nimodipine, nilvadipine, manidipine, bamidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine or the pharmaceutically acceptable salts or esters thereof The preferred calcium channel blocker drug is Amlodpine Besylate.

The non-polymeric water soluble pharmaceutically acceptable excipient that is used in the present invention is preferably a carbohydrate. Suitable, non-limiting examples of non-polymeric carbohydrates for use in the present invention include sucrose, dextrose, mannitol, fructose, lactose, sorbitol, xylitol, trehalose, maltitol, dextrates, lactitol, maltose etc; preferably mannitol.
The solid dosage form disclosed in the present document, in its preferred form, comprises Olmesartan medoxomil, Amlodipine Besylate, optionally other pharmaceutically acceptable excipients, and has less than 1% percent impurity formation, at the end of 3 months, when kept at 40°C and 75% RH.
The solid dosage form of the present invention also shows excellent dissolution characteristics. For e.g. the dosage form covers
a. at least approximately 75% of amlodipine besylate is
dissolved within 30 minutes;
b. at least and approximately 90% of amlodipine besylate is
within 60 minutes when dissolved;
c. at least approximately 75% of olmesartan medoxomil is
dissolved within 30 minutes; and
d. at least approximately 85% of olmesartan medoxomil is
within 60 minutes is dissolved
when tested in a pH 6.8 Phosphate buffer, 900 ml, USP II, 50 RPM apparatus.
In its most preferred form, the solid dosage form consists essentially of the following items:
• Amlodipine Besylate
• Olmesartan Medoxomil
• Croscarmellose Sodium (Ac-di-sol)

• Mannitol (Pearlitol SD 200)
• Low-substituted Hydroxypropyl cellulose (LH-11)
• Magnesium stearate
Optionally, the solid dosage form of the above invention may have a moisture protective coating over the tablets using conventional coating techniques. The moisture protective coating over the core tablets can be done by using one or more coating agents from the group comprising of zein, shellac, esterified shellac, polymethacrylates, bees wax, camauba wax etc. The coating composition may also have plasticizers and opacifiers.
The composition disclosed in the present invention may also have one or more additional excipients like lubricants, disintegrating agents, binders, coating agents etc.
The suitable disintegrating agent may be one or more from the group comprising crospovidone, croscarmellose sodium, sodium starch glycolate, polacrillin potassium starch etc.
The suitable lubricant may be one or more from the group comprising magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, hydrogenated cottonseed oil. Sodium lauryl sulfate, sodium benzoate, glyceryl monostearate, glyceryl behenate etc.
The suitable binder may be one or more from the group comprising low substituted hydroxypropyl cellulose, pregelatinized starch, etc.

The below are non-limiting examples.
Example 1

S.N. Ingredient Mg /unit
1 Amlodipine Besylate 13.88
2 Olmesartan Medoxomil 40.00
3 Croscarmellose Sodium (Ac-di-sol) 40.00
4 Mannitol (Pearlitol SD 200) 262.12
5 Low-substituted Hydroxypropyl cellulose (LH-11) 40.00
6 Magnesium stearate 4.00
Tablet Weight 400.00
Brief Manufacturing Process
1. Sift amlodipine besylate, olmesartan medoxomil, Croscarmellose sodium, mannitol and Low-substituted Hydroxypropyl cellulose through sieve no. 40.
2. Blend the ingredients of step no. 1 in blender for 30 minutes.
3. Sift magnesium stearate through sieve no. 40.
4. Add the sifted material of step no. 3 to the blend of step no. 2 and blend for 15 minutes.
5. Compress the blend of step no. 4 into tablets.
Example 2

S.N. Ingredient Mg /unit
1 Amlodipine Besylate 13.88
2 Olmesartan Medoxomil 40.00
3 Crospovidone 40.00

4 Dextrose 262.12
5 Low-substituted Hydroxypropyl cellulose (LH-11) 40.00
6 Stear-o-wet 4.00
Tablet Weight 400.00
prief Manufacturing Process
1. Sift amlodipine besylate, olmesartan medoxomil, crospovidone, dextrose and Low-substituted Hydroxypropyl cellulose through sieve no. 40.
2. Blend the ingredients of step no. 1 in blender for 30 minutes.
3. Sift Stear-o-wet through sieve no. 40.
4. Add the sifted material of step no. 3 to the blend of step no. 2 and blend for 15 minutes.
5. Compress the blend of step no. 4 into tablets.
Example 3

S.N. Ingredient Mg /unit
1 Amlodipine Besylate 13.88
2 Olmesartan Medoxomil 40.00
3 Crospovidone 40.00
4 Sugar spheres (150 - 180 microns) 262.12
5 Low-substituted Hydroxypropyl cellulose (LH-11) 40.00
6 Stear-o-wet 4.00
Tablet Weight 400.00
Brief Manufacturing Process
1. Sift amlodipine besylate, olmesartan medoxomil, crospovidone, sugar spheres
and Low-substituted Hydroxypropyl cellulose through sieve no. 40.

2. Blend the ingredients of step no. 1 in blender for 30 minutes.
3. Sift Stear-o-wet through sieve no. 40.
4. Add the sifted material of step no. 3 to the blend of step no. 2 and blend for 15 minutes.
5. Compress the blend of step no. 4 into tablets.
Example 4
This is an extension of Example 1. The compressed tablets of Example 1 are
further coated with following coating composition

S.N. Ingredient mg /unit
1 Esterified shellac 5.80
2 Methylated spirit q.s.
3 Titanium Dioxide 0.86
4 Talc 1.34
5 Isopropyl Alcohol q.s.
Tablet Weight 400.00
The solution of esterified shellac in methylated spirit is available as Opaglos, manufactured by Colorcon.
Titanium dioxide and talc were dispersed in isopropyl alcohol and added to the solution of esterified shellac, such that final solid content in the coating dispersion is from 4 - 12 % w/w. The coating dispersion is then sprayed onto the tablets prepared as per example 1, till a weight built-up of 1 - 3 % w/w is achieved.

The dosage form of the present invention shows excellent stability as is evidenced by the following data:

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WE claim:
1. A solid dosage form comprising:
an angiotensin II receptor antagonist drug, calcium channel blocker drug,
a non-polymeric, water-soluble, pharmaceutically acceptable excipient and
optionally other pharmaceutically acceptable excipients, such that said drugs are present in an intimately mixed state in said dosage form.
2. A process to make a solid dosage form comprising the following steps:
vi) mixing an angiotensin II receptor antagonist drug, a calcium channel blocker drug, a non-polymeric water soluble pharmaceutically acceptable excipient, optionally in presence of other excipients,
vii) blending ingredients of step [i] in blender;
viii) optionally adding a lubricant;
ix) compressing the blend of step [iii] into tablets; and
x) Optionally coating the tablets of step [iv] with a coating layer.
3. A solid dosage form as claimed in preceding claims, wherein said angiotensin II receptor antagonist drug is selected from losartan, candesartan cilexetil, valsartan, telmisartan, pratosartan, olmesartan medoxomil and irbesartan or their pharmaceutically acceptable salts or esters.
4. A solid dosage form as claimed in preceding claims, wherein said angiotensin II receptor antagonist drug is Olmesartan Medoxomil.
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5. A solid dosage form as claimed in preceding claims, wherein said calcium channel blocker drug is selected from nifedipine, nimodipine, nilvadipine, manidipine, bamidipine, nitrendipine, benidipine, nicardipine, lercanidipine, amlodipine, nisoldipine, efonidipine, cilnidipine, azelnidipine, felodipine or their pharmaceutically acceptable salts or esters.
6. A solid dosage form as claimed in preceding claims, wherein said calcium channel blocker drug is Amlodpine Besylate.
7. A solid dosage form as claimed in preceding claims, wherein said non-polymeric water soluble pharmaceutically acceptable excipient is a carbohydrate selected from a group consisting of sucrose, dextrose, mannitol, fructose, lactose, sorbitol, xylitol, trehalose, maltitol, dextrates, lactitol, maltose etc, preferably mannitol.
8. A solid dosage form comprising Olmesartan medoxomil, Amlodipine Besylate, optionally other pharmaceutically acceptable excipients, such that said formulation has less than 1% percent impurity formation, at the end of 3 months, when kept at 40°C and 75% RH.
9. A solid dosage form comprising an Olmesartna medoxomil, Amlodipine Besylate, optionally other pharmaceutically acceptable excipients, wherein

a) at least approximately 75% of amlodipine besylate is dissolved within 30 minutes;
b) at least and approximately 90%) of amlodipine besylate is within 60 minutes when dissolved;
c) at least approximately 75% of olmesartan medoxomil is dissolved within 30 minutes;
and
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d) at least approximately 85% of olmesartan medoxomil is within 60 minutes is dissolved when tested in a pH 6.8 Phosphate buffer, 900 ml, USPII, 50 RPM apparatus.
10. A solid dosage form consisting essentially of the following items:
• Amlodipine Besylate
• Olmesartan Medoxomil
• Croscarmellose Sodium (Ac-di-sol)
• Mannitol (Pearlitol SD 200)
• Low-substituted Hydroxypropyl cellulose (LH-11)
• Magnesium stearate

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