Technical Field
[0001] The present invention relates to a bilayer pharmaceutical
composition comprising telmisartan and hydrochlorothiazide, wherein the hydrochlorothiazide layer does not contain a disintegrant.
1. Description of the Related Art
0002] Telmisartan belongs to the category of "angiotensin II receptor
antagonist" of antihypertensive agents. Telmisartan is chemically described as 4'- [(1, 4'-dimethyI-2 '-propyl [2,6'-bi-IH-benzimidazol]-1-yl)methyl]-1,1'--biphen yI]-2- carbox ylic acid. Its empirical formula is C33H30N402, its molecular weight is 514.63, and its structural formula is:

[0003] Telmisartan is a white to slightly yellowish solid. It is practically insoluble
in water and in the pH range of 3 to 9, sparingly soluble in strong acid (except insoluble in hydrochloric acid), and soluble in strong base. Telmisartan has very poor solubility in aqueous systems at the physiological pH range of the gastro-intestinal tract of between pH 1-7. Telmisartan, its pharmaceutically acceptable salts and its use in treatment of hypertension was first described in U.S. Patent No. 5,591,762. Boehringer Ingelheim Corporation developed and markets telmisartan compositions globally.
]0004] In the United States, telmisartan is available as MICARD1S® tablets.
MICARDIS® is available as tablets for oral administration, containing 20 mg, 40 mg or 80 mg of telmisartan. The tablets contain the following inactive ingredients: sodium hydroxide, meglumine, povidone, sorbitol, and magnesium stearate. MICARDIS® tablets are hygroscopic and require protection from moisture. The
[5] The combination of telmisartan and hydrochlorothiazide is available in United State as MICARDIS® HCT bi-layer tablet. The bi-layer tablet comprises following excipients: sodium hydroxide, meglumine, povidone, sorbitol, magnesium stearate, lactose monohydrate, microcrystalline cellulose, maize starch, sodium starch glycolate and colorant.
[6] Hydrochlorothiazide (HCTZ) is a thiazide diuretic which is orally administered in the treatment of edema and hypertension. The chemical name of HCTZ is 6-chloro-3,4-dihydro-2H-l ,2,4-benzothi-adiazine-7-sulfonamide-l ,1 -dioxide. and its structural formula as shown below, with molecular formula, C7H8C1N304S2 and molecular weight of 297.74.

Combination therapy of telmisartan with a diuretic like HCTZ has shown synergistic therapeutic efficacy in the treatment of hypertension,
[7] US Patent Publication No. 20050089575 (the '575 publication), discloses the pharmaceutical composition containing telmisartan and a hydrochlorothiazide (HCTZ) in a form of bilayer pharmaceutical tablet, comprising a first layer containing telmisartan in substantially amorphous form in a dissolving tablet matrix, and a second layer containing a diuretic in a disintegrating tablet matrix. In the '575 publication, several galenical approaches were evaluated for making composition of telmisartan and HCTZ. Therein, the approach of putting HCTZ in conventional telmisartan compositions was not found to be feasible due to the presence of basic compounds such as, meglumine (N-methyl-D-glucamine) which are components of conventional telmisartan formulations. Further, the presence of basic compounds was augmented with the reduced dissolution rate of HCTZ from a dissolving matrix as compared with dissolution from a disintegrating matrix. Prompted by the incompatibility between telmisartan and HCTZ, the '575 publication disclosed a bilayer tablet composition, wherein telmisartan was dispersed in amorphous dissolving matrix and HCTZ dispersed in disintegrating matrix.
[8] The prior art pharmaceutical compositions of telmisartan. or its combinations with HCTZ essentially use either a surfactant or the spray dried telmisartan. Spray drying, which is a complex and expensive process in the pharmaceutical industry. It is well known fact that the surfactant controls the dissolution and bioavailability of formulation, therefore the use of surfactant in formulation, adds another parameter in formulation which needs a close monitoring. Moreover the quantity of surfactant, method of handling surfactant influences dissolution of active ingredient. The surfactant-free pharmaceutical composition of telmisartan, or pharmaceutical^ acceptable salts thereof, as described herein, neither compromises dissolution and bioavailability.
SUMMARY OF INVENTION:
[9] The present invention provides pharmaceutical composition comprising surfactant-free telmisartan and hydrochlorothiazide.
[10] In a preferred embodiment, present invention further provides pharmaceutical compositions comprising telmisartan and hydrochlorothiazide, in the form of a bilayer tablet.
[11] The present invention further provides a bilayer pharmaceutical tablet comprising telmisartan and hydrochlorothiazide, wherein the hydrochlorothiazide layer does not contain a disintegrant.
[12] The present invention further provides a bilayer pharmaceutical tablet comprising telmisartan and hydrochlorothiazide, wherein the hydrochlorothiazide layer contains hydroxypropyl methylcellulose.
The present invention further provides an immediate release bilayer pharmaceutical tablet comprising telmisartan and hydrochlorothiazide plus hydroxypropyl methylcellulose.
[0014J The present invention further provides an immediate release bilayer
pharmaceutical tablet comprising a telmisartan layer and a hydrochlorothiazide layer, wherein the hydrochlorothiazide layer is free of disintegrating agent, which releases about 90% of hydrochlorothiazide within 10 minutes .
DETAILED DESCRIPTION OF INVENTION:
[15] The present invention is directed to a bilayer pharmaceutical composition comprising telmisartan layer and hydrochlorothiazide layer, wherein the hydrochlorothiazide layer does not contain a disintegrating agent. Surprisingly, the composition of present invention has a similar or faster dissolution rate compared to the HCTZ tablet compositions comprising disintegrating agents.
[16] The pharmaceutical composition of present invention can be which is prepared by wet granulation or dry granulation or direct compression, however wet granulation is more preferred. The term "granulation", used herein, includes physical adherence, complexation, and association at molecular level, between more than one material, achieved with or without any solvent.
[17] The telmisartan layer of present invention comprises telmisartan or pharmaceutically acceptable salts thereof, a basic agent, one or more fillers, one or more binders, one or more disintegrants, one or more lubricants.
[0018] The first tablet layer composition generally comprises an active ingredient
(from about 3 wt.% to about 50 wt%, preferably from about 5 wt% to about 25 wt %), basic agent (from about 0.25 wt% to about 20 wt. %, preferably from about 1 wt% to about 15 wt. %), water-soluble diluent (from about 30wt% to about 95 wt%, preferably from about 60 wt% to about 85wt%), binder (from about 2wt% to about lOwt.%, preferably from about 3wt% to about 6wt%), and disintegrant (from about 2wt% to about 15wt. %, preferably from about 3wt% to about 10wt%).
(0019) The pharmaceutical composition of present invention, optionally
comprises one or more of the following excipients and/or adjuvants in the amounts indicated below: lubricants (from about 0.5wt% to about 5wt%, preferably from about lwt% to about 3wt%), flow control agents (from about lwt% to about 8wt%, preferably from about 2wt% to about 3wt%), crystallization retarders (from about lwt% to about 10wt%, preferably from about 2wt% to about 8wt%), and coloring agents (from about 0.05wt% to 1.5wt%, preferably from about 0.1 wt% to about 0.8wt%).
[0020] The present invention provides the pharmaceutical composition
comprising telmisartan and hydrochlorothiazide in two distinct layers wherein telmisartan is in substantially amorphous form and hydrochlothiazide is dispersed in dissolving matrix.
[0021] The dissolving matrix of present invention, is a matrix system which is
essentially free from disintegrant. Preferably the dissolving matrix of present invention consists of sorbitol or xylitol or mannitol or lactose, or combinations thereof.
[22] The pharmaceutical composition of the present invention further comprises fillers, basic agents, binders, disintegrants, lubricants, and additional conventional excipients.
[23] The suitable fillers may be selected from lactose monohydrate, lactose, sugar, starches, modified starches, mannitol, sorbitol, inorganic salts, cellulose derivatives (e.g. microcrystalline cellulose, cellulose), calcium sulfate, xylitol and lactitol, preferably mannitol.
[24] The suitable basic agents may be selected from alkali metal hydroxides, such as sodium or potassium hydroxide; sodium or potassium bicarbonate, sodium or potassium carbonate, sodium or potassium biphosphatc, basic amino acids such as arginine, and meglumine (N-methyl-D-glucamine), preferably sodium hydroxide and/or meglumine.
[25] The suitable binders may include polyvinylpyrrolidone, lactose, starches, modified starches, sugars, gum acacia, gum tragacanth, guar gum, pectin, wax binders, microcrystalline cellulose, methylcellulose, carboxymethylcellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, copolyvidone, gelatin and sodium alginate, preferably HPMC and polyvinylpyrrolidone.
[26] The suitable disintegrants may include crospovidone, crosscaramellose sodium, polyvinylpyrrolidone, sodium starch glycolate, corn starch, microcrystalline cellulose, Low substituted hydroxypropyl cellulose, preferably crospovidone.
[27] The suitable lubricants may be selected from magnesium stearate, stearic acid, palmitic acid, calcium stearate, talc, carnauba wax, hydrogenated vegetable oils, mineral oil, PEG and sodium stearyl fumarate, preferably magnesium stearate.
The additional conventional excipients may include preservatives, stabilizers, anti-oxidants, silica flow conditioners, anti-adherents or glidants, preferably anti-adherent such as silicon dioxide.
[29] In addition to hydrochlorothiazide, the second tablet layer composition further comprises; fillers (from about 60wt% to about 90wt%, preferably from about 70wt% to about 85wt %), binder (from about 2wt% to about 10wt%, preferably from
about 3wt% to about 8wt %). The other optional excipients and adjuvants are generally employed in the same proportion as in the first tablet layer composition.
[30] The present invention provides a process for preparing a pharmaceutical composition comprising telmisartan and hydrochlorothiazide comprising: dissolving basic agent and binder in weighed purified water and stirred well, to this solution telmisartan was added under continuous stirring; co-sifting disintegrant and filler and transferred to Glatt fluidized bed granulator. Over this blend, the solution comprising telmisartan, basic agent and binder was sprayed and dried. The dried granules obtained were passed through a suitable mesh to get desired size of the granules. Some portion of extragranular filler and disintegrant were sifted and added to the granule and finally lubricated and compressed.
[31] While the present invention is disclosed by reference to the preferred embodiments and examples below, it is understood that these examples are intended in an illustrative, rather than in a limiting sense. It is contemplated that modifications and combinations will readily occur to those skilled in the art, which modifications and combinations will be within the spirit of the invention.
EXAMPLES
[32] Example I: Telmisartan and Hydrochlorothiazide in a single layer:
The pharmaceutical composition proposed herein is free of surfactant and includes non- spray dried telmisartan.

[33] MANUFACTURING PROCESS:
[34] Dissolve telmisartan in a clear aqueous solution containing sodium hydroxide, meglumine, and povidone K-25. Spray this solution to the uniform blend of mannitol and Crospovidone® XL-10 by using a Glatt coater, keeping inlet temperature of 65°C and product temperature 38°C. Dry the drug loaded blend at an inlet temperature of 65°C till a limit of detection (L.O.D.) of not more than (NMT) 2.0 % w/w, shift the dried mass through #30 mesh. The granules of hydrochlorothiazide were prepared by spraying the suspension of hydrochlorothiazide and HPMC on mannitol. The prepared granules of telmisartan and HCTZ were blended with mannitol and crospovidone; and magnesium stearate was used to lubricate the blend lubricated blend was compressed into single layer tablets.
[0035] Example II: Double layer tablet of Telmisartan and
Hydrochlorothiazide, wherein hydrochlorothiazide is in dissolving matrix
Description of batch 80/25 mg
Telmisartan Layer
Telmisartan (Form-A) 80
Meglumine 24
Sodium Hydroxide 6.7
Povidone® K -25 24
Purified, water qs
Mannitol (Pearlitol® SD 200) 250
Crospovidone XL -10 20
Extra Granular
Mannitol (Pearlitol® SD 200) 235.5
Magnesium Stearate 19.8
Total weight of TMS layer 660
Hydrochlorothiazide Layer
Hydrochlorothiazide 25
Mannitol 25 C 184.6
HPMC - 3 cps (solution) 4.4
Iron Oxide 0.5
Purified, water q.s.
Extra Granular Part
Magnesium, stearate 5.5
Total weight of HCTZ Layer 220
Total weight of Tablet 880
% of water soluble material 76.15

[36] MANUFACTURING PROCESS:
[37] The granules of telmisartan and HCTZ were prepared in the same way as disclosed in EXAMPLE I. The dried granules of telmisartan and HCTZ were independently blended with mannitol and the resulted blend was lubricated with magnesium stearate. Lubricated blend of telmisartan and HCTZ were compressed into bilayer tablet.
[0038] Example HI: Double layer tablet of Telmisartan and
Hydrochlorothiazide, wherein hydrochlorothiazide is in dissolving matrix

Ingredient Qty/Tab. (mg)
Telmisartan Layer Strengths (mg
Telmisartan (Form A) 40.00 80.00 80.00
Sodium Hydroxide 3.35 6.70 6.70
Meglumine 12.00 24.00 24.00
Povidone K-25 (Kollidon K 25) 12.00 24.00 24.00
Purified water q.s. q.s. q.s.
Lactose Monohydrate (Pharmatose DCL-11) 134.25 268.50 268.50
Iron Oxide Red (Sicovit Red) 17.50 35.00 35.00
Crospovidone (Polyplasdone XL) 0.25 0.50 0.50
Extra granular ingredients
Lactose Monohydrate (Pharmatose DCL-11) 51.85 103.70 103.70
Crospovidone (Polyplasdone XL) 17.50 35.00 35.00
Iron Oxide Red (Sicovit Red) 0.25 0.50 0.50
Talc 6.30 12.60 12.60
Magnesium Stearate (Veg.) (Merck) 4.75 9.50 9.50
Weight of Telmisartan Layer 300 600.00 600
Hydrochlorothiazide Layer
Hydrochlorothiazide 12.50 12.50 25.00
Iron Oxide Yellow (Sicovit Yellow) NA NA 0.20
Lactose Monohydrate (Pharmatose 200 M) 122.20 122.20 109.50
Mannitol (Pearlitol SD 200) 50.00 50.00 50.00
Colloidal Silicon Dioxide (Aerosil 200) 3.00 3.00 3.00
Talc 3.00 3.00 3.00
HPMC-3cps (Methocel LV - 3 cps) 2.50 2.50 2.50
Purified Water q.s. q.s. q.s.
Colloidal Silicon Dioxide (Aerosil 200) 1.70 1.70 L70
Talc 1.70 1.70 1.70
Sodium stearyl fumarate (Pruv) 3.40 3.40 3.40
Weight of Hydrochlorothiazide Layer 200.00 200.00 200.00
Total weight 500 800 800
[39] MANUFACTURING PROCESS:
Telmisartan Layer: Lactose and crospovidone were co-sifted through # 30 mesh; and red iron oxide through # 80 mesh. The sifted mass was uniformly mixed in fluid bed processor and granulated with aqueous solution comprising povidone, sodium hydroxide, meglumine and telmisartan. The granules were dried in fluid bed processor; dried granules were passed through ASTM mesh #30. The extragranular components (lactose, crospovidone, and talc were shifted through ASTM mesh # 30 and red iron oxide was shifted through ASTM mesh # 80). The shifted dried granules and shifted extragranular components were lubricated with magnesium stearate in a bin blender. HCTZ Layer: Hydrochlorothiazide, lactose monohydrate, and red iron oxide were uniformly mixed and blended with mannitol. Co-sift the blend (Hydrochlorothiazide, lactose monohydrate, and red iron oxide) with colloidal silicon dioxide and talc through ASTM mesh # 40, and load into fluid bed processor. Granulate the loaded mass with aqueous solution of HPMC 3cps, dry the granules in fluid bed processor and shift the dried granules through ASTM mesh # 40. Mix the dried granules with colloidal silicon dioxide and talc; lubricate the mixture with sodium stearyl fumarate.
Compress the lubricated blend of telmisartan layer and HCTZ layer into bilayer using bilayer compression machine.
[41] COMPARATIVE DISSOLUTION STUDIES:
[42] The dissolution profile of bilayer tablets, prepared as in EXAMPLES II, and MICARDIS HCT®, was undertaken in a 900 ml of pH 7.5 phosphate buffer at 37°C using USP Dissolution Apparatus Type II at an agitation of 75rpm. The data obtained from the dissolution studies shows that more than 90 % hydrochlorothiazide was released after 10 minutes, which is comparable to the dissolution rate of the marketed formulation (MICARDIS HCT®). The dissolved hydrochlorothiazide is expressed in cumulative percent of drug dissolved over an elapsed time period in minutes (See Table, Cumulative Release Profile of HCTZ).
Table: Cumulative Release Profile of HCTZ:
Time in minutes Percent release of HCTZ from Product Prepared as in EXAMPLE II Percent release of HCTZ from Marketed Product
0 0 0
5 94 85
10 98 93
15 98 95
20 98 94
30 98 94
45 98 94
60 98 94

CLAIMS:
1. A pharmaceutical composition comprising surfactant-free telmisartan and hydrochlorothiazide.
2. The pharmaceutical composition of claim 1, wherein the telmisartan is in non- spray dried form.
3. An immediate release bilayer pharmaceutical tablet comprising telmisartan and hydrochlorothiazide, wherein telmisartan layer is free from surfactant.
4. A bilayer tablet comprising telmisartan in one layer and hydrochlorothiazide in another layer, wherein hydrochlorothiazide layer is free from disintegrant.
5. The tablet according to claim 1, 3 and 4, further comprises fillers, disintegrants, binder, alkalizer.
6. The filler according to claim 5, selected from mannitol, lactose, sorbitol, xylitol; the most preferred one is mannitol and lactose.
7. The disintegrant according to claim 5, selected from crospovidone, crosscaramellose sodium, sodium starch glycolate, and low-substituted HPC; the preferred one is crospovidone.
8. The binder according to claim 5, is selected from polyvinylpyrrolidone, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxypropyl cellulose, and copolyvidone, preferably HPMC and polyvinylpyrrolidone
9. The alkalizer according to claim 5, is selected from sodium or potassium hydroxide; sodium or potassium bicarbonate, sodium or potassium carbonate, sodium or potassium biphosphate, basic amino acids such as arginine, and meglumine (N-methyl-D-glucamine), preferably sodium hydroxide and/or meglumine.