DESC:Field of the Invention
The present invention relates to the field of pharmaceutical formulations, specifically to the formulation of a tablet for the treatment of hypertension, comprising Telmisartan in an immediate release form with two or more active ingredients.
Background of the Invention
Hypertension, a common and chronic condition characterized by elevated blood pressure, significantly increases the risk of heart disease, stroke, and other cardiovascular complications. Effective management of hypertension often requires a combination of therapeutic agents to achieve optimal blood pressure control and address multiple physiological pathways involved in the disease. Telmisartan, an angiotensin II receptor blocker (ARB), is widely used for its efficacy in lowering blood pressure and providing cardiovascular protection. However, monotherapy is frequently insufficient for controlling hypertension, necessitating the use of combination therapies that include additional antihypertensive agents.
Telmisartan, when used in combination with other antihypertensive agents, poses significant formulation challenges. Telmisartan is preferably administered in an immediate release form to ensure rapid onset of action. However, combining telmisartan with additional active ingredients, which may be required in immediate release or extended release forms, introduces stability and compatibility issues. Specifically, these challenges include chemical incompatibility between telmisartan and other active ingredients, leading to increased impurity levels, and interference with the in vitro dissolution profiles of the additional active agents.
Existing combination products containing telmisartan and other antihypertensive agents typically employ a bilayer tablet design. In this configuration, immediate release drugs like telmisartan are combined with other drugs, such as chlorthalidone, hydrochlorothiazide, amlodipine, or cilnidipine, in one layer, while drugs with extended release profiles like metoprolol are placed in a separate layer. However, this approach has limitations. Placing telmisartan in the same layer with another immediate release drug can result in the chemical instability of the additional drug. The alkaline environment created by telmisartan can hinder the dissolution of the other active ingredients, further complicating the formulation.
Prior art teachings further highlight that whenever a sustained/extended or modified release layer is incorporated into a bi layer or multi layer tablet, moisture and pH gradients across the strata can intensify migration of alkaline or acidic species, leading to layer to layer instability, plasticity mismatch during compression, and accelerated degradation of sensitive APIs or polymers. Formulators have reported delamination, loss of release rate control and failure to meet ICH stability limits, underscoring the need for an improved multilayer design that isolates incompatible actives while preserving the mechanical integrity of the whole tablet.
Korean patent (WO?2020?256350) likewise discloses bilayer and trilayer tablets in which an immediate release telmisartan layer is present with amlodipine and chlorthalidone, using sodium stearyl fumarate merely to curb delamination. Crucially, that document neither contemplates integrating a ß blocker such as metoprolol nor offers any guidance on how to co formulate telmisartan alongside a extended/sustained release (SR) matrix; its teaching stops at IR telmisartan and does not tackle the well known pH , moisture and impurity driven instabilities that arise when an alkaline ARB shares a tablet with an SR polymer system. Because the Korean approach focuses solely on mechanical cohesion, it leaves unresolved key challenges—alkaline migration that retards acidic/neutral actives, moisture induced impurity spikes, dose scaling rigidity, and tablet bulk—limitations that our trilayer design overcomes by (i) isolating telmisartan in a dedicated IR stratum, (ii) permitting an independent metoprolol SR layer, and (iii) enabling bespoke barrier and polymer selections for each outer layer to secure long term chemical and functional stability.
The present invention addresses the aforementioned challenges by providing a trilayer tablet formulation. This innovative approach ensures the stability and efficacy of each drug by isolating them into distinct layers:
Layer 1: Contains active agent exhibiting extended/sustained release
Layer 2: Contains Telmisartan in an immediate release form, where it is converted to its alkaline salt in situ to enhance dissolution and absorption.
Layer 3: Contains active agent which is different from the active agent in layer one in an immediate release form or extended release form, isolated from Telmisartan to maintain stability and facilitate rapid dissolution.
To address these issues, the inventor of the present invention has surprisingly found that preparing a trilayer tablet design wherein telmisartan is kept completely separate. This innovative design separates telmisartan from the additional active agents into distinct layers, thereby enhancing the physicochemical stability and dissolution rates of each component. By isolating telmisartan in its own immediate release layer, the chemical incompatibility and impurity formation associated with its presence are minimized. The additional antihypertensive agents, which may require immediate or extended release, are placed in separate layers tailored to their specific release profiles and stability requirements.
The trilayer tablet approach offers several advantages over traditional bilayer tablets with dual or triple drug release profiles. It ensures the rapid release and therapeutic efficacy of telmisartan while maintaining the stability and controlled release of the other active ingredients. This configuration enhances the overall clinical effectiveness of the combination therapy, providing a more stable and reliable treatment option for patients with hypertension.
In summary, the development of a trilayer tablet containing telmisartan in an immediate release form, along with two additional antihypertensive agents in immediate or extended release forms, addresses the critical challenges of chemical incompatibility and dissolution interference. This advanced formulation strategy holds promise for improving the management of hypertension through more effective and stable combination therapies.
Objective of the Invention
The objective of the present invention is to provide a pharmaceutical composition comprising telmisartan or pharmaceutically acceptable salts thereof and atleast two pharmaceutical active ingredients.
Another objective of the present invention is to provide a pharmaceutical composition comprising Telmisartan in an immediate release form, and at least two additional pharmaceutically active ingredients wherein one of the first active ingredients exhibits either immediate or extended drug release profile and wherein the other active ingredient exhibits immediate drug release profile.
Another objective of the present invention is to provide a pharmaceutical composition comprising Telmisartan in an immediate release form, and atleast two additional pharmaceutically active ingredients wherein one of the first active ingredients exhibits either immediate or extended drug release profile and wherein the other active ingredient exhibits extended drug release profile
Another objective of the present invention is to provide a trilayer tablet comprising
a) A sustained release layer comprising the first active agent
b) An immediate release layer comprising Telmisartan
c) An immediate or modified release layer comprising the second active agent
BRIEF DESCRIPTION OF FIGURE
Figure 1 represents a diagrammatic representation of triple layer formulation of the present invention.
Detailed Description
Those skilled in the art will be aware that the present disclosure is subject to variations and modifications other than those specifically described. It is to be understood that the present disclosure includes all such variations and modifications. The disclosure also includes all such compositions, components of the composition, referred to or indicated in this specification, individually or collectively and all combinations of any or more of such components or composition.
Definitions
For convenience, before further description of the present disclosure, certain terms employed in the specification, and examples are collected here. These definitions should be read in the light of the remainder of the disclosure and understood as by a person of skill in the art. The terms used herein have their meanings recognized and known to those of skill in the art, however, for convenience and completeness, particular terms and their meanings are set forth below.
The articles “a”, “an” and “the” are used to refer to one or to more than one (i.e., to at least one) of the grammatical object of the article.
The terms “comprise” and “comprising” are used in the inclusive, open sense, meaning that additional elements may be included. It is not intended to be construed as “consists of only”.
Throughout this specification, unless the context requires otherwise the word “comprise”, and variations such as “comprises” and “comprising”, will be understood to imply the inclusion of a stated element or step or group of element or steps but not the exclusion of any other element or step or group of element or steps.
The term “including” is used to mean “including but not limited to”. “Including” and “including but not limited to” are used interchangeably.
The term “trilayer” and “triple layer” as used herein can be used interchangeably
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although any methods and materials similar or equivalent to those described herein can be used in the practice or testing of the disclosure, the preferred methods, and materials are now described. All publications mentioned herein are incorporated herein by reference.
Unless otherwise specified, all %?w/w values disclosed herein are relative to the total weight of the finished tablet. These values are set for the stated active-ingredient strengths; a person skilled in the art will appreciate that when the strength of one or more actives is varied, the %?w/w of one or more excipients may be correspondingly adjusted so that overall tablet weight, processing characteristics, release profile, and mechanical integrity are maintained.
The present disclosure is not to be limited in scope by the specific embodiments described herein, which are intended for the purposes of exemplification only. Functionally equivalent products and processes are clearly within the scope of the disclosure, as described herein.
The term “pharmaceutical composition” refers to delivery system in which active agents are delivered to the patients. This could be in the form of tablet, capsule, injection, liquid etc.
The term “pharmaceutically acceptable excipient” refers to inert substances other than active ingredients which are used in the preparation of pharmaceutical products.
The term “excipients” as used herein means a component of a pharmaceutical product that is not an active ingredient. The excipients that are useful in preparing a pharmaceutical composition are generally safe and non-toxic.
The term “modified release,” as used herein, refers to any dosage-form technology or formulation strategy that intentionally alters the timing?and/or?rate at which an active pharmaceutical ingredient (API) is liberated from the dosage unit after administration when compared with a conventional immediate-release reference formulation. Modified-release profiles include, without limitation, sustained-release (SR), extended-release (ER/XR), controlled-release (CR), delayed-release (DR), pulsatile-release, targeted-release, and combinations thereof, whether achieved by matrix systems, coated multiparticulates, osmotic devices, ion-exchange resins, polymeric membranes, or other physicochemical or mechanical means.
The terms “sustained release,” “extended release,” “SR,” and “ER” are used interchangeably herein to denote a dosage-form system that delivers an active pharmaceutical ingredient (API) at a controlled, slower-than-immediate rate such that therapeutically effective plasma concentrations are maintained for a prolonged period—typically =?8?hours and often up to 24?hours
In an embodiment the present invention provides a pharmaceutical composition comprising Telmisartan or its pharmaceutically acceptable salts thereof and atleast two or more pharmaceutically active ingredients.
In an embodiment the present invention provides a pharmaceutical composition comprising Telmisartan or its pharmaceutically acceptable salts thereof and atleast two additional pharmaceutical active ingredients.
In an embodiment the present invention provides a fixed dose composition comprising Telmisartan or its pharmaceutically acceptable salts thereof and atleast two additional pharmaceutical active ingredients.
In an embodiment the present invention provides a fixed dose composition comprising, Telmisartan or its pharmaceutically acceptable salts thereof, and atleast two additional ingredients, wherein telmisartan exhibits immediate drug release profile, wherein the additional two active ingredient exhibits either immediate or modified/extended drug release profile.
In an embodiment the fixed dose combination of the present invention is present in the form of a conventional tablet, tablet-in-tablet, capsules, multilayer pellets, bilayer tablets or triple layer tablets. In a preferred embodiment the present in invention is present in the form of a triple layer tablet.
In an embodiment the first active agent and second active agent are present in the amount of 1mg to 1000mg, preferably in the amount of 1mg to 100mg.
In an embodiment Telmisartan is present in the amount of 1mg to 500mg, preferably in the amount of 10 mg to 100mg, more preferably between 40mg to 80mg.
In an embodiment, the present invention provides a triple layer tablet comprising three distinct layers compressed into a single unit, wherein the central layer contains Telmisartan, and the layers on either side of the central layer each contain a different pharmaceutically active agent, distinct from each other and from Telmisartan.
In one embodiment, the present invention provides a triple layer tablet comprising three distinct layers compressed into a single unit, wherein the central layer comprises Telmisartan, and the two outer layers each comprise a different pharmaceutically active agent, such that one outer layer contains a first active agent and the other outer layer contains a second active agent, with both active agents being different from each other and from Telmisartan.
In an embodiment the present invention provides a pharmaceutical composition, wherein the pharmaceutical composition is a triple layer tablet, wherein the triple layer tablet comprises of first active ingredient layer, a middle/central telmisartan layer and second active ingredient layer. In an embodiment the first active ingredient and the second active ingredient can be selected from Metoprolol, Chlorthalidone, Hydrochlorothiazide, Cilnidipine, Amlodipine, Ivabradine, Benidipine, Bisoprolol, Efonidipine, Atorvastatin, Indapamide, Nebivolol, Ramipril or the likes thereof.
In an embodiment the present invention provides a triple layer tablet (40) comprising a first active ingredient layer (10), a telmisartan layer (20) and second active ingredient layer (30) wherein each layer is stacked upon one another as shown in Figure 1.
In an embodiment the first active ingredient layer is a sustained/extended drug release layer, the telmisartan layer is immediate drug release layer and the second active agent layer is either modified or immediate drug release layer.
The first active ingredient layer is composed of first active agent in the amount of 0.1% to 30% of the total weight of the composition and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are prolonged release polymers, diluents, disintegrants, binders, coating agents, lubricants, anti-adherants, colorant and the likes thereof, wherein the first active agent layer exhibits Extended drug release profile
In an embodiment the first active agent layer is composed of
a) First active agent in the range of 0.1% to 20 % w/w by the total weight of the composition
b) Extended release polymers selected from but not limited to xantham gum, Hydroxypropyl Methylcellulose (HPMC), polyvinylpyrrolidine (polyvinylpyrrolidone), hydroxypropyl cellulose (HPC), methyl cellulose (MC), methacrylic acid copolymers, Polyethylene Oxide (PEO), Eudragit, Polyvinyl Alcohol (PVA), Ethylcellulose or combination thereof.
c) Diluent selected from lactose e.g., directly compressible lactose, lactose monohydrate, lactose anhydrous, and spray dried lactose; microcrystalline cellulose sugar alcohols, e.g., sorbitol, erythritol, xylitol, and mannitol, dibasic calcium or potassium phosphate, starch, microcrystalline cellulose or combination thereof.
d) Binder selected from microcrystalline cellulose, starch, pregelatinized starch, polyethylene glycol (PEG), sorbitol, celluloses for example hydroxypropyl methylcellulose (HPMC); hydroxy ethylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose, Polyvinylpyrrolidone (also known as polyvidone or povidone), or combination thereof.
e) Lubricant selected from calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, talcum or sodium benzoate or combinations thereof.
f) Glidant selected from calcium phosphate tribasic, magnesium silicate, colloidal silicon dioxide, talc or combination thereof.
g) Colorant selected from but not limited to red ferric oxide, titanium oxide, lead oxide, copper sulfate, and carbon black or combination thereof.
h) Solvent selected from but not limited to water, Isopropyl alcohol, Ethanol or the likes thereof
In an embodiment the first active agent layer is composed of
a) First active agent in the range of 0.1% to 15% w/w by the total weight of the composition
b) Extended release polymers in the range of 1% to 30% w/w by the total weight of the composition
c) Diluent in the amount of 0.5% to 20% w/w by the total weight of the composition
d) Binder in the amount of 0.1% to 10% w/w by the total weight of the composition
e) Lubricant in the amount of 0.01% to 5% w/w by the total weight of the composition
f) Glidant in the amount of 0.01% to 4% w/w by the total weight of the composition
g) Colorant in the amount of 0.001% to 2% w/w by the total weight of the composition
h) Solvent as required.
In an embodiment the first active agent layer is composed of
a) A first active agent in the amount of 1% to 15% w/w by the total weight of the composition, wherein the first active agents are metoprolol or the likes thereof
b) Extended release polymers in the amount of 4% to 25% w/w by the total weight of the composition, wherein one or more extended release polymers are preferably present, and wherein Xantham gum, Hydroxypropyl Methylcellulose or similar cellulosic polymers, methacrylic acid copolymers are examples of extended release polymers that can be used to prepare the first active agent layer
c) Diluent in the amount of 0.5% to 8% w/w by the total weight of the composition, wherein one or more diluent is preferably present, and wherein microcrystalline cellulose, starch, hydroxypropyl methylcellulose (HPMC); hydroxy ethyl cellulose, hydroxypropyl cellulose, methylcellulose, and ethyl cellulose, Polyvinylpyrrolidone are examples of diluents that can be used to prepare the first active agent layer.
d) Binder in the amount of 0.1% to 5% w/w by the total weight of the composition, wherein one or more binders are preferably present, and wherein hydroxypropyl cellulose, povidone are examples of binders that can be used to prepare the first active agent layer.
e) Lubricant in the amount of 0.05% to 1% w/w by the total weight of the composition, wherein one or more lubricant are preferably present and wherein Magnesium stearate, Sodium stearyl fumarate are examples of lubricant that can be used to prepare the first active agent layer.
f) Glidant in the amount of 0.1% to 2% w/w by the total weight of the composition, wherein one or more glidant are preferably present and wherein colloidal silicon dioxide or the likes thereof are examples of glidant that can be used to prepare the first active agent layer.
g) Colorant in the amount of 0.001% to 0.5% w/w by the total weight of the composition, wherein one or more colorant are preferably present, and wherein colorant can be any pharmaceutically acceptable colorant.
h) Solvent, used to dissolve the respective excipient as required, wherein water, isopropyl alcohol are examples of solvent that can be used in the preparation of the first active agent layer
In an embodiment the telmisartan immediate release layer is composed of telmisartan in the amount of 0.1% to 30% by the total weight of the composition, and pharmaceutically acceptable salts thereof, wherein the pharmaceutical excipients are diluents, disintegrants, binders, coating agents, lubricants, anti-adherants, colorant and likes thereof.
In an embodiment the telmisartan immediate release layer is composed of
a) Telmisartan in the amount of 0.1% to 20%, w/w by the total weight of the composition
b) Solubilizing agent selected from are selected Polyethylene glycol, Water-insoluble Lipids or oils, Organic Liquids, cyclodextrins, surfactants, phospholipids, poloxamers, triglycerides, polysorbates or combination thereof.
c) pH modifying agent are selected from but not limited to citric acid, sodium citrate, lactic acid, tartaric acid, malic acid, fumaric acid, sodium bicarbonate, calcium carbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, monosodium phosphate, disodium phosphate or combination thereof.
d) Surfactant selected from but not limited to Sodium Lauryl Sulfate (SLS), Polysorbates, Sorbitan Esters, Lecithin, Poloxamers, Sodium Stearyl Fumarate, Polyoxyethylene Alkyl Ethers, Lauryl Lactate or combination thereof.
e) Diluent selected from but not limited to selected from lactose e.g., directly compressible lactose, lactose monohydrate, lactose anhydrous, and spray dried lactose; microcrystalline cellulose sugar alcohols, e.g., sorbitol, erythritol, xylitol, and mannitol, dibasic calcium or potassium phosphate, starch, microcrystalline cellulose or combination thereof.
f) Disintegrant selected from croscarmellose sodium, crospovidone, starch, potato starch, pregelatinized starch, com starch, sodium starch glycolate, microcrystalline cellulose, low substituted hydroxypropyl cellulose or combinations thereof.
g) Binder selected from but not limited to microcrystalline cellulose, starch, pregelatinized starch, polyethylene glycol (PEG), sorbitol, celluloses for example hydroxypropyl methylcellulose (HPMC); hydroxy ethylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose, Polyvinylpyrrolidone (also known as polyvidone or povidone), or combination thereof.
In an embodiment the telmisartan immediate release layer is composed of
a) Telmisartan in the amount of 1% to 15%, w/w by the total weight of the composition
b) Solubilizing agent in the amount of 0.01% to 10%, w/w by the total weight of the composition
c) pH modifying agent in the amount of 0.01% to 5%, w/w by the total weight of the composition
d) Surfactant in the amount of 0.01% to 5%, w/w by the total weight of the composition
e) Diluent in the amount of 0.5% to 20%, w/w by the total weight of the composition
f) Disintegrant in the amount of 0.1% to 10%, w/w by the total weight of the composition
g) Binder in the amount of 0.01% to 10%, w/w by the total weight of the composition
In an embodiment the telmisartan immediate release layer is composed of
a) Telmisartan in the amount of 1% to 15%, w/w by the total weight of the composition
b) Solubilizing agent in the amount of 0.1% to 10% w/w by the total weight of the composition, wherein one or more solubilizing agents are preferably present, and wherein sorbimine A or meglumine or the likes thereof are examples of solubilizing agents that can be used in the preparation of the telmisartan immediate release layer.
c) pH modifying agent in the amount of 0.01% to 2% w/w by the total weight of the composition, wherein one or more pH modifying agents are preferably present, and wherein Sodium Hydroxide or the likes thereof are the examples of pH modifying agents that can be used in the preparation of the telmisartan immediate release layer.
d) Surfactant in the amount of 0.05% to 2% w/w by the total weight of the composition, wherein one or more surfactant is preferably present, and wherein polysorbate, cremophor or the likes thereof are examples of surfactant that can be used in the preparation of the telmisartan immediate release layer
e) Diluent in the amount of 4% to 15% w/w by the total weight of the composition, wherein one or more diluents are preferably present, and wherein starch, microcrystalline cellulose, hydroxypropyl methylcellulose (HPMC) are examples of diluents that can be used in the preparation of the telmisartan immediate release layer.
f) Disintegrant in the amount of 0.1% to 5% w/w by the total weight of the composition, wherein one or more disintegrants are preferably present, wherein sodium starch glycolate, Crospovidone are examples of disintegrant that can be used in the preparation of the telmisartan immediate release layer
g) Binder in the amount of 0.01% to 2% w/w by the total weight of the composition, wherein one or more binders are preferably present, wherein povidone or the likes thereof are examples of binders that can be used in the preparation of the telmisartan immediate release layer
In an embodiment the second active ingredient layer is composed of the second active agent in the amount of 0.1% to 30% w/w by the total weight of the composition and pharmaceutically acceptable excipients, wherein the pharmaceutically acceptable excipients are polymers, diluents, disintegrants, binders, coating agents, lubricants, anti-adherants, colorant and likes thereof.
In an embodiment the second active agent layer exhibits immediate drug release profiled and is composed of
a) Second active agent in the amount of 0.1% to 10% w/w by the total weight of the composition
b) Optionally, Solubilizing agent in the amount of 0.01% to 10% w/w by the total weight of the composition
c) Optionally, pH modifying agent in the amount of 0.01% to 5% w/w by the total weight of the composition
d) Optionally, Surfactant in the amount of 0.01% to 5% w/w by the total weight of the composition
e) Diluent in the amount of 0.5% to 20% w/w by the total weight of the composition
f) Disintegrant in the amount of 0.1% to 10% w/w by the total weight of the composition
g) Binder in the amount of 0.01% to 10% w/w by the total weight of the composition
In another embodiment the second active layer exhibits modified drug release profile and is composed of
a) Second active agent in the range of 0.1% to 20% w/w by the total weight of the composition
b) Modified release polymers in the range of 1% to 30% w/w by the total weight of the composition
c) Optionally, surfactant in the amount of 0.01% to 5% w/w by the total weight of the composition
d) Optionally, pH modifying agent in the amount of 0.01% to 5% w/w by the total weight of the composition
e) Optionally, solubilizing agent in the amount of 0.01% to 10% w/w by the total weight of the composition
f) Diluent in the amount of 0.5% to 20% w/w by the total weight of the composition
g) Binder in the amount of 0.1% to 10% w/w by the total weight of the composition
h) Lubricant in the amount of 0.01% to 5% w/w by the total weight of the composition
i) Glidant in the amount of 0.01% to 4% w/w by the total weight of the composition
j) Colorant in the amount of 0.001% to 2% w/w by the total weight of the composition
Examples of modified release polymers present in the second active agent layer are selected from but not limited to xantham gum, Hydroxypropyl Methylcellulose (HPMC), polyvinylpyrrolidine (polyvinylpyrrolidone), hydroxypropyl cellulose (HPC), methyl cellulose (MC), methacrylic acid copolymers, Polyethylene Oxide (PEO), Eudragit, Polyvinyl Alcohol (PVA), Ethylcellulose or combination thereof.
Examples of Diluent present in the second active agent layer are selected from but not limited to lactose e.g., directly compressible lactose, lactose monohydrate, lactose anhydrous, and spray dried lactose; microcrystalline cellulose sugar alcohols, e.g., sorbitol, erythritol, xylitol, and mannitol, dibasic calcium or potassium phosphate, starch, microcrystalline cellulose or combination thereof.
Examples of Binder present in the second active agent layer are selected from but not limited to microcrystalline cellulose, starch, pregelatinized starch, polyethylene glycol (PEG), sorbitol, celluloses for example hydroxypropyl methylcellulose (HPMC); hydroxy ethylcellulose, hydroxypropyl cellulose, methylcellulose, and ethylcellulose, Polyvinylpyrrolidone (also known as polyvidone or povidone), or combination thereof.
Examples of Lubricant present in the second active agent layer are selected from but not limited to calcium stearate, glyceryl monostearate, glyceryl palmitostearate, magnesium stearate, sodium lauryl sulfate, sodium stearyl fumarate, zinc stearate, stearic acid, hydrogenated vegetable oil, polyethylene glycol, talcum or sodium benzoate or combinations thereof.
Examples of Glidant present in the second active agent layer are selected from but not limited to calcium phosphate tribasic, magnesium silicate, colloidal silicon dioxide, talc or combination thereof.
Example of solubilizing agent present in the second active agent layer are selected Polyethylene glycol, Water-insoluble Lipids or oils, Organic Liquids, Cyclodextrins, Surfactants, Phospholipids, Poloxamers, triglycerides, Polysorbates or combination thereof.
Examples of pH modifying agent present in the second active agent layer are selected from but not limited to citric acid, sodium citrate, lactic acid, tartaric acid, malic acid, fumaric acid, sodium bicarbonate, calcium carbonate, magnesium hydroxide, sodium hydroxide, potassium hydroxide, hydrochloric acid, phosphoric acid, monosodium phosphate, disodium phosphate or combination thereof.
Examples of surfactant present in the second active agent layer are selected from but not limited to Sodium Lauryl Sulfate (SLS), Polysorbates, Sorbitan Esters, Lecithin, Poloxamers, Sodium Stearyl Fumarate, Polyoxyethylene Alkyl Ethers, Lauryl Lactate or combination thereof.
In an embodiment the second active agent layer exhibits immediate drug release profile and is composed of
a) Second active agent in the amount of 0.1% to 8% w/w by the total weight of the composition, wherein the second active agent is chlorthalidone, amlodipine, cilnidipine and hydrochlorothiazide
b) Optionally, surfactant in the amount of 0.01% to 5% w/w by the total weight of the composition, wherein one or more surfactants are preferably present, and wherein polysorbate, Cremophor or the likes thereof are examples of surfactant that can be used in the preparation of the immediate release second active agent layer
c) Diluent in the amount of 1 % to 15 % w/w by the total weight of the composition, wherein one or more, two or more, three or more diluent are preferably present, and wherein starch, lactose, microcrystalline cellulose are examples of diluent that can be used in the preparation of the immediate release second active agent layer
d) Disintegrant in the amount of 0.1% to 5% w/w by the total weight of the composition, wherein one or more disintegrants are preferably present, and wherein Sodium starch glycolate, crospovidone, are examples of disintegrant that can be used in the preparation of the immediate release second active agent layer
e) Binder in the amount of 0.01% to 2% w/w by the total weight of the composition, wherein one or more binders are preferably present, and wherein povidone or the likes thereof are examples of binders that can be used in the preparation of the immediate release second active agent layer
f) Glidant in the amount of 0.05% to 1.5% w/w by the total weight of the composition, wherein one or more glidants are preferably present, and wherein colloidal silicon dioxide or the likes thereof are examples of glidant that can be used in the preparation of the immediate release second active agent layer
g) Lubricant in the amount of 0.05% to 1.5% w/w by the total weight of the composition, wherein one or more lubricants are present, and wherein magnesium stearate or the likes thereof are examples of lubricant that can be used in the preparation of the immediate release second active agent layer.
In one embodiment, the first and second active agent layers are positioned on either side of the Telmisartan layer, with no fixed orientation, such that either active agent layer may be positioned above or below the Telmisartan layer in the triple layer tablet.
In an embodiment the present invention provides a drug delivery system in the form of pharmaceutical composition for the delivery of Telmisartan, a first active agent, and a second active agent, the composition being formulated as a trilayer tablet comprising:
a) a first layer comprising a first active agent, wherein the first layer exhibits an extended drug release profile;
b) a central layer comprising Telmisartan, wherein the Telmisartan layer exhibits an immediate drug release profile; and
c) a third layer comprising a second active agent, wherein the second layer exhibits either an immediate or modified drug release profile;
wherein:
i) the first and second active agents are different from each other;
ii) the three layers are stacked and compressed together to form a single oral dosage unit; and
iii) the first and second active agent layers are stacked on either side of the Telmisartan layer,
In an embodiment the present invention provides a drug delivery system in the form of pharmaceutical composition for the delivery of Telmisartan, Metoprolol, and Cilnidipine or Amlodipine or Chlorthalidone or Hydrochlorothiazide, the composition being formulated as a trilayer tablet comprising:
a) a first layer comprising a Metoprolol, wherein the first layer exhibits an extended drug release profile;
b) a central layer comprising Telmisartan, wherein the Telmisartan layer exhibits an immediate drug release profile; and
c) a third layer comprising cilnidipine or amlodipine or chlorthalidone or hydrochlorothiazide, wherein the second layer exhibits either an immediate or modified drug release profile;
In an embodiment Metoprolol is present in the amount of 25 mg or 50 mg or 100 mg or 200 mg.
In another embodiment Telmisartan is present in the amount of 20mg, 40mg, 80mg
In another embodiment Cilnidipine is present in the amount of 5mg, 10mg, 20mg
In another embodiment Amlodipine is present in the amount of 2.5mg, 5mg, 10mg
In another embodiment Chlorthalidone is present in the amount of 6.25 mg,12.5 mg, 25mg and 50mg
In another embodiment Hydrochlorothiazide is present in the amount of 12.5mg and 25mg.
In still another embodiment Metoprolol is present in its base form or any other pharmaceutically suitable salt form. Preferably as Metoprolol succinate.
In still another embodiment Telmisartan is present in its base form or any other pharmaceutically suitable salt form. Preferably as Telmisartan base form.
In still another embodiment Cilnidipine is present in its base form or any other pharmaceutically suitable salt form. Preferably as Cilnidipine base form.
In still another embodiment Amlodipine is present in its base form or any other pharmaceutically suitable salt form. Preferably as Amlodipine Besilate.
In still another embodiment Chlorthalidone is present in its base form or any other pharmaceutically suitable salt form. Preferably as Chlorthalidone base form.
In still another embodiment Hydrochlorothiazide is present in its base form or any other pharmaceutically suitable salt form. Preferably as Hydrochlorothiazide base form.
In yet another embodiment the active ingredient used is present in its micronized form.
In an embodiment the present invention provides a process for preparation of the triple layer tablets,
a) preparing granules comprising the first active agent, wherein the granules are formulated to provide extended drug release profile;
b) preparing granules comprising Telmisartan, wherein the granules are formulated to provide an immediate release profile;
c) preparing granules comprising a second active agent, wherein the granules are formulated to provide either an immediate or modified release profile; and
d) compressing the granules obtained from steps (a) to (c) to form a single trilayer tablet, wherein the Telmisartan granules are positioned as the middle layer between the first and second active agent layers.
In an embodiment, the granules comprising the first active ingredient are prepared by any suitable granulation method known in the art, including but not limited to wet granulation, dry granulation (roller compaction or slugging), melt granulation, or spray drying, optionally in the presence of one or more pharmaceutically acceptable excipients such as binders, diluents, disintegrants, lubricants, glidants, or release-modifying agents. The choice of granulation technique may vary depending on the physicochemical properties of the active ingredient and the desired release profile.
In one embodiment, the granules comprising Telmisartan are prepared by any suitable granulation method known in the art, including but not limited to wet granulation, dry granulation (such as roller compaction or slugging), melt granulation, or spray drying. The granulation may be carried out in the presence of one or more pharmaceutically acceptable excipients selected from binders, disintegrants, fillers, lubricants, glidants, or immediate-release enhancers, depending on the desired release characteristics and physical properties of Telmisartan.
In one embodiment, the granules comprising the second active ingredient are prepared by any suitable granulation technique known in the art, including but not limited to wet granulation, dry granulation (e.g., roller compaction or slugging), melt granulation, or spray drying. The granulation process may incorporate pharmaceutically acceptable excipients such as release-modifying agents, diluents, binders, disintegrants, glidants, or lubricants to achieve either immediate or modified release, depending on the therapeutic objective and formulation design.
Examples-
The formulation percentages given in the below examples correspond to the specified active ingredient strengths. It is to be understood that with any change in the strength, provided in the above description, of one or more active ingredients, the percentage composition of excipients may also be adjusted accordingly to maintain consistent tablet weight, functionality, manufacturability, and performance characteristics.
a) Example 1. Triple layer tablet comprising Metoprolol 23.75 mg (ER), Telmisartan 40mg and Chlorthalidone 12. 5 mg First active ingredient layer
Metoprolol Layer (1st active ingredient)
Ingredients %age Role
1 METOPROLOL SUCCINATE IP 7.73 Active
2 MICROCRYSTALLINE CELLULOSE IP 3.11 Diluent
3 XANTHAN GUM IP 18.17 Polymer
5 COL BRILLIANT BLUE LAKE 0.047 Colorant
COL TARTRAZINE LAKE 0.07 Colorant
6 METHOCEL K100 M PREMIUM (DOW CHEMICALS) 8.7 Polymer
7 HYDROXYPROPYL CELLULOSE IP(HPC-L) NIPPON 1.3 Binder
8 POVIDONE IP (PVPK 30) 0.47 Binder
9 ISOPROPYL ALCOHOL IP (IPA) Solvent
10 COLLOIDAL SILICON DIOXIDE IP 0.66 Glidant
11 M.C.C. PH-102 IP 1.9 Diluent
12 MAGNESIUM STEARATE IP 0.15 Lubricant
13 SODIUM STEARYL FUMARATE BP 0.55 Lubricant
Film Coating
1 H.P.M.C. IP E15 2.08 Film former
2 H.P.M.C. IP E5 2.08 Film former
3 P.E.G. 6000 IP 0.41 Plasticizer

b) Telmisartan middle layer
Sr.No Ingredients %age Function
1 TELMISARTAN IP (MICRONISED) 6.51 Active
2 MEGLUMINE 1.98 Solubilizing Agent
3 SODIUM HYDROXIDE (PELLETS) IP 0.39 pH Modifier
4 POLYSORBATE 80 IP (TWEEN 80) 0.31 Surfactant
5 POVIDONE IP (PVPK 30) 0.31 Binder
6 MICROCRYSTALLINE CELLULOSE IP 13.94 Diluent
7 COLLOIDAL SILICON DIOXIDE IP 0.55 Glidant
8 STARCH IP (MAIZE) 7.3 Diluent
9 MAGNESIUM STEARATE IP 0.34 Lubricant
10 CROSPOVIDONE INF10/XL-10 1.9 Disintegrant
11 SODIUM STARCH GLYCOLATE IP(PRIMOJEL) 1.58 Disintegrant

c) Second active ingredient layer
Sr.No Ingredients %age Function
1 CHLORTHALIDONE IP (MICRONIZED) (2nd active ingredient) 2.03 Active
2 STARCH IP (MAIZE) 3.17 Diluent
3 LACTOSE IP 3.96 Diluent
4 MICROCRYSTALLINE CELLULOSE IP 7.93 Diluent
5 SODIUM STARCH GLYCOLATE IP (S.S.G) 0.79 Disintegrant
6 COL TARTRAZINE LAKE 0.07 Colorant
7 POVIDONE IP (PVPK 30) 0.47 Binder
9 SODIUM STARCH GLYCOLATE IP(PRIMOJEL) 0.79 Disintegrant
10 M.C.C. PH-102 IP 3.17 Diluent
11 COLLOIDAL SILICON DIOXIDE IP 0.39 Glidant
12 MAGNESIUM STEARATE IP 0.39 Lubricant
*The percentage of the excipient can be changed based on the change in the strength of the active ingredients
Examples 2. Process of preparation Metoprolol, Telmisartan and Chlorthalidone triple layer tablets of Example 1
Part 1 – Preparation of the First Active Ingredient Layer (Metoprolol):
The process begins with the dispensing of raw materials followed by sifting of Metoprolol succinate, Methocel, Xanthan Gum, Microcrystalline Cellulose, and Colour Brilliant Blue Lake through appropriate mesh sizes using a vibro sifter. The sifted materials are collected in double polyethylene bags lined with HDPE containers. The dry powders are then mixed in a high-shear mixer at an impeller speed of 75 RPM for 10 minutes. A binder solution is prepared separately by dissolving Hydroxypropyl Cellulose and Polyvinylpyrrolidone in isopropyl alcohol. This binder solution is slowly added to the dry mix to perform wet granulation in a rapid mixer granulator (RMG), with additional isopropyl alcohol added if required to obtain granules of desired size. The wet mass is milled using a multi-mill fitted with an 8.0 mm screen at slow speed with forward knife direction, and the wet granules are collected in an FBD bowl. The granules are initially air-dried, followed by drying in a fluidized bed dryer (FBD) at a temperature of 50°C to 55°C until the moisture content is reduced to 2.0–3.0% w/w (measured at 105°C). The dried granules are then passed through sieve #24 using a mechanical sifter, and retained granules are further milled through a 1.0 mm screen. Lubricants including colloidal silicon dioxide, sodium stearyl fumarate, and magnesium stearate are sifted and added to the dried granules. The final blend is prepared by mixing the granules for 12 minutes, followed by blending with the lubricants for an additional 3 minutes.
Part 2 – Preparation of the Telmisartan Layer:
Raw materials are accurately weighed and dispensed according to the weight sheet. Colloidal silicon dioxide, starch, and microcrystalline cellulose are sifted through appropriate mesh sizes and transferred to an RMG. Telmisartan is solubilized by first dissolving sodium hydroxide in purified water, followed by the addition of meglumine with stirring until a clear solution is obtained. Telmisartan is then added slowly with continuous stirring until fully dissolved. Separately, polyvinylpyrrolidone is dispersed in purified water with stirring to obtain a clear solution, and both solutions are combined. Polysorbate is added to the final drug solution and stirred for 15 minutes. The granulation is carried out in a fluidized bed processor (FBP), wherein the drug solution is top-sprayed onto the pre-sifted excipients while maintaining uniform fluidization and avoiding lump formation. After spraying, the equipment is rinsed, and the granules are dried until the moisture content reaches 3.0–4.0% w/w at 80°C. The dried granules are passed through a #24 sieve using a vibro sifter, with oversized material passed through a multi-mill fitted with a 1.0 mm screen. Lubricants including sodium starch glycolate, crospovidone, and magnesium stearate are sifted and blended with the granules. The blend is first mixed with the disintegrants for 10 minutes, followed by blending with magnesium stearate for 5 minutes.
Part 3 – Preparation of the Second Active Ingredient Layer (Chlorthalidone):
Raw materials are accurately dispensed and sifted through appropriate mesh sizes using a vibro sifter. The excipients include chlorthalidone, microcrystalline cellulose, starch, lactose, sodium starch glycolate, and Colour Tartrazine Lake. The sifted materials are dry mixed for 10 minutes at 75 RPM in a high-shear mixer with the chopper turned off. A binder solution is prepared by dissolving polyvinylpyrrolidone in purified water with stirring for 10 minutes to obtain a clear solution. The binder solution is slowly added to the dry blend in an RMG over 2–3 minutes, with additional water added if needed, and the mass is granulated at low speed to obtain desired granules. The wet granules are passed through a multi-mill using an 8.0 mm screen and collected in an FBD bowl. These granules are dried in a fluidized bed dryer for 10 minutes at 55°C to 60°C. The dried granules are screened through sieve #24 using a mechanical sifter, and the retained granules are passed through a multi-mill with a 1.0 mm screen. Lubricants including magnesium stearate, microcrystalline cellulose, sodium starch glycolate, and colloidal silicon dioxide are sifted and collected. The granules are first blended with all excipients except magnesium stearate for 10 minutes in an octagonal or rotocube blender. Magnesium stearate is then added and blended for an additional 5 minutes.
Final Steps – Compression and Coating:
The granules from Part 1 (Metoprolol), Part 2 (Telmisartan), and Part 3 (Chlorthalidone) are compressed sequentially to form uncoated triple-layered tablets using appropriate tooling. The resulting tablets are then subjected to film coating using a suitable coating solution and standard coating equipment to obtain the final finished product.
Example 3- Triple layer formulation of Cilnidipine 10mg, Telmisartan 40mg and Metoprolol 47.5mg
a) First active ingredient layer
Sr.No Ingredients %age Function
1 METOPROLOL SUCCINATE IP 4.349 Active
2 MICROCRYSTALLINE CELLULOSE IP 8.274 Diluent
3 XANTHAN GUM IP 11.607 Polymer
4 COL BRILLIANT BLUE LAKE 0.107 Colorant
5 METHOCEL K100 M PREMIUM (DOW CHEMICALS) 8.929 Colorant
6 HYDROXYPROPYL CELLULOSE IP(HPC-L) NIPPON 1.071 Binder
7 POVIDONE IP (PVPK 30) 0.536 Binder
8 ISOPROPYL ALCOHOL IP (IPA) ---- Solvent
9 COLLOIDAL SILICON DIOXIDE IP 0.571 Glident
10 MAGNESIUM STEARATE IP 0.179 Diluent
11 SODIUM STEARYL FUMARATE BP 0.536 Lubricant

b) Telmisartan layer
Sr.No Ingredients %age Function
1 TELMISARTAN IP (MICRONISED) 7.325 Active
2 MEGLUMINE 2.232 Solubilizing Agent
3 SODIUM HYDROXIDE (PELLETS) IP 0.446 pH Modifier
4 POLYSORBATE 80 IP (TWEEN 80) 0.357 Surfactant
5 POVIDONE IP (PVPK 30) 0.352 Binder
7 MICROCRYSTALLINE CELLULOSE IP 15.687 Diluent
8 COLLOIDAL SILICON DIOXIDE IP 0.629 Glident
9 STARCH IP (MAIZE) 8.214 Diluent
10 MAGNESIUM STEARATE IP 0.393 Lubricant
11 CROSPOVIDONE INF10/XL-10 2.143 Disintegrant
12 SODIUM STARCH GLYCOLATE IP(PRIMOJEL) 1.786 Disintegrant

c) Second active agent layer
Sr.No Ingredients %age Function
1 CILNIDIPINE IP 1.831 Active
2 DIBASIC CALCIUM PHOSPHATE IP (ANHYDROUS) 3.214 Diluent
3 MICROCRYSTALLINE CELLULOSE IP 5.123 Diluent
4 LACTOSE IP 5.804 Diluent
5 STARCH IP (MAIZE) 5.804 Diluent
6 SODIUM STARCH GLYCOLATE IP(PRIMOJEL) 0.893 Disintegrant
7 SODIUM LAURYL SULPHATE IP (S.L.S.) 0.536 Surfactant
8 COLOUR PONCEAU 4R LAKE 0.054 Colorant
9 HYDROXY PROPYL CELLULOSE IP(KLUCEL EXF) 0.446 Binder
10 ISOPROPYL ALCOHOL IP (IPA) ----- Solvent
11 SODIUM STARCH GLYCOLATE IP(PRIMOJEL) 0.893 Disintegrant
12 CROSPOVIDONE INF10/XL-10 0.893 Disintegrant
13 SODIUM LAURYL SULPHATE IP (S.L.S.) 0.357 Surfactant
14 COLLOIDAL SILICON DIOXIDE IP 0.143 Glident
15 MAGNESIUM STEARATE IP 0.321 Lubricant

d) Film coating over the final triple layer tablet
Sr.No Ingredients %age Function
1 H.P.M.C. IP E15 2.170 Film former
2 H.P.M.C. IP E5 2.170 Film former
3 P.E.G. 6000 IP 0.434 Plasticizer

Example 4- Process for preparation of the triple layer formulation of Cilnidipine, Telmisartan and Metoprolol as per example 2
The process for manufacturing the Cilnidipine, Telmisartan, and Metoprolol Succinate (ER) triple-layer tablet involves the preparation of three distinct granule blends—one for each active pharmaceutical ingredient (API)—followed by sequential compression and coating.
Step 1: Preparation of the Cilnidipine Layer (Second active ingredient Layer)
The process begins with the dispensing of raw materials for the Cilnidipine layer, which includes Cilnidipine, Dibasic Calcium Phosphate (anhydrous), Microcrystalline Cellulose, Lactose, Starch, Sodium Starch Glycolate, Sodium Lauryl Sulphate, Colour Ponceau 4R Lake, and Hydroxypropyl Cellulose. These materials are sifted using appropriate mesh sizes (generally 40#, with colorant through 100#) under controlled humidity (=60%) and temperature (=25°C). The sifted materials are collected in double polyethylene bags lined with HDPE containers. The dry mixing of the excipients is performed in a Rapid Mixing Granulator (RMG) at an impeller speed of 75 RPM for 10 minutes with the chopper turned off.
A binder solution is prepared by dissolving Hydroxypropyl Cellulose (Klucel EXF) in Isopropyl Alcohol in a stainless-steel container with continuous stirring for 10 minutes to yield a clear solution. This solution is added slowly to the dry mix over 2–3 minutes. Granulation is carried out in the RMG, initially at low speed for 4 minutes followed by high-speed impeller mixing for 2 minutes to form granules of the desired size. The wet granules are passed through a multi-mill fitted with an 8.0 mm screen at slow speed and forward knife rotation. The resulting wet granules are transferred to a Fluidized Bed Dryer (FBD), where they undergo an initial 10-minute air-drying step, followed by drying at an inlet temperature of 55–60°C (with outlet temperature maintained at 30–35°C) for approximately 50–55 minutes, with intermittent raking. Drying continues until a loss on drying (LOD) of 3.0–4.5% (measured at 105°C) is achieved.
After drying, the granules are passed through a mechanical sifter fitted with sieve #24. Oversized granules are milled again through a 1.0 mm screen. Lubricants and disintegrants—including Magnesium Stearate, Sodium Lauryl Sulphate, Sodium Starch Glycolate, Colloidal Silicon Dioxide, and Crospovidone—are sifted through 40# mesh and added to the dried granules. Blending is conducted in an octagonal or rotocube blender. The dried granules are first blended with all excipients except Magnesium Stearate for 10 minutes, followed by a 5-minute final blending with Magnesium Stearate to ensure uniform distribution.
Step 2: Preparation of the Telmisartan Layer (Middle Layer)
Telmisartan (micronized) is solubilized by first dissolving Sodium Hydroxide in purified water, followed by the addition of meglumine to form a clear solution. Telmisartan is then added slowly under continuous stirring until fully solubilized. In a separate container, Polyvinylpyrrolidone K-30 is dispersed in purified water and stirred to form a clear binder solution. The two solutions are combined, and Polysorbate 80 is added with additional stirring for 15 minutes.
Simultaneously, excipients including Colloidal Silicon Dioxide, Starch (maize), and Microcrystalline Cellulose are sifted using appropriate mesh sizes and collected. The granulation is performed using a Fluidized Bed Processor (FBP). The sifted excipients are loaded into the bowl and preheated to a product temperature of approximately 43°C. The drug solution is top-sprayed using a 1.0 mm nozzle at an atomization pressure of 1.5–2.5 kg/cm². Granulation is conducted under controlled conditions (inlet temperature 50–70°C, product temp 35–55°C, exhaust temp 35–55°C) with a spray rate of 130–260 g/min, ensuring uniform fluidization and minimal lump formation. After spraying, the system is rinsed with purified water.
The wet granules are dried in the same FBP to achieve an LOD of 3.0–4.0% w/w at 80°C. The dried granules are passed through a 24# sieve using a vibro sifter. Retained granules are milled through a 1.0 mm screen and again sifted to ensure uniform sizing. Lubricants and disintegrants including Sodium Starch Glycolate, Crospovidone, and Magnesium Stearate are sifted through 40# mesh. The dried granules are blended first with Sodium Starch Glycolate and Crospovidone for 10 minutes, followed by Magnesium Stearate for 5 minutes in a rotocube or V-blender to complete the Telmisartan layer blend.
Step 3: Preparation of the Metoprolol Succinate Layer (1st active agent Layer)
The Metoprolol Succinate layer is prepared by first sifting Metoprolol Succinate, Methocel K100M, Xanthan Gum, Microcrystalline Cellulose, and Colour Brilliant Blue Lake (through respective sieves of 40# or 100#). The materials are collected in polyethylene-lined HDPE containers. The sifted mixture is dry-blended in an RMG for 10 minutes at 75 RPM with the chopper off.
The binder solution is prepared in a stainless steel container by dissolving Hydroxypropyl Cellulose (HPC-L) and Polyvinylpyrrolidone K-30 in Isopropyl Alcohol with continuous stirring for 5–8 minutes. The solution is slowly added to the dry mix over 2–3 minutes. Granulation proceeds in the RMG—first at low speed for 4 minutes, followed by high-speed impeller mixing for 2 minutes to obtain granules of the desired size. Wet granules are passed through a multi-mill (8.0 mm screen, slow speed, forward knife direction) and collected in an FBD bowl.
Drying is carried out in a Fluidized Bed Dryer with an initial 10-minute air-drying step, followed by drying at 50–55°C (outlet temperature 30–32°C) with intermittent raking every 20 minutes. Drying is continued until an LOD of 2.0–3.0% is reached. Dried granules are screened through a #24 sieve; retained material is milled through a 1.0 mm screen. Lubricants including Colloidal Silicon Dioxide, Sodium Stearyl Fumarate, and Magnesium Stearate are sifted through 40# mesh and added to the dried granules. The blend is mixed in a rotocube blender—initially for 12 minutes with all excipients except lubricants, then with Sodium Stearyl Fumarate and Magnesium Stearate for an additional 3 minutes at 12 ± 1 RPM.
Step 4: Compression and Coating
The final granules from the Cilnidipine, Telmisartan, and Metoprolol Succinate layers are compressed using a tri-layer tablet compression machine equipped with 11.0 mm round, concave punches (plain upper and lower). Each layer is compressed sequentially to form a single, stable, uncoated tri-layer tablet. The uncoated tablets are then subjected to film coating in a coating pan. The coating solution comprises HPMC E-15, HPMC E-5, PEG-6000, and purified water. Coating parameters include an inlet air temperature of 60–70°C, pan rotation at 15–20 RPM, spray rate of 10–15 g/min/gun, and a gun-to-bed distance of 8–9 inches. The final product temperature is maintained at 35–45°C.
Finished Product Specifications
The final coated tablets are round, biconvex, and color-coded: pink (Cilnidipine layer), white (Telmisartan layer), and blue (Metoprolol layer). Each tablet weighs approximately 576 mg ± 5.0%, has a thickness of 6.10 ± 0.3 mm and a diameter of 11.10 ± 0.2 mm. The hardness is maintained at not less than 100 N, and friability does not exceed 1.0% w/w. Finished tablets are subjected to visual inspection, leakage tests, and analytical testing before being packed in approved packaging materials.
Example 5 – Triple layer composition of Amlodipine 5mg, Telmisartan 40mg and Metoprolol 23.75mg
a) Second active ingredient
Sr.No Ingredients % age Function
1 AMLODIPINE BESILATE IP 1.284 Active
2 DIBASIC CALCIUM PHOSPHATE IP (ANHYDROUS) 3.214 Diluent
3 MICROCRYSTALLINE CELLULOSE IP 10.823 Diluent
4 STARCH IP (MAIZE) 5.804 Diluent
5 SODIUM STARCH GLYCOLATE IP(PRIMOJEL) 0.893 Disintegrant
6 SODIUM LAURYL SULPHATE IP (S.L.S.) 0.536 Surfactant
7 COL QUINOLINE YELLOW LAKE 0.071 Colorant
8 COL SUNSET YELLOW FCF LAKE 0.036 Colorant
9 HYDROXY PROPYL CELLULOSE IP (KLUCEL EXF) 0.446 Binder
10 ISOPROPYL ALCOHOL IP (IPA) ------ Solvent
11 SODIUM STARCH GLYCOLATE IP(PRIMOJEL) 0.893 Disintegrant
12 CROSPOVIDONE INF10/XL-10 0.893 Disintegrant
13 SODIUM LAURYL SULPHATE IP (S.L.S.) 0.357 Surfactant
14 COLLOIDAL SILICON DIOXIDE IP 0.143 Glidant
15 MAGNESIUM STEARATE IP 0.321 Lubricant

b) Telmisartan Layer
Sr.No Ingredients % age Function
1 TELMISARTAN IP (MICRONISED) 7.325 Active
2 MEGLUMINE 2.232 Solubilizing Agent
3 SODIUM HYDROXIDE (PELLETS) IP 0.446 pH Modifier
4 POLYSORBATE 80 IP (TWEEN 80) 0.357 Surfactant
5 POVIDONE IP (PVPK 30) 0.352 Binder
7 MICROCRYSTALLINE CELLULOSE IP 15.687 Diluent
8 COLLOIDAL SILICON DIOXIDE IP 0.629 Glidant
9 STARCH IP (MAIZE) 8.214 Diluent
10 MAGNESIUM STEARATE IP 0.393 Lubricant
11 CROSPOVIDONE INF10/XL-10 2.143 Disintegrant
12 SODIUM STARCH GLYCOLATE IP(PRIMOJEL) 1.786 Disintegrant

c) First active agent layer
Sr.No Ingredients % age Function
1 METOPROLOL SUCCINATE IP 4.349 Active
2 MICROCRYSTALLINE CELLULOSE IP 15.411 Diluent
3 COL BRILLIANT BLUE LAKE 0.089 Colorant
4 HYPROMELLOSE USP 2208 (BENECEL K100M) 11.607 Colorant
5 HYDROXYPROPYL CELLULOSE IP(HPC-L) NIPPON 1.071 Binder
6 POVIDONE IP (PVPK 30) 0.536 Binder
7 ISOPROPYL ALCOHOL IP (IPA) ------- Solvent
8 COLLOIDAL SILICON DIOXIDE 0.571 Glidant
9 MICROCRYSTALLINE CELLULOSE 2.143 Diluent
10 MAGNESIUM STEARATE IP 0.179 Diluent
11 SODIUM STEARYL FUMARATE 0.357 Lubricant
d) Film Coating
Sr.No Ingredients % age Function
1 H.P.M.C. IP E15 2.170 Film former
2 H.P.M.C. IP E5 2.170 Film former
3 P.E.G. 6000 IP 0.434 Plasticizer

Example 6- Process for preparation of the triple layer formulation of Amoldipine, Telmisartan and Metoprolol
Preparation of the Amlodipine, Telmisartan, and Metoprolol Succinate extended-release triple-layered tablet comprises three distinct granulation and blending processes corresponding to each active pharmaceutical ingredient (API), followed by trilayer tablet compression and film coating.
Step 1: Preparation of the Amlodipine Layer (2nd active ingredient)
The process commences with dispensing and verification of raw materials for the Amlodipine layer, including Amlodipine Besilate, Dibasic Calcium Phosphate (anhydrous), Microcrystalline Cellulose, Maize Starch, Sodium Starch Glycolate, Sodium Lauryl Sulphate, Colouring agents (Quinoline Yellow Lake and Sunset Yellow FCF Lake), and Hydroxypropyl Cellulose. These materials are sifted using vibro sifters through appropriate mesh sizes (mostly 40#, and 100# for colors), maintaining environmental conditions under 60% relative humidity and below 25°C. The sifted materials are collected in double polyethylene-lined HDPE containers.
The sifted dry mix is transferred to a Rapid Mixing Granulator (RMG) and blended for 10 minutes at 75 RPM with the chopper turned off. A binder solution is separately prepared by dissolving Hydroxypropyl Cellulose (Klucel EXF) in Isopropyl Alcohol, stirred until a clear solution is formed (about 10 minutes). This solution is added slowly over 2–3 minutes into the dry mix in the RMG, followed by kneading at slow speed for 4 minutes and high speed for 2 minutes to yield uniform wet granules.
The wet mass is passed through a multi-mill with an 8.0 mm screen at slow speed and forward knife rotation, and the coarse granules are collected in the Fluidized Bed Dryer (FBD). The granules are air-dried for 10 minutes, followed by drying at 55–60°C inlet temperature with an outlet air temperature of 30–35°C for 50–55 minutes. Intermittent raking is performed every 20 minutes. Drying continues until the loss on drying (LOD) reaches 3.0–4.5% w/w (measured at 105°C).
The dried granules are then passed through a 24# sieve, and retained material is milled through a 1.0 mm screen using a cad mill. Sifted lubricants and disintegrants, including Magnesium Stearate, Sodium Lauryl Sulphate, Sodium Starch Glycolate, Colloidal Silicon Dioxide, and Crospovidone, are blended with the granules in an octagonal or rotocube blender. Blending is conducted in two stages: all materials except Magnesium Stearate are blended for 10 minutes, followed by an additional 5 minutes of blending after adding Magnesium Stearate, ensuring uniform distribution.
Step 2: Preparation of the Telmisartan Layer (Middle Layer)
Preparation of the Telmisartan layer involves solubilization of Telmisartan and separate preparation of a binder phase. Sodium Hydroxide pellets are first dissolved in purified water, followed by addition of meglumine, stirred until a clear solution form. Telmisartan is added slowly to this mixture with continuous stirring until completely solubilized. Separately, Povidone K-30 is dispersed in purified water to form a binder solution. The two solutions are combined, and Polysorbate 80 is added and stirred for 15 minutes.
Meanwhile, excipients including Colloidal Silicon Dioxide, Maize Starch, and Microcrystalline Cellulose are sifted through appropriate mesh sizes (40# to 100#), and transferred to a Fluidized Bed Processor (FBP). The processor is preheated to reach a product temperature of 43°C. The Telmisartan solution is sprayed using a top spray system with a 1.0 mm nozzle, under controlled parameters: pump speed 30–110 RPM, inlet air 50–70°C, product temperature 35–55°C, exhaust temperature 35–55°C, atomizing air pressure 1.5–2.5 kg/cm², and spray rate 130–260 g/min. Granules are formed with uniform fluidization and minimal lumping. Upon completion, the equipment is rinsed with purified water.
Drying is conducted in the same FBP under the following conditions: inlet temperature 55–65°C, product temperature 50–60°C, and exhaust temperature 50–60°C, with intermittent raking. Drying continues until the granules reach an LOD of 3.0–4.0% w/w at 80°C. The dried granules are sized by passing through a 24# sieve; retained granules are milled using a 1.0 mm screen and then re-sifted through the same mesh.
Lubricants and disintegrants including Sodium Starch Glycolate, Crospovidone, and Magnesium Stearate are sifted and blended with the dried granules using a rotocube or V-blender. The granules are first mixed with disintegrants for 10 minutes, followed by an additional 5 minutes blending with Magnesium Stearate to ensure uniformity.
Step 3: Preparation of the Metoprolol Succinate (ER) Layer (First active ingredient)
The preparation of the extended-release Metoprolol layer begins with sifting Metoprolol Succinate, Hypromellose USP 2208 (Benecel K100M), Microcrystalline Cellulose, and Colour Brilliant Blue Lake through 40# or 100# mesh sizes. These materials are then blended in an RMG for 10 minutes at 75 RPM, chopper off. A binder solution is prepared separately by dissolving Hydroxypropyl Cellulose (HPC-L) and Povidone K-30 in Isopropyl Alcohol with stirring for 5–8 minutes.
This solution is slowly added to the dry mix over 2–3 minutes, and granulation is carried out in the RMG—first at slow speed for 4 minutes, then at high speed for 2 minutes—to form granules of desired size. The wet mass is milled through an 8.0 mm screen at slow speed and collected in an FBD bowl.
Drying is carried out initially via air drying for 10 minutes, followed by FBD drying at 50–55°C inlet temperature (with outlet temperature 30–32°C), continuing until a moisture content of 2.0–3.0% w/w (at 105°C) is achieved. Dried granules are passed through a 24# sieve, and oversized granules are milled through a 1.0 mm screen.
The granules are then blended with sifted excipients including Colloidal Silicon Dioxide, Sodium Stearyl Fumarate, Magnesium Stearate, and MCC PH-102. Blending is carried out in an octagonal or rotocube blender, with an initial 12-minute blend without lubricants followed by 3 minutes after addition of lubricants. The process is conducted under controlled temperature (<25°C) and humidity (<60%).
Step 4: Compression and Coating
The three prepared granule blends are sequentially compressed using a tri-layer tablet compression machine equipped with 11.00 mm round, concave punches (plain on both sides). The compression sequence follows: Amlodipine, Telmisartan (middle layer), and Metoprolol Succinate.
The resulting uncoated tablets are subjected to film coating in a coating pan. The coating solution consists of HPMC E15, HPMC E5, PEG-6000, and purified water. Coating is performed at an inlet air temperature of 60–70°C, with a pan rotation speed of 15–20 RPM, spray rate of 10–15 g/min per gun, and a gun-to-bed distance of 8–9 inches. Product temperature is maintained between 35–45°C, with a peristaltic pump speed of 3–4 RPM.
Final Product Specifications
The final product is a yellow-white-blue colored, round, biconvex, film-coated extended-release trilayer tablet. Each layer contributes to the delivery of a different active: the yellow layer contains 5 mg of Amlodipine, the white middle layer contains 40 mg of Telmisartan, and the blue layer contains 23.75 mg of Metoprolol Succinate. Each tablet weighs approximately 576 mg ± 5%, with a thickness of 6.10 ± 0.3 mm and a diameter of 11.10 ± 0.2 mm. The tablets exhibit a hardness of not less than 100 N and a friability of not more than 1.0% w/w.
Finished tablets are subjected to quality testing, including leakage and visual inspection, and are packed in approved packaging systems.
Example 7: Stability data of formulation prepared according to example 1
Acceptance Criteria Initial Testing After 3 Months After 6M Months
Description

Yellow, White & Green, coloured, round, bioconvex, both side plain & film coated tri-layered tablets Yellow, White & Green, coloured, round, bioconvex, both side plain & film coated tri-layered tablets Yellow, White & Green, coloured, round, bioconvex, both side plain & film coated tri-layered tablets Yellow, White & Green, coloured, round, bioconvex, both side plain & film coated tri-layered tablets
Identification In the assay, the major peaks in the chromatogram obtained with the test solution correspond to the major peaks in the chromatogram obtained with the standard solution In the assay, the major peaks in the chromatogram obtained with the test solution correspond to the major peaks in the chromatogram obtained with the standard solution Complies Complies
Average Weight 648.0 mg ±5% 646.93 mg 645.28 mg 648.89 mg
Dissolution
Chlorthalidone Not less than 70% in 60 minutes Min 92.41% 90.09% 92.68%
Max 98.88% 93.70% 94.46%
Avg 95.88% 91.63% 93.75%
Telmisartan Not less than 70% in 60 minutes Min 96.41% 105.28% 102.63%
Max 98.66% 106.57% 105.28%
Avg 97.55% 105.93% 103.93%
Metoprolol
After 1 hour Not more than 35% Min 15.09% 14.97% 17.00%
Max 22.59% 16.93% 18.87%
Avg 18.40% 16.53% 17.93%
After 4 hour Between 30% to 70% Min 36.29% 47.83% 46.25%
Max 58.85% 51.07% 46.97%
Avg 51.03% 49.99% 46.72%
After 8 hour Between 50% to 90% Min 55.28% 70.04% 77.06%
Max 81.51% 80.15% 81.18%
Avg 74.33% 76.92% 79.50%
After 20 hour Not less than 75% Min 88.35% 94.22% 103.51%
Max 100.73% 104.74% 105.75%
Avg 97.90% 102.22% 104.54%
Chlorthalidone
Chlorthalidone impurity A Not more than 1.0% 0.037% 0.034% 0.056%
Single maximum unknown impurity Not more than 0.5% 0.141% Not detected 0.034%
Total impurities Not more than 2.0% 0.357% 0.034% 0.122%
Telmisartan
Single maximum impurity Not more than 0.5% 0.085% 0.078% 0.059%
Total impurities Not more than 2.0% 0.168% 0.140% 0.059%
Metoprolol succinate
Metoprolol related compound A Not more than 0.1% Not detected NA NA
Metoprolol related compound B Not more than 0.1% 0.024% NA NA
Metoprolol related compound C Not more than 0.1% Not detected NA NA
Metoprolol related compound D Not more than 0.1% 0.005% NA NA
Single maximum impurity Not more than 0.5% 0.032% NA NA
Total impurities Not more than 2.0% 0.121% NA NA
Microbial Contamination
Total viable count
Total aerobic bacterial count Not more than 1000 cfu/gm <10 cfu/gm NA <10 cfu/gm
Total Combined Yeast and mould count Not more than 100 cfu/gm <10 cfu/gm NA <10 cfu/gm
Test for specified microorganism
Escherichia coli Should be absent/gm absent/gm NA absent/gm
Salmonella Should be absent/10gm absent/10gm NA absent/10gm
Pseudomonas
aeruginosa Should be absent/gm absent/gm NA absent/gm
Staphylococcus aurous Should be absent/gm absent/gm NA absent/gm
Assay: Each film coated Tri-layered tablet contains:
Chlorthalidone Not less than 11.25 mg & not more than 13.75mg
(Not less than 90.00% and not more than 110.00% of label claimed) 12.44 mg
99.52% 11.98
95.84% 12.31
98.48%
Talmisartan Not less than 36.00 mg & not more than 44.00 mg
(Not less than 90.00% and not more than 110.00% of label claimed) 40.09 mg
100.23% 41.09 mg
102.73% 40.72
101.80%
Metoprolol Succinate 47.5 mg Not less than 42.75 mg & not more than 52.25 mg
(Not less than 90.00% and not more than 110.00% of label claimed) 47.94 mg
100.93%
48.49 mg
102.08% 48.45 mg
102.00%
Conclusion Product compiles with stability (Temp 40°C ±2°C & RH 75% ±5%)

Example 8: Stability data of formulation prepared according to example 5
Acceptance Criteria Initial Testing After 3 Months
Description

Yellow, White & blue, coloured, round, bioconvex, both side plain & film coated extended release tri-layered tablets Yellow, White & blue, coloured, round, bioconvex, both side plain & film coated extended release tri-layered tablets Yellow, White & blue, coloured, round, bioconvex, both side plain & film coated extended release tri-layered tablets
Identification In the assay, the major peaks in the chromatogram obtained with the test solution correspond to the major peaks in the chromatogram obtained with the standard solution Complies Complies
Average Weight 576.0 mg ±5% 580.60 mg 583.30 mg
Dissolution
Amlodipine Not less than 75% in 60 minutes Min 86.03% 82.73%
Max 88.79% 88.86%
Avg 87.20% 86.62%
Telmisartan Not less than 75% in 60 minutes Min 82.98% 98.62%
Max 100.07% 102.42%
Avg 96.74% 100.85%
Metoprolol
After 1 hour Not more than 35% Min 17.37% 16.48%
Max 28.83% 19.96%
Avg 20.98% 18.38%
After 4 hour Between 30% to 70% Min 41.55% 45.12%
Max 68.54% 60.45%
Avg 57.71% 53.83%
After 8 hour Between 50% to 90% Min 58.83% 68.71%
Max 85.86% 86.31%
Avg 78.58% 80.36%
After 20 hour Not less than 75% Min 85.33% 102.40%
Max 96.77% 108.61%
Avg 94.01% 104.25%
Amlodipine
Amlodipine impurity D Not more than 1.0% Not detected Not detected
Single maximum unknown impurity Not more than 0.5% 0.111% 0.080%
Total impurities Not more than 2.0% 0.218% 0.223%
Telmisartan
Single maximum impurity Not more than 0.5% 0.091% 0.044%
Total impurities Not more than 2.0% 0.091% 0.044%
Metoprolol succinate
Metoprolol related compound A Not more than 0.1% Not detected Not detected
Metoprolol related compound B Not more than 0.1% Not detected Not detected
Metoprolol related compound C Not more than 0.1% Not detected Not detected
Single maximum impurity Not more than 0.5% BDL 0.079%
Total impurities Not more than 1.5% BDL 0.140%
Microbial Contamination
Total viable count
Total aerobic bacterial count Not more than 1000 cfu/gm <10 cfu/gm NA
Total Combined Yeast and mould count Not more than 100 cfu/gm <10 cfu/gm NA
Test for specified microorganism
Escherichia coli Should be absent/gm absent/gm NA
Salmonella Should be absent/10gm absent/10gm NA
Pseudomonas
aeruginosa Should be absent/gm absent/gm NA
Staphylococcus aurous Should be absent/gm absent/gm NA
Assay: Each film coated Tri-layered tablet contains:
Amlodipine Besylate Not less than 4.50 mg & not more than 5.50mg
(Not less than 90.00% and not more than 110.00% of label claimed) 4.94 mg
98.80% 5.02
100.40%
Talmisartan Not less than 36.00 mg & not more than 44.00 mg
(Not less than 90.00% and not more than 110.00% of label claimed) 41.05 mg
102.63% 40.63 mg
101.58%
Metoprolol Succinate 47.5 mg Not less than 21.37 mg & not more than 26.12 mg
(Not less than 90.00% and not more than 110.00% of label claimed) 22.84 mg
96.17%
22.86 mg
96.25%
Conclusion Product compiles with stability (Temp 40°C ±2°C & RH 75% ±5%)
,CLAIMS:We Claim,
1. A pharmaceutical composition for the delivery of Telmisartan, a first active agent, and a second active agent, the composition being formulated as a trilayer tablet comprising:
a. a first layer comprising a first active agent, wherein the first layer exhibits an extended drug release profile;
b. a central layer comprising Telmisartan wherein the Telmisartan layer exhibits an immediate drug release profile; and
c. a third layer comprising a second active agent, wherein the second layer exhibits either an immediate or modified drug release profile;
wherein:
i) the first and second active agents are different from each other;
ii) the three layers are stacked and compressed together to form a single oral dosage unit; and
iii) the first and second active agent layers are stacked on either side of the Telmisartan layer.
2. The pharmaceutical composition according to claim 1, wherein the first active agent is metoprolol.
3. The pharmaceutical composition according to claim 1, wherein the second active agent is either cilnidipine or amlodipine or chlorthalidone or hydrochlorothiazide.
4. The pharmaceutical composition according to claim 1 and 2 wherein first active agent layer is composed of Metoprolol in the amount of 1% to 15% and one or more pharmaceutically acceptable excipient selected from:
a. Extended release polymers in the amount of 1% to 30%
b. Diluent in the amount of 0.5% to 20%
c. Binder in the amount of 0.1% to 10%
d. Lubricant in the amount of 0.01% to 5%
e. Glidant in the amount of 0.01% to 4%
f. Colorant in the amount of 0.001% to 2%
g. Solvent as required.
5. The pharmaceutical composition according to claim 1 and 3, wherein the second active agent layer is composed of Cilnidipine or Amlodipine or Chlorthalidone or Hydrochlorothiazide, in the amount of 0.1% to 10% and one or more pharmaceutically acceptable excipients selected from
a. Diluent in the amount of 0.5% to 20%
b. Binder in the amount of 0.1% to 10%
c. Lubricant in the amount of 0.01% to 5%
d. Glidant in the amount of 0.01% to 4%
e. Colorant in the amount of 0.001% to 2%
f. Optionally, modified release polymers in the range of 1% to 30%
g. Optionally, surfactant in the amount of 0.01% to 5%
h. Optionally, pH modifying agent in the amount of 0.01% to 5%
i. Optionally, solubilizing agent in the amount of 0.01% to 10%
6. The pharmaceutical composition according to claim 1, wherein central layer comprising Telmisartan is composed of Telmisartan in the amount of 1% to 15% and one or more pharmaceutically acceptable excipients selected from
a. Solubilizing agent in the amount of 0.01% to 10%, w/w
b. pH modifying agent in the amount of 0.01% to 5%, w/w
c. Surfactant in the amount of 0.01% to 5%, w/w
d. Diluent in the amount of 0.5% to 20%, w/w
e. Disintegrant in the amount of 0.1% to 10%, w/w
f. Binder in the amount of 0.01% to 10%, w/w
7. The pharmaceutical composition according claim 1, comprising
a. a first layer comprising a Metoprolol, wherein the first layer exhibits an extended drug release profile;
b. a central layer comprising Telmisartan wherein the Telmisartan layer exhibits an immediate drug release profile; and
c. a third layer comprising Cilnidipine or Amlodipine or Chlorthalidone or Hydrochlorothiazide, wherein the second layer exhibits immediate drug release profile;
8. A process for preparation of the pharmaceutical composition according to claim 1, comprising
a. preparing granules comprising the first active agent, wherein the granules are formulated to provide extended drug release profile;
b. preparing granules comprising Telmisartan, wherein the granules are formulated to provide an immediate release profile;
c. preparing granules comprising a second active agent, wherein the granules are formulated to provide either an immediate or modified release profile; and
d. compressing the granules obtained from steps (a) to (c) to form a single trilayer tablet, wherein the Telmisartan granules are positioned as the middle layer between the first and second active agent layers.
9. The process according to claim 8, wherein the first active agent is Metoprolol and the second active agent is Cilnidipine or Amlodipine or Chlorthalidone or Hydrochlorothiazide.
10. The process according to claim 8 and 9, wherein
a. The first active agent granules are composed of
i) Metoprolol in the amount of 1% to 15%
ii) Extended release polymers in the amount of 1% to 30%
iii) Diluent in the amount of 0.5% to 20%
iv) Binder in the amount of 0.1% to 10%
v) Lubricant in the amount of 0.01% to 5%
vi) Glidant in the amount of 0.01% to 4%
vii) Colorant in the amount of 0.001% to 2%
viii) Solvent as required.
b. The second active agent granules are composed of
i) Cilnidipine or Amlodipine or Chlorthalidone or Hydrochlorothiazide, in the amount of 0.1% to 10%
ii) Diluent in the amount of 0.5% to 20%
iii) Binder in the amount of 0.1% to 10%
iv) Lubricant in the amount of 0.01% to 5%
v) Glidant in the amount of 0.01% to 4%
vi) Colorant in the amount of 0.001% to 2%
vii) Optionally, modified release polymers in the range of 1% to 30%
viii) Optionally, surfactant in the amount of 0.01% to 5%
ix) Optionally, pH modifying agent in the amount of 0.01% to 5%
x) Optionally, solubilizing agent in the amount of 0.01% to 10%
c. Telmisartan granules are composed of
i) Telmisartan in the amount of 1% to 15%
ii) Solubilizing agent in the amount of 0.01% to 10%, w/w
iii) pH modifying agent in the amount of 0.01% to 5%, w/w
iv) Surfactant in the amount of 0.01% to 5%, w/w
v) Diluent in the amount of 0.5% to 20%, w/w
vi) Disintegrant in the amount of 0.1% to 10%, w/w
vii) Binder in the amount of 0.01% to 10%, w/w

Dated this 16-07-2024

Siddhartha Dulakakhoria
DGM-IPR
Akums Drugs & Pharmaceuticals limited