Ready-to-use non-aqueous oral solution of losartan

Abstract

Disclosed herein is a ready-to-use, non-aqueous oral solution of losartan. Also disclosed herein is a method of preparing a ready-to-use, non-aqueous oral solution of losartan and its method of use.

Claims

1. A ready-to-use, non-aqueous oral solution, comprising: losartan potassium in an amount of 10 mg/ml; a solubilizer comprising polyethylene glycol 400 in an amount of about 115 mg/mL; a thickening agent comprising xanthan gum in an amount of about 1.5 mg/mL; one or more pharmaceutically acceptable excipients; and a vehicle comprising glycerin, wherein the ready-to-use, non-aqueous oral solution has a water content of less than about 1% w/w and excludes a buffering agent a pH adjusting agent, propylene glycol, an alkyl ester of p-hydroxybenzoic acid, povidone, hydroxypropyl methylcellulose, hydroxyethyl cellulose, and saccharin sodium.

2. The oral solution of claim 1, wherein the one or more pharmaceutically acceptable excipients is selected from a preservative, a sweetener, a wetting agent, a co-solvent, a flavorant, a suspending agent, a taste masking agent, an antioxidant, a stabilizer, or any combination thereof.

3. The oral solution of claim 1, wherein the oral solution has 1.0% or less of losartan related total impurities after storage for 6 months at 402 C. and not more than 25%5% RH or 252 C. and 60%5% RH.

4. The oral solution of claim 1, wherein the oral solution when administered as a single dose of about 100 mg to a subject provides a T/R ratio of from about 50% to about 125%, wherein T is a C.sub.max-value of the single dose after administration to a human, and wherein R is a C.sub.max-value of a tablet comprising 100 mg losartan potassium after administration to the human.

5. The oral solution of claim 1, wherein the oral solution when administered as a single dose of about 100 mg to a subject under fast condition provides the following (meanSD) pharmacokinetic parameters: T.sub.max (h): 0.500 (0.333-2.667); C.sub.max (ng/ml): 806.187362.8349; AUC.sub.0-t (ng.Math.h/mL): 1530.980948.0597; AUC.sub.0- (ng.Math.h/mL): 1560.0221013.3460; and T.sub.1/2 (h): 2.7771.7685.

6. The oral solution of claim 1, wherein the oral solution when administered as a single dose of about 100 mg to a subject under fed condition provides the following (meanSD) pharmacokinetic parameters: T.sub.max (h): 1.517 (0.333-5.333); C.sub.max (ng/ml): 391.357119.2530; AUC.sub.0-t (ng.Math.h/mL): 1261.942332.9989; AUC.sub.0- (ng.Math.h/mL): 1273.174336.8092; and T.sub.1/2 (h): 1.9710.8227.

7. The oral solution of claim 1, wherein the water content is less than about 0.5% w/w.

8. The oral solution of claim 1, wherein the water content is less than about 0.2% w/w.

9. The oral solution of claim 1, wherein the water content is less than about 0.1% w/w.

10. The oral solution of claim 1, wherein a weight ratio of polyethylene glycol 400 to glycerin is from about 5:95 to about 15:85.

Description

DETAILED DESCRIPTION

(1) Before elaborating on embodiments and aspects disclosed herein in detail, it is to be understood that the formulation disclosed herein is not limited to particularly exemplified examples or process parameters that may, of course, vary. It is also to be understood that the terminology used herein is to describe particular embodiments of the disclosed formulation only, and is not intended to limit the scope of the claimed formulation in any manner.

(2) The detailed description set forth below is intended as a description of exemplary embodiments and is not intended to represent the only forms in which the exemplary embodiments may be constructed and/or utilized. The description sets forth the functions and the sequence of steps for constructing and/or operating the exemplary embodiments. However, it is to be understood that the same or equivalent functions and sequences that may be accomplished by different exemplary methods are also intended to be encompassed within the spirit and scope of the formulation claimed herein.

(3) As defined herein, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill with respect to pharmaceutical sciences.

(4) Although any process and materials similar or equivalent to those described herein can be used in the practice or testing of the formulation disclosed herein, the methods and materials are now described.

(5) The singular forms a, an and the specifically also encompass the plural forms of the terms to which they refer, unless the content clearly dictates otherwise.

(6) The term about is used synonymously with the term approximately. As one of ordinary skill would understand, the exact boundary of about will depend on the component of the composition. Illustratively, the use of the term about indicates that values slightly outside the cited values, i.e., plus or minus 0.1% to 10%, which are also effective and safe. Thus, compositions slightly outside the cited ranges are also encompassed by the scope of the present claims.

(7) As stated herein the word RTU refers to ready-to-use and can interchangeably use for the expression ready-to-use.

(8) As stated herein, the expressions comprise(s) and comprising have their customary meaning. When used in the context of a process, the term comprising means that the process includes at least the recited steps, but may include additional steps. When used in the context of a composition, the term comprising means that the composition includes at least the recited features or components, but may also include additional features or components.

(9) One will understand that the expression consisting of may replace the expression comprising for a claimed formulation, process, or method.

(10) One will further understand that the expression consisting essentially of may replace the expression comprising for a claimed formulation, process or method.

(11) Where appropriate, effective amounts are generally those amounts listed as the ranges or levels of ingredients in the description.

(12) The expressions therapeutically effective amount or effective amount refers to an amount of a pharmaceutical agent to achieve a pharmacological effect. The term therapeutically effective amount includes, for example, a prophylactically effective amount.

(13) As used herein, the term therapeutically effective amount can be understood to include an amount of losartan potassium that is effective in treating, preventing, or ameliorating a condition requiring antihypertensive therapy.

(14) As used herein, the term active agent can be understood to include any substance or formulation or combination of substances or composition of matter which, when administered to a human or animal subject, induces a desired pharmacologic and/or physiologic effect by local and/or systemic action. The terms are used interchangeably herein: active, drug, and active ingredient.

(15) As used herein, the terms dose and dosage can be understood to mean a specific amount of active or therapeutic agents for administration.

(16) As used herein, the term excipient can be understood to include any inert substance combined with an active agent such as losartan potassium to prepare a convenient dosage form.

(17) As used herein, the term glycerin can be interchangeably used with term glycerol as both are same.

(18) As per one embodiment, the oral solution as mentioned herein is defined as the liquid dosage form that has no suspended particles and is present as a clear liquid solution.

(19) As per one embodiment, the formulation disclosed herein is ready-to-use, i.e. ready to be administered directly to a patient for a treatment, without an additional step, such as reconstitution or dilution.

(20) The main embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution of losartan potassium.

(21) Another main embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution comprising a therapeutically effective amount of losartan potassium, a solubilizer, a thickening agent, a preservative, and one or more pharmaceutically acceptable excipients.

(22) An embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution comprising a therapeutically effective amount of losartan potassium for the treatment of a cardiac condition like hypertension, hypertensive patients with left ventricular hypertrophy, nephropathy in Type 2 diabetic patients, wherein losartan potassium may be used alone or in combination with other antihypertensive agents.

(23) An embodiment disclosed herein may be associated with the expression free of water where the amount of water in the formulation is less than about 1% w/w, about 0.5% w/w, about 0.4% w/w, about 0.3% w/w, about 0.25% w/w, about 0.2% w/w, about 0.1% w/w, about 0% w/w, or 0% w/w (i.e., the formulation is completely devoid of water). One will appreciate that the water content expressed in percent by weight (i.e., % w/w) is based on the total weight of the formulation. Thus, for example, 1% w/w corresponds to 1 g of H.sub.2O in 100 g of the formulation. In the presence of water, losartan potassium tends to degrade and results in an unstable product on storage. The expressions free of water and non-aqueous are used interchangeably herein.

(24) In one aspect, the ready-to-use, non-aqueous oral solution disclosed herein does not include water, a buffer (for example, phosphate buffer, citrate buffer, etc.), or a pH adjusting agent (for example, NaOH, HCl, etc.), a solubilizer (for example, propylene glycol (PG)), a preservative (for example, an alkyl ester of p-hydroxybenzoic acid which includes methyl paraben, propyl paraben, ethyl paraben, etc.), a polymer (for example, polyvinylpyrrolidone (or povidone), hydroxypropyl methylcellulose (or hypromellose), cyclodextrin, hydroxy ethyl cellulose), a chelating agent (for example, ethylenediaminetetraacetic acid (EDTA or a salt thereof), and a sweetener (for example, saccharin sodium). One will appreciate that povidone (aka, polyvinylpyrrolidone (or PVP)) is available commercially (e.g., Kollidon) with different grades that relate generally to the weight average molecular weight (Mw). For example, Kollidon 25 (aka PVPK25) has a Mw of from 28,000 Daltons (Da) to 34,000 Da, Kollidon 30 (aka PVPK30) has a Mw of from 44,000 Da to 54,000 Da, while Kollidon 90 (aka PVPK90) has a Mw of from 900,000 Da to 1,200,000 Da. See Handbook at 581.

(25) The term losartan as used herein is in the form of potassium salt. Wherever losartan is mentioned is to be interpreted as losartan potassium.

(26) As per one embodiment, losartan relates to losartan potassium.

(27) In one aspect, the ready-to-use, non-aqueous oral solution comprises losartan potassium.

(28) As per one embodiment, the amount of losartan potassium may range from about 0.01 mg/mL to about 50 mg/mL, and all values in between, such as about 0.01 mg/mL to about 40 mg/mL, about 0.1 mg/mL to about 30 mg/mL, about 1 mg/mL to about 20 mg/mL and all values in between, such as for example about 1 mg/mL, about 5 mg/mL, about 10 mg/mL, about 15 mg/mL, about 20 mg/mL, about 25 mg/mL, about 30 mg/mL, about 35 mg/mL, about 40 mg/mL, about 45 mg/mL, and about 50 mg/mL.

(29) As per one embodiment, the solubilizer used herein is defined as an agent that increases the solubility of a losartan potassium. Solubilizers can increase the bioavailability of active pharmaceutical ingredients.

(30) As per one embodiment, the solubilizer can be selected from, but not limited to, alcohols such as ethanol, a polyethylene glycol (PEG), glycerin, triacetin, dimethylsulfoxide (DMSO), benzyl benzoate, or any combination thereof.

(31) As per one embodiment, a polyethylene glycol (PEG) can be selected from PEG 200, PEG 400, PEG 600, PEG 1500, PEG 4000, and PEG 6000.

(32) In one aspect, the solubilizer comprises PEG 400.

(33) According to one embodiment, the amount of solubilizer may be present in range from about 50 mg/mL to about 500 mg/mL, and all values in between, such as from about 50 mg/mL to about 300 mg/mL, from about 50 mg/mL to about 250 mg/mL, from about 50 mg/mL to about 200 mg/mL, and from about 70 mg/mL to about 150 mg/mL, as well as about 50 mg/mL, about 60 mg/mL, about 70 mg/mL, about 80 mg/mL, about 90 mg/mL, about 100 mg/mL, about 110 mg/mL, about 115 mg/mL, about 120 mg/mL, about 140 mg/mL, about 160 mg/mL, about 180 mg/mL, about 200 mg/mL, about 250 mg/mL, about 300 mg/mL, about 400 mg/mL, and about 500 mg/mL.

(34) In one aspect, a variable amount of PEG 400-to-glycerin may be used, such that the weight ratio of PEG 400-to-glycerin in the oral solution disclosed herein ranges from about 5:95 to about 50:50 and all values in between, such as 10:90, 15:85, 20:80, 25:75, 30:70, 35:65, 40:60, and 45:55. In yet another aspect, the weight ratio of PEG 400-to-glycerin in the oral solution disclosed herein ranges from about 5:95 to 15:85.

(35) As per one embodiment, the thickening agent relates to an agent that can increase the viscosity of a liquid without substantially changing its other properties.

(36) As per one embodiment, said thickening agent can be selected from methylcellulose, bentonite, hectorite, microcrystalline cellulose, sodium carboxymethylcellulose, magnesium aluminum silicate, xanthan gum, acacia, tragacanth, an alginate, guar gum, colloidal silicon dioxide, or any combination thereof.

(37) In one aspect, the thickening agent comprises xanthan gum.

(38) According to one embodiment, the amount of thickening agent may be present in the range from about 0.01 mg/mL to about 15 mg/mL, and all values in between, such as from about 0.01 mg/mL to about 12 mg/mL, from about 0.01 mg/mL to about 10 mg/mL, from about 0.05 mg/mL to about 10 mg/mL, from about 0.1 mg/mL to about 10 mg/mL, from about 0.5 mg/mL to about 10 mg/mL, as well as about 0.1 mg/mL, about 0.3 mg/mL, about 0.5 mg/mL, about 0.7 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 1.1 mg/mL, about 1.2 mg/mL, about 1.3 mg/mL, about 1.4 mg/mL, about 1.5 mg/mL, about 1.7 mg/mL, about 2 mg/mL, about 4 mg/mL, about 6 mg/mL, about 8 mg/mL, about 10 mg/mL, and about 15 mg/mL.

(39) In one aspect, the thickening agent comprises xanthan gum in an amount of about 1.5 mg/mL.

(40) As per one embodiment, the preservative relates to a substance that prevents decomposition by microbial growth or by undesirable chemical changes. Herein the expressions preservative and antimicrobial agent are used interchangeably.

(41) As per one embodiment, preservative can be selected from, but not limited to, sorbic acid, sodium sorbate, potassium sorbate, benzoic acid, and benzoates such as sodium benzoate, nitrates, lactic acid, or any combination thereof.

(42) As per an embodiment, the preservative comprises sodium benzoate.

(43) According to one embodiment the amount of preservative may be present in the range from about 0.01 mg/mL to about 20 mg/mL, and all values in between, such as from about 0.01 mg/mL to about 15 mg/mL, from about 0.01 mg/mL to about 12 mg/mL, from about 0.01 mg/mL to about 10 mg/mL, and from about 0.01 mg/mL to about 5 mg/mL, as well as about 0.01 mg/mL, about 0.05 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.7 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 5 mg/mL, about 7 mg/mL, about 9 mg/mL, about 11 mg/mL, about 13 mg/mL, about 15 mg/mL, and about 20 mg/mL.

(44) As per one embodiment, the sweetener relates to an additive used or intended to be used to impart a sweet taste to a formulation disclosed herein.

(45) As per one embodiment, the sweetener can be selected from sucrose, fructose, lactose, maltose, sucralose, maltitol, aspartame, acesulfame potassium (Ace-K), neotame, advantame, or any combination thereof.

(46) As per a preferred embodiment, the sweetener comprises sucralose.

(47) According to one embodiment, the amount of sweetener may be present in the range from about 0.01 mg/mL to about 15 mg/mL, and all values in between, such as from about 0.01 mg/mL to about 10 mg/mL, from about 0.1 mg/mL to about 10 mg/mL, from about 0.1 mg/mL to about 5 mg/mL, from about 0.5 mg/mL to about 3 mg/mL, as well as about 0.01 mg/mL, about 0.05 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.7 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 5 mg/mL, about 7 mg/mL, about 9 mg/mL, about 11 mg/mL, about 13 mg/mL, and about 15 mg/mL.

(48) As per one embodiment, the flavoring agent relates to a pharmaceutical additive added to improve the taste or odour of a formulation disclosed herein.

(49) As per one embodiment the flavoring agent can be selected from but not limited to vanilla, citrus oil, including lemon, orange, grape, lime and grapefruit, and fruit essences, including apple, banana, orange pear, peach, strawberry, raspberry, cherry, plums pineapple, apricot, frozen peppermint, tutti frutti flavor and so forth and the like, or any combination thereof.

(50) As per an embodiment, the flavoring agent comprises frozen peppermint.

(51) According to one embodiment, the amount of flavoring agent may be present in the range from about 0.01 mg/mL to about 15 mg/mL, and all values in between, such as from about 0.01 mg/mL to about 10 mg/mL, from about 0.01 mg/mL to about 5 mg/mL, from about 0.05 mg/mL to about 5 mg/mL, and from about 0.05 mg/mL to about 2 mg/mL, as well as about 0.01 mg/mL, about 0.05 mg/mL, about 0.1 mg/mL, about 0.2 mg/mL, about 0.3 mg/mL, about 0.4 mg/mL, about 0.5 mg/mL, about 0.7 mg/mL, about 0.9 mg/mL, about 1 mg/mL, about 2 mg/mL, about 5 mg/mL, about 7 mg/mL, about 9 mg/mL, about 11 mg/mL, about 13 mg/mL, and about 15 mg/mL.

(52) As per one embodiment, the vehicle comprises glycerin.

(53) According to one embodiment, the amount of vehicle may be present in sufficient quantity to make up the final volume.

(54) As per one embodiment, one or more pharmaceutically acceptable excipients are selected from preservative, a viscosity enhancer or a viscosity enhancing agent, a solubilizer or a solubilizing agent, a sweetener or a sweetening agent, a wetting agent, a co-solvent, a flavor or a flavour, a vehicle, a suspending agent or a thickening agent, a taste masking agent, an antioxidant, a stabilizer, a colorant and any other excipient known to the art for making formulations, or any combination thereof.

(55) Another embodiment disclosed herein related to a process for preparing a ready-to-use, non-aqueous oral solution of losartan potassium, which comprises: (a) Adding the vehicle to a vessel; (b) Adding solubilizer into the glycerin-containing mixing vessel of step (a) with continuous stirring; (c) Adding preservative into the solution obtained in step (b) with continuous stirring; (d) Adding sweetener into the solution obtained in step (c) with continuous stirring; (e) Adding losartan potassium (API) into the solution obtained in step (d) with continuous stirring; (f) Adding xanthan gum in glycerin in a separate vessel to prepare a slurry; (g) Adding slurry obtained in step (f) in the solution obtained in step (e); (h) Adding flavoring agent into solution obtained in step (g) under continuous stirring; (i) Adjusting the volume of bulk solution into the mixing vessel using a vehicle with continuous stirring; (j) Filtering bulk solution obtained in step (i) to get a clear solution; (k) Storing the final formulation obtained in step (j) in the suitable container.

(56) An embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution comprising about 0.01 mg/mL to about 50 mg/mL losartan potassium, about 50 mg/mL to about 500 mg/mL solubilizer, about 0.01 mg/mL to about 15 mg/mL thickening agent, about 0.01 mg/mL to about 20 mg/mL preservative, about 0.01 mg/mL to about 15 mg/mL sweetener, about 0.01 mg/mL to about 15 mg/mL flavoring agent, and glycerin.

(57) Another embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution comprising about 1 mg/mL to about 15 mg/mL losartan potassium, about 70 mg/mL to about 150 mg/mL solubilizer, about 0.5 mg/mL to about 10 mg/mL thickening agent, about 0.01 mg/mL to about 5 mg/mL preservative, about 0.5 mg/mL to about 3 mg/mL sweetener, about 0.5 mg/mL to about 3 mg/mL flavoring agent, and glycerin.

(58) And yet another embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution comprising about 10 mg/mL losartan potassium, about 115 mg/mL solubilizer, about 1.5 mg/mL thickening agent, about 0.40 mg/mL preservative, about 1 mg/mL sweetener, about 1 mg/mL flavoring agent, and glycerin.

(59) And a further embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution comprising about 10 mg/mL losartan potassium, about 115 mg/ml solubilizer, about 1.5 mg/mL thickening agent, about 0.40 mg/mL preservative, about 1 mg/mL sweetener, about 1 mg/mL flavoring agent, and glycerin; wherein the non-aqueous oral solution is free of (or excludes) a buffering agent (e.g., sodium phosphate buffer, potassium phosphate buffer, a sodium citrate buffer, and the like), a pH adjusting agent (e.g., NaOH and/or HCl), propylene glycol, an alkyl ester of p-hydroxybenzoic acid, povidone (e.g., PVP K30 and PVP K90), hydroxypropyl methylcellulose, hydroxyethyl cellulose, and saccharin sodium.

(60) Another embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution comprising about 10 mg/mL losartan potassium, about 115 mg/mL polyethylene glycol 400, about 1.5 mg/mL xanthan gum, about 0.40 mg/mL sodium benzoate, about 1 mg/mL sucralose, about 1 mg/mL frozen peppermint, and glycerin.

(61) Yet another embodiment disclosed herein relates to a ready-to-use, non-aqueous oral solution comprising about 10 mg/mL losartan potassium, about 115 mg/mL polyethylene glycol 400, about 1.5 mg/mL xanthan gum, about 0.40 mg/mL sodium benzoate, about 1 mg/mL sucralose, about 1 mg/mL frozen peppermint, and glycerin; wherein the non-aqueous oral solution is free of (or excludes) a buffering agent (e.g., sodium phosphate buffer, potassium phosphate buffer, a sodium citrate buffer, and the like), a pH adjusting agent (e.g., NaOH and/or HCl), propylene glycol, an alkyl ester of p-hydroxybenzoic acid, povidone (e.g., PVP K30 and PVP K90), hydroxypropyl methylcellulose, hydroxy ethyl cellulose, and saccharin sodium.

(62) In one aspect, the ready-to-use, non-aqueous oral solution disclosed herein is independent of the pH effect and hence no need to add any buffering agent or pH adjusting agent to maintain the pH and still provide a stable formulation.

(63) According to one embodiment, the formulation disclosed herein may be administered orally.

(64) According to one embodiment, a ready-to-use, non-aqueous oral solution of losartan potassium is stable for at least 1 month, 3 months, and 6 months while storage at 40 C.2 C./not more than (NMT) 25% RH or while stored at 25 C.2 C./60% RH5% RH.

(65) According to one embodiment, a ready-to-use, non-aqueous oral solution of losartan potassium is stable at 20 C.5 C. under stress conditions of UV light.

(66) According to one embodiment, the total impurities are less than 1.0% and any single impurities is less than 0.2% after 1 month, 3 months, and 6 months while storage at 40 C.2 C./NMT 25% RH or while stored at 25 C.2 C./60% RH5% RH.

(67) According to one embodiment, the ready-to-use, non-aqueous oral solution of losartan, when administered as a single dose of about 100 mg to a subject under fasted condition provides a mean (SD) of the following pharmacokinetic parameters: T.sub.max (h): 0.500 (0.333-2.667); C.sub.max (ng/mL): 806.187362.8349; AUC.sub.0-t (ng.Math.h/mL): 1530.980948.0597; AUC.sub.0- (ng.Math.h/mL): 1560.0221013.3460; and T.sub.1/2 (h): 2.7771.7685.

(68) According to one embodiment, the ready-to-use, non-aqueous oral solution of losartan, when administered as a single dose of about 100 mg to a subject under fasted condition provides a geometric least square ranges of maximum plasma concentration (C.sub.max) from about 300 ng/mL to about 1200 ng/ml; area under the plasma concentration versus time curve from time 0 to the last measurable concentration time (AUC.sub.0-t) from about 800 ng.Math.h/mL to about 1800 ng.Math.h/mL; and area under the plasma concentration versus time curve from time 0 to infinity (AUC.sub.0-) from about 800 ng.Math.h/mL to about 1800 ng.Math.h/mL.

(69) According to one embodiment, the ready-to-use, non-aqueous oral solution of losartan, when administered as a single dose of about 100 mg to a subject under fasted condition which provides a geometric least square means of pharmacokinetic profiles like maximum plasma concentration (C.sub.max) 729.456 ng/ml; area under the plasma concentration versus time curve from time 0 to the last measurable concentration time (AUC.sub.0-t) 1352.590 ng.Math.h/mL; and area under the plasma concentration versus time curve from time 0 to infinity (AUC.sub.0-) 1369.275 ng.Math.h/mL.

(70) According to one embodiment, the ready-to-use, non-aqueous oral solution of losartan, when administered as a single dose of about 100 mg to a subject has a T/R ratio of from about 50% to about 125%, wherein T is a C.sub.max-value of the dose after administration to a human, and wherein R is a C.sub.max-value of a tablet comprising 100 mg losartan potassium (COZAAR) after administration to the human.

(71) According to one embodiment, the ready-to-use, non-aqueous oral solution of losartan, when administered as a single dose of about 100 mg to a subject has a T/R ratio of from about 80% to about 125%, wherein T is a C.sub.max-value of the dose after administration to a human, and wherein R is a C.sub.max-value of a tablet comprising 100 mg losartan potassium (COZAAR) after administration to the human.

(72) According to one embodiment, the ready-to-use, non-aqueous oral solution of losartan, when administered as a single dose of about 100 mg to a subject under fed condition which provides a mean (SD) of pharmacokinetic profiles as mentioned below: T.sub.max (h): 1.517 (0.333-5.333); C.sub.max (ng/ml): 391.357119.2530; AUC.sub.0-t (ng.Math.h/mL): 1261.942332.9989; AUC.sub.0- (ng.Math.h/mL): 1273.174336.8092; and T.sub.1/2 (h): 1.9710.8227.

(73) According to one embodiment, the ready-to-use, non-aqueous oral solution of losartan, when administered as a single dose of about 100 mg to a subject under fed condition which provides a geometric least square ranges of pharmacokinetic profiles like maximum plasma concentration (C.sub.max) from about 100 ng/ml to about 700 ng/ml; area under the plasma concentration versus time curve from time 0 to the last measurable concentration time (AUC.sub.0-t) from about 800 ng.Math.h/mL to about 1600 ng.Math.h/mL; and area under the plasma concentration versus time curve from time 0 to infinity (AUC.sub.0-) from about 800 ng.Math.h/mL to about 1600 ng.Math.h/mL.

(74) According to one embodiment, the ready-to-use, non-aqueous oral solution of losartan, when administered as a single dose of about 100 mg to a subject under fed condition which provides a geometric least square means of pharmacokinetic profiles like maximum plasma concentration (C.sub.max) 374.396 ng/mL; area under the plasma concentration versus time curve from time 0 to the last measurable concentration time (AUC.sub.0-t) 1210.894 ng.Math.h/mL; and area under the plasma concentration versus time curve from time 0 to infinity (AUC.sub.0-) 1221.448 ng.Math.h/mL.

(75) The following examples, which include exemplified embodiments, serve to illustrate the ready-to-use, non-aqueous solution disclosed herein, it being understood that the particulars shown are by way of example and for illustrative discussion and not meant to limit the ready-to-use, non-aqueous solution claimed herein.

EXAMPLES

Example 1. Solubility Study of Losartan Potassium

(76) The solubility of losartan potassium below pH 5.5 was checked in the presence of different solubilizers and pH modifying agent. Table 1 summarizes results of this study.

(77) TABLE-US-00001 TABLE 1 Solubility study of losartan potassium in presence of different solubilizers and pH modifying agent Batch Number Composition Observations S1 Losartan Potassium 10 mg/mL, Insoluble (Milky white Citrate buffer 50 mM 60% v/v, insoluble particles) PEG 400 40% v/v S2 Losartan Potassium 10 mg/mL, Insoluble (Milky white Citrate buffer 50 mM 60% v/v, insoluble particles) Propylene glycol 40% v/v S3 Losartan Potassium 10 mg/mL, Insoluble (Milky white Citrate buffer 50 mM 60% v/v, insoluble particles) Glycerin 40% v/v S4 Losartan Potassium 10 mg/mL, Insoluble (Milky white Citrate buffer 50 mM 90% v/v, insoluble particles) Labrasol 10% v/v S5 Losartan Potassium 10 mg/mL, Insoluble (Milky white Citrate buffer 50 mM 95% v/v, insoluble particles) Tween 5% v/v

(78) The findings indicated that losartan potassium showed insolubility across all tested solubilizers.

Example 2. Solubility Study of Losartan Potassium with Different Concentration of Solubilizers

(79) The losartan exhibited insolubility in tested solubilizers, hence, further study was conducted to investigate the impact of different solubilizers concentration and pHW modifying agent on the solubility of losartan potassium. Table 2 summarizes the results of this study.

(80) TABLE-US-00002 TABLE 2 Solubility study of Losartan Potassium in presence of different solubilizers concentration and pH modifying agent Batch Number Composition Observations S6 Losartan Potassium 10 mg/mL, Insoluble (Milky white PEG 400 20% v/v, Glycerin 30% insoluble particles) v/v, 100 mM citrate buffer 50% v/v S7 Losartan Potassium 10 mg/mL, Insoluble (Milky white PEG 400 16% v/v, Glycerin insoluble particles) 25% v/v, Liquid sorbitol 16%, 100 mM citrate buffer 42% v/v S8 Losartan Potassium 10 mg/mL, Insoluble (Milky white PEG 400 25% v/v, Glycerin insoluble particles) 15% v/v, Liquid sorbitol 60%, 10% citric acid to adjust pH 4 S9 Losartan Potassium 10 mg/mL, Clear Solution PEG 400 25% v/v, Glycerin 15% v/v, Liquid sorbitol 60%, 2.5% citric acid to adjust pH 4.85

(81) It was inferred that a clear solution was achieved by combining PEG 400 and glycerin when adjusting the pH below 5 with a 2.5% citric acid solution.

(82) Citric acid was included in the formulation to assess its impact on enhancing the solubility of the active pharmaceutical ingredient (API) in the non-aqueous base. However, an increase in the content of an unspecified impurity was observed, which was attributed to the presence of water in the citric acid buffer. Given the presence of the increased impurity content in the presence of water, a decision was made to minimize (and/or eliminate) water content. Based on these and other results showing degradation in the presence of water, a decision was made to utilize a non-aqueous formulation. Accordingly, the finalized formulation was independent of pH, and therefore, no pH-modifying agents were added in further trials related to non-aqueous formulations.

Example 3. Comparative Dissolution Trials of Formulation with Varied Excipients

(83) The study was conducted to check effect of varied excipients on dissolution profile of the formulation as compared to reference product.

(84) TABLE-US-00003 TABLE 3 Dissolution trial with different concentration and grade of PVP with varied concentration of Xanthan gum Batch No. B1 B2 B3 B4 Ingredients Quantity (mg/mL) Losartan 10.00 10.00 10.00 10.00 Potassium PEG-400 113.00 113.00 113.00 113.00 Sodium benzoate 1.00 1.00 1.00 1.00 Sucralose 1.00 1.00 1.00 1.00 Xanthan gum 0.25 0.50 0.50 PVP K90 5.0 10.0 PVP K30 10.0 Frozen 1.00 1.00 1.00 1.00 peppermint Glycerin Q.S to 1 mL Q.S to 1 mL Q.S to 1 mL Q.S to 1 mL

(85) TABLE-US-00004 TABLE 4 Results of dissolution trial with different concentration and grade of PVP with varied concentration of Xanthan gum Media Deaerated water Volume 900 mL Apparatus USP typeII Paddle RPM 50 RPM Dissolution Average % Drug Release Time (Min) 10 20 30 45 60 RLD COZAAR 100 mg 35 51 79 95 97 B1 99 99 99 99 98 B2 65 96 97 97 96 B3 65 95 99 99 99 B4 75 98 98 99 99

(86) In the comparison of dissolution profiles among different batches, batch B4 containing PVP K30 (10 mg/mL) and xanthan gum (0.5 mg/mL) demonstrated higher cumulative % drug release than batch B3, which contained PVP K90 (10 mg/mL) and xanthan gum (0.5 mg/mL). Similarly, batch B2, formulated with PVP K90 (5 mg/mL) and xanthan gum (0.25 mg/mL), exhibited a dissolution profile similar to that of batch B3.

(87) Notably, batch B1, which did not contain xanthan gum or PVP K90/PVP K30, displayed faster dissolution compared to all other batches with varying grades and concentrations of PVP and xanthan gum. Hence these batches were further evaluated.

Example 4. Biostudy of Batch B1 Evaluating Bioavailability and Pharmacokinetic/Pharmacodynamic Parameters with Respect to Reference Product (COZAAR)

(88) The results of bio study of batch B1 with reference product are as follows:

(89) TABLE-US-00005 TABLE 5 Results of bio study of Batch B1 Geometric Least Squares Mean T/R % Parameters (T) (R) (%) ISCV 90% CI C.sub.max (ng/ml) 1007.629 918.893 109.66 38.30 83.07-144.75 AUC (ng*hr/mL) 1288.548 1332.386 96.71 8.87 90.5-103.35

(90) Based on the results, it was observed that the 90% confidence interval for C.sub.max was skewed towards the upper limit (144.75%). Therefore, this formulation was excluded from further consideration.

Example 5. Biostudy of Batches B5 and B2 with Reference Product (COZAAR)

(91) The biostudy was conducted for formulations containing xanthan gum with and without PVP K90 with reference product.

(92) TABLE-US-00006 TABLE 6 Formulation details for Bio study Batch No. B5 B2 Ingredients mg/mL mg/mL Losartan potassium 10.00 10.00 Polyethylene glycol 400 113.0 113.0 Sodium benzoate 1.00 1.00 Sucralose 1.00 1.00 Xanthan Gum 2.0 0.25 PVP K90 5.00 Frozen peppermint 1.00 1.00 Glycerin Q.S. to 1 mL Q.S. to 1 mL

(93) TABLE-US-00007 TABLE 7 Geometric least squares mean and 90% CI of batch B5 vs reference product Geometric Least Squares Mean T/R % Parameters (T) (R) (%) ISCV 90% CI C.sub.max (ng/ml) 635.993 695.073 91.50 31.154 79.36-105.49% AUC (ng*hr/mL) 883.158 974.198 90.65 22.988 82.97-99.05%

(94) TABLE-US-00008 TABLE 8 Geometric least squares mean and 90% CI of batch B2 vs reference product Geometric Least Squares Mean T/R % Parameters (T) (R) (%) ISCV 90% CI C.sub.max (ng/mL) 754.497 695.015 108.56 31.154 95.15-123.86% AUC (ng*hr/mL) 867.822 972.584 89.23 22.988 82.20-96.85%

(95) Based on the results, it was observed that the 90% confidence interval for C.sub.max was slightly lower for batch B5 and slightly higher for batch B2. The use of PVP K90 resulted in prolonged dissolution times and increased formulation viscosity, leading to its exclusion from selection.

(96) Consequently, batch B5 was chosen for further development with a reduced concentration of xanthan gum. Additionally, minor adjustments were made to the concentrations of xanthan gum and PEG 400 to achieve the desired outcomes.

(97) Further, preservative efficacy testing (PET) was conducted for higher to lower concentration of sodium benzoate, and based on the results of the PET studies, concentration of sodium benzoate was optimised.

Example 6. Comparative Dissolution Trials with Different Concentration of Xanthan Gum

(98) The study aimed to evaluate how concentration of xanthan gum affect the release of the losartan potassium (API) in comparison to the reference product (COZAAR).

(99) TABLE-US-00009 TABLE 9 Composition details for dissolution trial with different concentration of thickening agent Batch No. B6 B5 Ingredients Quantity (mg/mL) Losartan Potassium 10.00 10.00 PEG-400 113.00 113.00 Sodium benzoate 1.00 1.00 Sucralose 1.00 1.00 Xanthan gum 1.00 2.00 Frozen peppermint 1.00 1.00 Glycerin Q.S to 1 mL Q.S to 1 mL

(100) TABLE-US-00010 TABLE 10 Results of comparative dissolution trials with different concentration of thickening agent Media Deaerated water Volume 900 mL Apparatus USP typeII Paddle RPM 50 RPM Dissolution Average % Drug Release Time (Min) 10 15 30 45 60 RLD COZAAR 100 mg 35 51 79 95 97 B6Xanthan gum1.0 mg/ml 74 92 97 97 97 B5Xanthan gum2.0 mg/ml 61 81 97 96 96

(101) Based on the results, it was noted that there is a trend of decreasing cumulative % drug release with higher concentrations of xanthan gum. This indicates that xanthan gum can effectively be utilized to regulate the release of losartan potassium, potentially achieving extended-release characteristics.

Example 7. Formulation of a Non-Aqueous Oral Solution of Losartan Potassium (B7)

(102) TABLE-US-00011 TABLE 11 Formulation of a ready-to-use non-aqueous oral solution of losartan potassium (B7) No. Ingredients Quantity (mg/mL) 1 Losartan potassium 0.01-50 2 Sodium benzoate 0.01-20 3 Xanthan gum 0.01-15 4 Sucralose 0.01-15 5 Frozen peppermint 0.01-15 6 Polyethylene glycol 400 50-500 7 Glycerin Q.S.

Example 8. Formulation of a Non-Aqueous Oral Solution of Losartan Potassium (B8)

(103) TABLE-US-00012 TABLE 12 Formulation of a ready-to-use non-aqueous oral solution of losartan potassiu No. Ingredients Quantity (mg/mL) 1 Losartan potassium 1-15 2 Sodium benzoate 0.01-5 3 Xanthan Gum 0.5-10 4 Sucralose 0.5-3 5 Frozen peppermint 0.5-3 6 Polyethylene glycol 400 70-150 7 Glycerin Q.S.

Example 9. Formulation of a Non-Aqueous Oral Solution of Losartan Potassium (B9)

(104) TABLE-US-00013 TABLE 13 Formulation of a ready-to-use non-aqueous oral solution of losartan potassium (I Quantity Quantity No. Ingredients (mg/mL) (% w/v) 1 Losartan potassium 10.00 1 2 Sodium benzoate 0.40 0.04 3 Xanthan Gum 1.50 0.15 4 Sucralose 1.00 0.1 5 Frozen peppermint 1.00 0.1 6 Polyethylene glycol 400 115.0 11.5 7 Glycerin Q.S. to 1 mL Q.S. to 100%
Procedure: (a) Glycerin was added in a vessel having a temperature; (b) Polyethylene glycol 400 was added into the glycerin-containing mixing vessel of step (a) with continuous stirring; (c) Sodium benzoate was added into the solution obtained in step (b) with continuous stirring; (d) Sucralose was added into the solution obtained in step (c) with continuous stirring; (e) Losartan potassium (API) was added into the solution obtained in step (d) with continuous stirring; (f) Xanthan gum was added in glycerin in a separate vessel to prepare a slurry; (g) The slurry obtained in step (f) was added to the solution obtained in step (e); (h) Frozen peppermint was added into the solution obtained in step (g) under continuous stirring; (i) The volume of bulk solution was adjusted into the mixing vessel using glycerin with continuous stirring; (j) The bulk solution obtained in step (i) was filtered to get a clear solution; (k) The final formulation (having a density of 1.240.03 g/mL) obtained in step (j) was stored in the suitable container.

Example 10. Thermal Stability Study

(105) The stability study was conducted for 3 and 6 months at 40 C./NMT 25% RH & 25 C./60% RH.

(106) TABLE-US-00014 TABLE 14 Results of Thermal Stability Study of Formulation B9 Batch No. Formulation B9 Pack Details 185 CC HDPE bottle packed in secondary white box Storage 40 C. + 2 C./NMT 25% RH 25 C. + 2 C./60 + 5% RH Test condition 1M 3M 6M 1M 3M 6M parameters Specification Initial Invert Invert Invert Invert Invert Invert Description A clear Clear Clear Clear Clear Clear Clear Clear colorless to Colorless Colorless Colorless Colorless Colorless Colorless Colorless light yellow Solution Solution Solution Solution Solution Solution Solution color solution. Assay of 95.0% to 102.80% 99.60% 100.60% 99.90% 100.60% 100.60% 100.60% Losartan 105.0% of Potassium labelled amount Assay of 90.0% to 103.40% 101.10% 102.30% 101.50% 101.00% 101.00% 101.00% Sodium 110.0% of benzoate labelled amount Related Substances Single Any BQL BQL 0.06 0.11 BQL BQL 0.05 maximum unspecified unknown Impurity: NMT impurity 0.2% Total Total 0.0 0.0 0.06 0.11 0.0 0.0 0.5 impurities impurities: NMT 1.0%

(107) The results indicates that the final formulation was found to be stable at 40 C.2 C./NMT 25% & 25 C.2 C./605% RH at least for 6 months.

Example 11. Photostability Studies

(108) A photostability study was performed on the formulation B9.

(109) TABLE-US-00015 TABLE 15 Results of Photostability Study of Formulation B9 Batch No Formulation B9 Specification/ HDPE bottle Clear PET Test Limits Initial (Primary pack) bottle Description A clear colorless to A clear A clear A clear light yellow color colorless colorless colorless solution. solution. solution. solution. Assay of 95.0% to 105.0% of 98.4 99.5 97.2 Losartan labelled amount Potassium Assay of 90.0% to 110.0% of 99.3 100.3 98.1 Sodium labelled amount benzoate Related substances Single A) Any unspecified BQL BQL 0.06 maximum impurity: unknown NMT 0.2%, impurity B) Total impurities: Total NMT 0.55% ND ND 0.06 impurities *NMTNot more than; BQLBelow limit of quantification; NDNot detected

(110) The results indicates that the final formulation was found to be stable at photostability condition.

Example 12. Freeze-Thaw Study

(111) Freeze-thaw studies were performed at a temperature cycle of 20 C.5 C. for 2 days followed by 40 C.2 C. for 2 days.

(112) TABLE-US-00016 TABLE 16 Results of the freeze-thaw study Batch No. Formulation B9 Specification/ At the end Test Limits Initial of 3.sup.rd cycle) Description A clear colorless to A clear A clear light yellow colorless colorless color solution. solution. solution. Assay of Losartan 95.0% to 105.0% of 98.3 98.2 Potassium labelled amount Assay of Sodium 90.0% to 110.0% of 98.8 98.5 benzoate labelled amount Related substances Single maximum A) Any unspecified BQL BQL unknown impurity impurity: NMT 0.2%, Total impurities B) Total impurities: ND ND NMT 0.55% *NMTNot more than; BQLBelow limit of quantification.

(113) The results indicated that the final formulation was found to be stable at freeze-thaw conditions.

Example 13. Comparative Study of Batch B9 and Solution Compositions Disclosed in Delmarre and Kolla

(114) TABLE-US-00017 TABLE 17 Comparison of batch B9 with solution compositions disclosed in examples of Delmarre and Kolla Batch Delmarre Kolla's Solution Exs. 4-5 and 10-12 B9 Ex. 3 Ex. 4 Ex. 5 Ex. 10 Ex. 11 Ex. 12 Ingredient Quantity (mg/mL) Losartan 10 12.5 10 10 10 10 10 potassium Preservative Sodium MP & MP & PP Sodium MP & MP & Benzoate - PP Benzoate - PP PP 0.40 2 Thickening Xanthan HEC HPMC & Xanthan agent gum - Xanthan gum - 2.5 1.50 gum - 1 pH Adjusting KPB NaOH PB PB PB agent Chelating DSE agent Sweetening Sucra- Saccharin Sucra- Sucralos - agent lose - 1 sodium lose - 4 5 Flavouring Frozen agent Pepper- mint - 1 Solubilising PEG PG and PEG PEG agent 400 - 115 Glycerin 400 - 400 - 25 & 25 & PG PG Crystallization PVP K90 PVP K30 Inhibitor & HPMC Vehicle Glycerin Glycerin Purified Purified Glycerin Pur- Water (Q.S. to 1 water water ified mL) water pH 8.2 6 NR NR NR NR Water (% w/w) <<1 12.sup.(a) >90 80-90 >2.4.sup.(b) 80- >90 90 Notes and Abbreviations: .sup.(a)Delmarre's Ex. 3 solution uses aqueous potassium phosphate buffer, which serves as the source of water. .sup.(b)Kolla's Ex. 10 solution dissolves losartan potassium in water, initially, and then adds the remaining excipients. The estimated amount of water is based on reports that losartan potassium is freely soluble in water. See Remington's, 212. MP: Methyl Paraben; PP: Propyl Paraben; PG: Propylene glycol; PB: Phosphate Buffer; HEC: Hydroxy Ethyl Cellulose; KPB: Potassium Phosphate Buffer; DSE: Disodium edetate; HPMC: Hydroxy Propyl Methyl Cellulose (Hypromellose); NR (not reported).

(115) Table 17 shows that Batch B9 of the non-aqueous oral solution does not contain buffering agents, pH modifiers or pH adjusting agents, parabens, chelating agents, purified water, propylene glycol, or crystallization inhibitors, hydroxypropyl methylcellulose, hydroxyethyl cellulose. Despite the absence of these excipients, the formulation remains stable, safe and effective.

(116) This demonstrates that the non-aqueous oral solution maintains stability even in the absence of pH modifiers or buffering agents.

Example 14. Pharmacokinetic Study of Batch B9 with Respect to Reference Product (COZAAR Tablet)

(117) Bioavailability Study Under Fasting Condition:

(118) An open label, balanced, randomized, two-treatment, four-period, two-sequence, single oral dose, full replicate comparative bioavailability study of losartan potassium 10 mg/mL (Administered as 100 mg/10 mL) oral solution of batch B9 was conducted with 100 mg of COZAAR tablets in normal, healthy, adult human volunteers under fasting condition.

(119) TABLE-US-00018 TABLE 18 Descriptive Statistics of Formulation Means for Losartan Mean SD (Untransformed Data) Parameters Test ProductT Reference ProductR (Units) (N = 69 Observations) (N = 69 Observations) T.sub.max (h).sup.# 0.500 (0.333-2.667) 1.250 (0.333-5.000) C.sub.max (ng/ml) 806.187 362.8349 858.961 449.0213 AUC.sub.0-t (ng .Math. h/mL) 1530.980 948.0597 1664.487 1068.3865 AUC.sub.0- (ng .Math. h/mL) 1560.022 1013.3460 1689.837 1114.6129 .sub.Z (1/h) 0.310 0.1110 0.321 0.1124 T.sub.1/2 (h) 2.777 1.7685 2.596 1.4939 AUC_% Extrap_obs (%) 1.220 1.3686 1.110 1.2216 R.sup.2 adjusted 0.990 0.0117 0.986 0.0174 .sup.#T.sub.max is represented as median (min-max) value
Relative Bioavailability Analysis:

(120) Relative bioavailability analysis (i.e. geometric least squares means, ratio, 90% confidence interval, 95% upper confidence bound and power) of Test ProductT vs. Reference ProductR for losartan are summarized in the following table:

(121) TABLE-US-00019 TABLE 19 Relative Bioavailability Results for Losartan Geometric Least Squares Means Reference 95% Test Product - Product - R Ratio 90% Upper T (N = 69 (N = 69 (T/R) Confidence Confidence Power Parameters Observations) Observations) % Interval Bound (%) InC.sub.max 729.456 755.417 96.6 N/AP 0.0568 N/AP InAUC.sub.0-t 1352.590 1455.594 92.9 89.19-96.81 N/AP 100.0 InAUC.sub.0- 1369.275 1471.837 93.0 89.32-96.90 N/AP 100.0

(122) As per results, the test product has demonstrated bioavailable to the Reference product with respect to C.sub.max, AUC.sub.0-t and AUC.sub.0-.

(123) Bioavailability Study Under Fed Condition:

(124) An open label, balanced, randomized, two-treatment, four-period, two-sequence, single oral dose, full replicate comparative bioavailability study of losartan potassium 10 mg/mL (Administered as 100 mg/10 mL) oral solution of batch B9 was conducted with 100 mg COZAAR tablets in normal, healthy, adult human volunteers under fed condition.

(125) TABLE-US-00020 TABLE 20 Descriptive Statistics of Formulation Means for Losartan Mean SD (Untransformed Data) Test ProductT Reference ProductR Parameters (Units) (N = 67 Observations) (N = 67 Observations) T.sub.max (h).sup.# 1.517 (0.333-5.333) 4.333 (0.667-6.033) C.sub.max (ng/ml) 391.357 119.2530 686.390 285.9055 AUC.sub.0-t (ng .Math. h/mL) 1261.942 332.9989 1379.713 409.5859 AUC.sub.0- (ng .Math. h/mL) 1273.174 336.8092 1393.984 413.3287 .sub.Z (1/h) 0.397 0.1206 0.390 0.1315 T.sub.1/2 (h) 1.971 0.8227 2.034 0.8537 AUC_% Extrap_obs (%) 0.871 0.4207 1.038 0.6812 R.sup.2 adjusted 0.990 0.0100 0.982 0.0194 .sup.#T.sub.max is represented as median (min-max) value
Relative Bioavailability Analysis:

(126) Relative bioavailability analysis (i.e. geometric least squares means, ratio, 90% confidence interval, and power) of Test ProductT vs. Reference ProductR for losartan are summarized in the following table:

(127) TABLE-US-00021 TABLE 21 Relative Bioavailability Results for Losartan Geometric Least Squares Menas Test Reference ProductT ProductR Ratio 90% (N = 67 (N = 67 (T/R) Confidence Power Parameters Observations) Observations) % Interval (%) lnC.sub.max 374.396 634.747 59.0 52.32-66.49 92.3 lnAUC.sub.0-t 1210.894 1329.911 91.1 88.46-93.72 100.0 lnAUC.sub.0- 1221.448 1343.663 90.9 88.34-93.55 100.0

(128) As per results, the test product has demonstrated bioavailable to the reference product with respect to C.sub.max, AUC.sub.0-t and AUC.sub.0-.

(129) Disclosed Information

(130) COZAAR (losartan potassium) 2.5 mg-ml Powder and Solvent for Oral Suspension, UK Prescribing Information, Merck Sharp and Dohme Limited, June 2019, 22 pp.

(131) COZAAR (losartan potassium) Tablets, US Prescribing Information, Organon & Co., October 2021, 19 pp.

(132) Foley et al., Investigation of the Physical, Chemical and Microbiological Stability of Losartan Potassium 5 mg/mL Extemporaneous Oral Liquid Suspension, Molecules (2021), 26(2), 301, 9 pp.

(133) Handbook of Pharmaceutical Excipients, 6.sup.th Ed. (2009), 13 pp. (Handbook).

(134) International Publication No. WO2009112800A1, Losartan composition, published on Sep. 17, 2009 to Tiernery, C. (Tiernery).

(135) International Publication No. WO2022076746A1, Losartan liquid formulations and methods of use, published on Apr. 14, 2022 to Kolla et al.

(136) Ora-Plus Product Information (2010), 2 pp.

(137) Ora-Sweet SF Product Information (2010), 2 pp.

(138) Rahamathulla et al., Design and Evaluation of Losartan Potassium Effervescent Floating Matrix Tablets: In Vivo X-ray Imaging and Pharmacokinetic Studies in Albino Rabbits, Polymers (2021), 13(20), 3476, 16 pp.

(139) Remington's: The Science and Practice of Pharmacy, Chapter 16 (in part) Solutions of Phase Equilibria, pp. 211-212, reporting that freely soluble is a descriptive term for solubility where 1 part of solute is soluble in 1-10 parts of solvent, 4 pp. (Remington's).

(140) U.S. Patent Application Publication No. US20070026026 A1, Oral liquid losartan compositions, published on Feb. 1, 2007 to Delmarre et al. (Delmarre).

(141) U.S. Pat. No. 11,890,273, Losartan liquid formulations and methods of use, to Kolla et al. (Kolla).

(142) U.S. Pat. No. 5,138,069, Angiotensin II receptor blocking imidazoles, issued on Aug. 11, 1992 to Carini et al. (Carini).

(143) U.S. Pat. No. 5,266,583, Angiotensin II antagonist, issued on Nov. 30, 1993 to Ohtawa, M. (Ohtawa).

(144) Subject matter disclosed herein is hereby incorporated by reference to the extent necessary to understand the subject matter disclosed herein.