FORM 2
THE PATENTS ACT, 1970
(39 OF 1970)
&
PATENTS RULES, 2006
COMPLETE SPECIFICATION (SECTION 10; RULE 13)
“PHARMACEUTICAL COMPOSITION COMPRISING ENALAPRIL”
ALKEM LABORATORIES LIMITED, A COMPANY INCORPORATED UNDER THE COMPANIES ACT, 1956, HAVING ITS CORPORATE. OFFICE AT ALKEM HOUSE, DEVASHISH, ADJACENT TO MATULYA CENTRE, S.B.MARG, LOWER PAREL, MUMBAI – 400013, MAHARASHTRA, INDIA
THE FOLLOWING SPECIFICATION DESCRIBES THE NATURE OF THE INVENTION AND THE MANNER IN WHICH IT IS TO BE PERFORMED

FIELD OF THE INVENTION
The invention relates to oral liquid pharmaceutical composition comprising enalapril and process for preparing thereof.
BACKGROUND OF INVENTION
Hypertension, which is another name for high blood pressure is caused by the force exerted by the blood against the walls of blood vessels. Severe complications such as heart attack, stroke and death can be caused by controlled hypertension. Various classes of anti-hypertensive drugs like alpha-adrenergic blockers, beta-adrenergic blockers, calcium-channel blockers, hypotensives, mineralcorticoid antagonists, central alpha-agonists, diuretics and rennin-angiotensin-aldosterone inhibitors which include angiotensin II receptor antagonists (ARB) and angiotensin-converting enzyme (ACE) inhibitors are available in the market which lower blood pressure by several mechanisms.
Among the different categories of anti-hypertensive drugs, the angiotensin-converting enzyme (ACE) inhibitors causes relaxation of blood vessels as well as decrease in blood volume, which leads to lowering of blood pressure and reduction of oxygen demand from the heart. Different ACE inhibitors are available in market like benazepril, zofenopril, perindopril, trandolapril, captopril, enalapril, lisinopril, and ramipril.
Among these, enalapril is a prodrug which post-administration is metabolized in liver to its active form enalaprilat, enalaprilat binds to ACE, the enzyme responsible for the conversion of angiotensin I (ATI) to angiotensin II (ATII) and leads to its inhibition. Further, enalapril maleate is the maleate salt form of enalapril, a dicarbocyl-containing peptide and angiotensin-converting enzyme (ACE) inhibitor with antihypertensive activity. The structural formula of enalapril is as follows:


Enalapril
Enalapril is available in market in dosage form of tablet, liquid formulation and powder (that has to reconstituted into liquid formulation). As mentioned below, various prior art discloses stable pharmaceutical composition comprising enalapril:
US patent No. 9,669,008 discloses oral liquid pharmaceutical composition comprising enalapril maleate. The composition further comprises citric acid and sodium citrate dehydrate as buffer with sodium benzoate as preservative.
US patent No. 9,808,442 discloses stable enalapril oral liquid formulations comprising enalapril maleate.
US patent No. 10,039,745 discloses stable oral liquid formulation comprising enalapril maleate.
US patent No. 10,154,987 discloses enalapril oral liquid formulations.
PCT Application No. WO2011128783 discloses stable liquid oily ready-to-use formulation comprising enalapril.
US patent No. 8,568,747 discloses powder composition comprising enalapril with addition of mannitol and silicon dioxide for stability and dissolution.
Chinese patent application No. 107951835 discloses formulation of enalapril maleate, characterized in that, pH of the enalapril maleate formulation is 6.4-7.4

PCT Application No. WO2017077425 discloses oral solution comprising ACE inhibitor lisinopril dehydrate which is stable at pH 5-9. Further discloses that buffer system and pH modifier is added for improving stability and palatability.
Inventors of different inventions have used various excipients to develop a stable pharmaceutical composition comprising enalapril. However, chemical composition, physio-chemical properties, quantity of excipients can affect the stability of pharmaceutical composition.
Further, interaction of excipients with drug or other excipients can widely affect the stability of pharmaceutical composition. The formation of adducts from interaction between the excipients is common and is undesirable for the formulation as it affect the stability of pharmaceutical composition. Such type of interaction is known between parabens and sugar/sugar alcohols, both of which are very commonly used in pharmaceutical compositions. As mentioned below, the possible incompatibility is due to the transesterification reaction that occur between parabens and sugar/sugar alcohol.
Ma et al have demonstrated the interaction of methyl paraben preservative with selected sugars and sugar alcohols.
Hotha et al have disclosed possible incompatibility because of transesterification reaction between parabens and sugar alcohols is concern during formulation development.
US patent Nos. 9669008, 9808442, 10039745 and 10154987 discloses enalapril oral liquid formulation and transesterification reaction products formed by reaction between paraben and selected sugars and/or sugar alcohols are undesirable for formulation. It is further disclosed that paraben preservatives can react with selected sugars (glucose, fructose, sucrose, lactose, maltose) and sugar alcohols (xylitol, mannitol, lactitol, maltitol, sorbitol) to form transesterification reaction products. This can be undesirable from a formulation and stability standpoint as the transesterification creates additional degradants.
It is therefore an object of the present invention to provide a stable liquid pharmaceutical composition comprising enalapril, one/more preservative and one or more sugar and/or sugar

alcohol. Specifically, the stable oral liquid pharmaceutical composition comprising enalapril, one/more paraben preservative and one or more sugar and/or sugar alcohol.
SUMMARY OF THE INVENTION
In one aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising enalapril, one/more pharmaceutically acceptable excipients comprising one/more preservative and one or more sugar and/or sugar alcohol.
In another aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising enalapril, one/more pharmaceutically acceptable excipients comprising one/more preservative wherein preservative is one/more paraben preservative selected from the group comprising methyl paraben, propyl paraben, ethyl paraben, butyl paraben and their salts and one or more sugar and/or sugar alcohol.
In another aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising enalapril, one/more pharmaceutically acceptable excipients comprising one/more preservative wherein preservative is paraben preservative selected from the group comprising methyl paraben and/or propyl paraben and one or more sugar and/or sugar alcohol.
In another aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising enalapril, one/more pharmaceutically acceptable excipients comprising one/more preservative wherein preservative is paraben preservative selected from the group comprising methyl paraben, propyl paraben, ethyl paraben, butyl paraben and their salts and one or more sugar and/or sugar alcohol.
In another aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising enalapril, one/more pharmaceutically acceptable excipients comprising one/more preservative wherein preservative is paraben preservative selected from the group comprising methyl paraben, propyl paraben, ethyl paraben, butyl paraben and their salts and one or more sugar and/or sugar alcohol; wherein sugar/sugar alcohol is selected from xylitol, sucralose, saccharin, mannitol.

In another aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising enalapril, one/more pharmaceutically acceptable excipients comprising one/more preservative wherein preservative is paraben preservative selected from the group comprising methyl paraben, propyl paraben, ethyl paraben, butyl paraben and their salts and one or more sugar and/or sugar alcohol wherein sugar/sugar alcohol is selected from xylitol, sucralose, saccharin, mannitol and wherein pH is in between 2-5.
In another aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising enalapril, one/more pharmaceutically acceptable excipients comprising one/more preservative wherein preservative is paraben preservative selected from the group comprising methyl paraben, propyl paraben, ethyl paraben, butyl paraben and their salts and one or more sugar and/or sugar alcohol wherein sugar/sugar alcohol is selected from xylitol, sucralose, saccharin, mannitol and wherein pH is in between 2-5 and wherein composition is stable at 5±3º C for at least 12 months.
In one aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising:
a. about 0.5 to 30% (w/w of solids) amount of enalapril
b. about 5 to 25% (w/w of solids) of methyl paraben and/or propyl paraben
c. about 2 to 25% (w/w of solids) of sugar and/or sugar alcohol
wherein the pH of formulation is less than 4.0.
In another aspect of the present invention, there is provided a stable oral liquid pharmaceutical composition comprising:
a. about 0.5 to 30% (w/w of solids) amount of enalapril
b. about 5 to 25% (w/w of solids) of methyl paraben and/or propyl paraben
c. about 2 to 25% (w/w of solids) of sugar and/or sugar alcohol
wherein the pH of formulation is less than 4.0 and wherein composition is stable at 5±3º C for at least 12 months.
DETAILED DESCRIPTION OF THE INVENTION
Provided is the stable oral liquid pharmaceutical composition comprising enalapril, one/more paraben preservative and one or more sugar and/or sugar alcohol. Further provided is the oral liquid pharmaceutical composition comprising enalapril, one or more pharmaceutically

acceptable excipients comprising one/more paraben preservative and one or more sugar and/or sugar alcohol and wherein the formulations described herein are useful for the treatment of hypertension, prehypertension, heart failure as well as ventricular dysfunction.
Sugar/sugar alcohol and parabens are commonly used ingredient in oral liquid formulations. However, their possible incompatibility due to transesterification reaction is a concern during formulation development. The inventors of the present invention however, have surprisingly found that stable oral liquid pharmaceutical composition comprising enalapril can be prepared in the presence of one or more pharmaceutically acceptable excipients comprising one/more paraben preservative and one or more sugar and/or sugar alcohol.
The inventors of the present invention have surprisingly found that oral liquid pharmaceutical composition can be prepared comprising enalapril, one or more pharmaceutically acceptable excipients comprising one/more paraben preservative and one or more sugar and/or sugar alcohol, wherein the formulation has a pH less than 4.0.
Furthermore, inventors of the present invention have surprisingly found that oral liquid pharmaceutical composition comprising enalapril can be prepared comprising one or more pharmaceutically acceptable excipients comprising one/more paraben preservative and one or more sugar and/or sugar alcohol, wherein the formulation has a pH less than 4.0 and; wherein the formulation is stable at about 5±3ºC for at least 12 months.
As used herein, enalapril refers to enalapril base, its salt or solvate or derivative or polymorph thereof. Suitable compound include the free base, the organic or inorganic salts, isomers, isomer salts, solvates, polymorphs, complexes etc. In some embodiments, the enalapril used herein is enalapril salt. In some embodiments, the enalapril salt is in the form of enalapril sodium. More preferably, enalapril used herein is enalapril maleate. In another embodiment, enalapril is present in the concentration range of 0.5 to 50% (w/w of solids). Preferably, enalapril is present in the concentration range of 0.5 to 40% (w/w of solids). More preferably, enalapril is present in the concentration range of 0.5 to 30% (w/w of solids).
In another embodiment, pharmaceutical composition may comprise ACE inhibitors selected from but not limited to quinapril, indolapril, ramipril, perindopril, lisinopril, benazepril,

imidapril, zofenopril, trandolapril, fosinopril, captopril, and their salts, solvates, derivatives, polymorphs, or complexes, thereof.
In another embodiment, oral liquids include, but are not limited to, solutions (both aqueous and nonaqueous), suspensions, emulsions, syrups, slurries, juices, elixirs, dispersions, and the like. More specifically the oral pharmaceutical composition is in the form of solution.
The “preservatives” as used herein include refers to anti-microbials, anti-oxidants and agents that enhance sterility. Preservatives may be selected but not limited to group comprising ascorbic acid, ascorbyl palmitate, BHA, BHT, citric acid, EDTA and its salts, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium metabisulfite, sodium sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts), benzoic acid, sodium benzoate, potassium sorbate, vanillin, butylparaben, ethyl paraben, methyl paraben, propylparaben, sodium propionate, benzalkonium chloride, benzethonium chloride, benzyl alcohol, cetypyridinium chloride, chlorobutanol, phenol, phenylethyl alcohol, 2-Penoxyethanol, Phenyl mercuric nitrate, thimerosal, meta-cresol or combinations thereof. More specifically, the liquid pharmaceutical composition comprises paraben as preservative.
In some embodiments, the pharmaceutical composition comprises enalapril and one or more pharmaceutically acceptable excipients comprising one/more preservative; wherein the preservative may be present in the concentration range of 0.5 to 40% (w/w of solids). Preferably, preservative is present in the concentration range of 0.5 to 35% (w/w of solids). More preferably, the preservative is present in the concentration range of 1 to 25% (w/w of solids).
In some embodiments, the pharmaceutical composition comprises enalapril, one or more pharmaceutically acceptable excipients comprising one/more preservative and one or more sugar and/or sugar alcohol.
The “sweetener” as used herein refers to any compounds that provide a sweet taste. This includes natural and synthetic sugars, natural and artificial sweeteners, natural extracts and any material that initiates a sweet sensation in a subject. In some embodiments, a solid/powder

sweetener is used in the oral liquid formulation described herein. In other embodiments, a liquid sweetener is used in the oral liquid formulation described herein.
Sugars illustratively include glucose, fructose, sucrose, xylitol, tagatose, sucralose, maltitol, isomaltulose, Isomalt.TM. (hydrogenated isomaltulose), lactitol, sorbitol, erythritol, trehalose, maltodextrin, polydextrose, and the like. Other sweeteners illustratively include glycerin, inulin, erythritol, maltol, acesulfame and salts thereof, e.g., acesulfame potassium, alitame, aspartame, neotame, sodium cyclamate, saccharin and salts thereof, e.g., saccharin sodium or saccharin calcium, neohesperidin dihydrochalcone, stevioside, thaumatin, and the like. Sweeteners can be used in the form of crude or refined products such as hydrogenated starch hydrolysates, maltitol syrup, high fructose corn syrup, etc., and as branded products, e.g., Sweet Am.TM. liquid (Product Code 918.003-propylene glycol, ethyl alcohol, and proprietary artificial flavor combination, Flavors of North America) and Sweet Am.TM. powder (Product Code 918.005--maltodextrin, sorbitol, and fructose combination and Product Code 918.010--water, propylene glycol, sorbitol, fructose, and proprietary natural and artificial flavor combination, Flavors of North America), ProSweet.TM. (1-10% proprietary plant/vegetable extract and 90-99% dextrose combination, Viriginia Dare), Maltisweet.TM. (maltitol solution, Ingredion), Sorbo.TM. (sorbitol and sorbitol/xylitol solution, SPI Polyols), Invertose T (high fructose corn syrup, Ingredion), Rebalance M60 and X60 (sucralose and maltodextrin, Tate and Lyle), and Ora-Sweet.RTM. sugar-free flavored syrup (Paddock Laboratories, Inc.). Sweeteners can be used singly or in combinations of two or more. Suitable concentrations of different sweeteners can be selected based on published information, manufacturers' data sheets and by routine testing. The sweetener may be present in the concentration range of 2 to 30% (w/w of solids). Preferably, sugar and/or sugar alcohol is present in the concentration range of 2 to 30 % (w/w of solids). More preferably, sugar and/or sugar alcohol is present in the concentration range of 2 to 20% (w/w of solids).
In further embodiments, the pharmaceutical composition comprises enalapril, one or more pharmaceutically acceptable excipients comprising one/more paraben preservative and one or more sugar and/or sugar alcohol. Specifically, the oral liquid composition comprises sugar and/or sugar alcohol selected from sucralose, mannitol, xylitol, saccharin or combination thereof.

In further embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable excipients comprising one/more paraben preservatives in the concentration range of 1 to 25% (w/w of solids) and one or more sugar and/or sugar alcohol in the concentration range of 2 to 20% (w/w of solids).
In another embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable excipients comprising methyl paraben and/or propyl paraben as preservatives in the concentration range of 1 to 25% (w/w of solids) and one or more sugar and/or sugar alcohol in the concentration range of 2 to 20% (w/w of solids).
In another embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable excipients comprising methyl paraben and/or propyl paraben as preservatives in the concentration range of 1 to 25% (w/w of solids) and one or more sugar and/or sugar alcohol selected from sucralose, xylitol, saccharin and mannitol in the concentration range of 2 to 20% (w/w of solids).
In another embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable excipients comprising methyl paraben and/or propyl paraben as preservatives in the concentration range of 1 to 25% (w/w of solids), and one or more sugar and/or sugar alcohol selected from sucralose, xylitol, saccharin and mannitol in the concentration range of 2 to 20% (w/w of solids) and one or more pharmaceutically acceptable excipients.
As used herein "excipient" refers to preservative, sugar/sugar alcohol, flavouring agent, isotonic agent, diluent, disintegrant, filler, glidant, buffer, lubricant, binder or the like, which is non-toxic, and inert, which does not have undesirable effects on a subject to whom it is administered and is suitable for delivering a therapeutically active agent to the target site without affecting the therapeutic activity of the said agent.
The term “pharmaceutical composition” refers to a composition comprising at least one active ingredient, whereby the composition is amenable to investigation for a specified, efficacious

outcome in a mammal (for example, without limitation, a human). Those of ordinary skill in the art will understand and appreciate the techniques appropriate for determining whether an active ingredient has a desired efficacious outcome based upon the needs of the artisan.
The term “pharmaceutically acceptable” refers to carrier, diluent or excipient compatible with the other ingredients of the formulation and not deleterious to the recipient thereof.
The term “therapeutically effective amount" or "effective amount" as used herein refers to the amount of active compound or pharmaceutical agent that elicits a biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician, which includes one or more of the following: (1) preventing the disease; for example, preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display the pathology or symptomatology of the disease, (2) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., arresting further development of the pathology and/or symptomatology), and (3) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e., reversing the pathology and/or symptomatology). As such, a non-limiting example of a "therapeutically effective amount" or "effective amount" of a formulation of the present disclosure may be used to inhibit, block, or reverse the activation, migration, or proliferation of cells or to effectively treat hypertension or ameliorate the symptoms of hypertension.
As used herein “isotonic agent” refers to a compound commonly used for such purposes at known concentrations. Isotonicity agents are selected but not limited to the group comprising glycerol, mannitol, sorbitol, lactose, dextrose, trehalose, sodium chloride, propylene glycol, dimethyl sulfone or mixture thereof.
As used herein “pH modifying agents” as used herein refers to a combination of acid and alkali. The pH modifying agents may be selected but not limited to the group comprising hydrochloric acid, o-phosphoric acid, citric acid, acetic acid, succinic acid, lactic acid, gluconic acid, tartaric acid, 1,2,3,4-butane tetracarboxylic acid, fumaric acid or malic acid. Alkali is selected from the

group comprising of sodium hydroxide, sodium citrate, potassium hydroxide, sodium hydroxide, ammonium hydroxide, magnesium oxide, calcium hydroxide, calcium carbonate, magnesium carbonate, magnesium aluminum silicates, diethanolamine, monoethanolamine, sodium carbonate, sodium bicarbonate or triethanolamine and combination thereof.
In some embodiment, the pH of the pharmaceutical composition as mentioned herein is in the range of of 2 to 5. Preferably, pH of the pharmaceutical composition is in the range of 2 to 4.
In another embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable excipients comprising methyl paraben and/or propyl paraben as preservatives in the concentration range of 1 to 25% (w/w of solids) and one or more sugar and/or sugar alcohol in the concentration range of 2 to 20% (w/w of solids), wherein pH of the pharmaceutical composition is in the range of 2 to 4.
In another embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable excipients comprising methyl paraben and/or propyl paraben as preservatives in the concentration range of 1 to 25% (w/w of solids) and one or more sugar and/or sugar alcohol selected from sucralose, xylitol, saccharin and mannitol in the concentration range of 2 to 20% (w/w of solids), wherein pH of the pharmaceutical composition is in the range of 2 to 4.
In another embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable excipients comprising methyl paraben and/or propyl paraben as preservatives in the concentration range of 1 to 25% (w/w of solids), and one or more sugar and/or sugar alcohol selected from sucralose, xylitol, saccharin and mannitol in the concentration range of 2 to 20% (w/w of solids) and one or more pharmaceutically acceptable excipients, wherein pH of the pharmaceutical composition is in the range of 2 to 4.
As used herein, buffer refers to agents that maintain the pH of the pharmaceutical composition. Buffering agent may be selected but not limited to sodium bicarbonate, potassium bicarbonate, magnesium hydroxide, magnesium lactate, magnesium gluconate, aluminum hydroxide, aluminum hydroxide/sodium bicarbonate co precipitate, mixture of an amino acid and a buffer,

a mixture of aluminum glycinate and a buffer, a mixture of an acid salt of an amino acid and a buffer, and a mixture of an alkali salt of an amino acid and a buffer. Additional buffering agents include citric acid, sodium citrate, sodium tartrate, sodium acetate, sodium carbonate, sodium polyphosphate, potassium polyphosphate, sodium pyrophosphate, potassium pyrophosphate, disodium hydrogenphosphate, dipotassium hydrogenphosphate, trisodium phosphate, tripotassium phosphate, sodium acetate, potassium metaphosphate, magnesium oxide, magnesium hydroxide, magnesium carbonate, magnesium silicate, calcium acetate, calcium glycerophosphate, calcium chloride, calcium hydroxide, calcium lactate, calcium carbonate, calcium bicarbonate, and other calcium salts. Some buffering agents also impart effervescent qualities when a powder is reconstituted in a solution In some embodiments, buffer is present in the concentration range of 5 to 50% (w/w of solids). Preferably, buffer is present in the concentration range of 5 to 40% (w/w of solids). More preferably, buffer is present in the concentration range of 5 to 30% (w/w of solids). Most preferably, buffer is present in the concentration range of 5 to 20% (w/w of solids).
As used herein, glidant refers to substances that improve flowability of a powder. Suitable glidants include, but are not limited to, calcium phosphate tribasic, calcium silicate, cellulose (powdered), colloidal silicon dioxide, magnesium silicate, magnesium trisilicate, silicon dioxide, starch, talc and the like. In some embodiments, the enalapril powder formulations described herein comprise a glidant.
As used herein, flavoring agent or flavorant refers to agent that enhance the taste or aroma of the formulation in liquid form. Suitable natural or synthetic flavoring agents can be selected from standard reference books, for example Fenaroli's Handbook of Flavor Ingredients, 3rd edition (1995). Non-limiting examples of suitable natural flavors, some of which can readily be simulated with synthetic agents or combinations thereof, include almond, anise, apple, apricot, bergamot, blackberry, blackcurrant, blueberry, cacao, caramel, cherry, cinnamon, clove, coffee, coriander, cranberry, cumin, dill, eucalyptus, fennel, fig, ginger, grape, grapefruit, guava, hop, lemon, licorice, lime, malt, mandarin, molasses, nutmeg, mixed berry, orange, peach, pear, peppermint, pineapple, raspberry, rose, spearmint, strawberry, tangerine, tea, vanilla, wintergreen, etc. Also useful, particularly where the formulation is intended primarily for pediatric use, is tutti-frutti or bubblegum flavor, a compounded flavoring agent based on fruit flavors. Presently preferred flavoring agents include anise, cinnamon, cacao, orange, peppermint, cherry (in particular wild cherry), grape, bubblegum, vanilla, and mixed

berry. In some embodiments, the enalapril liquid formulation described herein comprises a mixed berry flavoring agent. Flavoring agents can be used singly or in combinations of two or more. In some embodiments, the flavouring agent is present in the concentration range of 2 to 30% (w/w of solids). Preferably, flavouring agent is present in the concentration range of 2 to 20% (w/w of solids). More preferably, flavouring agent is present in the concentration range of 2 to 10% (w/w of solids).
Thickeners impart viscosity or weight to the resultant liquid forms from the enalapril formulation described herein. Exemplary thickeners include dextrin, cellulose derivatives (carboxymethylcellulose and its salts, ethylcellulose, hydroxyethyl cellulose, methylcellulose, hypromellose, and the like) starches, pectin, polyethylene glycol, polyethylene oxide, trehalose and certain gums (xanthan gum, locust bean gum, etc.). In certain embodiments, the enalapril liquid formulation comprises a thickener.
The terms "treat," "treated," "treatment," or "treating" as used herein refers to both therapeutic treatment in some embodiments and prophylactic or preventative measures in other embodiments, wherein the object is to prevent or slow (lessen) an undesired physiological condition, disorder or disease, or to obtain beneficial or desired clinical results. For the purposes described herein, beneficial or desired clinical results include, but are not limited to, alleviation of symptoms; diminishment of the extent of the condition, disorder or disease; stabilization (i.e., not worsening) of the state of the condition, disorder or disease; delay in onset or slowing of the progression of the condition, disorder or disease; amelioration of the condition, disorder or disease state; and remission (whether partial or total), whether detectable or undetectable, or enhancement or improvement of the condition, disorder or disease. Treatment includes eliciting a clinically significant response without excessive levels of side effects. Treatment also includes prolonging survival as compared to expected survival if not receiving treatment. A prophylactic benefit of treatment includes prevention of a condition, retarding the progress of a condition, stabilization of a condition, or decreasing the likelihood of occurrence of a condition. As used herein, "treat," "treated," "treatment," or "treating" includes prophylaxis in some embodiments.
In another embodiment, the oral liquid pharmaceutical composition comprising enalapril described herein is stable at refrigerated condition for at least 36 months, at least 24 months, at least 12 months, at least 6 months, at least 3 months and at least 1 month.

In some embodiments, refrigerated condition is about 1 to 9ºC. Preferably, refrigerated condition is about 1 to 8ºC. More preferably, refrigerated condition is about 2 to 8ºC.
In another embodiment, at accelerated conditions, the oral liquid pharmaceutical composition comprising enalapril described herein is stable for at least 36 months, at least 24 months, at least 12 months, at least 6 months, at least 3 months and at least 1 month.
The enalapril oral liquid formulations described herein are stable in various storage conditions including refrigerated, ambient and accelerated conditions. Stable as used herein refers to enalapril oral liquid formulations having about 95% or greater of the initial enalapril amount and about 5% w/w or less total impurities or related substances at the end of a given storage period. The percentage of impurities is calculated from the amount of impurities relative to the amount of enalapril. Stability is assessed by HPLC or any other known testing method. In some embodiments, the stable enalapril oral liquid formulations have about 5% w/w, about 4% w/w, about 3% w/w, about 2.5% w/w, about 2% w/w, about 1.5% w/w, about 1% w/w, or about 0.5% w/w total impurities or related substances. In other embodiments, the stable enalapril oral liquid formulations have about 5% w/w total impurities or related substances. In yet other embodiments, the stable enalapril oral liquid formulations have about 4% w/w total impurities or related substances. In yet other embodiments, the stable enalapril oral liquid formulations have about 3% w/w total impurities or related substances. In yet other embodiments, the stable enalapril oral liquid formulations have about 2% w/w total impurities or related substances. In yet other embodiments, the stable enalapril oral liquid formulations have about 1% w/w total impurities or related substances.
In some embodiments, at accelerated conditions described herein include temperature and/or relative humidity (RH) that are at or above ambient levels of (25±5ºC). In some instances, an accelerated condition is about 60ºC, about 55 ºC, about 50 ºC, about 45 ºC, about 40 ºC, about 35 ºC, about 30 ºC and more preferably about 25 ºC. In another embodiment, an accelerated condition is about 80% RH, about 75% RH, about 70% RH, about 65% RH, about 60% RH, about 55% RH, about 50% RH.
In another embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable

excipients comprising methyl paraben and/or propyl paraben as preservatives in the concentration range of 1 to 25% (w/w of solids) and one or more sugar and/or sugar alcohol in the concentration range of 2 to 20% (w/w of solids), wherein pH of the pharmaceutical composition is in the range of 2 to 4 and wherein the pharmaceutical formulation is stable for at least 6 months at 2-8 ºC.
In another embodiment, the pharmaceutical composition comprises enalapril in the concentration range of 0.5 to 30% (w/w of solids), one or more pharmaceutically acceptable excipients comprising methyl paraben and/or propyl paraben as preservatives in the concentration range of 1 to 25% (w/w of solids) and one or more sugar and/or sugar alcohol in the concentration range of 2 to 20% (w/w of solids), wherein pH of the pharmaceutical composition is in the range of 2 to 4 and wherein the pharmaceutical formulation is stable for at least 6 months at accelerated conditions at 25±2ºC and 60% RH.
EXAMPLES
Example 1:
Stable oral liquid pharmaceutical formulation (%w/w of solids) of enalapril at varying
concentrations of excipients
Stable oral liquid formulation comprising enalapril, paraben preservative and sweetener was
prepared according to the table 1. The pH of the solution was adjusted in the range of 2.0 to
4.0.
Table 1

Component Concentration (in %w/w of solids) of excipients in enalapril liquid
formulations

C1 C2 C3 C4 C5 C6
Enalapril 15-25 25-35 15-25 15-25 15-25 15-25
Citric acid 30-40 - 30-40 30-45 30-40 30-40
Sodium Citrate 1-5 - 1-5 1-5 - 1-5
Sodium benzoate - 25-35 - 5-15 5-15 -
Disodium Hydrogen Phosphate - - - - 1-5 -
Saccharin - 20-30 - - - -

Sucralose 10-20 - 10-20 10-20 10-20 10-20
Xylitol 1-5 - - - - -
Mannitol 10-20
Methyl Paraben 1-20 - 1-20 - - 1-20
Propyl Paraben 1-10 - 1-5 - - 1-5
Mixed berry flavour 1-10 10-20 10-20 5-15 5-15 1-10
Water q.s q.s q.s q.s q.s q.s
pH 2.0-4.0 2.0-4.0 2.0-4.0 2.0-4.0 2.0-4.0 2.0-4.0
The results of the HPLC analysis for the two main degradants, enalapril diketopiperazine and enalaprilat in the oral pharmaceutical formulation C1 is shown in table 2
Table 2

Tests Initial Stability Data

2-8°C 25±2°C/60±5%RH

3 months 6 months 3 months 6 months
pH 3.47 3.41 3.60 3.40 3.41
Specific gravity (g/mL) 1.006 1.003 1.002 1.003 1.002
Assay
Enalapril Maleate (%) 101.5 100.6 99.7 97.7 96.1
Methyl Paraben (%) 101.6 100.1 99.1 98.7 98.9
Propyl Paraben (%) 104.1 100.3 102.7 98.5 101.5
Organic impurities
Impurity C (Enalaprilat) ND ND 0.260 1.417 2.384
Impurity D (DKP) 0.063 0.085 0.093 0.418 0.652
Any unspecified degradation product … … 0.028 0.036 0.026
Total impurity 0.063 0.085 0.381 1.905 3.062

We Claim:
1. A stable oral liquid pharmaceutical composition comprising:
a. about 0.5 to 30% (w/w of solids) amount of enalapril
b. about 5 to 25% (w/w of solids) of methyl paraben and/or propyl paraben
c. about 2 to 25% (w/w of solids) of sugar and/or sugar alcohol, wherein the pH of formulation
is less than 4.0.
2. A stable oral liquid pharmaceutical composition of claim 1, wherein enalapril is present in the concentration range of 0.5 to 30% (w/w of solids).
3. A stable oral liquid pharmaceutical composition of claim 1, wherein one/more preservative is paraben preservative selected from the group comprising methyl paraben, propyl paraben, ethyl paraben, butyl paraben and their salts.
4. A stable oral liquid pharmaceutical composition of claim 1, wherein methyl paraben and/or propyl paraben is present in the concentration range of 5 to 25% (w/w of solids).
5. A stable oral liquid pharmaceutical composition of claim 1, wherein one or more sugar and/or sugar alcohol selected from sucralose, xylitol, saccharin and mannitol.
6. A stable oral liquid pharmaceutical composition of claim 1, wherein sugar and/or sugar alcohol is present in the concentration range of 2 to 25% (w/w of solids).
7. A stable oral liquid pharmaceutical composition of claim 1, wherein the pH of formulation is less than 4.0.
8. A stable oral liquid pharmaceutical composition comprising:
a. about 0.5 to 30% (w/w of solids) amount of enalapril
b. about 5 to 25% (w/w of solids) of methyl paraben and/or propyl paraben
c. about 2 to 25% (w/w of solids) of sugar and/or sugar alcohol, wherein the pH of formulation
is less than 4.0 and wherein composition is stable at 5±3°C for at least 12 months.

9. A stable oral liquid pharmaceutical composition of claim 8, wherein one/more preservative
is paraben preservative selected from the group comprising methyl paraben, propyl paraben,
ethyl paraben, butyl paraben and their salts.
10. A stable oral liquid pharmaceutical composition of claim 8, wherein one or more sugar
and/or sugar alcohol selected from sucralose, xylitol, saccharin and mannitol.