DESC:FILED OF THE INVENTION:
The present invention relates to stable pharmaceutical formulation of enalapril for oral administration.

BACKGROUND OF THE INVENTION:
Hypertension or high blood pressure is a common condition in which the long-term force of the blood against your artery walls is high enough that it may eventually cause health problems, such as heart disease. For most adults, normal blood pressure at rest is within the range of 100–130 millimeters mercury (mmHg) systolic and 60–80 mmHg diastolic. For most adults, high blood pressure is present if the resting blood pressure is persistently at or above 130/80 or 140/90 mmHg. High blood pressure often has no symptoms. Over time, if untreated, it can cause health conditions, such as heart disease and stroke. According to the National Heart Blood and Lung Institute, it is thought that about 1 in 3 adults in the United States alone have hypertension.

Treating high blood pressure can take a multi-pronged approach including diet changes, medication, and exercise. A number of antihypertensive drugs are available for treating hypertension. Various therapeutic classes of antihypertensive drugs include calcium channel blockers, diuretics, beta-adrenergic blockers, alpha-adrenergic blockers, inhibitors of the renin-angiotensin system (RAS), particularly angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs), are commonly used in the treatment of hypertension. Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), a peptydyl dipeptidase that catalyzes angiotension I to angiotension II, a potent vasoconstrictor involved in regulating blood pressure.

Enalapril is a prodrug belonging to the angiotensin-converting enzyme (ACE) inhibitor of medications. It is rapidly hydrolyzed in the liver to enalaprilat following oral administration. Enalaprilat acts as a potent inhibitor of ACE. In some embodiments, the enalapril is enalapril maleate. Enalapril maleate is chemically described as (S)-1[N-[1-(ethoxycarbonyl)-3-phenylpropyl]-L-alanyl]-L-proline, (Z)-2-butenedioate salt (1:1). Its empirical formula is C20H28N2O5•C4H4O4.The structural formulae of enalapril and enalaprilat are as follows:

According to EP0264888B1 the instability of ACE inhibitors susceptible to cyclization and hydrolysis could be decreased via the use of ascorbic acid alone or in combination with one or more of fumaric acid, citric acid, and maleic acid. It has been found; however, that for certain ACE inhibitors such as enalapril maleate, the addition of ascorbic acid actually increases the susceptibility of the active moiety to hydrolysis and cyclization reactions.

Further according to US4743450A the cyclization, hydrolysis, and coloration of certain ACE inhibitors is minimized when they are formulated with a metal-containing stabilizer and a saccharide. The alkaline stabilizers of the invention include the inorganic salts of metals of Groups I and II of the Periodic Table. Magnesium, calcium, and sodium are preferred. Magnesium is most preferred stabilizing agent.

US 20040157911A1 describe the manufacture of enalapril maleate formulations with improved resistance to decomposition. These formulations are said to be more resistant to decomposition due to minimal contact time between ACE inhibitors and water, while at the same time achieving intimate intermixing of the molecules of the ACE inhibitor and the metal compound. e.g. enalapril maleate, is first dissolved or dispersed in ethanol and then is contacted with the metal compound molecules via the addition of an aqueous solution of the metal compound to the alcoholic dispersion of the ACE inhibitor. Such methodology essentially eliminates the contact of enalapril maleate with water alone since ethanol is always present during the preparation, thereby not only accelerating the suspension or dispersion of the ACE inhibitor but also minimizing the deleterious hydrolytic effects of water on the stability of enalapril maleate.

Consequently, there is a need and a desire to stabilize certain ACE inhibitors so that pharmaceuticals containing such ACE inhibitors will maintain their effectiveness with minimal adverse effects. Further pediatric and geriatric patients may struggle to swallow large capsules and similar dosage forms, liquid oral formulation provide ideal routes of administration. Also liquid oral dosage forms provide more flexibility in dosage than capsules, and absorb more quickly into bodily fluids and tissues.

The objective of present invention is to provide stable pharmaceutical formulation of certain ACE inhibitors for oral administration for treatment of hypertension, more specifically for administration to geriatrics, pediatrics and those who have difficulty in swallowing the solid dosage form. The administration of liquid dosage form would increase patient compliance as well as would help in titrating the dose of antihypertensive as per the need.

SUMMARY OF THE INVENTION:
According to a first aspect of the present invention is provided a stable pharmaceutical formulation suitable for oral administration comprising enalapril or its salt, a pharmaceutically acceptable acidifying agent, one or more taste-enhancing/masking agents and one or more preservative, wherein said formulation has a pH from 3.0 to 5.2. The pharmaceutically acceptable acidifying agent can be selected from malic acid, tartaric acid, succinic acid, fumaric acid or maleic acid.
In another aspect, the enalapril oral liquid formulation comprises (i) about 1mg/ml of enalapril maleate; (ii) sweetener; (iii) acidifying agent; (iv) preservative; (v) flavoring agent and (vi)water; wherein the pH of the formulation is about 3.3; and wherein the formulation is stable.

In another aspect, the enalapril oral liquid formulation comprises (i) about 1mg/ml of enalapril maleate; (ii) about 1 mg/ml of sweetening agent that is sucralose; (iii) about 10 mM of an acidifying agent (iv) preservative that is sodium benzoate; (v) 0.50 mg/ml of flavoring agent that is mixed berry flavor and (vi) water; wherein the pH of the formulation is about 3.3; and wherein the formulation is stable.

One embodiment of the present invention is provided with a pharmaceutically stable formulation wherein said acidifying agent is malic acid.

Another embodiment of the present invention is provided with a pharmaceutically stable formulation wherein said acidifying agent is tartaric acid.

Another embodiment of the present invention is provided with a pharmaceutically stable formulation wherein said acidifying agent is fumaric acid.

Another embodiment of the present invention is provided with a pharmaceutically stable formulation wherein said acidifying agent is succinic acid.

Another embodiment of the present invention is provided with a pharmaceutically stable formulation wherein said acidifying agent is maleic acid.

Another embodiment of the present invention is provided with a pharmaceutically stable formulation wherein said acidifying agent is used as stabilizing agent.

Another embodiment of the present invention is provided with a pharmaceutical formulation wherein said pH is from 3.0 to 5.2.

Another embodiment of the present invention is provided with a pharmaceutical formulation wherein said pH is from 3.0 to 4.0.

Another embodiment of the present invention is provided with a pharmaceutical formulation wherein said pH is from 3.0 to 3.5.

Another embodiment of the present invention is provided with a pharmaceutical formulation wherein said pH is 3.3.

In some embodiments, the formulation further comprises a flavoring agent. In some embodiments, the pH modifier is hydrochloric acid or sodium hydroxide.

DETAILED DESCRIPTION OF THE INVENTION:
The present invention concerns an aqueous stable formulation for oral administration comprising enalapril or its salt, one or more pharmaceutically acceptable acidifying agent, one or more taste-enhancing/masking agents and one or more preservative, wherein said formulation has a pH from 3.0 to 5.2. Also provided herein are stable enalapril powder formulations for reconstitution for oral liquid administration. These enalapril formulations described herein are useful for the treatment of hypertension, prehypertension, heart failure as well as ventricular dysfunction.

Many of the elderly patients as well as pediatrics may require titrated doses of enalapril, to account for their body weights and diminished or undeveloped metabolic capabilities. In addition, for geriatric population having other concomitant disabilities like difficulty in swallowing a liquid formulation is easy to administer. Despite the availability of different technologies for liquid formulations of antihypertensive, there is a clinical need for better preparations that are simple, stable and manufactured by expedient manufacturing process and palatable for all elderly, pediatric and psychiatric patients.

Liquid oral formulation are composed of many types of formulations but are not limited to solutions (both aqueous and non-aqueous), suspensions, emulsions, syrup, elixirs, slurries, juices, dispersions, and the like. Oral solutions are mixtures of one or more solutes dissolved in a suitable solvent or mixture of mutually miscible solvents. In pharmaceutical terms, solutions are defined as “liquid preparations that contain one or more soluble chemical substances, usually dissolved in water”.

As used herein, “enalapril” refers to enalapril base, its salt, or solvate or derivative or isomer or polymorph thereof. Suitable compounds include the free base, the organic and inorganic salts, isomers, isomer salts, solvates, polymorphs, complexes etc. In some embodiments, the enalapril used in the formulations described herein is an enalapril salt. In some instances, the enalapril salt is enalapril maleate.

Other ACE inhibitors are contemplated in the formulations within and include but are not limited to quinapril, indolapril, ramipril, perindopril, lisinopril, benazepril, imidapril, zofenopril, trandolapril, fosinopril, captopril, and their salts, solvates, derivatives, polymorphs, or complexes, thereof.

The “taste-enhancing/masking agents” is an agent that reduces undesirable taste of formulation.

The term “preservative” means a substance used to preserve the formulation. Commonly used preservatives includes Nitrites (such as sodium nitrite) Sulphites (such as sulphur dioxide), sorbic acid, propyl gallate and salts. Na, K & Ca Benzoate, sodium sulfite, Sodium bisulfite, Sodium metabisulfite, Propylene glycol (15-30%), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tertiary butylated hydroquinone (TBHQ), benzaldehyde, Essential Oils, Phenol and Mercury compounds are acceptable for pharmaceutical use.

The inventors of the present invention have surprisingly found that a stable oral liquid formulation, particularly solution comprising enalapril maleate can be prepared with pharmaceutically acceptable acidifying agent selected from tartaric acid, malic acid, succinic acid, fumaric acid or maleic acid and having pH in range of 3.0- 5.2.

In some embodiments, enalapril or a pharmaceutically acceptable salt thereof, is present in about 0.5 to about 5 mg/ml in the oral liquid formulation. In some embodiments, enalapril maleate is present in about 1 mg/ml in the oral liquid formulation. In some embodiments, the formulation contains enalapril or another pharmaceutically acceptable salt of enalapril in a molar concentration equivalent to 1 mg/mL enalapril maleate.

Accordingly, examples of pharmaceutically acceptable acidifying agents include, but are not limited to fumaric acid, malic acid, maleic acid, succinic acid, tartaric acid, carbonic acid, acetic acid, phosphoric acid, gluconic acid, a mixture of an amino acid, a mixture of aluminum glycinate, a mixture of an acid salt of an amino acid, and a mixture of an alkali salt of an amino acid, glycin-HCl, lactic acid (propanoic acid), benzoic acid. Further it also encompasses any other suitable agent acting in the same way as acidifying agents disclosed above.

In some embodiments, the oral liquid formulation comprises a pharmaceutically acceptable acidifying agents.

In some embodiments, the pharmaceutically acceptable acidifying agents in the enalapril oral liquid formulation described herein comprises fumaric acid.

In some embodiments, the pharmaceutically acceptable acidifying agents in the enalapril oral liquid formulation described herein comprises maleic acid.

In some embodiments, the concentration of pharmaceutically acceptable acidifying agent plays an important role in reducing the rate of degradation of enalapril in the formulation. In some embodiments, acidifying agent also improves the taste of the enalapril oral liquid formulation. Generally, amount of acidifying agent used in formulation ranges from 3mM to 25mM.

In some embodiments, the pharmaceutically acceptable acidifying agent’s concentration is between about 03 mM and about 25 mM. In some embodiments, pharmaceutically acceptable acidifying agents concentration is about 03 mM, about 04 mM, about 05 mM, about 06 mM, about 07 mM, about 08 mM, about 09 mM, about 10 mM, about 11 mM, about 12 mM, about 13 mM, about 14 mM , about 15 mM, about 16 mM, about 17 mM, about 18 mM, about 19 mM, about 20 mM, about 21 mM, about 22 mM, about 23 mM, about 24 mM and about 25 mM.

Preferably the acidifying agent concentration is between 05 mM to 15 mM and more preferably the concentration is between 10 mM to 15 mM.

In some embodiments, the pH of the formulation affects the degradation rate of enalapril which would keep low impurity level. In the exemplary stability studies, the main enalapril degradants are enalapril diketopiperazine and enalaprilat:

In some embodiments, the pH of the enalapril oral liquid formulation described herein is less than about 5.2. In some embodiments, the pH of the enalapril oral liquid formulation described herein is between about 3 and about 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is about 3, about 3.1, about 3.2, about 3.3, about 3.4, about 3.5, about 3.6, about 3.7, about 3.8, about 3.9, or about 4. In some embodiments, the pH of the enalapril oral liquid formulation described herein is between about 3 and about 3.5. In some embodiments, the pH of the enalapril oral liquid formulation described herein is less than about 3.5. In some embodiments, the pH of the enalapril oral liquid formulation described herein is about 3.3.

In some embodiments, the “taste-enhancing/masking agents includes natural and synthetic sweeteners, natural extracts and any material that initiates a sweet sensation in a subject. Non-limiting examples of taste masking agent includes sweetening agents like sucralose, saccharin, aspartame, acesulfame potassium, alitame, neotame, stevia, monk fruit or lo han extract, yacon syrup, coconut nectar, xylitol, sorbitol etc.

In some embodiments, the enalapril oral liquid formulation described herein comprises sucralose. In some embodiments, sucralose is present in about 0.5 to about 3.5 mg/ml in the oral liquid formulation. In other embodiments, sucralose is present in about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 0.1 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml or about 1.5 mg/ml in the oral liquid formulation. In preferred embodiment, sucralose is present in about 1 mg/ml in the oral liquid formulation.

In another embodiments, the preservatives includes but not restricted to Methyl, ethyl, propyl and butyl Parabens and their salts, Sorbic acid and salts, Na, K & Ca Sorbate and propyl gallate, Benzoic acid, Na, K & Ca Benzoate, sodium sulfite, sodium bisulfite, Sodium metabisulfite, Propylene glycol (15-30%), butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA), tertiary butylated hydroquinone (TBHQ), benzaldehyde, Essential Oils, Phenol and Mercury compounds could be used in addition to this antimicrobial presrvatives. Organic and inorganic preservatives both can be used in the formulation.

In some embodiments, the preservative is a sorbic acid and propyl gallate. In some embodiments, the preservative is a tertiary butylated hydroquinone (TBHQ). In some embodiments, the preservative is a sodium metabisulfite.

In some embodiments, the preservative is a sodium benzoate.

In some embodiments, the sodium benzoate is present in about 0.5 to about 1.5 mg/ml in the oral liquid formulation. In other embodiments, sodium benzoate is present in about 0.5 mg/ml, about 0.6 mg/ml, about 0.7 mg/ml, about 0.8 mg/ml, about 0.9 mg/ml, about 0.1 mg/ml, about 1.1 mg/ml, about 1.2 mg/ml, about 1.3 mg/ml, about 1.4 mg/ml or about 1.5 mg/ml in the oral liquid formulation. In preferred embodiment, sodium benzoate is present in about 1 mg/ml in the oral liquid formulation.

In some embodiments, flavoring agent includes but not limited to mixed berry flavor, grape flavor, lemon-lime flavor, raspberry flavor, wild cherry syrup flavor, grenadine-strawberry flavor, lime flavor, portwine flavor, cherrywine flavor or wild-strawberry flavor.

In further embodiments, the enalapril formulation described herein comprises additional commonly used excipients including, but not limited to, fillers, extenders, glidants, flavoring agents, coloring agents and thickeners. Other excipients such as tonicity agents and chelating agents are within the scope of the embodiments.

In some embodiments, the enalapril oral liquid formulations described herein are provided in a dose per day from about 1 mg to 100 mg, from about 1 mg to about 80 mg, from about 1 to about 60, from about 2 mg to about 40 mg of enalapril. In certain embodiments, the enalapril oral liquid formulations described herein are provided in a daily dose of about 1 mg, about 5 mg, about 10 mg, about 15 mg, about 30 mg, about 35 mg, about 40 mg, about 45 mg, about 50 mg, about 55 mg, about 60 mg, about 65 mg, about 70 mg, about 76, mg, about 80 mg, about 85 mg, about 90 mg or about 100 mg, or any range derivable therein. In certain instances, more specifically in pediatrics recommended starting dose is 0.08 mg/kg (up to 5 mg) once daily.

The following examples illustrate the invention and they do not any way limit the scope of the invention. A person skilled in the art would easily modify the process for manufacturing the said pharmaceutical formulation or could modify the formulation with similar materials and finally a person skilled in the art could modify the method of administering the said formulation of this invention.

Oral Liquid Pharmaceutical Formulation:
The oral liquid pharmaceutical formulation of this instant invention comprises enalapril or its pharmaceutically equivalent derivative thereof and a pharmaceutically acceptable acidifying agents preferably fumaric acid, tartaric acid, maleic acid, succinic acid, malic acid etc. Its representative formulation shown below:

Example 1: Enalapril Oral Liquid Formulation
Components Quantity (mg/ml)
Enalapril Maleate 1.00
Fumaric acid 1.20
Sodium benzoate 1.00
Sucralose 1.00
Mixed berry flavor 0.50
Hydrochloric acid* q.s. to pH adjustment
Sodium Hydroxide* q.s. to pH adjustment
Purified water q.s. to 1.00 mL

Fumaric acid was dissolved in purified water in Stainless steel vessel under continuous stirring till clear solution is formed. The preservative, sodium benzoate was slowly added to the above solution under continuous stirring till clear solution is formed. Further sucralose was added to the above solution under continuous stirring. Then mixed berry flavor was mixed to the above solution and enalapril maleate was added under continuous stirring till clear solution was formed. Then pH of solution was adjusted to 3.3 and finally desired volume of solution was adjusted with purified water.

Example 2: Enalapril Oral Liquid Formulation
Components Quantity (mg/ml)
Enalapril Maleate 1.00
Tartaric acid 1.50
Sodium benzoate 1.00
Sucralose 1.00
Mixed berry flavor 0.50
Hydrochloric acid* q.s. to pH adjustment
Sodium Hydroxide* q.s. to pH adjustment
Purified water q.s. to 1.00 mL

Tartaric acid was dissolved in purified water in Stainless steel vessel under continuous stirring till clear solution is formed. The preservative, sodium benzoate was slowly added to the above solution under continuous stirring till clear solution is formed. Further sucralose was added to the above solution under continuous stirring. Then mixed berry flavor was mixed to the above solution and enalapril maleate was added under continuous stirring till clear solution was formed. Then pH of solution was adjusted to 3.3 and finally desired volume of solution was adjusted with purified water.

Example 3: Enalapril Oral Liquid Formulation

Components Quantity (mg/ml)
Enalapril Maleate 1.00
Maleic acid 0.40
Sodium benzoate 1.00
Sucralose 1.00
Mixed berry flavor 0.50
Hydrochloric acid* q.s. to pH adjustment
Sodium Hydroxide* q.s. to pH adjustment
Purified water q.s. to 1.00 mL

Maleic acid was dissolved in purified water in Stainless steel vessel under continuous stirring till clear solution is formed. The preservative, sodium benzoate was slowly added to the above solution under continuous stirring till clear solution is formed. Further sucralose was added to the above solution under continuous stirring. Then mixed berry flavor was mixed to the above solution and enalapril maleate was added under continuous stirring till clear solution was formed. Then pH of solution was adjusted to 3.3 and finally desired volume of solution was adjusted with purified water.
Components Quantity (mg/ml)
Enalapril Maleate 1.00
Succinic acid 2.95
Sodium benzoate 1.00
Sucralose 1.00
Mixed berry flavor 0.50
Hydrochloric acid* q.s. to pH adjustment
Sodium Hydroxide* q.s. to pH adjustment
Purified water q.s. to 1.00 mL
Example 4: Enalapril Oral Liquid Formulation

Succinic acid was dissolved in purified water in Stainless steel vessel under continuous stirring till clear solution is formed. The preservative (sodium benzoate) was slowly added to the above solution under continuous stirring till clear solution is formed. Further sucralose was added to the above solution under continuous stirring. Then mixed berry flavor was mixed to the above solution and enalapril maleate was added under continuous stirring till clear solution was formed. Then pH of solution was adjusted to 3.3 and finally desired volume of solution was adjusted with purified water.

Example 5: Enalapril Oral Liquid Formulation
Components Quantity (mg/ml)
Enalapril Maleate 1.00
Malic acid 1.35
Sodium benzoate 1.00
Sucralose 1.00
Mixed berry flavor 0.50
Hydrochloric acid* q.s. to pH adjustment
Sodium Hydroxide* q.s. to pH adjustment
Purified water q.s. to 1.00 mL

Malic acid was dissolved in purified water in Stainless steel vessel under continuous stirring till clear solution is formed. The preservative (sodium benzoate) was slowly added to the above solution under continuous stirring till clear solution is formed. Further sucralose was added to the above solution under continuous stirring. Then mixed berry flavor was mixed to the above solution and enalapril maleate was added under continuous stirring till clear solution was formed. Then pH of solution was adjusted to 3.3 and finally desired volume of solution was adjusted with purified water.

Stability studies of Example 1-5:
Formulations disclosed through Example 1-5 were subjected to stability test at 600C for 6 days. The aliquots of each formulation were analysed on HPLC for the two main degradants in the samples, enalapril diketopiperazine and enalaprilat.
The results of the HPLC analysis for the two main degradants are provided in below table 1.

Table 1: Primary Degradants Present in the Formulations(%w/w of enalapril maleate)

Time at 60oC Formulation
Example 1 Example 2 Example 3 Example 4 Example 5
Enalapril Diketopiperazine (%)
0 0.08 0.05 0.19 0.03 0.03
6 days 4.01 4.85 3.33 4.42 3.59
Enalaprilat (%)
0 0.04 0.10 0.04 0.05 0.05
6 days 6.00 6.02 4.61 5.53 5.27
,CLAIMS:
1. A stable oral liquid formulation comprising enalapril or a pharmaceutically acceptable salt or solvate thereof and a stabilizing agent.

2. The formulation of claim 1, wherein the stabilizing agent is an acid.

3. The formulation of claim 2, wherein said acid is selected from fumaric acid, malic acid, maleic acid, succinic acid, tartaric acid, carbonic acid, acetic acid, phosphoric acid, gluconic acid, a mixture of an amino acid, a mixture of aluminum glycinate, a mixture of an acid salt of an amino acid, a mixture of an alkali salt of an amino acid, glycin-HCl, lactic acid (Propanoic acid), and benzoic acid.

4. The formulation of claim 3, wherein the amount of an acid is about 3 mM to 25 mM.

5. The formulation of claim 1, further comprising a preservative selected from methyl, ethyl, propyl and butyl parabens and their salts; sorbic acid and salts; sodium, potassium & calcium sorbate and propyl gallate; benzoic acid; sodium, potassium & calcium benzoate; sodium sulfite; sodium bisulfite; sodium metabisulfite; propylene glycol (15-30%); butylated hydroxytoluene (BHT); butylated hydroxyanisole (BHA); tertiary butylated hydroquinone (TBHQ); benzaldehyde; essential oils; phenol and mercury.

6. The formulation of claim 1, wherein the pH is about 3.0 to about 5.2.

7. The formulation of claim 6, wherein the pH is about 3.3

8. The formulation of claim 1, further comprising about 0.50 mg/ml of a flavoring agent that is mixed berry flavor.

9. The formulation of claim 1, further comprising about 0.5 to about 3.5 mg/ml of a sweetening agent that is sucralose.

10. A stable oral liquid formulation comprising an enalapril maleate and an acid selected from fumaric acid, malic acid, maleic acid, succinic acid and tartaric acid.