Description:FIELD OF THE INVENTION

The present invention relates to a stable pharmaceutical liquid composition for oral administration comprising lisinopril or its pharmaceutically acceptable salt thereof, and one or more pharmaceutically acceptable excipients and process of its preparation. The invention also relates to methods of treating hypertension and other cardiovascular diseases, in a patient by administering composition comprising a therapeutically effective amount of Lisinopril.

BACKGROUND OF THE INVENTION
Hypertension, or high blood pressure, is a serious health issue in many countries. 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. Hypertension is considered a substantial risk factor for cardiovascular and other diseases including coronary heart disease, myocardial infarction, congestive heart failure, stroke and kidney failure.

A number of antihypertensive drugs are available for treating hypertension. Various therapeutic classes of antihypertensive drugs include 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. Angiotensin-converting enzyme (ACE) inhibitors inhibit angiotensin-converting enzyme (ACE), a peptidyl dipeptidase that catalyzes angiotensin I to angiotensin II, a potent vasoconstrictor involved in regulating blood pressure.

Lisinopril is a drug belonging to the angiotensin-converting enzyme (ACE) inhibitor class of medications. Chemically, Lisinopril is (1S)-1-carboxy-3-phenylpropyl-L-lysyl-L-proline. It has the following structure:

Lisinopril is disclosed in U.S. Patent Nos. 4,374,829 and 4,472,380.

US patent Numbers 9,463,183; 9,616,096; 9,814,751; 10,039,800; 10,265,370; 10,406,199 & 10,940,177 discloses oral liquid Lisinopril formulation and incorporated herein by reference, claims oral liquid composition comprising lisinopril, Xylitol, Citric acid and sodium citrate & Sodium benzoate with pH of about 4 to 5.

U.S. Food and Drug Administration has approved Azurity’s QBRELIS (Lisinopril Oral solution) for the treatment of hypertension in adults and pediatric patients 6 years of age and older, adjunct therapy for heart failure and acute myocardial infarction.

Inventors of the present invention have developed a stable oral solution composition of lisinopril or pharmaceutically acceptable salt and pharmaceutically acceptable excipients. The solution of the present invention has good stability.

The present invention provides a pharmaceutical composition for oral administration, particularly in the form of a solution comprising Lisinopril or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable excipients. The composition provides efficient stability of active ingredient and reproducible results.

SUMMARY OF THE INVENTION
In one aspect, the invention relates to a liquid pharmaceutical composition comprising lisinopril or its pharmaceutically acceptable salts thereof and at least one pharmaceutically acceptable excipient.

In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) Lisinopril or pharmaceutically acceptable salt thereof;
b) Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof.

In another aspect, the invention provides a liquid pharmaceutical composition, comprising:
a) 0.05- 2% w/w of Lisinopril or pharmaceutically acceptable salt;
b) 0.02 – 10% w/w of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.02 – 10% w/w of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof.

In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.05 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener.

In another aspect, the invention provides a liquid pharmaceutical composition, comprising:
a) 0.05- 2% w/w of Lisinopril or pharmaceutically acceptable salt;
b) 0.02 – 10% w/w of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.02 – 10% w/w of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 80 – 99% w/w of Xylitol as Sweetener.

In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener,

In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) Lisinopril or pharmaceutically acceptable salt thereof;
b) Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof,
wherein the composition contains less than 0.5% w/w of the individual impurity and not more than 1% w/w of total impurities relative to lisinopril when measured by HPLC after storage for 3 months at 40oC/75% relative humidity.

In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener,
wherein the weight ratio of lisinopril to buffering agent is 1:0.5 to 1:10.

In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener,
wherein said composition is having a pH of 3.0 to 5.5.
In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener;
wherein the weight ratio of lisinopril to preservative is 1:0.1 to 1: 5.

In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener;
wherein said composition comprising more than 90% by weight of xylitol based on total weight of the composition.

In another aspect, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener,
wherein said liquid composition is in the form of solution.

DETAILED DESCRIPTION OF THE INVENTION
The term “composition” or “pharmaceutical composition” or “liquid pharmaceutical composition” are used herein synonymously such as solutions (aqueous and non-aqueous), suspensions, emulsions, syrups, elixirs and the like meant for oral administration, preferably, solutions.

Within the context of this invention, the term “solution” refers to a mixture of one or more substances dispersed molecularly (i.e., dissolved) in a dissolving liquid medium or vehicle. The solution is preferably homogeneous, in the sense that API is essentially uniformly distributed and concentrated in the solution. The liquid solution may be viscous (such as syrup) or not. As already mentioned, a liquid solution differs from a suspension which comprises solid particles dispersed throughout a liquid phase in which they are not soluble.

The term “excipient” means a pharmacologically inactive component such as a preservative, a buffering agent, a sweetener, a flavor etc., of a pharmaceutical product. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and are acceptable for human pharmaceutical use. Reference to an excipient includes both one and more than one such excipients.

The term “Lisinopril” as used herein, refers to lisinopril 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. Preferably, the lisinopril used in the formulations described herein is lisinopril base.

The term "treating" or "treatment" refers to obtaining desired pharmacological and/or physiological effect. The effect can be therapeutic, which includes achieving, partially or substantially, one or more of the following results: partially or totally reducing the extent of the disease, disorder or syndrome; ameliorating or improving a clinical symptom or indicator associated with the disorder or delaying, inhibiting or decreasing the likelihood of the progression of the disease, disorder or syndrome.

The term “about” is used herein to mean approximately, roughly, around, or in the regions of. When the term "about" is used in conjunction with a numerical range, it modifies that range by extending the boundaries above and below the numerical values set forth. In general, the term "about" is used herein to modify a numerical value above and below the stated value by a variance of 10 percent.

The terms “stable” and “stability” mean that the evolution of the product with time and/or under specific environmental conditions (i.e., temperature, humidity, etc.) has no significant effects on its quality, safety and/or efficacy for a given time period. It can be measured through the formation of degradation products (impurities), variation of pH, appearance (precipitation), microbial growth, and/or color. The term “Stable” indicates both chemical and physical stability.

In another embodiment, the invention provides a liquid composition comprising a Lisinopril or a pharmaceutically acceptable salt thereof.

In another embodiment, the invention provides a liquid composition comprising Lisinopril or pharmaceutically acceptable salt thereof and further comprising at least one pharmaceutical acceptable excipient selected from the group comprising buffering agent, sweetener and Preservative.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) Lisinopril or pharmaceutically acceptable salt thereof;
b) Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof.
In another embodiment, the invention provides a liquid pharmaceutical composition, comprising:
a) 0.05- 2% w/w of Lisinopril or pharmaceutically acceptable salt;
b) 0.02 – 10% w/w of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.02 – 10% w/w of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.05 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener.

In another embodiment, the invention provides a liquid pharmaceutical composition, comprising:
a) 0.05- 2% w/w of Lisinopril or pharmaceutically acceptable salt;
b) 0.02 – 10% w/w of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.02 – 10% w/w of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 80 – 99% w/w of Xylitol as Sweetener.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) Lisinopril or pharmaceutically acceptable salt thereof;
b) Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof,
wherein the composition contains less than 0.5% w/w of the individual impurity and not more than 1% w/w of total impurities relative to lisinopril when measured by HPLC after storage for 3 months at 40oC/75% relative humidity.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener;
wherein weight ratio of lisinopril to buffering agent is 1:0.5 to 1:10.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener;
wherein said composition is having a pH between about 3 to about 5.5.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener;
wherein the weight ratio of lisinopril to preservative is 1:0.1 to 1: 5.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener;
wherein the weight ratio of preservative to buffering agent is 1:2 to 1: 10.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener;
wherein said composition comprising a xylitol content of more than 90% by weight based on total weight of the composition.

In another embodiment, the invention provides a liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.1 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate, acetic acid and Glacial acetic acid or combination thereof;
c) 0.01 – 15 mg/ml of Preservative selected from Benzyl alcohol, Sodium propionate, Potassium propionate, Calcium propionate and Zirconium propionate or combination thereof;
d) 100 – 200 mg/ml of Xylitol as Sweetener,
wherein said liquid composition is in the form of solution.

The term "buffering agent" as used herein is defined as an agent to maintain pH of the lisinopril oral liquid formulation. Non-limiting examples of buffering agents include, but are not limited to Citric acid, Sodium acetate, Dibasic sodium phosphate, acetic acid and Glacial acetic acid or combination thereof. Preferably the buffering agents are selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof. The buffering agents according to present invention may be present in an amount from about 0.02% to about 10% by weight with respect to total weight of the pharmaceutical composition, preferably 0.2% to about 8%, more preferably 0.5% to about 7%.

The term "Sweetener" as used herein is defined 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. Non-limiting examples of sweeteners include, but are not limited to sucralose, xylitol, saccharin. Preferably the sweetener is xylitol. The sweetener according to present invention may be present in an amount from about 75% to about 99% by weight with respect to total weight of the pharmaceutical composition, preferably 80% to 99% w/w, more preferably 90% to 98% w/w.

The term "Preservative" as used herein is defined as an agent prevent or retard spoilage caused by chemical changes, such as oxidation or the growth of microorganisms. Preservatives include anti-microbials, anti-oxidants, and agents that enhance sterility. Non-limiting examples of preservatives include, but are not limited to ascorbic acid, ascorbyl palmitate. BHA, BHT, citric acid, erythorbic acid, fumaric acid, malic acid, propyl gallate, sodium ascorbate, sodium bisulfate, sodium meta bisulfite, sodium Sulfite, parabens (such as methylparaben, ethylparaben, propylparaben, butylparaben and their salts), benzyl alcohol, benzoic acid, Sodium benzoate, Sodium propionate & potassium Sorbate. Preferably the preservatives are selected from benzyl alcohol or sodium propionate or combination thereof. The preservatives according to present invention may be present in an amount from about 0.05% to about 10% by weight with respect to total weight of the pharmaceutical composition, preferably 0.1% to 8% w/w, more preferably 0.15% to 5% w/w.

Inventors of the present invention have surprisingly found that a stable oral liquid formulation, particularly solution comprising lisinopril can be prepared with pharmaceutically acceptable buffering agents selected from Glacial acetic acid, sodium acetate, anhydrous citric acid, disodium phosphate or combination thereof with specific percentages and preservative selected from benzyl alcohol & sodium propionate or combination thereof with specific percentages.

Surprisingly, it has been found that pharmaceutical composition of the present invention showed good stability coupled with simple manufacturing process at industrial scale and it is bioequivalent to commercially available counterpart oral solution of QBRELIS®.

The following examples serve to illustrate the embodiments of the present invention. However, they do not intend to limit the scope of the invention. It is obvious to those skilled in the art to find out the composition for other dosage forms and substitute the equivalent excipients as described in this specification or with the one known to the industry.

Comparative Example: Lisinopril oral solution with acetate buffer and Potassium Sorbate as preservative:

S. No ingredient Category Comparative Example (mg/mL)
1. Lisinopril Drug 1.00
2. Glacial acetic acid Buffering agent 2.74
3. Sodium acetate Buffering agent 2.99
4. Xylitol Sweetener 150.00
5. Potassium sorbate Preservative 1.00
6. Purified water Vehicle q.s

Manufacturing process:
1. Dispense all ingredients as per the formula
2. Add Potassium sorbate to part of purified water under stirring and continue the stirring till clear solution formed.
3. Add sodium acetate followed by glacial acetic acid to above step under stirring and continue the stirring till clear solution formed.
4. Add Xylitol to above step under stirring and continue the stirring till clear solution formed.
5. Add Lisinopril to above step under stirring and continue the stirring till clear solution formed
6. Make up the volume with purified water
7. Adjust pH of the solution from 4.3 – 5.1.

Stability data:
Related Substances RLD (Qbrelis) Comparative Example
Initial 1M
(40°C/75%RH) Initial 2 M
(40°C/75%RH)
N-Alkyl-L-lysine (Impurity-H) 0.138 0.232 0.078 0.351
S, S, S-Diketopiperazine (Lisinopril Related compound A) 0.028 0.082 0.023 0.040
Any unspecified individual degradation product 0.000 0.062 1.371 2.926
Total Impurities 0.166 0.376 1.901 4.137

Example 1 - 2: Lisinopril oral solution with acetate buffer and Benzyl alcohol as preservative.

S. No ingredient Category Example- 1 Example- 2
mg/mL mg/mL
1. Lisinopril Drug 1.00 1.00
2. Glacial acetic acid Buffering agent 3.673 1.68
3. Sodium acetate Buffering agent 2.99 2.99
4. Xylitol Sweetener 150.00 150.00
5. Benzyl alcohol Preservative 1.00 0.7
6. Purified water Vehicle q.s q.s

Manufacturing process:
1. Dispense all ingredients as per the formula
2. Add benzyl alcohol to part of purified water under stirring and continue the stirring till clear solution formed.
3. Add sodium acetate followed by glacial acetic acid to above step under stirring and continue the stirring till clear solution formed.
4. Add Xylitol to above step under stirring and continue the stirring till clear solution formed.
5. Add Lisinopril to above step under stirring and continue the stirring till clear solution formed
6. Make up the volume with purified water
7. Adjust pH of the solution from 4.3 – 5.1.

Stability data:
Related Substances RLD (Qbrelis)
Comparative Example
Example 1 Example 2
Initial 1M
(40°C/75%RH) Initial 2M
(40°C/75%RH) Initial 1 M
(40°C/75%RH)
N-Alkyl-L-lysine (Impurity-H) 0.138 0.232 0.118 0.598 0.042 0.157
S, S, S-Diketopiperazine (Lisinopril Related compound A) 0.028
0.082 0.012 0.031 0.028 0.039
Any unspecified individual degradation product 0.000
0.062 0.000 0.000 0.000 0.000
Total Impurities 0.166 0.376 0.130 0.629 0.070 0.196

Example 3: Lisinopril oral solution with citrate- phosphate buffer and sodium propionate as preservative.

S. No ingredient Category Example - 3 (mg/ mL)
1. Lisinopril Drug 1.00
2. Anhydrous Citric acid Buffering agent 1.035
3. Di basic sodium phosphate anhydrous Buffering agent 0.710
4. Xylitol Sweetener 150.00
5. Sodium propionate Preservative 1.00
6. Purified water Vehicle q.s

Manufacturing process:
1. Dispense all ingredients as per the formula
2. Add Sodium propionate to part of purified water under stirring and continue the stirring till clear solution formed.
3. Add Citric acid followed by Dibasic sodium phosphate anhydrous acid to above step under stirring and continue the stirring till clear solution formed.
4. Add Xylitol to above step under stirring and continue the stirring till clear solution formed.
5. Add Lisinopril to above step under stirring and continue the stirring till clear solution formed
6. Make up the volume with purified water
7. Adjust pH of the solution from 4.3 – 5.1.

Stability data:
Related Substances RLD
(Qbrelis) Example-3
Initial Initial
N-Alkyl-L-lysine (Impurity-H) 0.138 0.039
S, S, S-Diketopiperazine (Lisinopril Related compound A) 0.028 0.043
Any unspecified individual degradation product 0.000
0.000
Total Impurities 0.166 0.082

Example 4: Lisinopril oral solution with citrate- phosphate buffer and Benzyl alcohol as preservative.

S. No ingredient Category Example 4 (mg/ mL)
1. Lisinopril Drug 1.00
2. Anhydrous Citric acid Buffering agent 0.572
3. Di basic sodium phosphate anhydrous Buffering agent 0.710
4. Xylitol Sweetener 150.00
5. Benzyl alcohol Preservative 3.00
6. Purified water Vehicle q.s

Manufacturing process:
1. Dispense all ingredients as per the formula
2. Add Benzyl alcohol to part of purified water under stirring and continue the stirring till clear solution formed.
3. Add Citric acid followed by Dibasic sodium phosphate anhydrous acid to above step under stirring and continue the stirring till clear solution formed.
4. Add Xylitol to above step under stirring and continue the stirring till clear solution formed.
5. Add Lisinopril to above step under stirring and continue the stirring till clear solution formed
6. Make up the volume with purified water
7. Adjust pH of the solution from 4.3 – 5.1.

Stability data:

Related Substances RLD (Qbrelis) Example - 4
Initial Initial 40°C/75%RH
3 M
N-Alkyl-L-lysine (Impurity-H) 0.138 0.017 0.154
S, S, S-Diketopiperazine (Lisinopril Related compound A) 0.028 0.036 0.342
Any unspecified individual degradation product 0.000 0.000 0.061
Total Impurities 0.166 0.053 0.557

, Claims:WE CLAIM:

1. A liquid pharmaceutical composition comprising:
a) Lisinopril or pharmaceutically acceptable salt thereof;
b) Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof.

2. A liquid pharmaceutical composition comprising:
a) 1mg/ml of Lisinopril or pharmaceutically acceptable salt;
b) 0.5 – 25 mg/ml of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.05 – 5 mg/ml of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof; and
d) 100 – 200 mg/ml of Xylitol as Sweetener,
wherein the composition contains less than 0.5% w/w of the individual impurity and not more than 1% w/w of total impurities relative to lisinopril when measured by HPLC after storage for 3 months at 40oC/75% relative humidity.

3. A liquid pharmaceutical composition comprising:
a) 0.05- 2% of Lisinopril;
b) 0.02 – 10% of Buffering agent selected from Citric acid, Sodium acetate, Dibasic sodium phosphate and Glacial acetic acid or combination thereof;
c) 0.05 – 10% of Preservative selected from Benzyl alcohol and Sodium propionate or combination thereof.
wherein the weight ratio of lisinopril to buffering agent is 1: 0.5 to 1:5.

4. The liquid pharmaceutical composition as claimed in claims 1 - 3, the weight ratio of lisinopril to preservative is 1:0.2 to 1: 10.

5. The liquid pharmaceutical composition as claimed in claims 1 - 3, weight ratio of buffering agent to preservative is 1 :2 to 1: 10.

6. The liquid pharmaceutical composition as claimed in claims 1 - 3, further comprises water.

7. The liquid pharmaceutical composition as claimed in claims 1 - 3, wherein the buffering agent maintains a pH from 3 to 5.5 in the composition.

8. The liquid pharmaceutical composition as claimed in claims 1 - 3, is in the form of solution.