DESC:A STABLE ORAL LIQUID PHARMACEUTICAL FORMULATION OF CLONIDINE

RELATED PATENT APPLICATIONS

This application claims priority to and benefit of the Indian Patent Application No. 202421025890 filed on March 29, 2024, the disclosures of which are incorporated herein by reference in its entirety as if fully rewritten herein.

Field of the invention

The present invention relates generally to a stable oral liquid pharmaceutical formulation of clonidine and one or more pharmaceutically acceptable excipients, a process for preparing such composition. The present invention relates particularly to a stable oral liquid pharmaceutical formulation of clonidine having buffer strength higher than 150 millimolar and process of preparing the same.

Background of the invention

Clonidine is a nearly 4 decades old antihypertensive medication that acts as an agonist on alpha-adrenergic and imidazoline receptors. Clonidine, (N-(2,6-dichloropheny1)-45-dihydro-1H-imidazol-2-amine), including its hydrochloride salt, is effective in treatment of a wide range of clinical disorders. Clonidine is particularly useful in treatment of circulatory disorders including hypertension and cardiovascular disease related thereto, congestive heart failure and cardiomyopathy.

Clonidine is available in multiple dosage forms, such as Transdermal Patch (extended-release), Tablet (immediate-release), Tablet (extended-release), Clonidine ER Oral Suspension and Injectable Solution. In recent times, Clonidine is also marketed as an oral solution. Oral liquid pharmaceutical compositions of clonidine are disclosed in WO2018002751A1, EP4122450A1, WO2023139464A1 and US20230149359A1.

In general, liquid formulations are rapidly available for absorption than tablets and capsules. Liquid formulations provide the maximum therapeutic response in patients who have problem of swallowing solid dosage forms and/or to produce rapid therapeutic effects. Liquid formulations have been widely used in pharmaceutics due to their high dosing flexibility, ease of swallowing, and quick onset of action. Thus, it is desirable to develop an alternative liquid pharmaceutical composition of Clonidine suitable for oral administration.
In the present invention, Inventors have surprisingly found that oral liquid pharmaceutical formulation of clonidine with a buffer strength exceeding 150 millimolar can be prepared with superior buffering capacity for enhanced stability and imparting unique salty-sweet taste. The present oral liquid pharmaceutical formulation of clonidine ensures optimal taste balance of salty and sweet notes for improved palatability.
Summary of the invention

The present inventors have surprisingly found that, oral liquid pharmaceutical formulation of clonidine with a buffer strength exceeding 150 millimolar can be prepared with superior buffering capacity for enhanced stability and imparting unique salty-sweet taste. The present oral liquid pharmaceutical formulation of clonidine ensures optimal taste balance of salty and sweet notes for improved palatability.
More specifically, the present invention describes Innovative buffering system using Di Potassium hydrogen Phosphate and Potassium dihydrogen Phosphate at a strength of 166 millimolar, resulting in enhanced palatability with a unique salty-sweet taste profile and improved stability.

As per one preferred embodiment the advantages of the present invention are:
1. Optimal buffering capacity: The buffer strength of 166 millimolar provided by Di Potassium hydrogen Phosphate and Potassium dihydrogen Phosphate ensures the maintenance of the solution's pH under unfavourable challenging condition.
2. Improved Patient Compliance: The unique salty-sweet taste potentially enhances patient compliance.
3. Improved Patient Comfort: The buffer strength of 166 milimolar and salty-sweet taste help to enhance patient comfort by reducing the adverse effects such as nausea or gastric upset.
4. Extended shelf life: The robust buffering capacity provided by the high buffer strength provides better shelf life.
In one of the aspects of the invention is provided stable oral liquid pharmaceutical formulation of clonidine comprising Clonidine hydrochloride, Methyl Parahydroxybenzoate as Preservative, Buffering agents, Sucralose as a Sweetening agent, Viscosity agent, and Water as a solvent; wherein the formulation has buffer strength higher than 150 millimolar.

In one of the aspects of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine, wherein the Buffering agents are Di Potassium hydrogen Phosphate and Potassium dihydrogen Phosphate.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine, wherein the Viscosity agent is Carmellose Sodium.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine, wherein the formulation has the pH between 5.5 to 6.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine, wherein the sucralose present in the composition has concentration of 0.1% w/v.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine having salty-sweet taste.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine having improved palatability.

In another aspect of the invention is provided a process for preparing stable oral liquid pharmaceutical formulation of clonidine; said process comprising:
a) taking required quantity of purified water in a main manufacturing vessel and heating it up to 50°C - 55°C;
b) adding methyl parahydroxybenzoate to hot water of step (a) and stirring the mixture until all the contents in the vessel are dissolved;
c) adding Potassium dihydrogen Phosphate to step (b) and stirring the mixture until all the contents in the vessel are dissolved;
d) adding Di Potassium hydrogen Phosphate to step (c) and stirring the mixture until all the contents in the vessel are dissolved;
e) adding Sucralose to step (d) and stirring the mixture until all the contents in the vessel are dissolved;
f) taking required quantity of purified water in another SS vessel and adding Carmellose sodium to it and stirring the mixture until all the contents in the vessel are dissolved;
g) adding Carmellose sodium of step (f) in a main manufacturing vessel by keeping the temperature below 35°C under continuous stirring;
h) taking required quantity of purified water in another SS vessel and adding Clonidine hydrochloride to it and stirring the mixture until all the contents in the vessel are dissolved;
i) transferring the step (h) solution to a main manufacturing vessel and stirring the mixture until all the contents in the vessel are dissolved and become clear;
j) adding purified water to make the bulk solution to the requisite batch weight;
k) filtering the step (j) solution through a 45 µm filter and storing the solution in SS storage tank;
l) filling the solution of step (k) into type III amber glass bottles.

In another aspect of the invention is provided a process for preparing stable oral liquid pharmaceutical formulation of clonidine; said process comprising specific steps wherein the buffers and preservative are added at more than 35°C in solution.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation, comprising less than about 1% total impurities following storage for three months at a temperature of 25°C, 30°C, and 40°C (±2°C). At temperature of 25°C the relative humidity is 60% (± 5 %) and at temperature of 30°C and 40°C the relative humidity is 75% (± 5 %).

DETAILED DESCRIPTION OF THE INVENTION

Reference will now be made to the exemplary embodiments, and specific language will be used herein to describe the same. It should nevertheless be understood that no limitation of the scope of the invention is thereby intended. Alterations and further modifications of the inventive features illustrated herein, which would occur to one skilled in the relevant art and having possession of this disclosure, are to be considered within the scope of the invention. It must be noted that, as used in this specification and the appended claims, the singular forms “a”, “an”, and “the” include plural referents unless the content clearly dictates otherwise.

The invention discloses a stable oral liquid pharmaceutical formulation of clonidine comprising clonidine hydrochloride and one or more pharmaceutically acceptable excipients, wherein the formulation has buffer strength higher than 150 millimolar, a process for preparing such compositions.

When referring to clonidine, unless otherwise specified or apparent from context it is understood that the inventors are also referring to the pharmaceutically acceptable salts of clonidine. One well-known commercially available salt for clonidine is its hydrochloride salt.

The terms “pharmaceutical composition,” “composition”, “formulation”, etc., refer to a pharmaceutical composition administered to a patient in need of treatment, including but not limited to tablet, oral suspension, oral solution, pellets, micro pellets, pills, compressed tablets, granules, spheres, capsules, powder for suspension, powder for solution and the like.

The terms “liquid pharmaceutical composition,” or “liquid composition” refer to a pharmaceutical composition administered to a patient in need of treatment, including solution or suspension.

The compositions according to the invention may further comprise one or more pharmaceutically acceptable excipients. Pharmaceutically acceptable excipients that can be used in the pharmaceutical composition of the present invention can be selected from a group comprising one or more preservatives, buffering agents, sweetening agents, viscosity agents, and solvents or the combinations thereof.

Preservatives are substances that are commonly added to pharmaceutical products in order to prolong their shelf life. The addition of preservatives to such products, especially to those that have higher water content, is essential for avoiding alteration and degradation by microorganisms during storage. A preservative is a natural or synthetic chemical added to various products which helps to prevent microbial decomposition. In the present invention, most preferable preservative is Methyl parahydroxybenzoate.
The term “buffer” or “buffering agent” as used herein, is an agent used to resist change in pH upon dilution or addition of acid or alkali. In certain embodiments, the pharmaceutical compositions of the present invention contain a buffer. In some embodiments as described herein, the buffer has buffer strength of more than 150 milimolar.
The term “sweetening agent” as used herein refers to sweeteners, which impart sweet taste to the preparation. In one embodiment, the pharmaceutically acceptable sweetener as described herein is sucralose. The concentration of the sweetening agent as described herein is 0.1% w/v.
Carboxymethylcellulose is a cellulose derivative that consists of the cellulose backbone made up of glucopyranose monomers and their hydroxyl groups bound to carboxymethyl groups. It is added as a viscosity modifier. Sodium carboxymethylcellulose (CMC) is the sodium salt of CMC or cellulose gum, an anionic derivative. Sodium CMC is widely used in oral, ophthalmic, injectable, and topical pharmaceuticals.
The term “shelf life” means the period beginning from the manufacture of a formulation and ending at a time after which the formulation cannot be expected beyond reasonable doubt to yield the therapeutic outcome approved by a government regulatory agency.

In one of the aspects of the invention is provided stable oral liquid pharmaceutical formulation of clonidine comprising Clonidine hydrochloride, Methyl Parahydroxybenzoate as Preservative, Buffering agents, Sucralose as a Sweetening agent, Viscosity agent, and Water as a solvent; wherein the formulation has buffer strength higher than 150 millimolar.

In one of the aspects of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine, wherein the Buffering agents are Di Potassium hydrogen Phosphate and Potassium dihydrogen Phosphate.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine, wherein the Viscosity agent is Carmellose Sodium.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine, wherein the formulation has the pH between 5.5 to 6.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine, wherein the sucralose present in the composition has concentration of 0.1% w/v.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine having salty-sweet taste.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation of clonidine having improved palatability.

In another aspect of the invention is provided a process for preparing stable oral liquid pharmaceutical formulation of clonidine; said process comprising:
a) taking required quantity of purified water in a main manufacturing vessel and heating it up to 50°C - 55°C;
b) adding methyl parahydroxybenzoate to hot water of step (a) and stirring the mixture until all the contents in the vessel are dissolved;
c) adding Potassium dihydrogen Phosphate to step (b) and stirring the mixture until all the contents in the vessel are dissolved;
d) adding Di Potassium hydrogen Phosphate to step (c) and stirring the mixture until all the contents in the vessel are dissolved;
e) adding Sucralose to step (d) and stirring the mixture until all the contents in the vessel are dissolved;
f) taking required quantity of purified water in another SS vessel and adding Carmellose sodium to it and stirring the mixture until all the contents in the vessel are dissolved;
g) adding Carmellose sodium of step (f) in a main manufacturing vessel by keeping the temperature below 35°C under continuous stirring;
h) taking required quantity of purified water in another SS vessel and adding Clonidine hydrochloride to it and stirring the mixture until all the contents in the vessel are dissolved;
i) transferring the step (h) solution to a main manufacturing vessel and stirring the mixture until all the contents in the vessel are dissolved and become clear;
j) adding purified water to make the bulk solution to the requisite batch weight;
k) filtering the step (j) solution through a 45 µm filter and storing the solution in SS storage tank;
l) filling the solution of step (k) into type III amber glass bottles.

In another aspect of the invention is provided a process for preparing stable oral liquid pharmaceutical formulation of clonidine; said process comprising specific steps wherein the buffers and preservative are added at more than 35°C in solution.

In another aspect of the invention is provided a stable oral liquid pharmaceutical formulation, comprising less than about 1% total impurities following storage for three months at a temperature of 25°C, 30°C, and 40°C (±2°C). At temperature of 25°C the relative humidity is 60% (± 5 %) and at temperature of 30°C and 40°C the relative humidity is 75% (± 5 %).

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the invention.

EXAMPLES
The following examples illustrate the embodiments of the invention that are presently best known. However, it is to be understood that the following are only exemplary or illustrative of the application of the principles of the present invention. Numerous modifications and alternative compositions, methods and systems may be devised by those skilled in the art without departing from the spirit and scope of the present invention. The appended claims are intended to cover such modifications and arrangements. Thus, while the present invention has been described above with particularity, the following examples provide further detail in connection with what are presently deemed to be the most practical and preferred embodiments of the invention.

The pharmaceutical compositions according to invention are formulated as oral solution. Table 1 provides the qualitative and quantitative compositions according to the invention.

Example 1: Clonidine HCl 50 mcg/5mL oral solution
The pharmaceutical composition as per below table 1 is formulated as oral solution.
Table 1. Pharmaceutical compositions according to the Example 1
Sr. Ingredients Function Mg / 5mL
1 Clonidine Hydrochloride * API 0.05
2 Methyl Parahydroxybenzoate * Preservative 9.00
3 Di Potassium hydrogen Phosphate Buffering agent 13.93
4 Potassium dihydrogen Phosphate Buffering agent 102.0
5 Sucralose Sweetening agent 5.00
6 Carmellose Sodium (Blanose 7H 3SFPH) Viscosity agent 0.01
7 Purified Water Solvent q.s
Quantity based on 100% potency.

Manufacturing Process in brief as under:

Dispense all the materials separately. Take sufficient quantity of purified water in jacketed stainless steel manufacturing vessel, stir and heat up-to 50 -55°C. Then to hot water, add Methyl Parahydroxybenzoate under continuous stirring and stir until dissolved. Add Potassium dihydrogen Phosphate and stir until dissolved. Add Di Potassium hydrogen Phosphate and stir until dissolved.
Then add Sucralose and stir until dissolved.
Take small qty of purified water in stainless steel vessel and dissolve Carmellose sodium (Blanose 7H 3SFPH).
When the bulk solution in main manufacturing vessel is less than 35°C, add Blanose solution under continuous stirring.
Take sufficient quantity of purified water in SS vessel, add carefully and dissolve Clonidine hydrochloride.
Transfer this API solution carefully to main manufacturing vessel. Rinse the SS vessel with sufficient quantity of purified water and add to above main manufacturing vessel. Stir until dissolved/homogeneous.
Check the clarity of the solution visually; it should be clear.
The bulk solution is made up to the requisite batch weight with purified water.
Filter the final solution through a 45 µm filter and store the solution in suitable SS storage tank.

BOTTLE FILING
Fill the solution and pack the filled bottles using packing materials - type III amber glass bottle and closure – tamper evident, child resistant white plastic cap (28 mm) consists of polypropylene inner, polyethylene outer, expanded polyethylene (EPE) liner.

Stability results:
The composition according to invention was tested for stability up to 12 months at a temperature of 25°C and at the relative humidity of 60% (± 5 %). The composition according to invention was also tested for stability up to 6 months at temperature of 30°C and 40°C and at the relative humidity of 75% (± 5 %). The results of the stability studies are provided in Table 2.

Table 2. Stability results of composition according to the invention
Condition Initial Temperature in °C/relative humidity in %
25°C/60% 30°C/75% 40°C/75%
1M 3 M 6M 12 M 1M 3 M 6 M 1M 2 M 3 M 6 M
Description Clear, colourless solution Complies Complies Complies Complies Complies Complies Complies Complies Complies Complies Complies
Weight/mL (g/mL) 1.0151 1.0150 1.01528 1.0147 1.0142 1.0153 1.01499 1.0148 1.0150 1.0154 1.01416 1.0147
pH 5.83 5.76 5.75 5.89 5.87 5.79 5.75 5.89 5.74 5.80 5.75 5.87
Assay Clonidine 100.9 % 101.3 101.7 101.6 103.7 100.7 100.7 104.0 101.2 103.9 101.6 101.8
Assay Methyl Paraben 98.4 % 102.3 100.5 100.7 98.9 102.8 100.5 100.6 102.7 100.7 99.8 99.0
Unspecified Impurities:
NMT 0.5 % Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected
Total impurities: NMT 1.0 % Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected Not detected

Based on the data presented in Table 2, the composition is stable.
,CLAIMS:We Claim:

1. A stable oral liquid pharmaceutical formulation of clonidine comprising:
Clonidine hydrochloride,
Methyl Parahydroxybenzoate as Preservative,
Buffering agents,
Sucralose as a Sweetening agent,
Viscosity agent, and
Water as a solvent;
wherein the formulation has buffer strength higher than 150 millimolar.
2. The liquid pharmaceutical formulation of clonidine as claimed in claim 1, wherein the Buffering agents are Di Potassium hydrogen Phosphate and Potassium dihydrogen Phosphate
3. The liquid pharmaceutical formulation of clonidine as claimed in claim 1, wherein the Viscosity agent is Carmellose Sodium
4. The liquid pharmaceutical formulation of clonidine as claimed in claim 1, wherein the formulation has the pH between 5.5 to 6
5. The liquid pharmaceutical formulation of clonidine as claimed in claim 1, wherein the sucralose present in the composition has concentration of 0.1% w/v.
6. The liquid pharmaceutical formulation of clonidine as claimed in claim 1 has salty-sweet taste.
7. The liquid pharmaceutical formulation of clonidine as claimed in claim 1 has improved palatability.
8. A process of preparation of stable oral liquid pharmaceutical formulation of clonidine comprises the steps of;
a) taking required quantity of purified water in a main manufacturing vessel and heating it up to 50°C - 55°C
b) adding methyl parahydroxybenzoate to hot water of step (a) and stirring the mixture until all the contents in the vessel are dissolved;
c) adding Potassium dihydrogen Phosphate to step (b) and stirring the mixture until all the contents in the vessel are dissolved;
d) adding Di Potassium hydrogen Phosphate to step (c) and stirring the mixture until all the contents in the vessel are dissolved;
e) adding Sucralose to step (d) and stirring the mixture until all the contents in the vessel are dissolved;
f) taking required quantity of purified water in another SS vessel and adding Carmellose sodium to it and stirring the mixture until all the contents in the vessel are dissolved;
g) adding Carmellose sodium of step (f) in a main manufacturing vessel by keeping the temperature below 35°C under continuous stirring;
h) taking required quantity of purified water in another SS vessel and adding Clonidine hydrochloride to it and stirring the mixture until all the contents in the vessel are dissolved;
i) transferring the step (h) solution to a main manufacturing vessel and stirring the mixture until all the contents in the vessel are dissolved and become clear;
j) adding purified water to make the bulk solution to the requisite batch weight;
k) filtering the step (j) solution through a 45 µm filter and storing the solution in SS storage tank;
l) filling the solution of step (k) into type III amber glass bottles.

9. The process according to Claim 8, wherein the buffers and preservative are added at more than 35°C in solution.