SUSTAINED-RELEASE GUANFACINE FORMULATION AND RELATED METHODS

Abstract

The sustained-release tablet composition features Guanfacine as an active ingredient, providing controlled-release delivery for extended therapeutic action and reduced dosing frequency. The composition includes a controlled-release matrix formed by hydroxypropyl methylcellulose (HPMC), which extends the release of Guanfacine, ensuring consistent delivery and steady blood levels. Additional components may include lubricants and disintegrant. The method of treating ADHD or hypertension involves administering the tablet once daily, maintaining steady-state plasma concentration over 12 to 24 hours, and reducing side effects associated with immediate-release formulations. The preparation process involves mixing, granulating, drying, and compressing the ingredients to form the tablet. Reference Fig 1

Specification

Description:DETAILED DESCRIPTION
[0025] In one embodiment, the sustained-release tablet composition comprises Guanfacine Hydrochloride as the active pharmaceutical ingredient, which is utilized for treating Attention Deficit Hyperactivity Disorder (ADHD) and hypertension. The amount of Guanfacine Hydrochloride in the tablet ranges from 1 mg to 4 mg, providing the therapeutic effect while benefiting from the sustained-release formulation.

[0026] [0026] In another embodiment, the composition includes Hydroxypropyl Methylcellulose (HPMC) as a controlled-release matrix former. The HPMC is present in an amount ranging from 10 mg to 40 mg per tablet. This excipient controls the release of Guanfacine over an extended period, allowing for steady therapeutic levels in the bloodstream and avoiding fluctuations typically seen with immediate-release formulations. In another embodiment, the ratio of Guanfacine to Hydroxypropyl Methylcellulose (HPMC) ranges from about 1:1 to about 1:10 by weight. The Guanfacine is present in an amount ranging from about 0.5 mg to about 10 mg per tablet, and the Hydroxypropyl Methylcellulose (HPMC) has a viscosity ranging from about 100 cps to about 100,000 cps.
[0027] In a further embodiment, the sustained-release tablet includes microcrystalline cellulose (MCC), which serves as both a filler and binder. The MCC is present in an amount ranging from 40 mg to 60 mg per tablet. Its function is to provide bulk and structural integrity, enabling efficient tablet formation during the manufacturing process.

[0028] In an additional embodiment, lactose monohydrate is used as a filler, present in an amount ranging from 40 mg to 60 mg per tablet. This excipient adds bulk to the tablet, ensuring uniformity and facilitating the binding of ingredients to maintain tablet integrity.

[0029] In yet another embodiment, magnesium stearate is used as a lubricant in an amount ranging from 1 mg to 4 mg per tablet. magnesium stearate helps to prevent sticking during the compression process, ensuring smooth ejection of the tablet from the press and improving the tablet's overall handling.

[0030] In one further embodiment, stearic acid is included as both a lubricant and a release modifier, in an amount ranging from 0.1 mg to 10 mg per tablet. stearic acid works in conjunction with magnesium stearate to enhance the manufacturing process by reducing friction and promoting controlled release of the active ingredient.

[0031] In another embodiment, the composition contains colloidal silicon dioxide as an anti-caking agent and flow enhancer. Present in an amount ranging from 0.1 mg to 5 mg per tablet, Colloidal Silicon Dioxide improves the flow properties of the powder mixture, ensuring uniformity during the tablet formation process and preventing clumping of the ingredients.

[0032] In a further embodiment, polyvinylpyrrolidone (PVP) is used as a binder, present in an amount ranging from 1 mg to 10 mg per tablet. The PVP binds the ingredients during tablet formation, ensuring the structural cohesion of the compressed mixture, thus enhancing the mechanical properties of the tablet.

[0033] In yet another embodiment, talc is used as an anti-adherent to prevent sticking during compression, present in an amount ranging from 0.1 mg to 10 mg per tablet. The inclusion of Talc ensures that the tablet surfaces remain smooth and that the production process is not interrupted by adhesion to equipment.

[0034] In a further embodiment, sodium starch glycolate is used as a disintegrant, present in an amount ranging from 1 mg to 5 mg per tablet. Sodium starch glycolate ensures that the tablet disintegrates appropriately in the gastrointestinal tract, facilitating the controlled absorption of Guanfacine.

[0035] Finally, in an additional embodiment, purified water is used as a granulating solvent during the wet granulation process. The water aids in the formation of granules, which, after drying, provide a uniform mixture for compression into tablets. The water evaporates during the drying process, leaving behind a cohesive granulated mixture that facilitates the sustained-release properties of the composition.

[0036] In one embodiment, the sustained-release tablet composition of Guanfacine Hydrochloride and Hydroxypropyl Methylcellulose (HPMC) is prepared by first weighing the required amounts of Guanfacine Hydrochloride (ranging from 1 mg to 4 mg per tablet), Hydroxypropyl Methylcellulose (HPMC) (ranging from 10 mg to 40 mg per tablet), and other excipients, such as Microcrystalline Cellulose (MCC), Colloidal Silicon Dioxide, and Sodium Starch Glycolate. The dry ingredients are then thoroughly mixed in a high-shear granulator to ensure uniform distribution of Guanfacine Hydrochloride within the powder blend.

[0037] Purified Water is then gradually added to the dry mixture as a granulating solvent, forming wet granules. The addition of water is carefully controlled to avoid overwetting, and the mixture is continuously agitated until cohesive granules are formed. This wet granulation process may be conducted using a high-shear mixer or a fluidized bed granulator.

[0038] After granulation, the wet granules are dried using a fluid bed dryer or tray dryer at temperatures typically ranging from 40°C to 60°C. The drying process continues until the moisture content of the granules falls below 2%, ensuring that the water used during granulation is completely evaporated. Once dry, the granules are passed through a sieve to break up any agglomerates, ensuring uniformity and free-flowing properties.

[0039] Next, the dried granules are blended with additional excipients, such as magnesium stearate (used as a lubricant) and stearic acid (used as a lubricant and release modifier). This ensures that the granules flow smoothly and do not stick to the tablet press during compression.

[0040] Finally, the granules are compressed into tablets using a rotary tablet press. The compression process is controlled to ensure that each tablet contains the appropriate amount of active ingredient and excipients and that the tablets exhibit the desired mechanical strength. The compressed tablets are then subjected to quality checks, including tests for hardness, friability, and dissolution, to confirm the integrity of the sustained-release formulation.


EXAMPLES
[0041] Oral composition of Guanfacine in a sustained-release tablet form:
Component Quantity (per tablet)
Guanfacine Hydrochloride 1 mg-4 mg
Hydroxypropyl Methylcellulose (HPMC) 10 mg-40 mg
Microcrystalline Cellulose (MCC) 40-60 mg
Lactose Monohydrate 40 mg-60 mg
Magnesium Stearate 1 mg-4 mg
Colloidal Silicon Dioxide 0.1mg-5 mg
Polyvinylpyrrolidone (PVP) 1 mg-10 mg
Stearic Acid 0.1mg-10 mg
Talc 0.1mg-10 mg
Sodium Starch Glycolate 1mg-5mg
Purified Water (used in granulation) QS (quantum sufficient)

[0042] Example 2
Component Quantity (per tablet)
Guanfacine Hydrochloride 2 mg
Hydroxypropyl Methylcellulose (HPMC) 20 mg
Microcrystalline Cellulose (MCC) 50 mg
Lactose Monohydrate 40 mg
Magnesium Stearate 1 mg
Colloidal Silicon Dioxide 0.5 mg
Polyvinylpyrrolidone (PVP) 5 mg
Stearic Acid 1 mg
Talc 1 mg
Sodium Starch Glycolate 3 mg
Purified Water (used in granulation) QS (quantum sufficient)


[0043] Example 3: Stability Testing Parameters- The following parameters were evaluated at different time points for each condition:
• Assay (% of active ingredient)
• Appearance (color, physical defects)
• Dissolution rate
• Hardness
• Friability (% weight loss)
• Moisture content

[0044] 1. Long-term stability conditions (25°C ± 2°C / 60% RH ± 5%)
Test Initial 1 Month 3 Months 6 Months
Assay (% of label claim) 100% 99.8% 99.6% 99.3%
Appearance White White White White
Dissolution (12 hrs) 85% 85% 84% 83%
Hardness (kP) 7.0 6.9 6.8 6.7
Friability (% weight loss) 0.2% 0.2% 0.3% 0.3%
Moisture Content (%) 1.0% 1.1% 1.2% 1.3%

2. Accelerated stability conditions (40°C ± 2°C / 75% RH ± 5%)

Test Initial 1 Month 3 Months 6 Months
Assay (% of label claim) 100% 98.5% 97.0% 95.5%
Appearance White Slightly discolored Discolored Discolored
Dissolution (12 hrs) 85% 83% 80% 78%
Hardness (kP) 7.0 6.6 6.3 6.0
Friability (% weight loss) 0.2% 0.4% 0.5% 0.6%
Moisture Content (%) 1.0% 1.3% 1.5% 1.8%

[0045] Example 4: In-vitro Release Profile-
Dissolution Conditions
Medium: 0.1 N Hydrochloric acid (pH 1.2) for 2 hours, followed by phosphate buffer (pH 6.8) for the remainder of the test.
Volume: 900 mL
Apparatus: USP Type II (Paddle)
Rotation speed: 50 rpm
Temperature: 37°C ± 0.5°C
Sampling Intervals: 1 hr, 2 hrs, 4 hrs, 6 hrs, 8 hrs, 12 hrs, and 24 hrs.

Time (hrs) % Guanfacine Released
1 19.5%
2 28.7%
4 44.8%
6 61.2%
8 74.6%
12 85.3%
24 94.7%

, Claims:CLAIMS
We claim:
1. A sustained-release tablet composition comprising:
guanfacine as an active ingredient, providing controlled-release delivery, extended therapeutic action, and reduced dosing frequency; and
a controlled-release matrix formed by hydroxypropyl methylcellulose (hpmc), which ensures consistent controlled release over time, prevents peaks and troughs typical of immediate-release formulations, and maintains steady blood levels.

2. The sustained-release tablet composition as claimed in claim 1, further comprising one or more excipients, including:
lubricants selected from magnesium stearate and stearic acid to ensure smooth tablet compression;
flow enhancers like colloidal silicon dioxide to maintain powder flow and improve the manufacturing process;
disintegrants such as sodium starch glycolate to aid tablet breakdown in the gastrointestinal tract for effective absorption.

3. The sustained-release tablet composition as claimed in claim 1, wherein the controlled-release matrix formed by hydroxypropyl methylcellulose (HPMC) improves therapeutic outcomes, reduces side effects, and enhances patient compliance by allowing for once-daily dosing.

4. The sustained-release tablet composition as claimed in claim 1, wherein:
the ratio of guanfacine to hydroxypropyl methylcellulose (HPMC) ranges from about 1:1 to about 1:10 by weight;
the guanfacine is present in an amount ranging from about 0.5 mg to about 10 mg per tablet; and
the hydroxypropyl methylcellulose (HPMC) has a viscosity ranging from about 100 cps to about 100,000 cps.
5. The sustained-release tablet composition as claimed in claim 1, further comprising purified water used during a wet granulation process, wherein the water assists in granulation and evaporates during drying, aiding in the uniformity of the granules.

6. The sustained-release tablet composition as claimed in claim 1, wherein the tablet is formulated for oral administration and provides extended release over a period of about 12 to about 24 hours.

7. A method of treating attention deficit hyperactivity disorder (ADHD) or hypertension, comprising administering to a patient a therapeutically effective amount of the sustained-release tablet composition as claimed in claim 1, wherein the composition is administered once daily to maintain steady-state plasma concentration of Guanfacine.

8. The method as claimed in claim 7, wherein the sustained-release tablet composition reduces side effects typically associated with immediate-release formulations of Guanfacine, such as drowsiness, sedation, and hypotension.

9. A process for preparing the sustained-release tablet composition as claimed in claim 1, comprising:
mixing guanfacine, hydroxypropyl methylcellulose (HPMC), and optionally one or more excipients;
granulating the mixture using purified water;
drying the granules, followed by optionally mixing with additional excipients; and
compressing the granules into tablets.

10. The process as claimed in claim 9, wherein:
the excipients in the mixture or during post-drying include lubricants, flow enhancers, and disintegrants;
the granulation step is performed using a wet granulation technique; and
the drying step is performed using a fluid bed dryer or a tray dryer.

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