Zero-Order 24 Hour Release Through the Use of Encapsulated Mini-Tab Technology

For applications with low-dose, highly water soluble drugs

Introduction

Extended release of highly soluble drugs using diffusion-driven systems such as

hydrophilic matrix tablets or encapsulated coated bead technologies, yields first-order dissolution kinetics. This study shows how encapsulated, coated mini-tabs can provide

near zero-order, 24-hour dissolution for a highly soluble drug.

Why Zero-Order?

Why Zero-Order?

• Drug – hydrochloride salt – MW~ 300 amu

• Solubility: – In water: >20mg/mL

– In buffered solutions between pH 2 – 7.4: >10mg/mL

API

API Particle Size Analysis

Three Formulation Approaches

Hydrophilic Matrix Tablet (HPMC-based)

• Yielded extended release for 10-12 hours – first order kinetics

Hydrophobic / Hydrophilic Matrix

Tablet

• Yielded extended release for 24+ hours – first order kinetics

Encapsulated, Coated Mini-Tabs

• Yielded extended release for 24+ hours – near zero order kinetics

• HPMC Based Formulations - Matrix Tablet – Good for soluble drugs but gives a first-order release

(diffusion driven)

– Poorly soluble drugs result in closer to a zero-order release (erosion driven)

– Simplest, quickest approach

– Can be manufactured by direct compression Doesn’t flow very well

Doesn’t compact very well

– HPMC K200M – highest molecular weight available (Benecel 874) Likely need to use high level ~ 30%

First Formulation Approach

• High mw HPMC polymer as primary release controlling component

• Dose: 0.75mg

• Process: direct compression

HPMC Formulations

Ingredients Mg/tab

Formulation A B C

Drug HCl 0.75 0.75 0.75

HPMC K200M – Benecel 874

52.0

(26%)

56.0

(28%)

60.0

(30%)

Microcrystalline Cellulose (Emcocel)

145.25 141.25 137.25

Silica 1.0 1.0 1.0

Magnesium Stearate 1.0 1.0 1.0

Total 200.0 200.0 200.0

HPMC-Based Formulations

Dissolution of API vs. Formulations Containing Various Amounts of HPMC (in pH 6.8, @ 37ºC, paddles, 50 rpm.)

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Drug

26%

28%

30%

HPMC-Based Formulations

• Failed to extend drug release out to 24-hours – Increasing polymer content slowed release more

– Adding more polymer would impact tablet integrity and may require granulation (challenging)

• Failed to yield a zero-order release profile

• HPMC as the primary control release excipient was dropped

HPMC-Based Formulations – Outcome

• Hydrophilic / Hydrophobic Matrix Tablet – Combination of TIMERx (proprietary hydrophilic matrix

consisting of xanthan and locust bean gums) and cetyl alcohol (fatty alcohol) and carnauba wax to further retard release

– Manufactured by wax granulation (melt granulation) process

– Two variants One with TIMERx and cetyl alcohol

One with TIMERx, cetyl alcohol and carnauba wax

Second Formulation Approach

Formulation A

Ingredients % w/w Mg/tab

Drug HCl 0.25 0.75

TIMERx M70A 65.22 195.66

SMCC (Prosolv 90) 22.20 66.60

Cetyl Alcohol 11.33 33.99

Silica (Aerosil 200) 0.50 1.50

Magnesium Stearate 0.50 1.50

Total 100.0 300.0

Wax-Based Formulations

Formulation B

Ingredients % w/w Mg/tab

Drug HCl 0.186 0.75

Cetyl Alcohol 4.197 17.00

Carnauba Wax 4.197 17.00

Dicalcium Phospate dihydrate (Emcompress) 11.32 45.85

TIMERx M70A 73.98 299.61

SMCC (Prosolv 90) 5.12 20.73

Silica (Aerosil 200) 0.50 2.03

Magnesium Stearate 0.50 2.03

Total 100.0 405.0

Wax-Based Formulations

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Wax A

Wax B

Dissolution of Wax Based Formulations (in pH 6.8, @ 37ºC, paddles, 50 rpm.)

Wax-Based Formulations

• Both hydrophilic/hydrophobic matrix formulations did produce more retardation of release (18-24 hrs) as compared to the HPMC matrix formulations

• Neither formulation produced a zero-order profile, but the results for formulation B (with added carnauba wax) suggest that further development of this formulation may yield a possible pseudo zero-order option (dissolution may be partly erosion-controlled)

Wax Based Formulations – Outcome

• Encapsulated, Coated Mini-Tab – 0.75mg dose divided into 3 mini-tabs of 0.25mg each – Dividing dose into three parts reduces chances of dose

dumping the entire dose

• Diffusion barrier coating - main method of release control – Varying levels of acrylate (Eudragit) based coating were

applied to spread release rates of each mini-tab over 24 hours

– Succinic acid added to core to alter coating permeability and modulate drug release to desired rate (provide a “lag-time” followed by a fast release of drug)

• A tri-modal or pulsed release could reduce the peak-to-trough plasma levels in vivo seen with multiple dosing of the IR equivalent

Third Formulation Approach

McNeil Consumer & Specialty Pharmaceuticals, Division of McNeil-PPC, Inc. Fort Washington, PA 19034. An ALZA OROS® Technology Product, Concerta® and OROS® are Registered Trademarks of Alza Corporation 10025001 PPI Edition: October 2004

Peak to Trough Variation – Example

McNeil Consumer & Specialty Pharmaceuticals, Division of McNeil-PPC, Inc. Fort Washington, PA 19034. An ALZA OROS® Technology Product, Concerta® and OROS® are Registered Trademarks of Alza Corporation 10025001 PPI Edition: October 2004

MTC MEC

Peak to Trough Variation – Example

Insoluble but permeable Diffusion of drug through the coating is solubility driven – The more soluble the drug, the higher the diffusion gradient

Rate of diffusion is proportional to coating thickness and coating permeability – The thicker and less permeable the coating, the slower the

diffusion – To decrease or increase rate, more or less coating can be applied – Addition of a “lag-time” is accompanied by a decrease in overall

release rate (ethylcellulose example)

With acrylic systems, permeability can be altered during release – a “lag-time” can be followed by an abrupt change in release rate

by using additives in the tablet core

About Diffusion Barrier Coatings

Coated Tablet Aqueous media begins to diffuse through the coating at a rate proportional to coating thickness.

Media reaches the tablet surface and begins to move into the core.

Time

Diffusion Mechanism – Ethylcellulose Coating

Soluble core ingredients begin to dissolve.

Drug dissolves, increasing concentration causing drug to diffuse out through coating. As drug is depleted, concentration gradient diminishes and rate of diffusion decreases.

Time

Diffusion Mechanism – Ethylcellulose Coating

As coating gets thicker diffusion rate is slower throughout the release of drug. Unable to provide a lag-time followed by a rapid release of drug.

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20% coat

30% coat

40% coat

50% coat

Diffusion Barrier Coatings – Ethylcellulose

Functional Group - Trimethyl ammonio-ethyl methacrylate Cl

Acrylate Coating – Eudragit RS

Functional Group - Trimethyl ammonio-ethyl methacrylate Cl

Acrylate Coating – Eudragit RS

The permeability of the polymer can be manipulated by replacing chloride with other anions (acetate, tartrate, succinate, citrate, etc.) causing the polymer to swell.

Acrylate Coating – Eudragit RS

Coated Tablet Aqueous media begins to diffuse through the coating at a rate proportional to coating thickness.

Media reaches the tablet surface and begins to move into the tablet core.

Time

Diffusion Mechanism – Acrylate Based Coating

Soluble core ingredients begin to dissolve.

Along with drug, succinic acid begins to diffuse through the coating. Eudragit+Cl- begins to swell as it is converted to the more permeable Eudragit+Succinate-

Eventually, the entire coating is converted to the more permeable material and drug begins to diffuse out at a higher rate and the lag-time ends abruptly.

Time

Diffusion Mechanism – Acrylate Based Coating

Tablet Cores

Ingredient % w/w Mg/tab

Drug HCl 0.5 0.25

Methocel E5LV 5.0 2.5

Mannitol 40.0 20.0

Prosolv 90M 30.0 15.0

Succinic Acid 24.0 12.0

Magnesium Stearate

0.5 0.25

Total 100.0 50.0

Coating Suspension

Ingredient Grams of Solids

Grams per Batch

Eudragit RS 30D

245.0 816.7

Triacetin 49.0 49.0

Syloid 244FP 73.5 73.5

Simethicone 1.2 1.2

Water NA 903.1

Total 368.7 1843.5

Mini-tab Formulation

• Batch Size: – Granulation: 1000g

– Coating: 700g

• Compression: – 0.1875” Round Tablets

– 300tpm

– Force ~ 2.5kN; Hardness ~ 2.5kP

• Coating: – Spray Rate ~ 4g/min

– Product Temperature 25 - 28°C

Process Flow

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% D

isso

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Time (hrs.)

0.25mg Mini-tabs Normalized, App. II, pH 6.8, 50 rpm

Coating Levels in % Weight Gain

4001-023.01; 5% 4001-023.05; 15%

4001-023.09; 25%

Mini-tab Dissolution

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% D

isso

lved

Time (hrs.)

Cumulative 3 x 0.25mg Mini-tabs Normalized, App. II, pH 6.8, 50 rpm

Calculated average; 0.75mg normalized

Capsule Dissolution – Calculated

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% D

isso

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d

Time (hrs.)

Encapsulated Mini-tabs Normalized, App. II, pH 6.8, 50 rpm

Calculated Average; 0.75mg

4001-045.01.02.03; 0.75mg Actual

Capsule Dissolution – Calculated vs. Actual

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% D

isso

lve

d

Time (hrs)

0.75mg Capsule Normalized Data, App. II, pH 6.8 , 50 rpm

4001-023.01.05.09; 0.75mg Capsule with 5%, 15%,and 25% Coated Tablets

Capsule Dissolution –Actual

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% D

isso

lve

d

Time (hrs)

0.75mg Capsule Normalized Data, App. II, pH 6.8 , 50 rpm

4001-023.01.05.09; 0.75mg Capsule with 5%, 15%,and 25% Coated Tablets

Capsule Dissolution –Actual

• Low dose, water soluble drugs are difficult to deliver over 24 hours in a zero order profile in a single tablet

• Low dose lends itself well to mini tabs due to the small size of the tablets

• Acrylate based coatings enable delivery of drug with steep slopes after extended lag times

• Using 5, 15, and 25% weight gain coating allows for a near zero order 24 hour release and would likely reduce fluctuation in plasma concentration and provide enhanced drug therapy.

Conclusions:

Questions ?