EXTENDED RELEASE (ER) FORMULATIONS OF A PRACTICALLY INSOLUBLE MACROLIDE ANTIBIOTIC CLARITHROMYCIN

N. VYAS*, J. HARGRAVE, J. LAI, S. LAMB, K. QIAN & G. VENKATESH

Eurand, Inc., 845 Center Drive, Vandalia, Ohio 45377
ABSTRACT
Purpose. To develop ER formulations of a practically insoluble macrolide antibiotic suitable for once-a-day oral administration. Methods. Clarithromycin is a broad-spectrum macrolide antibiotic, generally administered qd as two 500 mg tablets. Six tablet formulations all containing 500 mg drug, each utilizing different rate-controlling polymers were initially developed. The polymers investigated include carbopol 71G, low-viscosity (LV) hypromellose, polyox 750N, hypromellose K4M as well as LV-ethylcellulose (EC) interspersed with pore-formers like Klucel, LF and LV-hypromellose. A novel 1000 mg formulation of clarithromycin containing no dissolution-controlling polymer was subsequently devised. The formulation comprised of drug granulated and tableted with commonly employed tableting aids like MCC, talc, lactose, colloidal silicon dioxide and magnesium stearate. The effect of different LV conventional binders for granulation such as PVP, HPC and HPMC on the tableting characteristics of this erosion-based tablet matrix was studied. The effect of presence of an inorganic acid like HCl on the in vivo absorption of drug in the fed-state was investigated. Results. While approximately 7%-15% w/w each of carbopol, LV-hypromellose and polyox in the formulation resulted in release profiles that were comparable to the brand product, greater than 50% w/w combination of both EC:HPC and EC:HPMC was required in order to obtain comparable release. Tablets containing less than 4% hypromellose K4M were found to have better stability at 400C/75%RH than those with carbopol 71G. Similarly, the EC:HPC formulation was comparatively more stable than the EC:HPMC tablets. Tablet dosage forms without any rate-controlling polymers exhibited a near zero-order drug release when tested in 0.1 M Na acetate buffer at pH 5.0. HPMC was proven to be the best wet-granulation binder for this particular formulation. Plasma drug concentration profiles of formulations with and without HCl were similar. Conclusions. A broad range of extended-release tablet matrices of clarithromycin can be developed with and without the use of any rate-controlling polymers.

OBJECTIVES
To develop extended release tablet formulations of Clarithromycin suitable for once-a-day (qd) administration in humans, either as two 500 mg tablets or a single 1000 mg tablet comparable in shape and size to the prescribed brand product. To formulate the said 500 mg tablets utilizing either approximately no more than 4% or no less than 50% of a combination of different pharmaceutically acceptable polymers. To formulate the said 1000 mg tablet without the use of any dissolution rate-controlling agent, a polymer or esters of fatty acids. To evaluate the effect of use of an inorganic acid like HCl as the granulating medium on the in vivo absorption of this compound exhibiting a pH-dependent solubility behavior.
Figure 1 Dissolution of HPMC 2208 400 cps Formulations
Dissolution Profiles of Clarithromycin ER Tablets, 500 mg - Brand Vs Eurand Formulations
100
140

RESULTS
Figure 2 Dissolution of Carbopol 71G Formulations
Dissolution Profiles of Clarithromycin ER Tablets, 500 mg - Brand Vs Eurand Formulations
120

DISCUSSION
Figure 3 Dissolution of Polyox 750N Formulations
Dissolution Profiles of Clarithromycin ER Tablets, 500 mg - Brand Vs Eurand Formulations

90
120 100 % drug released
Brand

80 % Drug Released 70 60

Brand

100

Brand

4.5% Carbopol 71G

18% Polyox 750N

% Drug Released

80
18% 50:50 Polyox 750N:HPMC 2208(400 cps)

80
7% HP MC-2208, 400 cps

5% CArbopol 71G

50 40 30 20
7% Carbopol 71G

60

15% 50:50 Polyox 750N:HPMC2208 (400 cps)

60 40 20

11% HPMC-2208, 400 cps 18% HPMC-2208, 400 cps

40

15% 60:40 Polyox 750N:HPMC 2208 (400 cps)

11% Carbopol 71G 15% 40:60 Polyox 750N:HPMC 2208 (400 cps)

20
18% Carbopol 71G

10
0 0 1 2 4 Tim e (hours) 6 8 12

0 0 1 2 4 Time (hours) USP 2, 50 rpm 900 mL 0.1 M Sodium acetate (pH 5.0) 6 8 12

0 0 1 2 4 Time (hours) 6 8 12

PROCESS FLOW DIAGRAM

Binder Solution Wet Mass Milled Wet Dry Granules

US P 2, 50 rpm 900 mL 0.1 M Sodium acetate (pH 5.0)

USP 2, 50 rpm 900 mL 0.1 M Sodium acetate (pH 5.0)

Figure 4
Oscillating Granulator

Figure 5 Stability of HPMC K4M Formulation

Dissolution Profiles of HPMC K4M Formulation Subjected to ACC Stability

Figure 6 Instability of Carbopol 71G and EC7:HPMC 2208 400cps Formulations

Stability Studies of Clarithromycin ER 500 mg Carbopol and EC:HPM C Formulations
110 100

HPMC K4M Formulations Different Hardness

Comparison of Dissolution Profiles of 2.4% HPMC K4M Formulations with the Brand

Oscillating Granulator
Active + Diluent

Granules

High Shear Granulator Tray Drying Oven

Milled Dry Granules

100 90
Tableting Aids
V-Blender 20 CB

100 90

Friability failure @ 1 M ACC; carbopol tablets were very soft

Initial Carbopol 1 M ACC Carbopol Initial EC:HPMC 1 M ACC E C:HP MC 2 M ACC E C:HP MC

80
V-Blender

Brand 7 kp (F2 = 71.2)

% Released

80 70

Initial

90 80 70
% Released

% Drug Released

70 60 50 40 30 20

60 50 40 30

18 kp (F2 = 62.3) 20 kp (F2 = 62.8) 25 kp (F2 = 51.4)

3 M ACC

60 50 40 30

Coating Suspension Blends

Final Product

20 10

6 M ACC

20 10 0

10
Uncoated Tablets

Rapid burst @ 1 and 2 M ACC; with EC:HPMC t bl t

0 2 4 6
Time (hr)

0
Tablet Press Pan Coater

4 Time (hours)

12

0 0 2 4 6 Time (hr)
USP 2, 50 rpm, 370C 900 mL of 0.1 M Na acetate (pH 5.0) ACC = 40 degree C/75% RH in induction-sealed HDPE bottles

10

12

10

12

USP 2, 50 rpm, 37 degree C 900 mL 0.1 M Sodium acetate (pH 5.0)

Extended release tablet formulations of clarithromycin were prepared using conventional ER matrix polymers as well as a novel approach based on drug release purely by tablet erosion. HPMC hydrates rapidly when in contact with water forming a protective gel around the tablet4, a property essential for providing extended release. HPMC of higher viscosity grade swells to a greater extent as it has a greater intrinsic water uptake property than that of a lower viscosity grade. High polymer content results in greater amount of gel being formed. As a result, a reduction in drug release rate is obtained5. The drug release from the HPMC K4M formulations is controlled by polymer swelling and erosion and follows zero order kinetics. Carbopol 71G is a cross-linked polyacrylic acid homopolymer suitable for manufacturing of extended release tablets by direct compression6. Polyox water-soluble resins are nonionic poly (ethylene oxide) polymers forming hydrogels that regulate the drug release. Systems containing polyox resins often approach zero order release models7. Ethylcellulose is a water insoluble polymer that compacts well and also retards the drug release. In addition, matrices of this polymer display slow surface erosion which can be enhanced by the incorporation of suitable swelling agents, pore-formers or channeling agents7. Extended release formulations of practically insoluble compounds like clarithromycin can be formulated without the use of any rate-controlling polymers. In this case, the dosage form is composed of just commonly-used tableting aids, especially talc and magnesium stearate that are hydrophobic and serve as dissolution-retardants when used in excess of 1% w/w. Choice of the wet-granulation binder seems critical for this type of formulation. It was observed that for granules of this particular compound, HPMC E15 and HPMC K100 were superior to PVP K30, PVP K90 and HPC EXF. Tablets with HPMC as the binder were more robust (devoid of capping, sticking, etc), less friable and had little to no variation in their intraand inter-batch tablet hardness and weight uniformity values.

USP 2, 37 degree C, 900 mL of 0.1 M Na Acetate Buffer (pH 5.0)

Figure 7

Figure 8 Dissolution of EC10:HPC, LF Formulations

Dissolution Profiles of EC:HPC Formulations
100

Figure 9 Stability of EC:HPC Formulation

Dissolution Profiles of EC:HPC Formulation, 2% Opadry Yellow Coating
100

INTRODUCTION
Clarithromycin is a broad-spectrum semi-synthetic macrolide antibiotic used against a wide variety of gram-positive and gram-negative pathogens. It is indicated for the treatment of a wide variety of respiratory and dermatological infections in children and adults1. It is a white to off-white crystalline, odorless powder with a bitter metallic taste. It is practically insoluble in water and slightly soluble in alcohol and methanol2. It is rapidly absorbed from the GI tract and undergoes first-pass metabolism to 14-OH clarithromycin. The anti-microbial activity of the metabolite is superior to that of the parent compound2. Clarithromycin exhibits pH-dependent solubility. The solubility decreases with increase in the GI pH. 3
pH Profile
50 40
Solubility (m g/mL)

EXPERIMENTAL
Materials and Methods
The physico-chemical properties of Clarithromycin sourced from different API suppliers was first evaluated for suitability in formulating an extended release tablet dosage form. Initially clarithromycin granules were prepared in a 1-5 L high shear granulator by granulating drug and lactose monohydrate with binder solution comprised of PVP K29/32 in either water or 0.01N HCl . The dried and sieved granules were blended in a standard V-blender with different concentrations / ratios of suitable rate-controlling polymers as well as magnesium stearate. Alternatively, the drug was granulated with lactose and HPMC K4M using either water or 0.01N HCl, followed by blending with Magnesium stearate and colloidal silicon dioxide. The blends were compressed into replicate 500 mg tablet batches using either a carver or Betapress and tested for dissolution using 900 mL of 0.1 M Na acetate buffer (pH 5.0) in a USP 2 apparatus. A 1000 mg clarithromycin tablet was prepared by compressing blends composed of API-lactosePVP granules blended with only commonly employed tableting aids like talc, silicon dioxide, MCC and magnesium stearate at different levels. Two 1000 mg formulations, one granulated with water and the other with 0.01N HCl on a GMX-25 high shear granulator were tested in a 4-arm proof of concept study under fed and fasted conditions. PVP K29/32 was substituted by other commonly-employed tableting binders like PVP K90, HPC EXF, HPMC E15 and HPMC K100 in order to evaluate and select the most optimum binder for manufacture of robust 1000 mg tablets with acceptable hardness and friability. The tablets were provided with either a suitable Opadry over-coat or an enteric over-coat such as Eudragit L100-55 or HPMCP-50.

Dissolution of EC7:HPMC 2208 400 cps Formulations

Dissolution Profiles of EC:HPMC Formulations
100 90 80 % Drug Released 70
% Drug Released
Brand

CONCLUSIONS, REFERENCES AND ACKNOWLEDGMENTS

Initial

80
Brand

90 80

% Drug Released

60 50 40 30 20

EC:HPMC 0.8:0.2

60
EC:HPC 0.5:0.5

70 60 50 40 30 20 10 1 M ACC 2 M ACC 3 M ACC 6 M ACC

Conclusions
Extended release tablet formulations of a practically insoluble compound clarithromycin can be successfully formulated with and without the use of conventional rate-controlling polymers

EC:HPMC 0.7:0.3

40

EC:HPC 0.3:0.7

EC:HPMC 0.5:0.5

10 0 0 1 2 4 Time (hours) USP 2, 50 rpm 900 mL 0.1 M Sodium acetate (pH 5.0) 6 8 12

20

0 0 1 2 4 Time (hours)
USP 2, 50 rpm 900 mL 0.1 M Sodium acetate (pH 5.0)

0
6 8 12

6
Time (hours)

10

12 ACC = 40 degree C/75% RH in induction-sealed HDPE bottles

References
1. 2. 3. 4. Venkatesh, G. M., Vyas, N. H. and Qian, K. K., Jan, 2005. Extended Release Systems for Macrolide Antibiotics, WO 2005/004919 A2. Physicians Desk Reference, pages 402-411, 2003. Internet web-site - http://www.fhsu.edu/nursing/otitis/graphics/clarith.html. K. Mitchell, J. Ford, D. Armstrong, P. Elliot, C. Rostron and E. Hogan, 1990. The influence of additives on the cloud point, disintegration and dissolution of hydroxypropylmethylcellulose gels and matrix tablets. International Journal of Pharmaceutics, 66:233-242. S. Makhija and P. Vavia, 2000. Once daily sustained release tablets of venlafaxine, a novel antidepressant. European Journal of Pharmaceutics and Biopharmaceutics, 54:9-15. Noveon technical literature. Dow technical literature and posters.

USP 2, 50 rpm, 370C 900 mL of 0.1 M Na acetate (pH 5.0)

Figure 10 0% Polymer Formulation

D is so lu tio n P ro file s o f C la rith ro m yc in E R T ab le ts W ith o u t A n y R a te -C o n tro llin g P o lym ers

Figure 11 Stability of 0% Polymer Formulation

D iss o lu tio n P ro file s o f P ro to typ e C la rith r o m yc in E R T ab lets , 10 0 0 m g , O p a d ry W h ite Y S -1 -7 0 0 3 C o a tin g
2500

Figure 12 POC Prototypes Water versus HCl

Subjects (n= 8)

30 20 10 0 0.1N HCl SGF 4.0 pH 5.0 6.0 6.8

1 00 90 80 % Drug Released 70 60 50 40 30 20 10 0 0 1 2 4 Tim e (h o urs ) 6 8 12

Be ta p re ss , 2 .5 % t alc , 2.5 % M g s tea ra te , 1 5 k p Be ta p re ss , 2 % t alc , 2% M g s tea ra te , 1 5 k p Be ta p re ss , 1 .5 % t alc , 1.5 % M g s tea ra te , 1 6 k p Br a nd

10 0 90 80 % Drug Released 70 60 50
2 M A C C C o a te d 1 M A C C C o a te d In it ia l C o a te d

5.
Eurand - Formulation A 1000mg, tablet - Fed Eurand - Formulation B 1000mg, tablet - Fed

2000

Clarithromycin plasma levels (ng/ml)

1500

40 30 20 10 0 0 2 4 6 8 T i m e (h o u r s ) 10 12 14 16
6 M A C C C o a te d 3 M A C C C o a te d

6. 7.

1000

500

Acknowledgments
0 4 8 12 16 20 24 28 32 36 40 44 48 52 56

Structure of Clarithromycin MW ~ 798; pka = 8.76

pH Solubility Profile of Clarithromycin

U S P 2 , 3 7 d e g re e C , 9 0 0 m L o f 0 .1 M N a A c e ta te b uffe r (p H 5 .0 )

U S P 2 , 5 0 rp m , 3 7 0 C 9 0 0 m L o f 0 .1 M N a a ce ta t e (p H 5 .0 )

The authors wish to acknowledge Sam Nyambati and Marco Anelli for their contribution to the work presented herein.

hours