FIELD OF INVENTION
The present invention relates to oral modified release pharmaceutical compositions comprising erythromycin derivatives. The present invention focuses on the use of lactose and sugar alcohols to provide oral modified release pharmaceutical compositions for erythromycin derivatives such as clarithromycin. The invention further] relates to the process of preparation of such oral modified release pharmaceutical compositions.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
Clarithromycin is a macrolide antimicrobial agent that exhibits a broad spectrum of antimicrobial activity against gram-positive and gram-negative pathogens. Depending on the pharmacokinetic characteristics, antibacterial agents may be administered orally more than once per day to maintain a minimum effective concentration throughout the day and night. However, a more desirable dosage regimen is once a day administration. Clarithromycin is practically insoluble in water and shows pH dependent solubility profile. The solubility significantly increases at lower pH values (I. I. Salem, Analytical Profiles of Drug Substances and Excipients, Volume 24, Academic Press, (1996) at 46 85). It undergoes degradation in acidic medium, it degrades rapidly at normal gastric pH of 1.0- 2.0 (P. O. Erah et. al., J. Antimicrob. Chemother. 39, 512, (1997)). Marketed formulations of clarithromycin are in the form of film coated tablets, suspension and extended-release tablets.
Any discussion of the prior art throughout the specification should in no way be considered as an admission that such prior art is widely known or forms part of the common general knowledge in the field.
Various approaches exist for preparing modified or controlled release pharmaceutical formulations, for example, one method include coating the tablet with a release-retarding coating, or coating individual granules with such a coating, and compressing these coated granules into a tablet. One exemplary technique involves controlled release solid preparations for erythromycin

derivatives in an alginate matrix, such as a matrix having a water-soluble alginate
and a complex salt of alginic acid as described in US4842866. 'I US5705190 discloses a controlled release solid pharmaceutical
compositions adopted for oral administration comprising a water soluble alginate
salt, a complex salt of alginic acid, wherein the cation is selected from the group
consisting of calcium, strontium, iron or barium, and an organic carboxylic acid to
facilitate dissolution of basic drug. These formulations are said to be suitable for
once a day administration. The release rate of the clarithromycin is controlied
using a matrix based on a water-soluble alginate salt and a complex salt of alginic
acid.
US6010718 discloses extended release compositions containing clarithromycin and from about 5 to about 50% by weight of a pharmaceutically acceptable water soluble hydrophilic polymer.
US6068859 discloses controlied release azithromycin formulations wherein the drug is embedded in a polymer matrix, which releases the drug by diffusion.
US6340475 discloses controlled-release oral formulations wherein drug is dispersed in a polymeric matrix.
US2004043073 discloses controlled release matrixed formulations having a drug, a wax materia! and a pH modifying agent where the drug and the wax material are granulated, without melting the wax to form granules.
US2005053658 discloses extended release oral formulations having an erythromycin drug, about 2% to 40% water soluble excipients and a binder.
WO2004078164 discloses a sustained release composition having a drug core and approx 3 to 20% wt by wt of a hydrophobic material having a melting point between 40° C to 100"^ C.
WO2005060941 discloses extended-release antibiotic compositions having the drug and'ia hydrophilic polymer component having a viscosity of less than about 50 ops.

WO2005082331 discloses formulations having clarithromycin and a il mixture of lactose and microcryslalline cellulose in a ration ranging from 3:1 to
!
1:3 having an extended release profile.
WO2005102289 discloses extended release compositions containing an erythromycin drug and about SOVo to about 65% by weight of one or more pharmaceutically acceptable polymer(s).
WO2006030297 discloses erythromycin formulations made up of granules of a core comprising clarithromycin, hydrocolloids and acceptable excipients and a coating over the core comprising one or more pH dependent polymers that release drug at a pH above 4.5.
The above discussion shows that various alternatives have been considered for achieving a modified/extended release of erythromycin based drugs. Most of these approaches use'some form of polymers and the drug is embedded within a matrix of the polymer.
In order to incorporate 500-lOOOmg of clarithromycin in a relatively small matrix, so as to enable easy swallowing: there remains relatively a very little room for optimization of the composition using polymers for extending/sustaining the release of the drug. Further, processing of hydrophilic water-soluble polymers such as hydroxypropyl methylceliulose is difficult in such cases.
There is a need for modified release compositions of clarithromycin, that deliver the drug at a specified site in a specified rate.
We have now discovered that modified release pharmaceutical solid
compositions of erythromycin derivatives such as clarithromycin can be achieved
without the use of polymers. The compositions of the present invention, in one
embodiment, include clarithromycin, pharmaceutically acceptable carrier and
excipients. The carrier according to the present invention includes lactose, sugar
if alcohols or their mixtures.
OBJECTS Of THE INVENTION
It is an object of the invention to overcome or ameliorate at least one of the disadvantages of the prior art, or to provide a useful alternative.

It is an object of the invention in its preferred form to provide a modified/ extended release oral formulation for erythromycin derivatives such as clarithromycin.
It is a further object of the invention to provide a modified/extended
release oral composition of clarithromycin without the use of dissolution rate-
f controlling polymers.j
It is an object of the invention to provide the use of lactose, sugar alcohols or their mixtures for rnodifled release compositions of clarithromycin.
It is an object of the invention to provide modified release compositions of clarithromycin having similar dissolution profiles as that of commercially available B[AXlNXli™.

SUMMARY OF THE INVENTION
The present invention discloses oral modified release pharmaceutical
compositions comprising erythromycin derivatives. More particularly, the
invention discloses oral modified release pharmaceutical compositions comprising
clarithromycin. More particularly, the present invention further discloses the use
of lactose, sugar alcohols and their mixture to provide oral modified release
pharmaceutical compositions comprising clarithromycin. The invention also
discloses the process of preparation of such oral modified release pharmaceutical
compositions comprising clarithromycin.
In one aspect the invention provides an oral modified release pharmaceutical composition of clarithromycin without the use of any release modifying polymers, which have been previously used in the prior art.
The oral modified release pharmaceutical composition according to the present invention can include dosage forms such as tablets, multi-layered tablets, capsules, pellets, coated pellets, and the likes.
In one aspect the invention provides a pharmaceutical composition having clarithromycin from about 3% to 90% by weight, lactose from about 5% to about 70% by weight, sugar alcohols ft-om about 0% to about 50% by weight, and optionally other pharmaceuticaliy acceptable excipients, wherein the pharmaceutical composition provides modified release of clarithromycin having comparable in-vitro release profile as that of the commercially available marketed composition.
In an another aspect, the invention provides a pharmaceutical composition having clarithromycin from about 3% to about 90% by weight, anhydrous lactose from about 5% to about 70% by weight, and one or more pharmaceuticaliy acceptable excipienti, which is incorporated into tablet core and coated with a
i
coating layer of a pharmaceuticaliy acceptable coating material.
in an another aspect the invention provides a pharmaceutical composition having clarithromycin from about 3% to 90% by weight, sugar alcohols from about 5% to about 60% by weight, and optionally other pharmaceuticaliy acceptable excipients, wherein the pharmaceutical composition provides modified

release of clarithromycin having comparable in-vitro release profile as that of the commercially available marketed composition.
Further the invention provides for the process of preparation of oral modified release pharmaceutical composition comprising clarithromycin and pharmaceutical carriers, wherein the carriers includes lactose, sorbitol or their mixtures and optionally other pharmaceutically acceptable excipients.
In addition, a method of administering a modified release pharmaceutical composition is provided. The method includes administering a pharmaceutical composition in an effective amount to a mammal for the treatment of microbial infection.
DETAILED DESCRIPTION fNCLUDlNG PREFERRED EMBODIMENTS OF THE INVENTION:
The inventors have discovered that modified release pharmaceutical compositions comprising clarithromycin can be obtained without the use of any release modifying polymers.
The pharmaceutical composition of the invention includes a therapeutically active agent, especially erythromycin derivatives such as clarithromycin, lactose, sugar alcohol or their mixtures and one or more pharmaceutically acceptable excipient or processing aid. The pharmaceutical composition is generally prepared into an oral dosage form such as tablets, multi-layered tablets, capsules, pellets, coated pellets, and the likes. Other therapeutic
active agents which can be incorporated are erythromycin and/or its derivatives,
I such as azithromyciti, spiromycin. roxithromycin, dirithromycin, telithromycln,
i
spiramycin, josamycin etc.
In an embodiment of the invention, there is provided a pharmaceutical
composition having iclarithromycin from about 3% to 90% by weight, lactose
I from about 5% to about 70% by weight, sugar alcohol from about 0% to about
50% by weight, and optionally other pharmaceutically acceptable excipients.
wherein the pharmaceutical composition provides modified release of

clarithromycin having comparable in-vitro release profile as that of the commercially available marketed composition.
In an another embodiment, the invention provides a pharmaceutical composition having clarithromycin from about 3% to about 90% by weight, anhydrous lactose from about 5% to about 70% by weight, and one or more pharmaceuticaliy acceptable excipient or processing aid, which is incorporated into tablet core and coated with a coating layer of a pharmaceuticaliy acceptable coating material.
Lactose may be selected from amongst anhydrous lactose, spray-dried lactose and lactose monohydrate. Lactose is widely used as a filler or diluent in tablets and capsules. It is available in different grades with varying physical properties such as particle size, distribution and flow characteristics. In particular anhydrous lactose may be used.
Sugar alcoholiis selected from sorbitol, maltitol, mannitol, lactitol, xylitol, glycerol and their mixtures thereof More preferably sugar alcohol used is selected amongst sorbitol or mannitol.
Sorbitol used is preferably D-sorbitol, and includes various crystalline and
amorphous forms, it is available in a wide range of grades and polymorphic forms
I such as granules, flakes, or pellets.
In an another, aspect the invention provides a pharmaceutical composition
having clarithromycin from about 3% to 90% by weight, sorbitol from about 5%
fo about 60% by weight, and optionally other pharmaceuticaliy acceptable
ij
excipients. '
i The dosage form according to the invention can be prepared in the form of
granules, particles, beads, spherical beads, pellets, coated beads, coated pellets,
coated particles, tablets, and capsules.
The pharmaceutical composition of the invention also includes one or
more pharmaceuticaliy acceptable excipient or processing aid including, but not
limited to, binders, diluents, glidants, lubricants etc.

Binders may be selected from starches, polyvinyl pyrrolidone, low molecular weight hydroxypropyl methyl cellulose, hydroxyl propyl cellulose and the like.
Diluents like dicalcium phosphate; mannitol, microcrystalline cellulose,
and the like may be. added. Diluents may also include pH modifiers such as
organic acids such aslsuccinic acid, maleic acid, fumaric acid, citric acid, and the
like. - I
j The lubricant inay be one or more selected from the group of magnesium
stearate, stearic acid, sodium stearyl fumarate, glyceryl behenate, and the like.
The glidant may be one or more agent selected from the group of talc, colloidal silicon dioxide and the like.
The pharmaceutically acceptable coating material includes, but is not limited to, a rapid-disintegrating coating material, such as Opadry^'^ available from Colorcon, Inc.
The process of preparing the oral modified release erythromycin composition encompasses wet granulation, dry granulation, direct compression and melt granulation.,
Wet granulation process according to the invention includes the following steps:
a) blending clarithrornycin. lactose or sorbitol or their mixtures and other suitable
diluents;
b) granulating the above blend with water or other suitable solvents, with or
without binders L
;[
c) sizing the granules obtained from above step
d) lubricating the above sized granules with lubricants and glidants
e) compressing the above lubricated granules into tablets using suitable toolings
f) optionally applying a film coat over the tablet.
Dry granulation process according to the invention includes the following steps:
a) blending clarithromycin, lactose or sorbitol or their mixtures and other suitable diluents;

b) slugging the above blend to obtain slugs
c) sizing the slugs obtained from above step to form granules
d) lubricating the above sized granules with lubricants and gUdants
e) compressing the above lubricated granules into tablets using suitable toolings 0 optionally applying a film coat over the tablet.
Direct compression process according to the invention includes the
following steps; J
a) blending clarithromycin, lactose or sorbitol or their mixtures and other suitable diluents;
b) sizing the blend through sieves

d) lubricating the above sized blend with lubricants and glidants
e) compressing the above lubricated granules into tablets using suitable toolings t) optionally applying a film coat over the tablet.
Significance of lactose on release kinetics
Erythromycin derivatives are slightly alkaline, practically water insoluble, acid-sensitive drugs. A basic drug's solubility decreases with an increasing pH as it proceeds distally towards the large intestine {pH 6 to 8). Jt is soluble in stomach (pH 1.2) and upper or proximal region of small intestine (pH 5). Thus, a poorly soluble basic drug will lead to less drug being available for absorption in the lower or distal intestine.
It will be appreciated that increasing concentrations of lactose in the modified release tablets can compensate, progressively, the lower solubility of the drug, after the pH, change. The granulation with water of a water-soluble excipient, like lactose, will dissolve it in a variable degree. The part dissolved of this excipient is then distributed on the surface of the non-dissolving particles. After drying, the part dissolved remains as a solid layer deposited around the non-dissolving particles.! The re.st of the particles of the soluble excipient stay randomly distributedlafter this process.
Taking in account the granulation procesS; it is believed that lactose starts loosening the matrix structure through an increased porosity created after its slow

dissolution and release. This is effective after 3-4 hrs, being approximately coincident with the change in pH. Moreover, it is also believed that lactose acts loosening the structure by separation of particles, after dissolution of the lactose deposited around them.
There are reports which indicate that the drug release mechanism may be attributed to an anomalous transport for all cases, as would be expected for swellable matrices. There is a linear trend to decreasing values of the exponent 'n' as the matrices increase their lactose' content. Greater proportions of lactose exhibiting drug release profiles closer to a diffusion controlled process. Possibly due to a faster penetration of the water front through pores and channels produced by lactose dissolution. The consequence of this would be an earlier or faster hydration and establishment of a looser gel barrier as the lactose content increases. Matrices with swelling restrictions, like those with lower lactose proportions, exhibit a shift towards drug release by relaxation mechanism. Matrices with low lactose content would result in a more concentrated gel and increased gel tortuosity. Thus, the! diffusional path would become more convoluted and the diffusion rate would therefore decrease.
Although the invention has been described with reference to specific examples, it will be appreciated by those skilled in the art that the invention may be embodied in other forms also.

Examples: A B C D
Process : Direct Compression
Ingredients mg/unit % w/w mg/unit % w/w mg/unit % w/w mg/unit % w/w
Clariihromycin 500.00 47.8 500.00 47.8 500,00 47.8 500.00 47.8
Lactose anhydrous 250.001 23.9 150.00 14.3 300.00 28.7 200.00 19.1
Sorbitol 250.00! 23.9 350.00 33.5 200.00 19.i 300.00 28.7
Talc 15.00 i| 1.4 15.00 1.4 15.00 1.4 15.00 i.4
CoMoidal Silicon Dioxide 1.00 [ 0.1 1.00 0.1 1.00 0.1 1.00 0.1
Sodium Stearyl Fumarate 1
25.00 i 23.9 25.00 23.9 25.00 23.9 25.00 23.9
Magnesium Stearate 5.00 0.5 5.00 0.5 5.00 0.5 5.00 0.5
Total Weight 1046 1046 3046 1046

Examples: E 1 F
Process: Wet Granulation
Ingredients mg/unit % w/w mg/unit % w/w
Intra-granuiar
Clarithromycin 500.00 47.00 500.00 45.33
Lactose Monohydrate 200M 150.00 14.20 200.00 18.13
Purified Water;. q.s. ~ q.s. ~
Extra-granulav
Anhydrous Lactose 150.00 14.20 150.00 13.59
Sorbitol i| 150.00 14.20 150.00 13.59
Mannitol ;| 53.00 5.03 53.00 4.80
Colloidal Silicon dioxide 2.00 0.19 2.00 0.18
Talc 15.00 1.42 15.00 1.36
Sodium Stearyl Fumarate 25.00 2.37 25.00 2.27
Magnesium Stearate 5.00 0.47 5.00 0.45
Succinic acid 3.00 0.28 3.00 0.27
Total Weight 1053 1103

Examples: G H
Process: Wet Granulation
Ingredients mg/unit % w/w mg/unit % w/w
Clarithromycin 500 45.04% 500 38.16%
Anhydrous Lactose 600 54% 800 61.06%
Purified Water q.s. .. q.s. —
Magnesium Stearate 10 9.01% 10 7.60%
Totat Weight ii I no J3I0

Examples: i I I J
Process: Wet Granulation
Ingredients mg/unit % w/w mg/unit % w/w
Clarithromycin 500.00 59.88 500.00 53.16
Sorbitol 300.00 35.90 400.00 42.53%
Purified Water q.s. — q.s. —
Colloidal Silicon Dioxide 4.00 0.47 4.50 0.47
Talc 7.00 0.83 9.00 0.83
Sodium Stearyl Fumarate 20,00 2.39 22.50 2.39
Magnesium Stearate 4.00 0.47 4.50 0.47%
Total : 835.00 940.50

Dissolution Study:
The compositions according to the present invention were tested for the in-vitro drug release and'the profiles were compared with the commercially available BIAXfN XL^'^. The results showed that lactose or sorbitol and their mixtures used here according to the invention provide-comparable dissolution profiles of clarithromycin with that of the commercially available dosage forms.
Effect of both Lactose and Sorbitol

1 USP Dissolution Test 4
Time points (mins) BIAXIN-XL
ii A B C D
0 0.0 0.0 0.0 0.0 0.0
2 16.7 6.3 5.9 7.0 7.7
4 37.0 23.4 13.3 30.9 37.7
8 71.9 74.0 40.6 89.2 90.8
12 99.2 98.4 74.3 106.2 101.6
Effect of Intra and Extra-granular use of Lactose

1| USP Dissolution Test 4
Time points (mins) BIAXIN -XL E F
0 0.0 0.0 0.0
2 16.7 6.3 25.6
4 37.0 33.4- 72.5
8 71.9 91.6 96.4
12 99.2 98.7 101.3
Effect of Lactose DCL 21
li
[ USP Dissolution Test 1
Time points
(mins) BIAXIN-XL G H
0 0.0 0.0 0.0
30 31.3 34.4 14.5
45- 60.5 71.9 ■ 46.2
60 84.2 87.7 71.0
120 88.5 95.9 90.2

Effect of Sorbitol

USP Dissolution Test J
Time points (m'ws) BIAXIN XL i J
0 0.0 0.0 0.0
30 .) 31.3 14.1 4.1
45 1 60.5 28.5 8.4
60 ■ 84.2 46.6 14.3
120 . 88.9 84.4 43.7

CLAIMS:
1. A modified release pharmaceutical composition for oral administration
il comprising erythromycin or its derivatives, pharmaceutically acceptable carriers,
wherein said carriers comprise lactose or sugar alcohol or their mixtures and
optionally other pharmaceutically acceptable excipients.
I.
2. A modified release pharmaceutical composition for oral administration
comprising erythromycin and its derivatives and pharmaceutically acceptable
carriers, wherein said carriers constitute from about 0.1% to about 99%) by weight
of said excipients in said composition.
3. The modified release pharmaceutical composition according to claim 1 wherein
erythromycin derivative constitutes from about 25% to about 75% by weight of
the composition. f
4. A modified release pharmaceutical composition for oral administration
comprising:
i) clarithromycrn from about 25% to about 75% by weight; ii) lactose from about 5% to about 40% by weight: iii) sugar alcohol from about 5% to about 40% by weight; iv) optionally other pharmaceutically acceptable excipients; wherein the final dosage form may optionally be film-coated.
5. The modified release pharmaceutical composition according to claim 1 wherein said lactose is selected amongst anhydrous lactose, spray-dried lactose, lactose monohydrate and their mixtures thereof.
6. The modified release pharmaceutical composition according to claim i wherein said sugar alcohol is selected from sorbitol, maltitol, mannitol, iactilol. xylitol, glycerol and their mixtures thet-eof

7. The modified release pharmaceutical composition according to claim ] or 6
wherein said pharmaceutically acceptable excipients are selected from fillers,
binders, lubricants, glidants, coloring agents or flavoring agents.
8. A modified release pharmaceutical composition for oral administration
comprising erythromycin and its derivatives and lactose or sugar alcohol or their
mixtures, characterized in that the dissolution is similar with commercially
available BIAXIN XL™.
9. A process for preparation of modified release pharmaceutical composition for
oral administration comprising eriihromycin derivatives and lactose or sugar
alcohol and their mixtures thereof, wherein said process is selected from wet
granulation, dry granulation, direct compression and melt granulation.
I
10. The modified release pharmaceutical composition according to claim 1 or 3
used for treatment of bacterial infections in a mammal in need of such treatment.
i
I