FIELD OF INVENTION
The present Invention relates to solid oral pharmaceutical composition, more particularly to a sustained release composition, which maintains an effective plasma drug concentration over an extended period of time and a method of preparing the same. The composition comprises an active pharmaceutical agent and sorbitol and/or sucrose esters, as release retarding material for maintaining a uniform release rate of the drug. The invention further relates to the process of preparation of such oral sustained release pharmaceutical composition.
BACKGROUND OF THE INVENTION AND RELATED PRIOR ART
Oral ingestion is one of the primary routes used for drug administration. This route
provides a convenient method of effectively achieving both local and systemic effects.
In conventional oral drug delivery systems there is little or no control over the release
of the drug and an effective concentration can only be maintained by repeated
administrations.
Oral controlled release delivery systems should ideally be adaptable so that release rates and profiles can be matched to physiological and chronotherapeutic requirements. Sustained release systems provide a uniform concentration of drug at the absorption site for an extended period of time and thus, after absorption, allow maintenance of plasma concentrations within a desired therapeutic range.
The advantages of sustained release products are well known in the pharmaceutical field and include the ability to maintain a desired blood level of a medicament over a comparatively longer period of time while increasing patient compliance by reducing the number of administrations necessary to achieve the same, prevention of delay in recovery and ensuring successful therapy. These advantages have been attained by a wide variety of methods.
Various approaches exist for preparing sustained release pharmaceutical compositions, such as various extended release compositions in tablet or capsule form.
Literature discloses various approaches for therapeutic dosage forms, which are designed to deliver the drug at a sustained rate to the gastrointestinal tract. For

example, preparing a delayed or sustained release composition includes coating the tablet with a release-retarding coating, or coating individual granules with such a coating, and compressing these coated granules into a tablet. In another method different hydrogels have been described for use in controlled release medicines, some of which are synthetic, but most of which are semi-synthetic or of natural origin. A few contain both synthetic and non-synthetic material. However, some of the systems require special process and production equipment, and in addition some of these systems are susceptible to variable drug release. The various other techniques utilized include solvent evaporation, heat melting, direct compression and wet granulation methods.
While many sustained release formulations are already known, certain moderately to poorly soluble drugs present formulation difficulties which render them inapplicable for sustained release formulations which might be suitable for relatively soluble drugs. It is often not possible to readily predict whether a particular sustained release formulation will provide the desired sustained release for a relatively insoluble drug, and it has generally been found that it is necessary to carry out considerable experimentation to obtain sustained release formulations of such drugs having the desired bioavailability when ingested.
US Patent No. 4,389,393 describes sustained release therapeutic composition using less than about one third of the weight of the solid unit dosage form, of hydroxypropyl methylcellulose (HMPC) or a mixture of HMPC with certain other rate controlling polymers. The inventors disclose that they have been able to achieve sustained release from solid dosage forms containing as little as about 5 to about 30 weight percent of HMPC. All the examples disclose compositions containing 9% or more of the rate-controlling polymer.
US Patent No. 3,065,143 discloses the use of a specific hydrophilic polymers containing HMPC in the preparation of a sustained release tablet. US Patent No. 3,458,622 discloses a process for preparing a sustained release tablet using a combination of povidone and carbomer. US Patent No. 4,389,393 discloses a sustained release therapeutic composition based on a matrix comprising high molecular weight HMPC. US Patent No. 6,358,525 states that some excipients used as

sustained release polymers, such as hydroxypropylcellulose and methylcellulose, can improve the hardness of tablets as well as provide sustained release,
US Patent No. 6,010,718 and US Patent No. 6,551,616 disclose compositions of extended release clarithromycin containing 5 to 50% w/w of pharmaceutically acceptable polymer. The specification and examples of this patent disclose preferred compositions containing 10% 30% by weight of HMPC, the rate-controlling polymer, in the composition in addition to other excipients.
US Patent No. 6,790,459 discloses a method for treating patients having non-insulin-dependent diabetes mellitus (NIDDM) by administering a controlled release oral solid dosage form containing preferably a biguanide drug such as metformin.
US Patent No. 5,705,190 claims compositions using soluble alginate, a complex salt of alginic acid and an organic carboxylic acid. US Patent No, 6,068,859 discloses controlled release azithromycin compositions wherein the drug is embedded in a polymer matrix, which releases the drug by diffusion.
US Patent No. 6,340,475 discloses controlled-release oral compositions wherein drug is dispersed in a polymeric matrix.
US Patent No. 6,514,531 claims controlled release dosage forms of Zolpidem adapted to release Zolpidem over a predetermined time period, according to a biphasic profile of dissolution.
US Patent No. 6,287,599 and US Patent No. 6,811,794 related to guanfacine, disclose sustained release pharmaceutical compositions containing a combination of non-pH dependent and pH dependent polymer, wherein such compositions have minimized pH-dependent dissolution profiles or pH-independent dissolution profiles.
US Patent No. 4,792,452 describes controlled release pharmaceutical compositions which are said to provide pH-independent release for a basic drug such as metoprolol. The compositions include a pH-dependent polymer which is a salt of alginic acid, a pH-independent hydrocolloid gelling agent and a binder. The salt of the alginic acid is preferably sodium alginate or potassium alginate. The weight ratio of the alginic acid

salt to the hydrocolloid gelling agent is all within the range 0.1:1 to 10:1, and the composition is free of calcium ion and carbon dioxide-producing material.
US Patent No. 6,274,171 relates to extended release composition of venlafaxine hydrochloride comprising a therapeutically effective amount of venlafaxine hydrochloride in spheroids comprised of venlafaxine hydrochloride, microcrystalline cellulose and, optionally, HPMC coated with a mixture of ethyl cellulose and HPMC.
US Patent No. 4,957,745 also descnbes a controlled release metoprolol. The preparation includes a plurality of beads comprising metoprolol coated with a polymeric membrane comprising ethyl cellulose with or without HMPC. US Patent No. 5,081,154 is directed to metoprolol succinate in an oral composition coated with an anionic polymer soluble at pH over 5.5 and a water insoluble quaternary ammonium substituted acrylic polymer.
US Patent application No. 2004/043073 discloses controlled release matrixed compositions having a drug, a wax material and a pH modifying agent where the drug and the wax material are granulated, without melting the wax to form granules.
US Patent application No. 2005/053658 discloses extended release oral compositions having an erythromycin drug, about 2% to 40% water soluble excipients and a binder.
WO 97/45124 discloses a sustained release composition comprising a gelling agent and quetiapine or a pharmaceutically acceptable salt thereof, together with one or more pharmaceutically acceptable excipients. The gelling agent is HMPC and pharmaceutically acceptable excipient is selected from the group consisting of microcrystalline cellulose, lactose, magnesium stearate, sodium citrate and povidone, wherein sodium citrate is a pH modifier.
WO 99/58114 discloses a sustained release composition containing an active agent and specific amounts of a hydrophillc matrix (A) base and an inert medicament filler (B), A compound selected from among HMPC, hydroxypropylcellulose, methylcellulose and sodium carboxymethylcellulose is preferably used as the component A. A compound selected from among lactose, saccharose, fructose, dextrin, cyclodextrin, crystalline cellulose, powdery cellulose, mannitol, xylitol and sorbitol is preferably used as the component B.

wo 03/039516 discloses a method for improving dissolution of a poorly dispersible medicament like quetiapine, which comprises mixing the poorly dispersible medicament with a floating agent and/or a surfactant and granulating the mixture. WO 2005/041935 discloses a sustained release solid dosage composition comprising a matrix of quetiapine and a wax material.
WO 2005/082331 discloses compositions having clarithromycin and a mixture of lactose and microcrystalline cellulose in a ratio ranging from 3:1 to 1:3 having an extended release profile.
WO 2006/066399 relates to a sustained-release drug composition comprising substituted amylose as a matrix for sustained release of the drug contained in the tablet.
WO 2006/030297 discloses erythromycin compositions 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 sustained release of active agents. Nevertheless, it is well known that the materials used for providing the controlled release, most of these approaches use some form of polymers, in one or the other way.
The processing of hydrophilic water-soluble polymers such as hydroxy propyl methylcellulose is difficult and requires strict controls. For example, Koji et al, (JP 09095440) disclose a lyophilized composition of a fluid mixture of medicine and hydrogel forming polymer (such as hydroxypropyl cellulose, and hydroxypropyl methylcellulose). The Koji composition is said to float in the stomach and release a medicament slowly.
Presence of such a high concentration of soluble polymers often results in extremely slow drug dissolution, poor or variable drug release, poor or variable absorption, and acid instability at variable pH environments throughout the whole gastrointestinal (Gl) tract. This is especially significant for relatively insoluble active ingredients particularly

with high dose, such as macrolide antibiotics, acetazolamide, amoxicillin, ibuprofen, etodolac, naproxen, calcium fenoprofen, mefenamic acid, nabumetone, etc.
While many oral sustained release compositions are already known, certain drugs that are relatively insoluble in water and which further have relatively high dose requirements (based on weight) present formulation difficulties which render them unsuitable for inclusion in sustained release formulations. There is a need for sustained drug delivery compositions, which are free from the disadvantages offered by various existing sustained release systems, while delivering the drug at the specific site in the specified rate. It has been surprisingly found that compositions prepared using sorbitol/ sucrose esters or mixtures thereof, alone or in combination with pharmaceutically acceptable fillers produce sustained release profile, thus avoiding use of polymers in the composition.
OBJECTS OF THE INVENTION
It is an object of the present invention to provide a sustained release formulation for a
relatively insoluble active pharmaceutical agent.
It is a further object of the present invention to provide a sustained pharmaceutical composition in a solid dosage form comprising a pharmaceutically effective amount of active pharmaceutical agent, where the composition does not require polymeric materials to achieve sustained release effect.
It is a further object of the present invention to provide a sustained pharmaceutical composition comprising a pharmaceutically effective amount of active pharmaceutical agent and sorbitol/ sucrose esters or combinations thereof, as a release controlling agent.
It is a further object of the present invention to provide a sustained release formulation which provides blood plasma levels of the pharmaceutical agent for e.g., at least about 8 and preferably from about 12 to about 24 hours.
It is still another object of the present invention to provide a pharmaceutical composition for sustained release of active pharmaceutical agent for once daily administration comprising about 20% to about 70% by weight of sorbitol/ sucrose esters or combinations thereof.

In one embodiment, the invention is directed towards a method of preparing a sustained release pharmaceutical composition in tablet form which comprises
a. forming a mixture comprising sorbitol and/or sucrose ester and an active
pharmaceutical agent;
b. converting said mixture of step [a] to from granules;
c. optionally blending said granules of step [b] with one or more pharmaceutically
acceptable excipients;
d. compress said blend of step [c] to form tablets; and
e. optionally coating said tablets.
SUMMARY OF THE INVENTION
The present invention discloses sustained release pharmaceutical composition for relatively insoluble therapeutic agents. More particularly, the basic aspect of the present invention is to provide sustained release composition of a active pharmaceutical agent suitable for once daily oral administration, comprising about 20% to about 70% by weight of sorbitol/ sucrose esters or mixtures thereof, alone or in combination with pharmaceutically acceptable fillers.
In one aspect the sustained release composition of the present invention is prepared by utilizing the process of wet or melt-granulation, filling the granules into capsules, sachets or compressing to form tablets and optionally coating the tablets.
In one aspect, the invention is directed towards a method of preparing a sustained release pharmaceutical composition in tablet form which comprises
a. forming a mixture comprising sorbitol and/or sucrose ester and an active
pharmaceutical agent;
b. converting said mixture of step [a] to from granules;
c. optionally blending said granules of step [b] with one or more pharmaceutically
acceptable excipients;
d. compress said blend of step [c] to form tablets; and
e. optionally coating said tablets.
In one embodiment, the present invention is directed toward a process preparing sustained release pharmaceutical composition in tablet form comprising pharmaceutically effective amount of active pharmaceutical agent and an effective

amount of sorbitol and/or sucrose esters to control the release of said active pharmaceutical agent from the composition by utilizing wet or melt granulation, and said pharmaceutical composition comprises a core having said active pharmaceutical agent and said release controlling material but excluding any polymer, and said release controlling carrier is present in an amount ranging from about 20% to about 70% by weight of the pharmaceutical composition.
According to a preferred aspect, the invention provides a sustained release composition comprising relatively insoluble therapeutic agents like clarithromycin, erythromycin, amoxicillin, acetazolamide, ibuprofen & naproxen etc., 35% to about 55% by weight of sorbitol/ sucrose esters or mixtures thereof, alone or in combination with 20% to about 30% of pharmaceutically acceptable fillers, in addition to other pharmaceutically acceptable excipients.
DETAILED DESCRIPTION INCLUDING PREFERRED EMBODIMENTS OF THE
INVENTION:
As described hereinabove, an aspect of the present invention is directed to a sustained
release composition comprising active pharmaceutical agent and sorbitol/ sucrose
esters or mixtures thereof, to control the release of the medicament.
The inventors have discovered that sustained release composition comprising active pharmaceutical agent can be obtained without use of any release modifying polymers.
As used herein, the terms "drug", "medicament" and "active pharmaceutical agent" are used interchangeably.
By "sustained release", it is meant, for purposes of the present invention, a composition having an in-vitro drug release profile for at least twelve hours. Such composition is designed to release the drug in the body slowly over an extended period of time. Moreover, the terms "sustained release", and "controlled release" are used interchangeably.
Relatively insoluble drugs are those that have poor
solubility in water at or below normal physiological temperatures, that is
<5 mg/ml at physiological pH (6.5-7.4). Preferably their water
solubility is <1 mg/ml, and more preferably <0.1 mg/ml.

The sustained release composition of the present invention is to be administered to mammals in need of such treatment wherein the medicament present in the composition is administered in pharmaceutically effective amounts.
In the present invention, it has been found that a sustained release carrier comprising only sorbitol and/or sucrose esters may be sufficient to provide a suitable sustained release of an insoluble medicament to provide therapeutically effective blood levels for extended periods of time, e.g., 8 to about 24 hours.
The present pharmaceutical composition comprises a composition in unit dosage form. The term "unit dosage form", as employed herein, refers to a physically discrete unit suitable as unitary dosage to mammals, including humans, with each unit containing a predetermined quantity of active material calculated to produce the desired effect in association with sorbitol and/or sucrose esters, the lubricant and other pharmaceutically acceptable excipients or adjuvants if present, as described herein. The pharmaceutical composition is generally prepared into an oral dosage form such as tablets, capsules filled with granules, pellets or coated pellets, and the likes.
The composition usually comprises 1 to 75 % by weight and preferably 30 to 60 % and even more preferably 35 to 50 % by weight of the active pharmaceutical agent. The composition according to the invention also includes sorbitol/ sucrose ester or combination thereof, in an amount from 20% to about 70% by weight, more preferably 35% to about 60%. Especially preferred compositions according to the invention contain about 40% to 55% by weight of sorbitol/ sucrose esters.
Sorbitol is a sugar alcohol. Sugar alcohols are hydrogenated form of carbohydrates and are also known as polyol, polyhydric alcohol, or polyalcohol. Other members of sugar alcohol class that can be used in place of sorbitol include mannitol, maltitol, lactitol, xylitol, glycerol, isomalt and their mixtures thereof.
The fatty acid sucrose ester includes sucrose stearate, sucrose palmitate, sucrose oleate, sucrose laurate, sucrose behenate, and sucrose erucate, among which the preferred ones are sucrose stearate, sucrose palmitate, sucrose oleate, and sucrose laurate. Sucrose esters are commercially available in many grades depending upon the

fatty acid and HLB value such as sucrose stearate (S-270, S-970, S-1570 and S-1670), sucrose laurate (L-1695), sucrose palmitate (P-1570 and P-1670) etc.
The present sustained release composition is specifically devoid of rate controlling polymers like non pH dependent and pH dependant polymers, e.g. hydroxyl propyl cellulose, hydroxyl propyl methyl cellulose, hydroxyl methyl propyl cellulose, methyl cellulose, ethyl cellulose, carboxy methyl cellulose etc.
It has also been found that particularly preferred compositions further comprise of pharmaceutically acceptable filler in admixture with sorbitol/ sucrose esters or the medicament.
The present composition is applicable to a wide variety of drugs or active pharmaceutical agents, irrespective of dose, and especially to relatively insoluble therapeutic agents. The active pharmaceutical agents are selected from the group consisting of analgesics, anticonvulsants, anti-diabetic agents, anti-infective agents, anti-neoplastic agents, anti-parkinsonian agents, anti -rheumatic agents, cardiovascular agents, CNS (central nervous system) stimulants, dopamine receptor agonists, anti-emetics, gastrointestinal agents, psychotherapeutic agents, opioid agonists, opioid antagonists, anti-epileptic drugs, histamine H2 antagonists, anti¬asthmatic agents, and skeletal muscle relaxants.
The therapeutic agents suitable for use in present sustained release composition include, but are not limited to nifedipine, nisolidipine, nicardipine, nilvadipine, nivadipine, felodipine, nimodipine, nitrendipine, lercanidipine, bendroflumethazide, acetazolamide, methazolamide, chlorpropamide, triamcinolone, ibuprofen, atenolol, timolol, cimetidine, clonidine, diclofenac, venlafaxine, Zolpidem, quetiapine, metformin, guanfacine, metoprolol, sulfamethoxazole, metronidazole, indapamide, diazepam, mianserin, chlorpromazine, imipramine, promethazine, erythromycin, clarithromycin, azithromycin, spiromycin, dirithromycin, roxithromycin, josamycin, midecamycin, kitasamycin, rokitamycin, oleandomycin, miocamycin, flurithromycin, rosaramicin, compounds designated ABT-229 or ABT-269, amoxicillin, acetaminophen, naproxen, indomethacin, voriconazole, olanzapine, ondansetron, dipyridamole, carvedilol, lamotrigine,and the like and includes their pharmaceutically acceptable salt or ester forms.

The pharmaceutical composition of the invention also includes one or more pharmaceutically acceptable excipient or processing aid including, but not limited to, binders, diluents/ fillers, glidants, lubricants etc.
The binder may be one or more pharmaceutically acceptable sugar such as sucrose, fructose etc. The binder may also include one or more waxy material having a melting point in the range of 30 - 80 °C, such as glyceryl stearate, hydrogenated vegetable oil, hydrogenated castor oil, poloxamer etc.
Diluents like lactose, dicalcium phosphate, mannitol, microcrystalline cellulose, etc can be added.
The lubricant may be one or more selected from the group of magnesium stearate, stearic acid, sodium stearyl fumarate etc.
The glidant may be one or more agent selected from the group of talc, colloidal silicon dioxide etc.
The pharmaceutically acceptable coating material includes, but is not limited to, a rapid-disintegrating coating material such as Opadry™ available from Colorcon, Inc.
Generally, the amount of the pharmaceutically acceptable coating material surrounding the core is from about 1% to about 5%, such as about 0.5% to about 2% by weight, based on the total weight of the pharmaceutical composition. It is found that the release rate of the therapeutically active agent can be controlled not only by incorporating suitable pharmaceutically acceptable polymer and pharmaceutically acceptable acid therein, but also by the thickness of the pharmaceutically acceptable coating material applied.
In the pharmaceutical composition of the present invention, the sustained release agent is sorbitol and/or sucrose esters. The core of the pharmaceutical mixture can be prepared in a form of granules, particles, beads, spherical beads, pellets, coated beads, coated pellets, coated particles, and other pharmaceutically acceptable shapes and sizes. This can be done by wet granulation or melt granulation.

Sustained release composition prepared by melt granulation process includes the following steps;
(a) melting sorbitol and adding the active pharmaceutical agent with stirring to the molten mass of sorbitol to form granules;
(b) sizing the granules through a suitable screen;
(c) blending the dried granules with pharmaceutically acceptable excipients;
(d) compressing the above blend of step [c] to form tablets and;
(e) optionally applying a film coat over the tablets.
Sustained release composition prepared by melt granulation process includes the following steps:
(a) blending sucrose ester and add the active pharmaceutical agent and other suitable diluents;
(b) granulating the above blend of step [a] with water or other suitable solvent to form granules;
(c) sizing the granules obtained in step [b];
(d) blending the dried granules with pharmaceutically acceptable excipients;
(e) compressing the above blend of step [d] to form tablets and;
(f) optionally applying a film coat over the tablets.
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.
Example 1:

Sr. No. Ingredient Quantity (mg)
Core material
1 Clarithromycin 500.00
2 Sorbitol 490.00
3 Magnesium Stearate 10.00
Film Coat ng material
4 Mannitol 12.00
5 Propylene glycol 2.95
6 Titanium dioxide 2.95
7 Sorbitan monooleate 1.50
8 D&C Yellow No. 10 0.05
9 Vanillin 0.05
10 Sorbic acid 0.50
11 Purified Water q.s

Brief Manufacturing Process:
1. Clarithromycin and sorbitol were sifted through #30 mesh using mechanical sifter and mixed using bin blender.
2. The mixture of step 1 was heated on an oil bath in a SS vessel at about 90 -100°C, till a uniform semisolid mass was obtained. The hot mass was then allowed to cool and milled through mill using 1.5 mm screen
3. Magnesium stearate was sifted using mechanical stirrer and blended with the milled material of step 2 for 5 minutes using bin blender,
4. The blend of step 3 was then compressed on 16 station rotary tablet compression machine using 9.0 x 18.5 mm punch with the hardness in the range of 18 -26 kP
5. Mannitol, propylene glycol, sorbitan monoieate, sorbic acid, titanium dioxide, D&C yellow No. 10 and vanillin were dissolved in water under stirring and the resulting coating solution was sprayed onto the compressed tablets of step 4.
Example 2:

Sr. No. Ingredient Quantity (mg)
Core material
1 Acetazolamide 500.00
2 Anhydrous Lactose 50.00
3 Sorbitol 390.00
4 Magnesium Stearate 10.00
Brief Manufacturing Process:
1. Acetazolamide and Anhydrous lactose were sifted through #30 mesh using mechanical sifter.
2. Sorbitol was heated in a SS vessel at about 90 -100°C, till a molten mass was obtained. The sifted material of step 1 was mixed with molten sorbitol to get uniform mix. The molten mass was allowed to cool and milled through mill using 1.0 mm screen
3. Magnesium stearate was sifted using mechanical stirrer and blended with the milled material of step -2 for 5 minutes using bin blender.
4. The blend of step 3 was then compressed on 16 station rotary tablet compression machine using 8.8 x 19.0 mm punch with the hardness in the range of 15-25 kP
Example 3:

Sr. No. Ingredient Quantity (mg)
Core material
Granules A
1 Ibuprofen 200.00
2 Anhydrous Lactose 240.00
3 Purified water qs
Granules B
4 Ibuprofen 200.00
5 Sorbitol 250.00
Lubrication
6 Magnesium Stearate 10.00
Film Coating material
7 Mannitol 12.00
8 Propylene glycol 2.95
9 Titanium dioxide 2.95
10 Sorbitan monooleate 1.50
11 D&C Yellow No. 10 0.05
12 Vanillin 0.05
13 Sorbic acid 0.50
14 Purified Water q.s
Brief Manufacturing Process:
1. Ibuprofen (ingredient 1) and anhydrous lactose were sifted using a mechanical sifter and granulated in rapid mixer granulator by addition of water till dense granules were obtained. The granules were dried and milled.
2. Ibuprofen (ingredient 4) and sorbitol were mixed using a bin blender. The mixture was then heated on a water bath in a SS vessel at about 70 -90°C, till a uniform mass was obtained. The molten mass was then cooled and milled through multi mill using 1.5 mm screen. The milled material was then mixed with the granules of step 1 in the bin blender and further lubricated with sifted magnesium stearate.
3. The lubricated granules were then compressed into tablet using 16 station rotary compression machine (Cadmach) using 8.5 x 17.8 mm oval punches.
4. The compressed tablets of step 3 were further coated with the film coating material in a perforated coating pan.
Example 4:

Sr. No. Ingredient Quantity (mg)
Core material
1 Clarithromycin 500.00
2 Sucrose stearate (S-170) 490.00
3 Purified water q.s.
4 Magnesium stearate 10.00

Film coating material
5 Mannitol 12.00
6 Propylene glycol 2.95
7 Titanium dioxide 2.95
8 Sorbitan monooleate 1.50
9 D&C Yellow No. 10 0.05
10 Vanillin 0,05
11 Sorbic acid 0.50
12 Purified Water q.s
Brief Manufacturing Process:
1. Sift Clarithromycin, Sucrose ester through #30 mesh.
2. Granulate the material of step 1 with water and add additional water if required till the desired granules are obtained.
3. Dry the granules at suitable temperature and mill through 1.0 mm screen.
4. Sift magnesium stearate through #40 mesh and add to the blend of step no. 3 and blend for 5 minutes.
5. Compress the blend of step no. 4 into tablets.
6. Dissolve Mannitol/ Lactose, propylene glycol, sorbitan monoleate, sorbic acid,
titanium dioxide, D&C yellow No. 10 and vanillin in Water and Coat the tablets of step
no.6 till the desired weight build up is achieved.
Dissolution Study:
The composition according to the present invention disclosed in Example 1 and Example 2 were tested for the in-vitro drug release and the profiles were compared with commercially available formulation.
Dissolution profile of Example 1:
The dissolution test is done using USP II apparatus at 50 RPM, 900ml of phosphate buffer pH 6.0 at 37 ± 0.5 "C. The sampling was carried out at 2, 4, 8 and 12 hours. The dissolution profile was then compared with that of marketed product Biaxin XL, which is manufactured using hydrophilic polymer as release retarding excipient, The results showed that sorbitol used here according to the invention provide comparable dissolution profile of clarithromycin with that of Biaxin XL.
Table 1: Results of the dissolution study of Example 1, with Biaxin XL

Time points (hours) Biaxin XL Example 1

2.0 16.7 14.4
4.0 37,0 39.4
8.0 71.9 71.9
12.0 99.2 99.2
Dissolution profile of Example 2:
The dissolution test is done using USP II apparatus at 50 RPM, 900ml of phosphate buffer pH 4.5 at 37 ± 0.5 °C. The sampling was carried out at 2, 4, 6, 8 and 12 hours. The dissolution profile was then compared with that of marketed product DIAMOX SEQUELS. The results showed that sorbitol used here according to the invention provide comparable dissolution profile of clarithromycin with that of DIAMOX SEQUELS.
Table 2: Results of the dissolution study of Example 2, with DIAMOX SEQUELS

Time points (hours) DIAMOX SEQUELS Example 2
2.0 30,4 31.6
4.0 46.5 47.9
6.0 63.3 58,1
8.0 75.1 65,6
12.0 91.1 81.9
As shown in the above tables, the tablets obtained using above composition and method of preparation results in similar dissolution profile as that of the commercial product.

1. A sustained release pharmaceutical composition for oral administration, comprising an admixture of therapeutically effective amount of active pharmaceutical agent, a pharmaceutically acceptable sustained release carrier and optionally one or more pharmaceutically acceptable excipients, wherein said sustained release carrier is selected from sorbitol and/or sucrose esters in an amount from about 30% to about 70% by weight of said composition.
2. The pharmaceutical composition according to claim 1, wherein said active pharmaceutical agent is selected from relatively insoluble therapeutic agents.
3. The pharmaceutical composition according to claim 3, wherein relatively insoluble therapeutic agents is selected form but not limited to clarithromycin, erythromycin, amoxicillin, acetazolamide, ibuprofen and naproxen or their pharmaceutically acceptable salt or ester forms.
4. The pharmaceutical composition according to claim 1, wherein said sorbitol and/or sucrose ester in an amount of about 35 - 45% by weight of said composition.
5. The pharmaceutical composition according to claim 1, wherein said
pharmaceutically acceptable excipients are selected form fillers, binders, lubricants,
glidants, coloring agents or flavoring agents.
6, The pharmaceutical composition according to claim 1, wherein said dosage form
shows following drug release profile in an In-vitro dissolution test:
less than 25% released after 2 hour; less than 50% released after 4 hour; less than 65% released after 6 hour;

less than 80% released after 8 hour; and greater than 85% after 12 hours.
7. The pharmaceutical composition according to claim 1, wherein said dosage form
shows following drug release profile in an in-vitro dissolution test:
between 10 and 25% released after 2 hour; between 35 and 45% released after 4 hour; between 50 and 60% released after 6 hour; between 70 and 75% released after 8 hour; and greater than 85% after 12 hours.
8. A process for preparing sustained release pharmaceutical composition comprising
the steps of:
a. forming a mixture comprising sorbitol and/or sucrose ester and an active
pharmaceutical agent;
b. converting said mixture of step [a] to from granules;
c. optionally blending said granules of step [b] with one or more pharmaceutically
acceptable excipients;
d. compress said blend of step [c] to form tablets; and
e optionally coating said tablets.
9. A sustained release pharmaceutical composition for oral administration, comprising
an admixture of:
i) clarithromycin in an amount from about 30% to about 60%;
ii) sorbitol and/or sucrose esters in an amount from about 35% to about 55%; and
iii) optionally one or more pharmaceutically acceptable excipients;
wherein said composition has the following dissolution release:
about less than 20% is released after about 2.0 hours; about less than 50% is released
after about 4 hours; about less than 80% is released after about 8 hours; and greater
than 85% is released after about 12 hours, when measured using United States
Pharmacopoeia II dissolution apparatus.

10. A sustained release pharmaceutical composition for oral administration, comprising
an admixture of:
i) acetazolamide In an amount from about 30% to about 60%;
il) sorbitol and/or sucrose esters in an amount from about 35% to about 55%; and
iii) optionally one or more pharmaceutically acceptable excipients;
wherein said composition has the following dissolution release:
about less than 25% is released after about 2,0 hours; about less than 50% is released
after about 4 hours; about less than 65% is released after about 6 hours; about less
than 80% is released after about 8 hours; and greater than 85% is released after about
12 hours, when measured using United States Pharmacopoeia II dissolution
apparatus.