WO2003099197A2

WO2003099197A2 - Formulations of erythromycin derivatives with improved bioavailability

Info

Publication number: WO2003099197A2
Application number: PCT/IN2002/000183
Authority: WO
Inventors: Madhukant Mansukhlal Doshi; Milind Dattatraya Joshi; Bharat Pravinchandra Mehta
Original assignee: J.B. Chemicals & Pharmaceuticals Ltd.
Priority date: 2002-05-28
Filing date: 2002-09-05
Publication date: 2003-12-04
Also published as: AU2002343199A1; AU2002343199A8; WO2003099197A3

Abstract

The present invention describes a pharmaceutical composition for controlled release of Erythromycin derivatives, which provides better bioavailability by releasing the active agent with modified crystal characteristics immediately as well as in a controlled manner over a desired period for the treatment of various types of infections. The composition in the form of matrix tablet comprises of erythromycin derivative with modified crystal characteristics which exhibits better solubility and hence imparts improved bioavailability with negligible or no gastric side effects as compared to those immediate release compositions. More particularly, the said invention relates to pharmaceutical compositions of roxithromycin.

Description

FORMULATIONS OF ERYTHROMYCIN DERIVATIVES WITH IMPROVED BIOAVAILABILITY

FIELD OF THE INVENTION

The present invention describes a pharmaceutical composition for controlled release of Erythromycin derivatives, which provides better bioavailability by releasing the active agent with improved solubility in a controlled manner over a desired period for 5. the treatment of various types of infections. More particularly, the said invention relates to pharmaceutical compositions of roxithromycin.

BACKGROUND OF THE INVENTION

Roxithromycin, is the ether-oxime derivative of erythromycin which is a macrolide with antibacterial properties similar to erythromycin. Chemically it is 9-{O-[(2- 1₀. methoxyethoxy)methyl]oxime}erythromycin. Roxithromycin is active against Gram- positive bacteria like Staphylococci, Streptococci, Listeria, Corynebacteria & Gram- negative bacteria such as Haemophilus inβuenzae, Legionella, Campylobacter and atypical pathogens like Mycoplasma and Chlamydia.

Roxithromycin is highly concentrated in polymorphonuclear leucocytes and is. macrophages, enhances adhesiveness and chemotaxis of polymorphonuclear leukocytes, which in the presence of infection produce phagocytosis and bacterial lysis, thus supports host defense system. Roxithromycin also possesses intracellular bactericidal activity. Roxithromycin exerts its action by binding to the 50s bacterial subunit, thereby disrupting bacterial protein synthesis.

2,o . Roxithromycin is indicated for use in the treatment of mild to moderate infections of the ear, nose and throat, respiratory tract, in the skin and skin structure and genito- urinary tract caused by susceptible strains of organisms listed below: Pharyngitis, tonsillitis, sinusitis and otitis media, due to Group A beta-haemolytic Streptococci and Streptococcus pneumoniae. Pneumonia and acute bronchitis due to Streptococcus pneumoniae. Atypical pneumoniae, due to Mycoplasma pneumoniae. Ξ. Pyoderma and erysipelas, due to Staphylococcus aureus and Group A beta-haemolytic

Streptococci. Non-gonococcal urethritis in men, due to Chlamydia trachomatis and Ureaplasma urealyticum.

A particular aspect of the present invention is the preparation of roxithromycin with better solubility at pH 1.2 and is achieved by altering the crystal structure of 10. roxithromycin and formulating into a solid dosage form where the release is controlled over 24 hours. Roxithromycin is generally administered twice daily as a 150 mg. The conventional dosage form is only about 60% bioavailable.

Roxithromycin exhibits a peculiar solubility profile, i.e. it is soluble at acidic pH i.e. from 1.2 till 4.0 and then the solubility decreases as the pH increases from pylorus to is. intestine. Though the drug is soluble at pH 1.2, absorption of drug from the dosage form is incomplete resulting in poor bioavailability. The drug dissolves completely at about pH 4.0. Further the drug's solubility decreases with increasing pH, which leads to less drug being available for absorption after pH 5.0 to 6.0.

The most common side effects observed with conventional roxithromycin 2.0. formulations are gastric disturbances such as gastric irritation, gastric pain, nausea, vomiting and diarrhoea which are attributed to the free, unabsorbed drug available in stomach. Thus, the rate-limiting step in the availability of roxithromycin is solubilization of drug from tablet in the gastric milieu. When a conventional solid oral dosage form containing roxithromycin is ingested, its absorption is incomplete and S. bioavailability is only 50-60%. The free, unabsorbed drug remaining in stomach causes gastric disturbances. Thus, to avoid the gastric side effects, it is necessary to eliminate free drug in stomach i.e. making the drug available totally. A frequent drug administration may reduce patient compliance and also there is possibility of exhibiting toxic effects accompanied by side effect. Thus, there is a need of improvement in bioavailability which will help in lowering the total daily dose and also the frequency of dosing. This will be expected to result in a reduced ₅. incidence of side effects due to improved solubility at gastric pH and decreased total dose, and improved patient compliance, due to the increase in dosage interval.

Various approaches have been attempted to enhance the solubility and bioavailability of various bioactive agents eg solid solutions, complexation with beta cyclodextrin or polymers, solvated compounds, hydrogel polymerization, polymoφhism. The present

10. invention provides an improved roxithromycin having modified crystal characteristics. The improved roxithromycin exhibits good water solubility thereby increasing the bioavailability. Roxithromycin of improved crystal characteristics can be prepared as follows: roxithromycin is dissolved in an organic solvent(s) by stirring with a mechanical stirrer at ambient conditions. The drug is then precipitated by ι^- gradual addition of a non-solvent such as Water. The drug powder is obtained after filtration and drying. Roxithromycin with modified crystal characteristics exhibited improved absorption of roxithromycin.

The present invention provides a way of overcoming poor bioavailability by increasing the solubility and using controlled release formulation, which helps to Z . minimize the gastric side effects. The active ingredient i.e. Roxithromycin with modified crystal characteristics as described in the present invention is formulated in a controlled release oral dosage form. Also the advantages of reduced dosage regimens for the outpatient are convenience and, more importantly, better assurance of compliance.

2.S.. U.S. Pat. No. 4,842,866 describes controlled release formulations containing erythromycin derivatives to improve the possible non-compliance with the regimen. The active agent is present in an alginate matrix comprising a water-soluble alginate and a complex salt of alginic acid, having one cation that yields a soluble alginate salt and another cation that alone yields an insoluble alginate salt. However, in-vivo animal studies showed that reproducibly bioavailable controlled release formulation were not possible using alginates or any other monolithic hydrogel tablets.

Improved controlled release formulations for poorly soluble basic drugs such as 5. erythromycin derivatives including clarithromycin, have been developed and are described U.S. patent application Ser. No. 08/574,877. The formulations described in the patent application comprise a poorly soluble basic drug and citric acid in an alginate matrix which are administered once a day and are directed towards increasing the bioavailability of the active ingredient so that it is bioequivalent with the current 1₀. immediate release, twice-a-day compositions. However, these controlled release compositions do not purport to minimize the adverse effects related to gastrointestinal (GI) disorders including nausea and vomiting.

The formulations as described in U.S. Pat. No. 4,808,411, are administered twice-a- day for a period of 10 to 14 days and do not address the frequency and duration of the i s . administration regimen, or the adverse effects related to gastrointestinal disorders.

US patent 5,705,190 describes a controlled release formulation that comprises the use of a water-soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid for administration of a once a day dosage form for clarithromycin. Though the system claims improved bioavailability, the invention does not address .2.0. the frequency and duration of the administration regimen, or the adverse effects related to GI disorders.

US patent 6,010,718 relates to pharmaceutical compositions of erythromycin derivatives with an extended release of an active compound in the gastrointestinal environment. The composition comprises an erythromycin derivative and a .15. pharmaceutically acceptable polymer. Though the composition of the invention claims improved taste profile and reduced gastrointestinal side effects as compared to those for the immediate release composition but the release of drug in stomach will have considerable side effects due to presence of free drug.

United States Patent 5,156,842 teaches a non-aqueous pharmaceutical liquid suspension having improved bioavailability for oral administration of antibiotics in the form of controlled release particles which are suspended in an edible, non- 5. aqueous carrier oil and dispensed in the form of capsule.

All the above inventions attempt to improve the bioavailability of the said active ingredients (erythromycin derivative) but the amount of drug released in stomach is only partially absorbed due to crystalline nature of conventional roxithromycin drug. This gives rise to free drug in gastric tract which causes gastric disturbances, which / O- are the major side effects, associated with the therapy of Erythromycin and its derivatives. Therefore, there still exists a need for developing a pharmaceutical composition which minimizes the gastrointestinal adverse effects described above and provides a control over drug plasma concentration which is equivalent to or better than the immediate release tablet or liquid formulations currently used.

15. It may be desirable to extend release of active substance within the body where absoφtion is maximum. Various controlled absoφtion pharmaceutical formulations are available which have a particular dissolution pattern, resulting in a controlled absoφtion of the active substance, and therefore more medication. The pharmaceutical composition as mentioned in the present invention is designed to

Z . release the drug with modified crystal characteristics gradually over a specified period of time. Once the dosage form of the present invention reaches the GI environment of pH 1.2, the drug will be slowly released in a controlled manner over a specified period of time. Other preparations, which employ conventional roxithromycin, which gives incomplete absoφtion causing major gastric disturbances. This problem was

25_. overcome in the present invention which employs active ingredient with modified crystal characteristics. The said active ingredient of the present invention exhibits better solubility at pH 1.2, enabling improved absoφtion thereby minimizing free drug at stomach hence, eliminating the gastric side effects, a major drawback of Roxithromycin therapy. To attain and maintain a blood level which exceeds the minimum effective level required for response, but does not exceed the minimum toxic level, the doses of 150mg and 300mg in controlled release formulation are convenient.

₅. Knowing the state of the art and knowing the need which has existed for years to find a formulation which has better bioavailability and a long duration of action of Erythromycin derivative at desired site with negligible gastrointestinal disturbances, a composition has been developed according to the invention which so far as known, no one has heretofore formulated.

1₀ . The inventors of the present invention have come out with simple and inexpensive way of producing once-a-day extended release formulation of erythromycin derivative, which leads to good therapeutic effectiveness in various types of infections with minimum side effects. The present invention not only provides an effective means to provide relatively low dose treatment of various types of infections but also

₁5_. helps to maintain patient compliance.

OBJECTS OF THE INVENTION

1. It is the object of the invention to develop once a day extended release formulation of erythromycin derivative with improved bioavailability and non-significant side effects. _Q 2. It is further objective of the invention to prepare erythromycin derivative with improved crystal characteristics which exhibits better solubility profile at pH 1.2 and minimises free drug at gastric milieu which would otherwise cause severe gastric disturbances.

3. It is further object of the invention to provide controlled release of roxithromycin . with improved crystal characteristics suitable for once-a-day administration, which is particularly effective for 12 hrs to 24hrs.

4. It is still a further object of the invention to develop an antibiotic formulation maintaining a high antibacterial activity with less or negligible side effects by improving the solubility of roxithromycin with changed crystal characteristics and facilitating the release in a controlled manner to allow the maximum absoφtion to occur.

S . BRIEF DESCRIPTION OF THE INVENTION

The present invention is a novel pharmaceutical composition in the form of a controlled release matrix system that is adapted to deliver Erythromycin derivative, particularly Roxithromycin with a modified crystal characteristics in a controlled manner over a specific time period. The pharmaceutical composition as described in ι_0, the present invention comprises of a compressed core containing an active ingredient, designed in a such a manner to release the drug in a controlled manner over a period of time which ensures complete absoφtion due to improved solubility.

The improved crystal characteristics of roxithromycin exhibits good solubility at pH 1.2 also, thereby increasing the bioavailability. The conventional is incompletely

,_s absorbed thereby giving rise to free drug which causes gastric disturbances. The present invention describes a method of preparing roxithromycin with improved crystal characteristics which is as follows: roxithromycin is dissolved in an organic solvent(s) such as lower alcohols, lower ketones, chloroalkanes. The preferred solvents are selected from methanol, alcohol, iso propyl alcohol, butyl alcohol,

^o acetone, ethylmethyl ketone, dichloromethane, carbon tetrachloride. The most preferred being methanol. The dissolution is affected by stirring with a mechanical stirrer at temperature between 30°C-40°C. Preferably dissolution is carried out at 37°C. The drug is co-precipitated by gradual addition of a non-solvent such as Water. The precipitated drug is collected after filtration and dried at ambient temperature to S. obtain dry powder of roxithromycin. The drying can be carried out with the help of tray dryer, spray dryer or fluid bed granulator, preferably with tray dryer at anbient temperature. An amount of roxithromycin in the organic solvent is 4 to 10% and preferably 5% by weight. The physical changes of roxithromycin was confirmed by scanning electron micrographs (fig 1, 2).

Roxythromycin prepared by method as described in the present invention has particle 5_ size is about 50microns as compared to about 500microns of the conventional roxithromycin. The reduced particle size in the submicron range alongwith the changed crystal characteristics may attribute to the improved solubility and better absoφtion of the drug.

The term "Erythromycin derivative" as used herein, means erythromycin having no ι_θ . substituent groups, or having conventional substituent groups.

The present invention preferably provides a controlled release pharmaceutical composition comprising an active ingredient. Additionally it may contain a hydrophilic controlled release polymer, a filler, a binder, disintegrant and lubricants.

A preferred embodiment of the present invention comprises about 30% to about 70% is. of an active ingredient, about 10% to about 40% of hydrophilic matrix forming polymer, about 10 to about 30% of filler, about 2% to 10% of disintegrant, about 2 to about 5% of binder and about 1.0 to 10.0% of each of the lubricants. As used herein, percentage amounts for an ingredient are the percent weights of the ingredients based on the total weight of the composition.

_2o. The active agent as described in the present invention comprises therapeutic compounds with modified crystal characteristics which can be formulated into the present controlled release system include antibacterial substances.

Representative active agents are beta-lactam antibiotics, tetracycline, oxytetracycline, chlorotetracycline, chloramphenicol, neomycin, sulfonamides, sulphamethoxazole, s. aminoglycoside antibiotics, nitrofurazone, metronidazole, penicillin, oxybutanin, cephalosporins, nalidixic acid, fluoroquinolones and macrolides such as erythromycin and its derivatives.

The pharmaceutical composition as described in the present invention where active agent is macrolide antibiotic and is selected from azithromycin, clarithromycin, 5. dirithromycin, flurithxomycin, josamycin, kitasamycin, miocamycin, oleandamycin, rokitamycin, spiramycin, erythromycin and its derivatives. The most preferred being 9-{O-[(2-methoxyethoxy)methyl] oxime} erythromycin, roxithromycin.

The active ingredient as mentioned in the present invention is modified with respect to crystal characteristics and results in better solubility at pH 1.2 thus improving the 10 • absoφtion and minimizing gastric side effects.

The daily dose of the composition of this invention administered to a host in single dose can be in the amounts from 150mg to 300mg once-a-day for three to five days.

Hydrophilic matrix forming polymer is selected from any one or more of the pharmaceutically accepted inert polymer or mixture of such polymers normally is- employed and described in literature, such as alkylcellulose, poly vinyl pyrrolidone, polyethylene glycol, modified polymethacrylate copolymers and the like, preferably employed are alkyl celluloses such as methylcellulose, ethylcellulose, polyvinylpyrrolidone, hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropyl methylcellulose, and sodium

_Z0. carboxymethylcellulose, with hydroxypropylmethyl cellulose being particularly preferred. Hydroxypropyl methylcellulose available under commercial names Methocel® and is selected from various grades available. The most preferred grades being Methocel® K100 LV and Methocel K4M which is present in the range of 15% to 35%, preferably in the range of 15% to 30% and the most preferred concentration

•2S . being 25% by weight of the said composition. The ratio of roxithromycin and hydroxypropylmetnylcellulose ranges between 1 :0.2 to 1 :2. The most preferred being 1 :0.5. The pharmaceutical composition of the invention where filler is selected from lactose, microcrystalline cellulose, starch, partially pregelatinised starch, dicalcium phosphate, glucose, sucrose, mannitol, lactose, sorbitol or dextrose. The most preferred being lactose and is present in an amount from 10% to 30%, preferably from S. 15% to 25%o and the most preferred being 20% by weight based on the total weight of the composition.

The preferred embodiment of the invention where disintegrant is included in a Immediate Release core and can be selected from starch, sodium starch glycollate, pregelatinised starch, cross linked sodium carboxymethyl cellulose, cross linked ι_θ povidone, ion exchange resin. The most preferred being sodium starch glycollate and is present in an amount from 0.5% to 5%, preferably in an amount from 0.75% to 3% and the most preferred quantity being 1% by weight based on the total weight of the composition.

The lubricants included in the core are magnesium stearate and talc, preferably 0.5% 5_ to 5% of magnesium stearate and 1% to 5% by weight of talc, the most preferred being 1% of magnesium stearate and 3.0% of talc.

The pharmaceutical composition of the present invention where binder employed when the core tablets are prepared by wet granulation method, can be selected from starch paste, aqueous or organic solutions of different polymers such as polyvinyl _jø. pyrrolidone, different grades of hydroxypropyl methylcellulose, hydroxypropyl cellulose, ethyl cellulose. The most preferred being alcoholic solution of polyvinyl pyrrolidone which is preferred in the range of 2-5% by weight of the composition.

The core tablets of the pharmaceutical composition of the present invention can also be prepared by slugging the mixture of polymer, filler, erythromycin derivative, ,25. lubricants and other excipients. The excipients required to be used at various stages of the process are selected from pharmaceutically acceptable excipients normally employed in pharmaceutical formulation. Those skilled in the art can decide as to the particular excipients and quantities thereof to be employed in the process, having regard for the quantity of the

5. active drug to be taken and rates and periods of release of the active drug desired in the final formulation.

The compositions of the invention can also be in any form commonly employed for adminstration i.e. tablets, capsules, pills caplets, powders lozenges, granules, capsule, waffers, and chewables or liquids such as emulsions, microemulsions, solutions, J _Q_ suspensions, syrups and elixirs. It can also be administered in the form of modified release, sustained release, controlled release, timed release formulation. It can also be adminstered by ocular, intranasal, buccal, sublingual, rectal, vaginal and other related administration routes.

It will be appreciated from whatever stated above, clearly shows that roxithromycin 15. can be administered as oral dosage forms in controlled manner over a specified period.

The invention will be more fully understood from the following examples. These examples are to be constructed as illustrative of the invention and not limitative thereof :

Λo. Example 1

ΛS.

Roxithromycin with improved crystal characteristics, lactose, sodium starch glycolate, Methocel K100 LV and Methocel K 4M are sifted and mixed together which is 5. further mixed with talc and magnesium stearate in a blender for 5minutes. The blended mixture was sifted through 40 mesh sieve and then slugged on a rotary compression machine. The slugs were sized through 16 mesh sieve and further mixed with talc and magnesium stearate in a blender for 5minutes. The blended mixture was sifted through 40mesh sieve and then compressed on a rotary compression machine.

Example 2 :

The composition is similar to that mentioned in Example 1 , but the procedure used for preparation of core tablet is wet granulation instead of slugging and polyvinyl pyrrolidone K-30 solution 2% is employed as the binder for granulation.

Example 3 :

I s . The composition employed was similar to that in Example 1 , except that the

Methocel® K-100 LV was replaced with Sodium carboxymethylcellulose HVP.

Example 4 :

The composition employed was similar to that in Example 1, except that the roxithromycin is replaced with azithromycin.

io. Example 5 :

The composition employed was similar to that in Example 1, except that the roxithromycin is replaced with Olendamycin.

Example 6 :

The composition employed was similar to that in Example 1, except that the _pgg; _^ roxithromycin is replaced with clarithromycin. A drug release study was also performed to confirm in-vitro dissolution. The dissolution medium for first 2 hours was 0.1N HC1 and then the medium used was pH 4.5 buffer. Samples were drawn at different time intervals and results obtained were tabulated below. An in vitro trials have shown that the formulation prepared by this method shown controlled effect and constant rate of absorption for desired period of time, ensures maintaining the degree of bioavailability.

o.

13. The results of the above studies indicates that all the Examples product clearly showed the control release profile.

Clinical Trials :

To investigate the effectiveness of the composition of this invention for the treatment of various types of infection, the following clinical trial were conducted. These o. studies are not disclosed to the public and the trials are done in confidence. The results of clinical study in India are given below.

A) Evaluation and Comparison of Safety and Efficacy or Roxithromycin Controlled Delivery of the present invention with Conventional Roxithromycin in Patients with Lower Respiratory Tract Infection.

S. In a open, comparative, prospective clinical trial, roxithromycin controlled delivery

300mg once-a-day of the present invention was evaluated in patients with lower respiratory tract infection (LRTI) and compared with conventional roxithromycin 300mg. A total of 50 patients with LRTI diagnosed clinically, bacteriologically and with the investigations were included and then divided in two groups of 25 patients each after the inclusion. Two groups were well matched demographically. One group received Roxithromycin controlled delivery 300mg once-a-day of the present

5. invention while the other group received conventional roxithromycin 300mg till the symptomatic, bacteriological and radiological cure. All the patients were assessed clinically, radiologically and bacteriologically before inclusion, immediately after the study and I month later. The pathogens isolated from sputum was Streptococcus pneumoniae in 26/50 (52%), Staphylococcus aureus, Haemophilus influenzae or

10. Moraxella catarrhalis occurred in 10/50 patients, mixed organisms isolated from the sputum of 18/50 (36%) and atypical pathogens were detected by serology in 7/50 patients. The severity of infection was rated as mild to moderate at the beginning and during the trial period. All patients received treatment for a minimum of 3 days. At the end of the study, clinical cure rate were 25/25 (100%) for roxithromycin is. controlled delivery 300mg once-a-day of the present invention and 23/25 (92%) for conventional roxithromycin (p<0.05). 2 patients with conventional roxithromycin group were classed as partial responder. One patient of conventional roxithromycin was classed as failure and withdrawn. No patient in controlled delivery roxithromycin of the present invention group required further antibiotic therapy or any shift to any

^_lo. antibiotic. The treatment with roxithromycin of the present invention was well tolerated without any serious side effects as compared to the conventional roxythromycin. Thus, roxithromycin of the present invention 300mg controlled delivery was an effective and well-tolerated treatment superior to conventional roxithromycin with respect to clinical cure rates and number of responders.

5 . B) Evaluation of Safety and Efficacy of Roxithromycin Controlled Delivery

System of the present invention in Patients with Upper Respiratory Tract Infection

STUDY OBJECTIVE: Comparison of efficacy and safety of roxithromycin Controlled Delivery System of the present invention (ROXI) vs. sparfloxacin (Spfx) for the treatment of Upper Respiratory Tract Infection (URTI) DESIGN: Randomized, double blind comparative prospective clinical study. PATIENTS: Total of 100 adult patients (>or = 18 years of age) with URTI were included. Patients were divided in two groups. INTERVENTION: Randomization 1 :1 DOSING: Spfx 400mg 5. on day 1 then 200mg once daily to one group and ROXI 300mg controlled release once daily, 3 days. Clinical and bacteriological evaluation done at baseline and at the end of the study. RESULTS: Staphylococcus aureus, streptococcus pyogenes and streptoccus pneumoniae were the commonest pathogens found. Treatment with Spfx produced satisfactory response in 19/20 (95%), 15/17 (88%) and 12/13 (92%) patients

I O . with pharyngitis/tonsillitis, sinusitis and otitis media against in 22/22 (100%) in pharygitis/tonsillitis, 15/16 (94%) in sinusitis and 12/12 (100%) in otitis media (p<0.05). Of the 22 and 20 patients with pharyngitis/tonsillitis treated with Spfx and ROXI, respectively, who were clinically and bacterologically evaluable, Streptococcus pyogenes persisted at the end of the treatment in 4/22 (18%) in the Spfx

_\S. group and 3/20 (15%) in the ROXI group at follow-up (p<0.05). There was no evidence of S.pyogenes reinfection in either of the groups. Neither Spfx treated nor ROXI treated patients withdrawn because of side effects. In conclusion, for adults with acute URTI, a 3 day course of roxithromycin 300mg controlled release was found to be more effective than Sparfloxacin 400mg on day 1 and 200mg once daily

2.C.. for 2 successive days. Both the treatment enjoy good tolerability without any major side effect.

Above clinical studies confirm the efficacy of the present pharmaceutical composition of this invention:-

From these trials it can be concluded that roxithromycin controlled release of the )g present invention as described in present invention exhibited better efficacy than conventional roxithromycin and was as efficient as other antibacterial agents in the management of bacterial infections.

Claims

WE CLAIM

1. A pharmaceutical composition for extended release of a therapeutically active agent in the gastrointestinal environment comprises of a compressed core containing active agent with modified crystal characteristics for immediate as well

_ as controlled delivery.

2. A pharmaceutical composition for extended release according to claim 1 comprises of an active ingredient with modified crystal characteristics, is prepared by following process: a. Dissolving active ingredient in organic solvent(s) by stirring with a mechanical '£> • stirrer at temperature of 37°C. b. Co-precipitating the drug by gradual addition of a non-solvent. c. Filtering and drying to obtain dry powder.

3. A pharmaceutical composition for extended release according to claim 1 comprises of an active ingredient with modified crystal characteristics,

'^- hydrophilic matrix forming polymer, filler, binder, disintegrant, lubricants. The said core is coated with methacrylic acid co-poymer, plasticizer and antiadherant.

4. A pharmaceutical composition for extended release according to claim 1 wherein the active ingredient is erythromycin derivatives such as the most preferred being Roxithromycin, present in an amount from 30% to about 70% by weight of the

_2J> composition. The most preferred being 50%.

5. A pharmaceutical composition for extended release according to claim 1, wherein said hydrophilic matrix forming polymer is selected from alkyl-cellulose hydroxymethylcellulose, hydroxyethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose and sodium carboxymethylcellulose,

-25. polyvinylpyrrolidone and mixture thereof, the most preferred polymer being hydroxypropyl methylcellulose and present in the range of 10% to 40% preferably in the range of 15% to 35% and the most preferred concentration being 25% by weight of the composition.

6. A pharmaceutical composition for extended release according to claim 1, wherein the grades of said hydrophilic matrix forming polymer are Methocel K 100LV and

5- Methocel K4M employed in the ratio of 1 :0.1 to l .:2, the most preferred ratio being 1 :1.

7. A pharmaceutical composition for extended release according to claim 1, wherein ratio of Roxithromycin to hydroxypropy methylcellulose is between 1:1 to 1 :4. The most preferred being 1 :3.5.

10.

8. A pharmaceutical composition for extended release according to claim 1, wherein filler can be selected from lactose, mannitol, sucrose, sorbitol, glucose and the like. The most preferred being lactose which is present in an amount from 10% to 30%, preferably from 15% to 25% and the most preferred being 20% by weight based on the total weight of the composition.

is.

9. A pharmaceutical composition for extended release according to claim 1, wherein disintegrant included in the core of the present invention which can be selected from starch, sodium starch glycollate, pregelatinised starch, croscarmelose sodium, crospovidone, ion exchange resin, The most preferred being sodium starch glycollate and is present in an amount from 0.5% to 5%, preferably in an «2θ. amount from 0.75% to 3% and the most preferred being 1% by weight based on the total weight of the composition.

10. A pharmaceutical composition for extended release according to claim 1, wherein the binder used for wet granulation can be selected from starch paste, aqueous or organic solutions of different polymers such as polyvinyl pyrrolidone, different 5. grades of HPMC, HPC, ethyl cellulose. The most preferred being alcoholic solution of PVP which is preferred in the range of 2-5% by weight of the composition.

11. A pharmaceutical composition for extended release according to claim 1 , wherein the lubricants included in the core are magnesium stearate and talc, present in an amount ranging from 0.5% to 5% of magnesium stearate and 1% to 5% by weight of talc, preferably 1% of Magnesium stearate and talc 3.0% by weight of the composition.

12. A pharmaceutical composition for extended release according to claim 1, wherein the formulation of the invention can also be in any form commonly employed for administration i.e. suspension, caplets, powders lozenges, solutions, granules, capsule, waffers, and chewables and can also be administered by ocular, intranasal, buccal, sublingual, rectal, vaginal and other related administration routes.