1. A solid oral controlled release pharmaceutical composition for administration to humans comprising therapeutically effective amount of a pharmaceutically active ingredient, a controlled release modifying complex and other required pharmaceutically acceptable additives; the said controlled release modifying complex comprising a synergistic combination of (a) a primary release retardant selected from low molecular weight hydrophilic polymers and / or (b) a secondary release retardant selected from high molecular weight hydrophilic polymers and (c) an auxiliary release retardant selected from the starch derivatives; the said primary release retardant, secondary release retardant and auxiliary release retardant being present in synergistic effective amounts to extend the release of the pharmaceutically active ingredient.

2. The pharmaceutical composition of claim 1, wherein the dosage form may be in tablet or caplet form manufactured by using dry granulation, wet granulation or direct compression techniques.

3. The pharmaceutical composition of claim 1, wherein the active pharmaceutical ingredient is erythromycin or its derivatives

4. The pharmaceutical composition of claim 3 wherein the erythromycin derivative is clarithromycin.

5. The pharmaceutical composition of claim 5 wherein the primary release retardant is a polymer selected from the low molecular weight polyethylene oxides.

6. The pharmaceutical composition of claim 6 wherein the said polymer having a molecular weight of at least about 100,000. 39

7. The pharmaceutical composition of claim 7 wherein the said polymer having a molecular weight ranging from 100,000 to 900,000, preferably 200,000.

8. The pharmaceutical composition of claim 5 wherein the secondary release retardant is a polymer selected from the high molecular weight polyethylene oxides. P. The pharmaceutical composition of claim 9 wherein the said polymer having a molecular weight of at least about 1,000,000.

10. The pharmaceutical composition of claim 10 wherein the said polymer having a molecular weight ranging from 1,000,000 to 7,000,000, preferably 2,000,000.

11. The pharmaceutical composition of claim 5, wherein the auxiliary release retardant is a starch derivative selected from pregelatinized starch, partially pregelatinized starch, and retrograded starch or combinations thereof.

12. The pharmaceutical composition of claim 12, wherein the said auxiliary release retardant is preferably a retrograded starch.

13. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable additives are selected from the diluents/fillers, binders, glidants and lubricants.

14. The pharmaceutical composition of claiml, wherein the composition comprises from about 40 percent weight to about 60 percent weight of the active pharmaceutical ingredient.

15. The pharmaceutical composition of claiml, wherein the composition comprises from about 45 percent weight to about 55 percent weight of the active pharmaceutical ingredient. 40

16. The pharmaceutical composition of claim 1, wherein the composition comprises from about 10 percent weight to about 50 percent weight of the release retarding complex.

17. The pharmaceutical composition of claim 1, wherein the composition comprises from about 25 percent weight to about 45 percent weight of the release retarding complex.

18. The pharmaceutical composition of claim 5, wherein the primary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 5 percent weight to 90 percent weight of the release retardant complex.

19. The pharmaceutical composition of claim 19, wherein the primary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 15 percent weight to 70 percent weight of the release retardant complex.

20. The pharmaceutical composition of claim 20, wherein the primary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 35 percent weight to 55 percent weight of the release retardant complex.

21. The pharmaceutical composition of claim 5, wherein the secondary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 1 percent weight to 50 percent weight of the release retardant complex. 41

22. The pharmaceutical composition of claim 22, wherein the secondary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 5 percent weight to 35 percent weight of the release retardant complex.

23. The pharmaceutical composition of claim 23, wherein the secondary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 8 percent weight to 25 percent weight of the release retardant complex.

24. The pharmaceutical composition of claim 5, wherein the auxiliary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 5 percent weight to 90 percent weight of the release retardant complex.

25. The pharmaceutical composition of claim 25, wherein the auxiliary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 15 percent weight to 70 percent weight of the release retardant complex.

26. The pharmaceutical composition of claim 26, wherein the auxiliary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 35 percent weight to 55 percent weight of the release retardant complex.

27. A composition as claimed in claim 1 wherein, a release retarding complex and other required pharmaceutically acceptable additives, wherein the said release retarding complex comprises a synergistic combination of a polyethylene oxide polymer having a molecular weight of 200,000, a polyethylene oxide polymer having a molecular weight of 2,000,000 and a retrograded starch. 42

28. A composition as claimed in claim 1 wherein an erythromycin derivative, a release retarding complex and other required pharmaceutically acceptable additives; the said complex comprising a synergistic combination of a (a) primary release retardant selected from low molecular weight polyethylene oxides and (b) an auxiliary release retardant selected from the starch derivatives; the said primary release retardant and auxiliary release retardant being present in synergistic effective amounts to extend the release of the erythromycin derivatives.

29. A composition as claimed in claim 1 wherein, an erythromycin derivative, a release retarding complex, andT other required pharmaceutically acceptable additives the said complex comprising a synergistic combination of a (a) secondary release retardant selected from high molecular weight polyethylene oxides and (b) an auxiliary release retardant selected from the starch derivatives; the said secondary release retardant, and auxiliary release retardant being present in synergistic effective amounts to extend the release of the erythromycin derivatives.

30. A pharmaceutical such as herein described with reference to example 1-10, comprising of the erythromycin derivative, the release retarding complex and the other required pharmaceutically acceptable additives; the improvements comprising the synergistic combination of release retardant complex in synergistic effective amounts to expend the release of the erythromycin derivative. Dated this 16(sixteenth) day of December 2005 43 ABSTRACT The present invention is directed to a solid oral controlled release pharmaceutical - composition suitable for once-a-day administration, comprising - a., therapeutically effective amount of a pharmaceutical^ active ingredient erythromycin or a derivative.. - thereof, a release retardant complex and other required pharmaceutical ly acceptable additives; the said release retardant complex comprising a primary release retardant, a secondary release retardant and an auxiliary release retardant wherein the primary release retardant, secondary release retardant and auxiliary release retardant are being present in synergistic effective amounts to extend the release of said pharmaceutical active ingredient.

FORM 2 THE PATENTS ACT 1970 (39 of 1970) & THE PATENTS RULES, 2003 COMPLETE SPECIFICATION (See Section 10; rule 13) TITLE OF THE INVENTION "CONTROLLED RELEASE PHARMACEUTICAL COMPOSITON CONTAINING ERYTHROMYCIN OR ITS DERIVATIVES AND A PROCESS FOR ITS PREPARATION" APPLICANTS Glenmark Pharmaceuticals Limited, an Indian Company, registered under the Indian Company's Act 1957 and having its registered office at B/2, Mahalaxmi Chambers, 22, Bhulabhai Desai Road Post Box No. 26511 Mumbai - 400 026, India The following complete specification particularly describes the invention and the manner in which it is to be performed. DESCRIPTION Technical Field of the Invention: The present invention relates to a controlled release pharmaceutical composition of erythromycin or a derivative thereof, suitable for once-a-day administration and a process for its preparation. The pharmaceutical composition consists of an erythromycin or a derivative there of, a release retarding complex and other required pharmaceutically acceptable additives, in which the release retarding complex comprises of a synergistic effective amount of primary release retardant, secondary release retardant and auxiliary release retardant. Background of the invention: Pharmaceutically active medicaments or other active ingredients administered as conventional tablets or capsules become available to the body fluids at a rate that is initially very high followed by a rapid decline. This delivery pattern of the dosage form results in a transient overdose, followed by a long period of under dosing. This delivery pattern was improved by the introduction of controlled release dosage forms. A controlled release dosage form is one that delivers the pharmaceutically active ingredient in a planned, predictable and slower than normal manner for a longer period of time at a predetermined rate and thus reduces the drug plasma fluctuation observed when multiple doses of immediate release conventional dosage forms are administered. The most common types of controlled release dosage forms are for oral administration and these dosage forms normally extend the drug release profile for a 12 or 24 hour dosing interval. Dosing intervals for oral controlled release products beyond once-a-day dosing are limited by physiologic characterization of the gastrointestinal tract. Erythromycin and its derivatives are known for their antibacterial activity against a number of organisms or activity in a number of indications and are typically administered as immediate release compositions, two or three times a day, for a period of about 10 to 14 days. 2 The recent erythromycin derivatives include dirithromycin, roxithromycin, azithromycin, and clarithromycin. These drugs all appear to have essentially similar properties to erythromycin although they may differ in pharmacokinetics. Clarithromycin , and to a lesser "extentv azithromycin are more active than erythromycin against opportunistic bacteria such as mycobacterium avium complex. Clarithromycin is primarily bacteriostatic; it exerts its antimicrobial effect by the inhibition of protein synthesis on bacterial ribosome. Clarithromycin is active against the major pathogens responsible for respiratory tract infections in immuno-competent patients. Clarithromycin is also active against Helicobacter pylori. Clarithromycin is rapidly absorbed and its bioavailability after an oral dose of 250 mg. is approximately 55%, which is probably due to the first-pass metabolism, which produces, in particular the 14-hydroxy active metabolite. The maximal serum concentration following oral administration is dose dependent and the time to achieve peak blood concentration is about 2 hours. The food intake slightly delays the onset of absorption and the formation of the active metabolite, but does not affect the extent of the bioavailability. Clarithromycin is lipid soluble and extensively distributed both in body fluids and tissues. Clarithromycin also achieves tissue concentration markedly higher than circulating levels, due to its wide distribution and this aspect is relevant for clinical activity. The most usual way of oral administration of clarithromycin is conventional immediate release dosage forms to be taken twice daily, which may lead to a peak and trough blood level fluctuations. The twice daily dosing can result in a poor compliance due to its multiple dosing regimens. The most effective approach to overcome the above mentioned non-compliance causes have been to develop a controlled release oral solid pharmaceutical composition of clarithromycin. US Pat. No. 6,010,718 (Assignee: Abbott Laboratories, Filed date: April 11, 1997, Issued date: Jan 4 2000) discloses an extended release formulation of erythromycin derivatives. The formulation comprises an erythromycin derivative and a pharmaceutically acceptable polymer so that, when ingested orally, the composition induces significantly lower Cmax in the plasma 3 than an immediate release composition of the erythromycin derivative while maintaining bioavailability and minimum concentration substantially equivalent to that of the immediate release composition of the erythromycin derivative upon multiple dosing. The compositions of the invention have an improved taste profile and reduced gastrointestinal side effects as compared to those for the immediate release composition. However use of single polymer system may cause the problem of dose variation in drug release profile. US Pat No. 5,705,190 (Assignee: Abbott Laboratories, Filed date: Dec 19, 1995, Issued date: Jan 6 1998) is directed to a controlled release, oral, solid, pharmaceutical composition for a reduced daily dosage regimen, where the therapeutic ingredient is a poorly soluble basic drug. The formulation comprises the use of a water-soluble alginate salt, a complex salt of alginic acid and an organic carboxylic acid in admixture with the therapeutic drug. A particular embodiment comprising a once a day dosage from for clarithromycin is also described. The disadvantage of such an composition is that it forms a retardant matrix system in situ, therefore determination of the rate release profile is difficult and fluctuating. US Pat. No. 4,808,411 (Assignee: Abbott Laboratories, Filed date: Dec 05, 1987, Issued date: Feb 28 1989) describes compositions which comprise a complex of carbomer (acrylic acid polymers) and erythromycin or a derivative thereof such as 6-0-methylerythromycin, are disclosed. The compositions provide nontoxic, palatable dry and liquid dosage forms for oral administration. Use of single polymer system may cause the release variation depending on the swelling ability of the polymer. Use of single polymer may also not be able to provide sustained release profile for 24 hours. Further, the swelling of Carbomer is also affected by the pH variation. Thus there is a likelihood of variation in the drug release profile. While all the systems mentioned in the above prior art can provide for controlled release of clarithromycin, most of these systems have the disadvantage of some drawbacks such as relatively fast drug release profile, dose dumping, lack of stability, variation in drug release profile between the units and difficult or expensive manufacturing methods. It is therefore particularly desirable to design an efficient controlled release pharmaceutical composition that is capable of controlled drug delivery of clarithromycin, in order to provide extended - 4- therapeutic effects for over 24 hours without dose dumping. It is also highly desirable to develop a controlled delivery system that is relatively easy and inexpensive to manufacture and is capable of preventing dose dumping and providing a better controlled release of clarithromycin than the known systems. The further object of the invention is to develop a controlled release pharmaceutical composition of clarithromycin compressible to a size suitable for oral administration to —4a— humans and the said controlled release pharmaceutical composition also to be suitable for other high dose erythromycin derivatives. Another objective of the invention is to release the active pharmaceutical ingredient into the gastrointestinal tract predominantly in solution phase rather than a solid phase thus avoiding any chances of dose dumping. The present efforts are also directed to a controlled release pharmaceutical composition in which the variation in drug release among dosage units is reduced to a minimum. Summary of the invention The present invention is directed to a controlled release pharmaceutical composition of erythromycin or derivatives thereof, said composition comprising a pharmaceutically effective amount of an erythromycin derivative, a release retarding complex and the other required pharmaceutically acceptable additives. The said release retarding complex essentially comprises, a primary release retardant selected from the low molecular weight polyethylene oxides and / or a secondary release retardant selected from the high molecular weight polyethylene oxides and an auxiliary release retardant selected from the starch derivatives. The said release retarding complex when present in a synergistic effective amount is sufficient to extend the release of said erythromycin derivatives. The said composition of the invention comprises from about 40 percent weight to 60 percent weight of erythromycin derivative, preferably clarithromycin, from about 10 percent weight to 50 percent weight of release retarding complex and other required pharmaceutically acceptable additives. The release retarding complex comprises of a synergistic effective amount of a primary release retardant and / or a secondary release retardant and an auxiliary release retardant. The pharmaceutical composition of the invention provides clarithromycin in a novel release retarding hydrophilic complex matrix which slowly releases the active agent over an extended period of time so as to provide substantial therapeutic effective level of plasma concentration of clarithromycin following once-a-day dosing. 5 In another aspect, the present invention also provides a process for the preparation of a controlled release composition of erythromycin or their derivatives for once-a-day administration. The said controlled release composition can be prepared by wet granulation, dry granulation, and direct compression or by any other technique known in the pharmaceutical art. The composition of the present invention may be optionally coated with a polymer coating, whose materials are not specifically assigned for the modification of the drug release. Brief Description of the Drawings Fig. 1: Plasma Concentration profile of Clarithromycin 500 mg Extended Release Tablets of Example 8 Plasma Concentration of Clarithromycin 500 mg Extended Release tablets 0.9 -i 0.8 - •= 0.7 O) 3 § 0.6 | 0.5 -> -, :i Example 2 '-', • - Table 2.1 . ' ■"■ ' ' "v Sr.No. Ingredient Qty. / unit (mg) % w/w of unit dosage, , form 1. Clarithromycin 500.0 50.00 2. Polyethylene Oxide (Mol. Wt.:200,000) 140.00 14.00 3. Polyethylene Oxide (Mol. Wt.:2,000,000) 40.00 4.00 4. Retrograded Starch 140.00 14.00 5. Lactose Monohydrate 135.00 13.50 6. Talc 30.00 3.00 7. Magnesium Stearate 15.00 1.50 8. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 2. The drug release from the dosage form mentioned in example 2 was extended up to 12 h. 19 Table 2.2 % Time (h) % Cumulative Drug Released 1 8 2 17 4 37 6 56 8 72 10 88 12 95 20 Example 3 Table 3.1 i Sr.No. Ingredient Qty. / unit (mg) % w/w of unit dosage jorm ,' . 1. Clarithromycin 500.00 50.00 2. Polyethylene Oxide (Mol. Wt.:200,000) 87.50 8.75 3. Polyethylene Oxide (Mol. Wt.:2,000,000) 62.50 6.25 4. Retrograded Starch 100.00 10.00 5. Lactose Monohydrate 205.00 20.50 6. Talc 30.00 3.00 7. Magnesium Stearate 15.00 1.50 8. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 3. The drug release from the dosage form mentioned in example 3 was extended up to 12 h. 21 Table 3.2 Time (h) % Cumulative Drug Released 1 9 2 20 4 42 6 63 8 81 10 93 12 97 i ' : A Example 4 : * ; ■■■■■■ Table 4.1 Sr.No. Ingredient Qty. / unit (mg) % w/w of unit dosage1' form 1. Clarithromycin 500.00 50.00 2. Polyethylene Oxide (Mol. Wt.:200,000) 247.50 24.75 3. Polyethylene Oxide (Mol. Wt.:2,000,000) 36.00 3.60 4. Retrograded Starch 166.50 16.65 5. Lactose Monohydrate 5.00 0.50 6. Talc 30.00 3.00 7. Magnesium Stearate 15.00 1.50 8. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 4. The drug release from the dosage form mentioned in example 4 was extended up to 12 h. 23 Table 4.2 Time (h) % Cumulative Drug Released 1 8 2 17 4 35 6 53 8 69 10 83 12 94 Example 5 Table 5.1 Sr.No. Ingredient Qty. / unit (mg) % w/w of unit dosage form 1. Clarithromycin 500.00 50.00 2. Polyethylene Oxide (Mol. Wt.:200,000) 160.00 16.00 3. Polyethylene Oxide (Mol. Wt.:2,000,000) 70.00 7.00 4. Retrograded Starch 100.00 10.00 5. Lactose Monohydrate 125.00 12.50 6. Talc 30.00 3.00 7. Magnesium Stearate 15.00 1.50 8. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 5. The drug release from the dosage form mentioned in example 5 was extended up to 12 h. 25 f Table 5.2 IU Time (h) % Cumulative Drug Released 1 7 2 14 4 29 6 44 8 59 10 72 12 84 26 Example 6 Table 6.1 Sr.No. Ingredient Qty. / unit (mg) % w/w of unit dosage form 1. Clarithromycin 500.00 50.00 2. Polyethylene Oxide (Mol. Wt.:200,000) 170.00 17.00 3. Polyethylene Oxide (Mol. Wt.:2,000,000) 70.00 7.00 4. Retrograded Starch 70.00 7.00 5. Lactose Monohydrate 145.00 14.50 6. Talc 30.00 3.00 7. Magnesium Stearate 15.00 1.50 8. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 6. The drug release from the dosage form mentioned in example 6 was extended up to 12 h. 27 Table 6.2 '■■.,■..■'■ . , • 'f Time (h) % Cumulative Drug Released 1 7 2 13 4 27 6 44 8 58 10 72 12 84 Example 7 Table 7.1 Sr.No. Ingredient Qty. / unit (mg) % w/w of unit dosage form 1. Clarithromycin 500.00 50.00 2. Polyethylene Oxide (Mol. Wt.:200,000) 180.00 18.00 3. Polyethylene Oxide (Mol. Wt.:2,000,000) 65.00 6.50 4. Retrograded Starch 70.00 7.00 5. Lactose Monohydrate 140.00 14.00 6. Talc 30.00 3.00 7. Magnesium Stearate 15.00 1.50 8. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 7. The drug release from the dosage form mentioned in example 7 was extended up to 12 h. 29 li " : • ;' .V ■ Table 7.2 ■/..' V.-, Time (h) % Cumulative Drug Released 1 1 2 17 4 36 6 55 8 70 10 78 12 86 30 Example 8 Table 8.1 Sr.No. Ingredient Qty. / unit (mg) % w/w of unit dosage form 1. Clarithromycin 500.00 50.00 2. Polyethylene Oxide (Mol. Wt.:200,000) 185.00 18.50 3. Polyethylene Oxide (Mol. Wt.:2,000,000) 60.00 6.00 4. Retrograded Starch 70.00 7.00 5. Lactose Monohydrate 140.00 14.00 6. Talc 30.00 3.00 7. Magnesium Stearate 15.00 1.50 8. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 8. The drug release from the dosage form mentioned in example 8 was extended up to 12 h. 31 ( 1 •, i ■ '■' . ." ■■ r Table 8.2 ' ' ' ■ ■ ■■•.■' ■■: ' 77me (7jj % Cumulative Drug Released 1 9 2 18 4 35 6 52 8 66 10 79 12 89 Example 9 Table 9.1 Sr.No. Ingredient Qty. / unit (mg) % w/w of unit dosage form 1. Clarithromycin 500.00 50.00 2. Polyethylene Oxide (Mol. Wt.:200,000) 240.00 24.00 3. Retrograded Starch 120.00 1.20 4. Lactose Monohydrate 95.00 9.50 5. Talc 30.00 3.00 6. Magnesium Stearate 15.00 1.50 7. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 9. The drug release from the dosage form mentioned in example 9 was extended up to 12 h. 33 Table 9.2 Time (h) % Cumulative Drug Released 1 20 2 35 4 65 6 80 8 90 10 95 12 97 Example 10 Table 10.1 Sr.No. Ingredient Qty. / unit (mg) % w/w ofiitnit dosage ' form 1. Clarithromycin 500.00 50.00 2. Polyethylene Oxide (Mol. Wt.:2,000,000) 55.00 5.50 3. Retrograded Starch 120.00 12.00 4. Lactose Monohydrate 280.00 28.00 5. Talc 30.00 3.00 6. Magnesium Stearate 15.00 1.50 7. Purified Water q.s q.s The drug release profile from the dosage form of the invention was studied in 900 ml of pH 5.0 acetate buffer in USP Dissolution Apparatus Type II at 50 RPM and the results are tabulated below. The results showed a controlled release of the drug from the dosage form of the Example 10. The drug release from the dosage form mentioned in example 10 was extended up to 12 h. 35 Table 10.2 " v / Time (h) % Cumulative Drug Released 1 10 2 20 4 35 6 40 8 50 10 60 12 80 The pharmaceutical compositions of the present invention mentioned in the above examples shows a predictable and predetermined controlled drug release profile devoid of dose dumping and the drug release was almost complete over duration of 12 hours. The difference between the drug release from the individual unit dosage forms is insignificant. Pharmacokinetic Study The pharmaceutical composition of the invention as mentioned in Example 8 was subjected to bioavailability study against the commercially available Clarithromycin 500 mg Extended Release Tablets (Biaxin XL Filmtab, 500 mg). An open label, randomized, two-treatment, two-period, two-sequence, single dose, crossover oral bioavailability study in healthy, adult male subjects was conducted on the composition of 36 t Example 8 of the present invention administered once daily with Biaxin XL Filmtab, 'SOO mg tablet of Abbott Laboratories. The mean plasma concentration-time profiles for the single-dose study are illustrated in Fig. 1. The log transformed pharmacokinetic parameters for the two clarithromycin extended release compositions are tabulated in Table ll. Table 11 Formula Composition Comparison Cmax (/ig. /ml) AUCo-t(!ig.hr. /ml) Biaxin XL Filmtab, 500 mg (Reference) l.Ol 13.61 Clarithromycin Extended Release Composition of Example 8 (Test) 1.06 13.72 37 Point estimates of the relative bioavailability and 90 % confidence intervals from the log transformed values are tabulated in Table 12. Table 12 Formula Composition Comparison Cmax (fig. /ml) AUCo-t (ftg-hr. /ml) Ratio (%) Test / Reference 104.19 100.75 90% Confidence Interval 84.41-128.61 81.63-124.36 38 CLAIMS We claim: 1. A solid oral controlled release pharmaceutical composition for administration to humans comprising therapeutically effective amount of a pharmaceutically active ingredient, a controlled release modifying complex and other required pharmaceutically acceptable additives; the said controlled release modifying complex comprising a synergistic combination of (a) a primary release retardant selected from low molecular weight hydrophilic polymers and / or (b) a secondary release retardant selected from high molecular weight hydrophilic polymers and (c) an auxiliary release retardant selected from the starch derivatives; the said primary release retardant, secondary release retardant and auxiliary release retardant being present in synergistic effective amounts to extend the release of the pharmaceutically active ingredient. 2. The pharmaceutical composition of claim 1, wherein the dosage form may be in tablet or caplet form manufactured by using dry granulation, wet granulation or direct compression techniques. 3. The pharmaceutical composition of claim 1, wherein the active pharmaceutical ingredient is erythromycin or its derivatives 4. The pharmaceutical composition of claim 3 wherein the erythromycin derivative is clarithromycin. 5. The pharmaceutical composition of claim 5 wherein the primary release retardant is a polymer selected from the low molecular weight polyethylene oxides. 6. The pharmaceutical composition of claim 6 wherein the said polymer having a molecular weight of at least about 100,000. 39 7. The pharmaceutical composition of claim 7 wherein the said polymer having a molecular weight ranging from 100,000 to 900,000, preferably 200,000. 8. The pharmaceutical composition of claim 5 wherein the secondary release retardant is a polymer selected from the high molecular weight polyethylene oxides. P. The pharmaceutical composition of claim 9 wherein the said polymer having a molecular weight of at least about 1,000,000. 10. The pharmaceutical composition of claim 10 wherein the said polymer having a molecular weight ranging from 1,000,000 to 7,000,000, preferably 2,000,000. 11. The pharmaceutical composition of claim 5, wherein the auxiliary release retardant is a starch derivative selected from pregelatinized starch, partially pregelatinized starch, and retrograded starch or combinations thereof. 12. The pharmaceutical composition of claim 12, wherein the said auxiliary release retardant is preferably a retrograded starch. 13. The pharmaceutical composition of claim 1, wherein the pharmaceutically acceptable additives are selected from the diluents/fillers, binders, glidants and lubricants. 14. The pharmaceutical composition of claiml, wherein the composition comprises from about 40 percent weight to about 60 percent weight of the active pharmaceutical ingredient. 15. The pharmaceutical composition of claiml, wherein the composition comprises from about 45 percent weight to about 55 percent weight of the active pharmaceutical ingredient. 40 16. The pharmaceutical composition of claim 1, wherein the composition comprises from about 10 percent weight to about 50 percent weight of the release retarding complex. 17. The pharmaceutical composition of claim 1, wherein the composition comprises from about 25 percent weight to about 45 percent weight of the release retarding complex. 18. The pharmaceutical composition of claim 5, wherein the primary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 5 percent weight to 90 percent weight of the release retardant complex. 19. The pharmaceutical composition of claim 19, wherein the primary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 15 percent weight to 70 percent weight of the release retardant complex. 20. The pharmaceutical composition of claim 20, wherein the primary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 35 percent weight to 55 percent weight of the release retardant complex. 21. The pharmaceutical composition of claim 5, wherein the secondary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 1 percent weight to 50 percent weight of the release retardant complex. 41 22. The pharmaceutical composition of claim 22, wherein the secondary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 5 percent weight to 35 percent weight of the release retardant complex. 23. The pharmaceutical composition of claim 23, wherein the secondary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 8 percent weight to 25 percent weight of the release retardant complex. 24. The pharmaceutical composition of claim 5, wherein the auxiliary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 5 percent weight to 90 percent weight of the release retardant complex. 25. The pharmaceutical composition of claim 25, wherein the auxiliary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 15 percent weight to 70 percent weight of the release retardant complex. 26. The pharmaceutical composition of claim 26, wherein the auxiliary release retardant of the release retarding complex of the pharmaceutical composition of the invention comprised of about 35 percent weight to 55 percent weight of the release retardant complex. 27. A composition as claimed in claim 1 wherein, a release retarding complex and other required pharmaceutically acceptable additives, wherein the said release retarding complex comprises a synergistic combination of a polyethylene oxide polymer having a molecular weight of 200,000, a polyethylene oxide polymer having a molecular weight of 2,000,000 and a retrograded starch. 42 28. A composition as claimed in claim 1 wherein an erythromycin derivative, a release retarding complex and other required pharmaceutically acceptable additives; the said complex comprising a synergistic combination of a (a) primary release retardant selected from low molecular weight polyethylene oxides and (b) an auxiliary release retardant selected from the starch derivatives; the said primary release retardant and auxiliary release retardant being present in synergistic effective amounts to extend the release of the erythromycin derivatives. 29. A composition as claimed in claim 1 wherein, an erythromycin derivative, a release retarding complex, andT other required pharmaceutically acceptable additives the said complex comprising a synergistic combination of a (a) secondary release retardant selected from high molecular weight polyethylene oxides and (b) an auxiliary release retardant selected from the starch derivatives; the said secondary release retardant, and auxiliary release retardant being present in synergistic effective amounts to extend the release of the erythromycin derivatives. 30. A pharmaceutical such as herein described with reference to example 1-10, comprising of the erythromycin derivative, the release retarding complex and the other required pharmaceutically acceptable additives; the improvements comprising the synergistic combination of release retardant complex in synergistic effective amounts to expend the release of the erythromycin derivative. Dated this 16(sixteenth) day of December 2005 43 ABSTRACT The present invention is directed to a solid oral controlled release pharmaceutical - composition suitable for once-a-day administration, comprising - a., therapeutically effective amount of a pharmaceutical^ active ingredient erythromycin or a derivative.. - thereof, a release retardant complex and other required pharmaceutical ly acceptable additives; the said release retardant complex comprising a primary release retardant, a secondary release retardant and an auxiliary release retardant wherein the primary release retardant, secondary release retardant and auxiliary release retardant are being present in synergistic effective amounts to extend the release of said pharmaceutical active ingredient.