DESC:FIELD OF THE INVENTION

This present invention relates to extended release pharmaceutical composition of highly soluble active pharmaceutical substances comprising a drug matrix core containing the said active substance and non-swelling pH independent release retardant, and the said drug matrix core further comprises a functional coat, with the proviso that the said drug matrix core does not comprise water soluble fillers. The invention is particularly suitable for once-a-day solid oral pharmaceutical dosage forms which release therapeutically effective amount of the active ingredient over an extended time period.

BACKGROUND OF THE INVENTION

Metoprolol succinate is a beta selective adrenoreceptor blocking agent used in the treatment of hypertension, angina pectoris, cardiac arrhythmias, myocardial infarction, heart failure, hyperthyroidism and in the prophylactic treatment of migraine. The chemical name for Metoprolol succinate (±)1(isopropylamino)-3-[p-(2-methoxyethyl) phenoxy]-2-propanol succinate (2:1) (salt). Its structural formula is:

Metoprolol succinate is a white crystalline powder with a molecular weight of 652.8. It is freely soluble in water; soluble in methanol; sparingly soluble in ethanol; slightly soluble in dichloromethane and 2-propanol; practically insoluble in ethyl-acetate, acetone, diethylether and heptane.

Metoprolol succinate controlled release tablet is marketed in US by Astrazeneca under brand name of TOPROL-XL. TOPROL-XL has been formulated to provide a controlled and predictable release of metoprolol for once-daily administration. The tablets comprise a multiple unit system containing metoprolol succinate in a multitude of controlled release pellets. Each pellet acts as a separate drug delivery unit and is designed to deliver metoprolol continuously over the dosage interval. The tablets contain 23.75, 47.5, 95 and 190 mg of metoprolol succinate equivalent to 25, 50, 100 and 200 mg of metoprolol tartrate, USP, respectively. Inactive ingredients are silicon dioxide, cellulose compounds, sodium stearyl fumarate, polyethylene glycol, titanium dioxide, paraffin.

In the prior art, many techniques have been used to provide extended-release pharmaceutical compositions of metoprolol succinate in order to maintain therapeutic levels of medicaments and to minimize the effects of missed doses of drugs caused by a lack of patient compliance. Some of extended release compositions for metoprolol succinate described in prior art are as follows:

US5001161 discloses a pharmaceutical composition of metoprolol succinate comprising a core containing a therapeutically active compound, which core has been coated with a layer comprising 10 to 85% by weight of an anionic polymer soluble at a pH above 5.5, and 15 to 90% by weight of a water insoluble polymer selected from the group of quaternary ammonium substituted acrylic polymers.

US4792452 describes controlled release pharmaceutical compositions which are said to provide pH-independent release for a basic drug such as metoprolol. The formulations 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 formulation is free of calcium ion and carbon dioxide-producing material.

US4957745 also describes a controlled release metoprolol. The preparation includes a plurality of beads comprising metoprolol coated with a polymeric membrane comprising ethyl cellulose with or without hydroxypropylmethylcellulose.

US4871549 describes a time controlled explosion system comprising metoprolol, a swelling agent such as a low substituted hydroxypropylcellulose, sodium starch glycolate or carboxymethylcellulose sodium, coated with a water-insoluble coating material so that drug release is caused by the explosion of the membrane after a definite time period.

US5081154 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.

The above disclose a large number of literatures on extended release delivery systems of metoprolol succinate by using anionic polymer, pH dependent polymers, hydrocolloid gelling polymers, hydrophilic polymers such as cellulose ethers, carbomers, etc. These polymers however, fail to deliver the desired drug release characteristics for metoprolol succinate having high aqueous solubility and used in particularly high doses. The failure is particularly due to a typical release profile that is obtained with these systems, which comprises of a high initial burst release and a plateau with incomplete release towards end. High initial burst release is particularly undesirable as it leads to poor in vivo performance, and may result in dose dumping and/or poor local tolerability due to undesirable local effects of the active agent.

Several approaches have been described in prior art to tackle this limitation of hydrophilic polymers and use of non polymeric release retardant, pH-Independent/pH dependent release retardant or coating of the dosage forms to control the initial burst release. US20080248107 describes oral controlled release dosage form comprising granules of metoprolol succinate and at least one non polymeric release retardant, and combined with atleast one pH-Independent non swelling release retardant. Further the non polymeric release retardant are selected form the group of fatty acids, long chain alcohols, fats and oils, waxes, phospholipids, eicosonoids, terpenes, steroids and the like. Non swelling pH independent release retardants is selected from polyvinyl alcohol, polyvinyl acetate, mixture of polyvinyl actate and polyvinylpyrrolidone, polymethacrylic acid derivatives, cellulose derivatives, triglycerides , waxes etc.

US20090053310 describes a novel extended release oral dosage forms comprising a therapeutically effective amount of highly aqueous soluble compound cover metoprolol succinate, at least one non swelling pH dependent release retardant and atleast one non swelling pH independent release retardant wherein the dosage form provides pH independent drug release for a considerable period of time after administration.

There still exists a need for developing extended release pharmaceutical compositions of metoprolol succinate, devoid of limitations discussed above and having reduced initial burst release, enhanced bioavailability, improved patient compliance and therapeutic effectiveness.

The inventors of the present invention address the need to provide extended release pharmaceutical composition of metoprolol succinate comprising a drug matrix core containing metoprolol succinate and non-swelling pH independent release retardant and the said drug matrix core further comprises a functional coat with the proviso that the said drug matrix core does not comprise water soluble fillers. The absence of water soluble fillers slows down the release of highly soluble pharmaceutical active substance from the drug matrix core. The functional coat also provides the barrier for drug release from the drug matrix core. The process employed is simple, reproducible and amenable to large scale manufacture using conventional equipment.

The above approach is also applicable for high soluble pharmaceutical active substances to control the release of drug for extended period of time. Highly soluble active pharmaceutical substances are classified as BCS class 1 drug as per the Biopharmaceutics Classification System (BCS). The Biopharmaceutics Classification System (BCS) is a guide for predicting the intestinal drug absorption provided by the U.S. Food and Drug Administration, using the parameters of solubility and intestinal permeability. Examples of BCS Class I drugs include metoprolol and memantine.

OBJECTS OF THE INVENTION

The object of the present invention is to provide an extended release pharmaceutical composition of high soluble active pharmaceutical substances comprising a drug matrix core containing said active substance, and the said drug matrix core further comprises a functional coat.

Another object of the present invention is to provide an extended release pharmaceutical composition of high soluble active pharmaceutical substances comprising a drug matrix core containing said active substance and non-swelling pH independent release retardant, and the said drug matrix core further comprises a functional coat.

Another object of the present invention is to provide an extended release pharmaceutical composition of high soluble active pharmaceutical substances comprising a drug matrix core containing said active substance, and the said drug matrix core further comprises a functional coat, wherein the said functional coat comprises water insoluble film forming polymer and atleast one pharmaceutically acceptable excipient.

Another object of the present invention is to provide an extended release pharmaceutical composition of high soluble active pharmaceutical substances comprising a drug matrix core containing said active substance and non-swelling pH independent release retardant and the said drug matrix core further comprises a functional coat, wherein the said functional coat comprises water insoluble film forming polymer and atleast one pharmaceutically acceptable excipient.

Another object of the present invention is to provide an extended release pharmaceutical composition of high soluble active pharmaceutical substances comprising a drug matrix core containing said active substance and the said drug matrix core further comprises a functional coat, with the proviso that the said drug matrix core does not comprise water soluble fillers.

Another object of the present invention is to provide an extended release pharmaceutical composition of high soluble active pharmaceutical substances comprising a drug matrix core containing said active substance and non-swelling pH independent release retardant and the said drug matrix core further comprises a functional coat, wherein the said functional coat comprises water insoluble film forming polymer and atleast one pharmaceutically acceptable excipient, with the proviso that the said drug matrix core does not comprise water soluble fillers

Another object of the present invention is to provide an extended release pharmaceutical composition of metoprolol succinate comprising a drug matrix core containing metoprolol succinate and non-swelling pH independent release retardant and the said drug matrix core further comprises a functional coat, with the proviso that the said drug matrix core does not comprise water soluble fillers.

Another object of the present invention is to provide an extended release pharmaceutical composition of metoprolol succinate comprising a drug matrix core containing metoprolol succinate and non-swelling pH independent release retardant, and the said drug matrix core further comprises a functional coat, wherein the said functional coat comprises water insoluble film forming polymer and atleast one pharmaceutically acceptable excipient, with the proviso that the said drug matrix core does not comprise water soluble fillers.

Another object of the present invention is to provide a process for the preparation of an extended release pharmaceutical composition of highly soluble pharmaceutical active substances according to present invention.

Another object of the present invention is to provide a process for the preparation of an extended release pharmaceutical composition of metoprolol succinate according to present invention.

SUMMARY OF THE INVENTION

The present invention relates to an extended release pharmaceutical composition of highly soluble active pharmaceutical substances comprising a drug matrix core containing the said active substance and non-swelling pH independent release retardant, and the said drug matrix core further comprises a functional coat, with the proviso that the said drug matrix core does not comprise water soluble fillers.

DETAILED DESCRIPTION

Unless otherwise indicated, terms in this specification are intended to have their ordinary meaning in the relevant art.

The present inventors have addressed the need of developing an extended release pharmaceutical composition of high soluble active pharmaceutical substances providing reduced initial burst release.

In one embodiment of the present invention, the present invention relates to an extended release pharmaceutical composition of high soluble active pharmaceutical substances comprising a drug matrix core containing said active substance and non-swelling pH independent release retardant and the said drug matrix core further comprises a functional coat comprising water insoluble film forming polymer and atleast one pharmaceutically acceptable excipient with the proviso that said drug matrix core does not comprises water soluble fillers.

The term "Extended release" as used hereinbefore and throughout the description refers to that the therapeutically active medicament is released from the formulation at a controlled rate such that the therapeutically effective amount of active pharmaceutical ingredient is maintained in the blood plasma over an extended period of time to cause the Extended action of the drug, preferably up to 12 hour. Extended release can be used interchangeably with prolonged release, controlled release, modified release, slow release and other such dosage forms.

The term “Drug matrix core” as used hereinbefore and throughout the description refers to that containing highly soluble active pharmaceutical substances, preferably metaprolol succinate and memantine HCl and non-swelling pH independent release retardant and one or more pharmaceutically acceptable excipients. Further the said drug matrix core can form tablet, granules, pellets and powder or mixtures thereof present in below the functional coat. Non-swelling pH independent release retardant present optionally in intragranular and/or extragranular portion with one or more pharmaceutically acceptable excipients.

The term “Non-swelling pH independent release retardants” as used hereinbefore and throughout the description refers to excipients whose performance is independent of the pH of the environment and these excipients does not swell in water or may be swells moderately. Non-swelling pH independent release retardants may be selected from the sustained release excipients that includes polyvinyl alcohol, polyvinyl acetate, mixture of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w) (commercially known as Kollidon SR), Polymethacrylic acid derivatives, cellulose derivatives such as ethyl cellulose, triglycerides, waxes etc. Kollidon SR is the most preferred release retardant.

The term “Functional coat” as used hereinbefore and throughout the description refers to the coating of water insoluble film former polymer either alone or in combination, along with water soluble film forming polymer, plasticizers, colorants, opacifiers etc, on the drug matrix core. The functional coat may provide a reduction in initial burst release and release the drug in controlled manner.

The present invention overcome the above mentioned drawbacks of the background art by providing the extended release pharmaceutical composition of high soluble active pharmaceutical substances such as Abacavir, Acetaminophen, Acyclovirb, Amiloride, Amitryptyline, Antipyrine, Atropine, Buspironec, Caffeine, Captopril, Chloroquine, Chlorpheniramine, Cyclophosphamide, Desipramine, Diazepam, Diltiazem, Diphenhydramine, Disopyramide, Doxepin, Doxycycline, Enalapril, Ephedrine, Ergonovine, Ethambutol, Ethinyl Estradiol, Fluoxetine, Glucose, Imipramine, Ketorolac, Ketoprofen, Labetolol, Levodopa, Levofloxacin, Lidocaine, Lomefloxacin, Memantine, Meperidine, Metoprolol, Metronidazole, Midazolam, Minocycline, Misoprostol, Nifedipine, Phenobarbital, Phenylalanine, Prednisolone, Primaquine, Promazine, Propranolol, Quinidine, Rosiglitazone, Salicylic acid, Theophylline, Valproic acid, Verapamil, Zidovudine and their pharmaceutically acceptable salts thereof.

In preferred embodiment of the present invention high soluble pharmaceutical active substance is metoprolol succinate and memantine HCl.

In the one embodiment of the invention, the metoprolol succinate can be present in any suitable form. For example, it can be in the form of a particle, powder, a crystal, or a granule. Metoprolol succinate present in amount of 5 to 30% of the weight of the total weight of the composition.

According to one embodiment of the present invention drug matrix core may comprises intragranular portion and extragranular portion. Intragranular portion may comprises metoprolol succinate and one or more pharmaceutically acceptable excipients selected form fillers, binders, diluents or combination thereof described herein after. According to one of the embodiment of the present invention non-swelling pH independent release retardant optionally present in intragranular and/or extragranular portion of drug matrix core with additional pharmaceutical acceptable excipients.

According to one preferred embodiment of the invention, the drug matrix core does not comprise any water soluble fillers. Water soluble fillers selected from lactose, mannitol, xylitol, sorbitol, calcium sulfate dihydrate, inositol, dextrin, calcium sulfate anhydrous, fructose, sugar compressible, sucrose, lactitol, dextrates, confectioner's sugar, sucrose, sodium chloride, dextrose, inorganic salts or any combination thereof.

According to present invention drug matrix core comprises non-swelling pH independent release retardant, preferably Kollidon® SR.

Kollidon® SR is a sustained release matrix forming agent consisting of polyvinyl acetate (8 parts w/w) and polyvinylpyrrolidone (2 parts w/w). Kollidon SR has free-flowing, non-hygroscopic and directly compressible properties (high dry binding capacity). Further, in vitro drug release profiles of tablet formulations with Kollidon SR as sustained release matrix forming agent are not influenced by pH of dissolution media, ionic strength-of dissolution media and speed of agitation. This unique property of Kollidon SR makes it one of the most promising sustained release matrix forming agents especially where pH independent release is desired.

According to one embodiment of the invention Kollidon® SR is present in an amount of 30% to 70% by weight of the total weight of the composition.

According to preferred embodiments of the present invention drug matrix core further comprises of functional coat. Functional coat comprises water insoluble film former polymer that is suitable for extended release coating, preferably ethyl cellulose.

The water insoluble film former polymer is preferably present in an amount of about 5% to about 95% weight per weight over the total weight of the coating composition.

The functional coat comprises water insoluble film former polymer either alone or in combination, along with water soluble film forming polymer, plasticizers, colorants, opacifiers, coating solvents, preferably ethyl cellulose, hypromellose E5, Polyethylene glycol, isopropanol, dichloromethane. The functional coat may provide a further reduction in initial burst.

Further, the extended release pharmaceutical composition according to present invention comprises one or more pharmaceutically acceptable excipient(s) selected from fillers, diluents, binders, disintegrants, lubricants, glidants, solvent and other suitable excipients or mixtures thereof. It is commonly known to person skilled in the art that said pharmaceutical excipients can perform more than one function which can aid in developing the said pharmaceutical composition.

According to present invention filler optionally and preferably comprises microcrystalline cellulose which is water insoluble in nature. Microcrystalline cellulose is also used as filler in the formulation as an extragranular excipient. The water insoluble filler is preferably present in an amount of about 5% to about 70% weight per weight over the total weight of the composition.

The binder is preferably present in an amount of about 0.2% to about 5% weight per weight over the total weight of the composition. The binders can be either water soluble or water insoluble. The binders are selected from the group, comprising of polyvinylpyrrolidone, starch, microcrystalline cellulose, highly dispersed silica, mannitol, polyethylene glycol, hydroxypropyl methyl cellulose and hydroxypropylcellulose and natural and synthetic gums, most preferably polyvinylpyrrolidone.

The lubricant optionally and preferably comprises magnesium stearate.

The glidant optionally and preferably comprises talc or silica colloidal anhydrous, or a combination thereof.

All excipients can be used at levels well known to the persons skilled in the art. Solvents may be used in present invention include all the solvents well known in the art or their mixtures thereof.

The extended release pharmaceutical composition according to the present invention can be in the form of tablets, capsules, pellets, granules, powders etc.

According to present invention the extended release pharmaceutical composition may be prepared by process known to the person having ordinary skilled in the art of the pharmaceutical technology such as wet granulation, direct compression, dry granulation, most preferably wet granulation.

In one embodiment the extended release pharmaceutical composition of the present invention can be prepared by forming drug matrix core comprising metoprolol succinate with non-swelling pH independent release retardant and one or more pharmaceutically acceptable excipients. The functional coat comprising water insoluble film former polymer is further coated on drug matrix core.

In further embodiment of the invention the drug matrix core prepared by granulating the metoprolol succinate, microcrystalline cellulose, povidone with purified water. Further the said granules are blended with extragranular Kollidon SR with microcrystalline cellulose and magnesium stearate and further compressed. Further functional coat can be applied on said drug matrix core by a wide variety of method.

In one another embodiment an extended release pharmaceutical composition according to the present invention allow the release of therapeutically effective amount of the active ingredient over at least 24 hour period following oral administration, the in vitro release rate corresponds to the following % rate of active substance released as shown in below table 1:
Table 1
Time (HR) Drug release (%)
1 NMT 15%
4 NMT 50%
6 NMT 60%
8 NMT 70%
24 NLT 80%
NMT – Not more than NLT – Not less than

In one embodiment the extended release pharmaceutical composition of the present invention may optionally be used for treating or preventing a cardiac disease, angina attacks, hyperthyroidism, or an anxiety disease.

EXAMPLES

The present invention has been described by way of example only. It is to be recognized that modifications falling within the scope and spirit of the claims, which would be obvious to a person skilled in the art based upon the disclosure herein, are also considered to be included within the scope of this invention. The scope of the invention is in no manner limited by the disclosed example.
Example 1:

S.No. Ingredients % w/w of the total wt. of the
composition
Intragranular part
1 High soluble active substance 5-30%
2 Fillers 0.5-20%
3 Binder 0.2-5%
4 Purified water q.s.
Extragranular part
5 Fillers 20-50%
6 Non-swelling pH independent release retardant 30-70%
7 Lubricants 0.5-2%
Functional Coating %w/w of the total wt. of coating composition
8 Water insoluble film forming polymer 5-95%
9 Water soluble film former polymer 5-95%
10 Plastisizers 0.02-1%
11 Coating solvents q.s.

Brief Manufacturing Process:
1. Active substance, filers and binders is admixed to obtain uniform blend.
2. Granulate the blend obtained in step 1 with binder solution to obtain granules.
3. Blend dried granules of step 2 with extragranular fillers, non-swelling pH independent release retardant and lubricant.
4. Compress lubricated granules of step 3 to obtain compressed core tablets.
5. Prepare coating solution by dissolving water insoluble film forming polymer, water soluble polymer, and plasticizer in coating solvents.
6. Coat compressed core tablets of step 4 with solution of step 5 to obtain desired dosage form.
Example 2:
S.No. Ingredients Mg/tablet
Intragranular part
1 Metoprolol Succinate 23.75
2 Microcrystalline cellulose 2.50
3 Povidone K30 1.35
4 Purified water Q.S.
Extragranular part
5 Microcrystalline cellulose 99.60
6 Kollidon SR 150.00
7 Magnesium Stearate 2.80
Total weight of core tablet 280
Functional coating
8 Ethyl cellulose 2.52
9 Hypromellose 20.41
10 PEG 400 2.27
11 Isopropanol Q.S.
12 Dichloromethane Q.S.
Total weight of coated tablet 305.20
Brief manufacturing process:
1. Admix Metoprolol succinate and microcrystalline cellulose to obtain uniform blend.
2. Dissolve Povidone K-30 in sufficient quantity of purified water.
3. Granulate material of step 1 using solution of step 2.
4. Optionally wet mill the granules of step 3 using suitable mill and dry the granules using tray dryer or fluid bed dryer.
5. Sift dried granules of step 4 through suitable sieve and mill the retained granules using suitable mill.
6. Admix together extragranular microcrystalline cellulose, Kollidon SR, and magnesium stearate.
7. Blend together the dried granules obtained in step 5 and blended material obtained in step 6.
8. Compress lubricated granules of step 7 to obtain compressed core tablets.
9. Prepare coating solution by dissolving ethyl cellulose, hypromellose, and polyethylene glycol in isopropanol and dichloromethane.
10. Coat compressed core tablets of step 7 with solution of step 8.
Example 3

S.No. Ingredients Mg/tablet
Intragranular part
1 Metoprolol Succinate 47.50
2 Microcrystalline cellulose 5.00
3 Povidone K30 2.70
4 Purified water Q.S.
Extragranular part
5 Microcrystalline cellulose 91.80
6 Kollidon SR 150.00
7 Magnesium Stearate 3.00
Total weight of core tablet 300
Functional coating
8 Ethyl cellulose 2.70
9 Hypromellose 21.87
10 PEG 400 2.43
11 Isopropanol Q.S.
12 Dichloromethane Q.S.
Total weight of coated tablet 327.00

Brief manufacturing process:
1. Admix Metoprolol succinate and microcrystalline cellulose to obtain uniform blend.
2. Dissolve Povidone K-30 in sufficient quantity of Purified water.
3. Granulate material of step 1 using solution of step 2.
4. Optionally wet mill the granules of step 3 using suitable mill and dry the granules using tray dryer or fluid bed dryer until required LOD is achieved.
5. Sift dried granules of step 4 through suitable sieve and mill the retained granules using suitable mill.
6. Admix extragranular microcrystalline cellulose, Kollidon SR, magnesium stearate to obtain uniform blend.
7. Blend together the dried granules obtained in step 5 and blended material obtained in step 6.
8. Compress lubricated granules of step 7 to obtain compressed core tablets.
9. Prepare coating solution by dissolving ethyl cellulose, hypromellose, and polyethylene glycol in isopropanol and dichloromethane.
10. Coat compressed core tablets of step 8 with coating solution of step 9 up to weight gain of 7-9 % w/w.

In vitro dissolution study: The Dissolution study of the composition prepared according to example 3 was carried by in type II dissolution apparatus USP in pH 6.8 phosphate buffer, using 500 ml purified water as dissolution medium at 37°C and 50 RPM.
Table 2 shows the result of drug release profile of example 3 in pH 6.8 buffer
Time (Hours) % Drug release
1 12
4 38
6 51
8 62
24 100

Thus, an extended release pharmaceutical composition comprising metoprolol succinate suitable for once daily administration can be prepared according to the present invention wherein dissolution of metoprolol succinate from the said composition is extended up to 24 hours.
,CLAIMS:1. An extended release pharmaceutical composition of metoprolol succinate containing a drug matrix core wherein the drug matrix core comprises a functional coat with the proviso that drug matrix core does not contain water soluble fillers.

2. The extended release pharmaceutical composition of claim 1, wherein drug matrix core contains metoprolol succinate and a non-swelling pH independent release retardant polymer.

3. The extended release pharmaceutical composition of claim 1, wherein metoprolol succinate present in an amount of 5% to 30% of the weight of the total weight of the composition.

4. The extended release pharmaceutical composition of claim 1, wherein non-swelling pH independent release retardant polymer is selected from polyvinyl alcohol, polyvinyl acetate, mixture of polyvinyl acetate and polyvinylpyrrolidone (Kollidon SR), Polymethacrylic acid derivatives, cellulose derivatives such as ethyl cellulose, triglycerides, waxes and mixtures thereof.

5. The extended release pharmaceutical composition of claim 1, further comprises fillers, binders, disintegrants, glidants, lubricants and mixtures thereof.

6. The extended release pharmaceutical composition of claim 1, wherein the said pharmaceutical composition can be in the form of tablet, capsule, pellet, granule or powder.

7. The extended release pharmaceutical composition of claim 1, wherein the functional coat comprises water insoluble film forming polymer and at least one pharmaceutically acceptable excipient.

8. The extended release pharmaceutical composition of claim 1, wherein the functional coat present in an amount of about 5% to about 95% weight per weight over the total weight of the coating composition.

9. The extended release pharmaceutical composition of claim 1, wherein the said composition is prepared by wet granulation, dry granulation or direct compression.

10. A process for the preparation of an extended release pharmaceutical composition of metoprolol succinate comprising a drug matrix core wherein the drug matrix core comprises a functional coat with the proviso that drug matrix core does not contain water soluble fillers.