WO2004069234A1 - Pharmaceutical compositions and process of production thereof - Google Patents

Pharmaceutical compositions and process of production thereof Download PDF

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Publication number
WO2004069234A1
WO2004069234A1 PCT/IN2003/000312 IN0300312W WO2004069234A1 WO 2004069234 A1 WO2004069234 A1 WO 2004069234A1 IN 0300312 W IN0300312 W IN 0300312W WO 2004069234 A1 WO2004069234 A1 WO 2004069234A1
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WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
metoprolol
composition according
cellulose
pharmaceutically acceptable
Prior art date
Application number
PCT/IN2003/000312
Other languages
French (fr)
Inventor
Ramachandran Thembalath
Yatish Kumar Bansal
Subhrangshu Sengupta
Nivedita Singh
Original Assignee
Ipca Laboratories Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Ipca Laboratories Limited filed Critical Ipca Laboratories Limited
Priority to AU2003282375A priority Critical patent/AU2003282375A1/en
Priority to EP03773988A priority patent/EP1589957A1/en
Priority to NO20042890A priority patent/NO20042890L/en
Publication of WO2004069234A1 publication Critical patent/WO2004069234A1/en

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Classifications

    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/13Amines
    • A61K31/135Amines having aromatic rings, e.g. ketamine, nortriptyline
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/28Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2806Coating materials
    • A61K9/2833Organic macromolecular compounds
    • A61K9/286Polysaccharides, e.g. gums; Cyclodextrin
    • A61K9/2866Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00Drugs for disorders of the cardiovascular system
    • A61P9/10Drugs for disorders of the cardiovascular system for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/2027Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/20Pills, tablets, discs, rods
    • A61K9/2004Excipients; Inactive ingredients
    • A61K9/2022Organic macromolecular compounds
    • A61K9/205Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose

Definitions

  • the invention relates to the field of medicine and pharmacology. More specifically, the invention relates to an extended release oral dosage pharmaceutical composition comprising metoprolol or a pharmaceutically acceptable succinate salt thereof provided with an extended release polymer base retardant coating, and to a process for its production.
  • Metoprolol succinate is a beta-selective (cardioselective) adrenoreceptor blocking agent, for oral administration, available as extended release tablets to treat the heart condition angina.
  • the drug reduces the oxygen demand to the heart, slowing the heart rate, reducing cardiac output when at rest and on exercise and reduces systolic blood pressure among other things.
  • metoprolol formulations already known, which usually comprise controlled release pellets, wherein each pellet acts as a separate drug delivery unit. But in order to obtain a desirable release of a drug, a considerable amount of experimentation needs to be performed. So, in accordance with the present investigation, an extended release pharmaceutical formulation has been devised which releases the drug for up to 24 hours in a suitably controlled manner.
  • U.S. Patent 4792452 to Howard et al. describes a controlled release pharmaceutical formulation which releases the drug at a controlled rate regardless of the pH of the environment. Its formulation includes up to about 45% by weight of a pH dependent polymer, which is a salt of alginic acid in addition to a pH independent hydrocarbon gelling agent, such as hydroxypropylmethyl cellulose.
  • EP 0293347 to Henry A.C. and Christina E.E. describes metoprolol succinate as a new therapeutically active compound, and pharmaceutical preparations comprising it.
  • This invention discusses a new oral, therapeutically active compound, which is soluble in the pH range 1 to 8, which therefore can be released in the gastrointestinal tract below the upper part of the small intestine.
  • the sustained release excipient is prepared by dry blending the requisite amounts of xanthan gum, dextrose and calcium sulfate.
  • U.S. Patent 4871549 to Yoshio U. et al 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.
  • a swelling agent such as a low substituted hydroxypropylcellulose, sodium starch glycolate or carboxymethylcellulose sodium
  • U.S. Patent 4927640 to Dahlinder L-ED et al also describes controlled release beads having a glass or silicon dioxide core. Metoprolol succinate was sprayed onto the cores of silicon dioxide, glass and sodium chloride from a solution of ethanol 95% and methylene chloride. Then the coated beads were filled into hard gelatin capsules.
  • U.S. Patent 5081154 to Henry A.C. and Christina E.E. which is a continuation of EP 0293346 also relates to metoprolol succinate wherein an oral pharmaceutical composition comprising a core containing a therapeutically active compound is disclosed.
  • the core has been coated with a layer comprising an anionic polymer and a water insoluble polymer selected from the group of quaternary ammonium substituted acrylic polymers.
  • the investigators suggest that in order to achieve a steady blood plasma level of the therapeutically active compound, a split dose unit of the therapeutically active compound provided with a coating according to the present invention can be administered together with some particles/granules which are not coated.
  • U.S. Patent 5399358 to Stanoforth George N and Baichwal Anand R is directed to sustained release formulations which provide a 24 hour release of metoprolol using a combination of xanthan gum with locust bean gum as the preferred gum combination.
  • EP Application 110542 by McCall Troy W and Baichwal Anand R describes once-a- day oral dosage form of metoprolol to be released over a period of 24 hours in the gastrointestinal tract.
  • the sustained release matrix comprises heterosaccharide derivatives of xanthan gum.
  • a number of patents in the prior art deal with sustained or controlled release formulations of metoprolol. These include water insoluble glass, silicon dioxide or plastic resin beads, which are sprayed with metoprolol salt and then coated with controlled release polymeric membrane.
  • Another sustained release excipient commonly used is a heteropolysaccharide e.g., xanthan gum or a gum combination of xanthan and locust bean gum for delaying the drug release.
  • xanthan gum or a gum combination of xanthan and locust bean gum for delaying the drug release.
  • a pharmaceutical composition comprising a matrix material having metoprolol, or a pharmaceutically acceptable salt thereof, dispersed therein, the dispersion of the metoprolol or pharmaceutically acceptable salt thereof within the matrix material being effective to delay the release profile on administration of the pharmaceutical composition, the tablet being provided with a substantially water-insoluble polymeric coating effective further to delay the release profile on administration of the pharmaceutical composition.
  • pharmaceutically acceptable salt is a succinate.
  • the matrix material may be capable of forming a swelling gel when in contact with water and may comprise a cellulosic polymer and a carbomer.
  • the cellulosic polymer is preferably hydroxypropyl methyl cellulose.
  • the polymeric coating may comprises cellulose derivatives without protolysable groups, for example ethyl cellulose.
  • the metoprolol, or pharmaceutically acceptable salt thereof is preferably provided in the form of a granulated active ingredient. It may be present in an amount of from 12.5mg to 200mg in the composition, for example in an amount of 12.5mg, 25mg, 50mg, lOOmg or 200mg in the composition.
  • the pharmaceutical composition according to the invention may further comprise a binder, for example a povidone.
  • the hardness of the tablet may vary from 35 Nortons to 160 Nortons for tablets of different strengths.
  • One preferred pharmaceutical composition according to the invention comprises: metoprolol succinate 27 to 30% microcrystalline cellulose 17 to 30% carbomer 1 to 6% hydroxypropyl methyl cellulose 14 to 56%
  • the weight ratio of metoprolol, or pharmaceutically active salt thereof, to carbomer is in the range of 10: 1 to 1 : 12.
  • Also provided in accordance with the invention is a process for the production of a pharmaceutical composition according to the invention, comprising blending metoprolol, or a pharmaceutically acceptable salt thereof, with a matrix material, granulating the blended mixture and compressing to form a tablet, and spray coating the tablet with a polymeric coating.
  • At least one carbomer is preferably introduced into the composition during the blending and granulation steps.
  • the tablet is prepared by a wet granulation process, preferably a non-aqueous process, for example a process using a hydroalcoholic wetting material
  • the invention provides a process for preparing a pharmaceutical composition
  • a process for preparing a pharmaceutical composition comprising: a) introduction of metoprolol succinate, carbomer and hydroxy polymethyl cellulose by blending, milling and sieving prior to granulation b) introduction of a solution of polymer in non-aqueous / hydroalcoholic solvent during granulation of the blended material as in (a) c) spray coating of the compressed tablets as in (c), with a water-insoluble polymeric membrane containing derivatives of cellulose without protolyasable groups d) thereby incorporating the tablet and the coating into a matrix forming a swelling gel in contact with water.
  • a process for producing pharmaceutically extended-release preparations of metoprolol succinate is provided.
  • the object of this invention is to obtain a solid preparation with high bioavailability of the drug in combination with an extended absorption in the gastrointestinal tract thus achieving an even effect of up to 24 hours after one (or twice in case of a lower dosage such as 12.5mg) daily administration.
  • the present invention further provides a process for producing oral solid extended release pharmaceutical formulations, which releases metoprolol succinate over a time period of up to 24 hours.
  • the carbomer is included in an amount from about 4.54% to about 11.5%, by weight of the final product.
  • the drug to carbomer ratio may be, from about 10:1 to about 1:12 for example.
  • the drug to carbomer ratio is from about 10:1.25 to about 1:12 by weight of formulation.
  • the preparation of the said tablet is by compression and mixing of polymers.
  • the carbomers are used in both granulation as well as mixing stages.
  • extended release it is meant for purposes of the present invention that the therapeutically active medicament is released from the formulation at an extended rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a 24 hour dosage form.
  • the term "environment" is meant for purposes of the present invention to encompass a mammalian body, an organ of such a body or area of such a body, for example, the gastro-intestinal area. Such an environment can be tested by means of in-vitro dissolution testing, as is standard practice for testing of therapeutically active substances prior to use in mammalian bodies.
  • the preparation may be manufactured into a commercially acceptable form, e.g. a tablet that shows unexpectedly good bioavailability of both active compounds as well as a prolonged duration of action.
  • the active ingredient, MCC, carbopol and HPMC were blended together, and then the blend milled through a screen with appropriately size mesh.
  • the blended material was then granulated with a solution of polymer in non-aqueous/ hydroalcoholic solvent.
  • the granules were then dried at a suitable temperature and screened through a mesh of appropriate size.
  • the blend was lubricated with a soluble or insoluble lubricant.
  • the tablets were then formed by compression.
  • composition of the tablets containing lOOmg metoprolol succinate without carbomer had the following composition:
  • the coating solution to be applied to the tablets had the following composition:
  • Titanium dioxide 3.8 %
  • Tablets containing 12.5mg, 25 mg, 50 mg, and 200 mg were similarly prepared.
  • a retarding coating solution with the following composition was used to further coat the tablets from Examples 1 and 3.
  • Opadry OY-C-7000A (M/S coloreon) 4.5 % Ethyl cellulose 1.0 % Iso propyl alcohol qs Methylene chloride qs
  • Dissolution tests were then carried out for the tablets produced in Examples 1-4.
  • the dissolution tests were conducted in an automated USP dissolution apparatus (Paddle type II, pH 6.8 buffer, 50 rpm). The results are given in Table 5 & 6.
  • Beta-blockers in chronic heart failure considerations for selecting an agent. Mayo Clin Proc 2002 Nov;77(l 1):1199-206.
  • Metoprolol CR XL in female patients with heart failure analysis of the experience in

Abstract

A novel extended release oral solid dosage formulation of metoprolol succinate is provided which includes an extended release polymer base retardant coating and a process of production thereof. In the present invention metoprolol succinate tablets comprising of strengths varying from 12.5 to 200mg are prepared via a wet granulation method and the formulation for release of metoprolol for upto 24 hours is provided.

Description

PHARMACEUTICAL COMPOSITIONS AND PROCESS OF PRODUCTION
THEREOF
Related Applications:
This application claims priority from India National application serial No. 151/MUM/2003, filed 05 February 03.
Field of the Invention
The invention relates to the field of medicine and pharmacology. More specifically, the invention relates to an extended release oral dosage pharmaceutical composition comprising metoprolol or a pharmaceutically acceptable succinate salt thereof provided with an extended release polymer base retardant coating, and to a process for its production.
Description of Related Art
Metoprolol succinate is a beta-selective (cardioselective) adrenoreceptor blocking agent, for oral administration, available as extended release tablets to treat the heart condition angina. The drug reduces the oxygen demand to the heart, slowing the heart rate, reducing cardiac output when at rest and on exercise and reduces systolic blood pressure among other things. There are many controlled and sustained release metoprolol formulations already known, which usually comprise controlled release pellets, wherein each pellet acts as a separate drug delivery unit. But in order to obtain a desirable release of a drug, a considerable amount of experimentation needs to be performed. So, in accordance with the present investigation, an extended release pharmaceutical formulation has been devised which releases the drug for up to 24 hours in a suitably controlled manner.
U.S. Patent 4792452 to Howard et al., describes a controlled release pharmaceutical formulation which releases the drug at a controlled rate regardless of the pH of the environment. Its formulation includes up to about 45% by weight of a pH dependent polymer, which is a salt of alginic acid in addition to a pH independent hydrocarbon gelling agent, such as hydroxypropylmethyl cellulose.
EP 0293347 to Henry A.C. and Christina E.E. describes metoprolol succinate as a new therapeutically active compound, and pharmaceutical preparations comprising it. This invention discusses a new oral, therapeutically active compound, which is soluble in the pH range 1 to 8, which therefore can be released in the gastrointestinal tract below the upper part of the small intestine. The sustained release excipient is prepared by dry blending the requisite amounts of xanthan gum, dextrose and calcium sulfate.
U.S. Patent 4871549 to Yoshio U. et al, 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.
U.S. Patent 4957745 to Jonsson U.E. et al describes the pharmaceutical preparation of a controlled release preparation containing a number of beads comprising metoprolol salts, their production and use in cardiovascular disorders.
U.S. Patent 4927640 to Dahlinder L-ED et al also describes controlled release beads having a glass or silicon dioxide core. Metoprolol succinate was sprayed onto the cores of silicon dioxide, glass and sodium chloride from a solution of ethanol 95% and methylene chloride. Then the coated beads were filled into hard gelatin capsules.
U.S. Patent 5081154 to Henry A.C. and Christina E.E. which is a continuation of EP 0293346 also relates to metoprolol succinate wherein an oral pharmaceutical composition comprising a core containing a therapeutically active compound is disclosed. The core has been coated with a layer comprising an anionic polymer and a water insoluble polymer selected from the group of quaternary ammonium substituted acrylic polymers. The investigators suggest that in order to achieve a steady blood plasma level of the therapeutically active compound, a split dose unit of the therapeutically active compound provided with a coating according to the present invention can be administered together with some particles/granules which are not coated.
U.S. Patent 5399358 to Stanoforth George N and Baichwal Anand R is directed to sustained release formulations which provide a 24 hour release of metoprolol using a combination of xanthan gum with locust bean gum as the preferred gum combination.
EP Application 110542 by McCall Troy W and Baichwal Anand R describes once-a- day oral dosage form of metoprolol to be released over a period of 24 hours in the gastrointestinal tract. The sustained release matrix comprises heterosaccharide derivatives of xanthan gum.
A number of patents in the prior art deal with sustained or controlled release formulations of metoprolol. These include water insoluble glass, silicon dioxide or plastic resin beads, which are sprayed with metoprolol salt and then coated with controlled release polymeric membrane. Another sustained release excipient commonly used is a heteropolysaccharide e.g., xanthan gum or a gum combination of xanthan and locust bean gum for delaying the drug release. In other cases there is the use of a heteropolysaccharide gum along with a homopolysaccharide gum, which can cross-link with the heteropolysaccharide gum in the gastro-intestinal fluid. Thus there is a need for a simple and economical process of formulation of metoprolol succinate extended release drug which the present invention attempts to address with the use of wet granulation method with carbomers and a water insoluble hydrophobic polymer retarding coating of ethyl cellulose to provide up to 24 hours of extended release of metoprolol.
Summary of the Invention
It is an object of the invention to provide an improved pharmaceutical composition, in particular for the treatment of angina. It is a further object of the invention to overcome or ameliorate one of more of the problems associated with the prior art pharmaceutical preparations. It is also an object of the present invention to provide a sustained release oral dosage pharmaceutical composition comprising metoprolol or a succinate salt thereof. It is further an object of the invention to provided a process for the production of such a pharmaceutical composition.
According to the present invention, there is provided a pharmaceutical composition comprising a matrix material having metoprolol, or a pharmaceutically acceptable salt thereof, dispersed therein, the dispersion of the metoprolol or pharmaceutically acceptable salt thereof within the matrix material being effective to delay the release profile on administration of the pharmaceutical composition, the tablet being provided with a substantially water-insoluble polymeric coating effective further to delay the release profile on administration of the pharmaceutical composition. Detailed Description
Preferably, pharmaceutically acceptable salt is a succinate. The matrix material may be capable of forming a swelling gel when in contact with water and may comprise a cellulosic polymer and a carbomer. The cellulosic polymer is preferably hydroxypropyl methyl cellulose.
The polymeric coating may comprises cellulose derivatives without protolysable groups, for example ethyl cellulose.
The metoprolol, or pharmaceutically acceptable salt thereof, is preferably provided in the form of a granulated active ingredient. It may be present in an amount of from 12.5mg to 200mg in the composition, for example in an amount of 12.5mg, 25mg, 50mg, lOOmg or 200mg in the composition.
The pharmaceutical composition according to the invention may further comprise a binder, for example a povidone.
The hardness of the tablet may vary from 35 Nortons to 160 Nortons for tablets of different strengths.
One preferred pharmaceutical composition according to the invention comprises: metoprolol succinate 27 to 30% microcrystalline cellulose 17 to 30% carbomer 1 to 6% hydroxypropyl methyl cellulose 14 to 56%
(K100M) hydroxypropyl methyl cellulose 4 to 10%
(K4M) povidone 8 to 12% magnesium stearate 1 to 1.5% isopropyl alcohol q.s. and the coating comprises: opadry 04-C-7000 A (colorcon) 4 to 5% ethyl Cellulose 1 to 2% isopropyl alcohol q.s. methylene chloride q.s.
Preferably, the weight ratio of metoprolol, or pharmaceutically active salt thereof, to carbomer is in the range of 10: 1 to 1 : 12.
Also provided in accordance with the invention is a process for the production of a pharmaceutical composition according to the invention, comprising blending metoprolol, or a pharmaceutically acceptable salt thereof, with a matrix material, granulating the blended mixture and compressing to form a tablet, and spray coating the tablet with a polymeric coating.
At least one carbomer is preferably introduced into the composition during the blending and granulation steps.
Preferably, the tablet is prepared by a wet granulation process, preferably a non-aqueous process, for example a process using a hydroalcoholic wetting material
Accordingly, the invention provides a process for preparing a pharmaceutical composition comprising: a) introduction of metoprolol succinate, carbomer and hydroxy polymethyl cellulose by blending, milling and sieving prior to granulation b) introduction of a solution of polymer in non-aqueous / hydroalcoholic solvent during granulation of the blended material as in (a) c) spray coating of the compressed tablets as in (c), with a water-insoluble polymeric membrane containing derivatives of cellulose without protolyasable groups d) thereby incorporating the tablet and the coating into a matrix forming a swelling gel in contact with water. This, in accordance with the present invention, there is provided a process for producing pharmaceutically extended-release preparations of metoprolol succinate. The object of this invention is to obtain a solid preparation with high bioavailability of the drug in combination with an extended absorption in the gastrointestinal tract thus achieving an even effect of up to 24 hours after one (or twice in case of a lower dosage such as 12.5mg) daily administration.
The present invention further provides a process for producing oral solid extended release pharmaceutical formulations, which releases metoprolol succinate over a time period of up to 24 hours.
In the embodiments of the invention, the carbomer is included in an amount from about 4.54% to about 11.5%, by weight of the final product. The drug to carbomer ratio may be, from about 10:1 to about 1:12 for example. Preferably, the drug to carbomer ratio is from about 10:1.25 to about 1:12 by weight of formulation.
The preparation of the said tablet is by compression and mixing of polymers. The carbomers are used in both granulation as well as mixing stages.
By "extended release" it is meant for purposes of the present invention that the therapeutically active medicament is released from the formulation at an extended rate such that therapeutically beneficial blood levels (but below toxic levels) of the medicament are maintained over an extended period of time, e.g., providing a 24 hour dosage form.
The term "environment" is meant for purposes of the present invention to encompass a mammalian body, an organ of such a body or area of such a body, for example, the gastro-intestinal area. Such an environment can be tested by means of in-vitro dissolution testing, as is standard practice for testing of therapeutically active substances prior to use in mammalian bodies.
By using a careful choice of fillers and binders as well as gel forming materials the preparation may be manufactured into a commercially acceptable form, e.g. a tablet that shows unexpectedly good bioavailability of both active compounds as well as a prolonged duration of action.
Specific embodiments of the present invention will now be described by way of example only with reference to and as illustrated in the following examples.
EXAMPLE 1
Wet Granulation Method for Compression
The active ingredient, MCC, carbopol and HPMC were blended together, and then the blend milled through a screen with appropriately size mesh. The blended material was then granulated with a solution of polymer in non-aqueous/ hydroalcoholic solvent. The granules were then dried at a suitable temperature and screened through a mesh of appropriate size. The blend was lubricated with a soluble or insoluble lubricant. The tablets were then formed by compression.
The pharmaceutical composition of the tablets containing lOOmg metoprolol succinate without carbomer had the following composition:
TABLE 1
Ingredients Parts by weight of tablet
Metoprolol succinate 27.14 %
Micro Crystalline Cellulose 25.71 %
Hydroxy propyl methly cellulose (K4M) 4.28 %
Hydroxy propyl methly cellulose (Kl 00M) 14.29 %
Povidone 8.57 %
Isopropyl alcohol qs
Hydroxy propyl methly cellulose (K4M) 4.28 %
Hydroxy propyl methly cellulose (Kl 00M) 14.29 %
Magnesium stearate 1.43
Tablets containing 12.5mg, 25 mg, 50 mg, and 200 mg metoprolol succinate were similarly prepared. EXAMPLE 2
The coating solution to be applied to the tablets had the following composition:
TABLE 2
Ingredients Parts by weight of tablet
Hydroxy propyl methyl cellulose 15cps 5 %
Poly ethyene glycol 400 0.5 %
Talc 0.7 %
Titanium dioxide 3.8 %
Isopropyl alcohol qs
Methylene chloride qs
There was a 3% weight gain by coating.
EXAMPLE 3
Tablets containing 100 mg dose of metoprolol with carbomer were produced and had the following composition: TABLE 3
Ingredients Parts by weight of tablet
Metoprolol succinate 28.35 % Micro Crystalline Cellulose 17.91 % Carbomer 1.49 %
Hydroxy propyl methyl cellulose (K100M) 28.35 % Povidone 10.45 %
Iso propyl alcohol qs Carbomer 4.47 %
Hydroxy propyl methyl cellulose (Kl OOM) 28.35 % Magnesium stearate 1.49 %
Tablets containing 12.5mg, 25 mg, 50 mg, and 200 mg were similarly prepared.
EXAMPLE 4
Retarding Coating Solution
A retarding coating solution with the following composition was used to further coat the tablets from Examples 1 and 3. TABLE 4
Ingredients Parts by weight of Tablet
Opadry OY-C-7000A (M/S coloreon) 4.5 % Ethyl cellulose 1.0 % Iso propyl alcohol qs Methylene chloride qs
In this case, a 6-7% weight gain after coating was noted.
EXAMPLE 5
Dissolution tests were then carried out for the tablets produced in Examples 1-4. The dissolution tests were conducted in an automated USP dissolution apparatus (Paddle type II, pH 6.8 buffer, 50 rpm). The results are given in Table 5 & 6.
TABLE 5: Carbomers with matrix control only
Time in Example 1 (core) Example 2 (coated) USP Limits hours
1 15.19% 13.90% NMT 25%
4 35.32% 34.46% 20-40%
8 52.43% 51.70% 40-60%
20 101.92% 103.19% NLT 80% TABLE 6: Polymers with retardant coating.
Time in Example 3 (core) Example 4 (coated) USP Limits hours
1 21.28% 17.51% NMT 25%
4 37.45% 39.24% 20-40%
8 59.05% 58.88% 40-60%
20 96.38% 103.11% NLT 80%
From the dissolution results in Table 5 & 6, it can be inferred that formulations made with carbomer had slower drug release rates compared to formulations made without carbomer. Furthermore, it was also noticed that formulations with the retarding coating had slower drug release rates when compared to those not coated with retarding coating.
Similar dissolution results were seen with 12.5, 25, 50 and 200mg formulations.
References
Beta-blockers in chronic heart failure: considerations for selecting an agent. Mayo Clin Proc 2002 Nov;77(l 1):1199-206.
Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: analysis of the experience in metoprolol CR/XL randomized intervention trial in chronic heart failure. J Am Coll Cardiol 2002 Aug 7;40(3):491-8. Successful blood pressure control in the African American Study of Kidney Disease and
Hypertension. Arch Intern Med 2002 Jul 22;162(14):1636-43.
Metoprolol CR XL in female patients with heart failure: analysis of the experience in
Metoprolol Extended-Release Randomized Intervention Trial in Heart Failure.
Circulation 2002 Apr 2;105(13):1585-91.
Tolerability of beta-blocker initiation and titration in the Metoprolol CR XL
Randomized Intervention Trial in Congestive Heart Failure.Circulation 2002 Mar
12;105(10):1182-8.
Effects of metoprolol CR/XL on mortality and hospitalizations in patients with heart failure and history of hypertension. J Card Fail 2002 Feb;8(l):8-14.
Effect of controlled release/extended release metoprolol on carotid intima-media thickness in patients with hypercholesterolemia: a 3 -year randomized study. Stroke
2002 Feb;33(2):572-7.
Longitudinal myocardial contraction improves early during titration with metoprolol
CR/XL in patients with heart failure. Heart 2002 Jan;87(l):23-8.

Claims

1. A pharmaceutical composition comprising a matrix material having metoprolol, or a pharmaceutically acceptable salt thereof, dispersed therein, the dispersion of the metoprolol or pharmaceutically acceptable salt thereof within the matrix material being effective to delay the release profile on administration of the pharmaceutical composition, the tablet being provided with a substantially water-insoluble polymeric coating effective further to delay the release profile on administration of the pharmaceutical composition.
2. A pharmaceutical composition according to claim 1, wherein the pharmaceutically acceptable salt is a succinate.
3. A pharmaceutical composition according to claim 1 or claim 2, wherein the matrix material is capable of forming a swelling gel when in contact with water.
4. A pharmaceutical composition according to any one of claims 1 to 3, wherein the matrix material comprises a cellulosic polymer and a carbomer.
5. A pharmaceutical composition according to claim 4, wherein the cellulosic polymer is hydroxypropyl methyl cellulose.
6. A pharmaceutical composition according to any one of claims 1 to 5, wherein the polymeric coating comprises cellulose derivatives without protolysable groups.
7. A pharmaceutical composition according to claim 6, wherein the polymeric coating comprises ethyl cellulose.
8. A pharmaceutical composition according to any one of claims 1 to 7, wherein the metoprolol, or pharmaceutically acceptable salt thereof is provided in the form of a granulated active ingredient.
9. A pharmaceutical composition according to any one of claims 1 to 8, further comprising a binder.
10. A pharmaceutical composition accoridng to claim 9, wherein the binder is a povidone.
11. A pharmaceutical composition according to any one of claims 1 to 10, wherein the metoprolol, or pharmaceutically acceptable salt thereof is present in an amount of from 12.5mg to 200mg in the composition.
12. A pharmaceutical composition according to claim 11, wherein the metoprolol, or pharmaceutically acceptable salt thereof is present in an amount of 12.5mg, 25mg, 50mg, lOOmg or 200mg in the composition.
13. A pharmaceutical composition according to any one of claims 1 to 12, wherein the hardness of the tablet varies from 35 Nortons to 160 Nortons for tablets of different strengths.
14. A pharmaceutical composition according to any one of claims 1 to 13, comprising: metoprolol succinate 27 to 30% microcrystalline cellulose 17 to 30% carbomer 1 to 6% hydroxypropyl methyl cellulose 14 to 56%
(K100M) hydroxypropyl methyl cellulose 4 to 10%
(K4M) povidone 8 to 12% magnesium stearate 1 to 1.5% isopropyl alcohol q.s. and wherein the coating comprises: opadry 04-C-7000 A (colorcon) 4 to 5% ethyl Cellulose 1 to 2% isopropyl alcohol q.s. methylene chloride q.s.
15. A pharmaceutical composition according to any one of claims 1 to 14, wherein the weight ratio of metoprolol, or pharmaceutically active salt thereof, to carbomer is in the range of 10:1 to 1 :12.
16. A process for the production of a pharmaceutical composition according to any one of claims 1 to 15, comprising blending metoprolol, or a pharmaceutically acceptable salt thereof, with a matrix material, granulating the blended mixture and compressing to form a tablet, and spray coating the tablet with a polymeric coating.
17. A process according to claim 16, wherein at least one carbomer is introduced into the composition during the blending and granulation steps.
18. A process according to claim 16 or claim 17, wherein the tablet is prepared by a wet granulation process.
19. A process according to claim 18, which is non-aqueous.
20. A process according to claim 19, which is hydroalcoholic.
21. A process according to any one of claims 16 to 20 comprising: a) introduction of metoprolol succinate, carbomer and hydroxy polymethyl cellulose by blending, milling and sieving prior to granulation b) introduction of a solution of polymer in non-aqueous / hydroalcoholic solvent during granulation of the blended material as in 1(a) c) spray coating of the compressed tablets as in 1(c), with a water- insoluble polymeric membrane containing derivatives of cellulose without protolyasable groups d) thereby incorporating the tablet and the coating into a matrix forming a swelling gel in contact with water.
PCT/IN2003/000312 2003-02-05 2003-09-17 Pharmaceutical compositions and process of production thereof WO2004069234A1 (en)

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NO20042890A NO20042890L (en) 2003-02-05 2004-07-07 Pharmaceutical preparations and processes for their preparation

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WO2007048233A1 (en) * 2005-10-24 2007-05-03 Orbus Pharma Inc. Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist
WO2007142546A2 (en) * 2006-06-02 2007-12-13 Zaklady Farmaceutyczne Polpharma S.A. Sustained release coated tablet with precisely regulated release profile
EP2255791A1 (en) * 2009-04-03 2010-12-01 Farmaprojects, S.A. Extended release pharmaceutical composition comprising metoprolol succinate
CN102085195A (en) * 2011-01-10 2011-06-08 中国药科大学 Metoprolol succinate sustained-release tablets and preparation method thereof
EP2361616A1 (en) 2009-12-25 2011-08-31 Dexcel Pharma Technologies Ltd. Extended release compositions for high solubility, high permeability active pharmaceutical ingredients
CN102008456B (en) * 2009-09-04 2015-01-14 鲁南制药集团股份有限公司 Novel skeleton sustained release tablet containing metoprolol succinate
WO2016138908A1 (en) 2015-03-03 2016-09-09 Saniona A/S Tesofensine, beta blocker combination formulation
WO2018204317A1 (en) * 2017-05-02 2018-11-08 Lubrizol Advanced Materials, Inc. Improved extended release highly loaded drug compositions
WO2020144146A1 (en) 2019-01-07 2020-07-16 Saniona A/S Tesofensine for reduction of body weight in prader-willi patients
WO2021214233A1 (en) 2020-04-22 2021-10-28 Saniona A/S Treatment of hypothalamic obesity

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Cited By (18)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007048233A1 (en) * 2005-10-24 2007-05-03 Orbus Pharma Inc. Stabilized extended release pharmaceutical compositions comprising a beta-adrenoreceptor antagonist
WO2007142546A2 (en) * 2006-06-02 2007-12-13 Zaklady Farmaceutyczne Polpharma S.A. Sustained release coated tablet with precisely regulated release profile
WO2007142546A3 (en) * 2006-06-02 2008-02-21 Zaklady Farm Polpharma Sa Sustained release coated tablet with precisely regulated release profile
EP2255791A1 (en) * 2009-04-03 2010-12-01 Farmaprojects, S.A. Extended release pharmaceutical composition comprising metoprolol succinate
CN102008456B (en) * 2009-09-04 2015-01-14 鲁南制药集团股份有限公司 Novel skeleton sustained release tablet containing metoprolol succinate
EP2361616A1 (en) 2009-12-25 2011-08-31 Dexcel Pharma Technologies Ltd. Extended release compositions for high solubility, high permeability active pharmaceutical ingredients
CN102085195A (en) * 2011-01-10 2011-06-08 中国药科大学 Metoprolol succinate sustained-release tablets and preparation method thereof
US9579288B2 (en) 2015-03-03 2017-02-28 Saniona A/S Tesofensine and beta blocker combination formulations
WO2016138908A1 (en) 2015-03-03 2016-09-09 Saniona A/S Tesofensine, beta blocker combination formulation
US10231951B2 (en) 2015-03-03 2019-03-19 Saniona A/S Tesofensine, beta blocker combination formulation
US10537551B2 (en) 2015-03-03 2020-01-21 Saniona A/S Tesofensine and beta blocker combination formulations
US10828278B2 (en) 2015-03-03 2020-11-10 Saniona A/S Tesofensine and beta blocker combination formulations
US11426383B2 (en) 2015-03-03 2022-08-30 Saniona A/S Tesofensine and beta blocker combination formulations
WO2018204317A1 (en) * 2017-05-02 2018-11-08 Lubrizol Advanced Materials, Inc. Improved extended release highly loaded drug compositions
CN110709068A (en) * 2017-05-02 2020-01-17 路博润先进材料公司 Improved sustained release high load pharmaceutical compositions
CN110709068B (en) * 2017-05-02 2022-11-08 路博润先进材料公司 Improved sustained release high load pharmaceutical compositions
WO2020144146A1 (en) 2019-01-07 2020-07-16 Saniona A/S Tesofensine for reduction of body weight in prader-willi patients
WO2021214233A1 (en) 2020-04-22 2021-10-28 Saniona A/S Treatment of hypothalamic obesity

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AU2003282375A1 (en) 2004-08-30
EP1589957A1 (en) 2005-11-02

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