AU2016210691A1 - Controlled release formulations of paracetamol - Google Patents

Controlled release formulations of paracetamol Download PDF

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AU2016210691A1
AU2016210691A1 AU2016210691A AU2016210691A AU2016210691A1 AU 2016210691 A1 AU2016210691 A1 AU 2016210691A1 AU 2016210691 A AU2016210691 A AU 2016210691A AU 2016210691 A AU2016210691 A AU 2016210691A AU 2016210691 A1 AU2016210691 A1 AU 2016210691A1
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Australia
Prior art keywords
controlled release
paracetamol
dosage form
release layer
hydroxyethylcellulose
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AU2016210691A
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Subodh Chandra Das
S.M. Rabbur Reza
Khalid Rafi
Md. Nadim Reza
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Beximco Pharmaceuticals Ltd
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Beximco Pharmaceuticals Ltd
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Priority claimed from AU2015903141A external-priority patent/AU2015903141A0/en
Application filed by Beximco Pharmaceuticals Ltd filed Critical Beximco Pharmaceuticals Ltd
Publication of AU2016210691A1 publication Critical patent/AU2016210691A1/en
Abandoned legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/16—Amides, e.g. hydroxamic acids
    • A61K31/165—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide
    • A61K31/167—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0053—Mouth and digestive tract, i.e. intraoral and peroral administration
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
    • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2086—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat
    • A61K9/209—Layered tablets, e.g. bilayer tablets; Tablets of the type inert core-active coat containing drug in at least two layers or in the core and in at least one outer layer
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A61P29/02—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID] without antiinflammatory effect
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Abstract

The present invention discloses modified release formulations of paracetamol. More particularly, the invention relates to controlled release multi-layer tablet formulations of paracetamol.

Description

2016210691 09 Aug 2016 CONTROLLED RELEASE FORMULATIONS OF PARACETAMOL Technical filed:
The present invention relates to modified release formulations of paracetamol. More particularly, the invention relates to controlled release multi-layer tablet compositions of paracetamol.
Background and prior art:
Acetaminophen, also known as paracetamol, is an analgesic and antipyretic agent which is widely used in prescription and non-prescription medicines in conventional dosage forms such as liquid, suppository, capsule, tablet and caplet. Acetaminophen is also prescribed in combination with other biologically active compounds selected from the group consisting of analgesics, muscle relaxants and non-steroidal anti-inflammatory drugs.
The elimination half-life of paracetamol is reported to be in the range of 1.9-2.5 hours. Its absorption following oral doses of conventional immediate release tablets is characterized by passive absorption with high bioavailability (80%) and rapidly occurring maximum plasma concentration (tmax 30-90 min). Therefore, a conventional dosage regimen of 1000 mg paracetamol being administered every 4 to 6 hours. It is very difficult to manage with such a higher dose for long term treatment in cases of sub-chronic or chronic pain. Therefore, sustained 1 2016210691 09 Aug 2016 release dosage forms have been developed to eliminate the early plasma clearance and also the administration of higher doses to maintain therapeutic efficacy.
Accordingly, there is available several patented and non-patented literature on Paracetamol sustained release tablets as monolayer as well as in bilayer tablet forms. A sustained release bilayer tablet containing paracetamol is described in EP-A-305051 (McNeil, Inc, US5004613). These tablets contain equal amounts of paracetamol in an immediate release layer and in sustained release layer. The sustained release layer in these tablets is provided by a matrix comprising a mixture of hydroxyethylcellulose and polyvinyl-pyrrolidone. EP’051 also teaches the use of Povidone and Hydroxyethylcellulose in an amount of 5 - 25 parts, i.e. 5-25 mg of each of Povidone and Hydroxyethylcellulose in the sustained release layer McNeil, Inc. markets such a bilayer tablet as Tylenol® Extended Relief in the US. US5773031 discloses an orally administrable sustained-release tablet dosage form, comprising a mixture of a pharmaceutically effective amount of uncoated acetaminophen particles and a pharmaceutically effective amount of acetaminophen particles coated with a polymeric material which is water-insoluble, said polymeric material being water-permeable, and wherein said polymeric material comprises a methacrylate ester copolymer. However, this patent fails to mention the release rate profile for the acetaminophen. 2 2016210691 09 Aug 2016
Another product described in US 6126969, by Shah et al. is a mixture of polymeric coated, sustained release acetaminophen particles and uncoated, quick release acetaminophen particles pressed together in a tablet. The coating is water permeable, but not soluble or pH dependent, e.g., a water-insoluble, pH independent coating. This patent does not describe a release rate profile for the acetaminophen. US7943170 B2 (SMITHKLINE BEECHAM LTD) teaches sustained release of Paracetamol having unique plasma profile and dissolution profile to have sustained action. US’170 teaches the use of a high viscosity and low viscosity mixture of hydroxypropylmethylcellulose in the sustained release matrix. Hydroxypropylmethylcellulose mixture, being a matrix polymer, is used in particular ratio. Glaxo SmithKline Beecham markets such a bilayer tablet as Panadol Osteo®.
In the light of the foregoing, there is a continuing need in the art to provide a better and cost-effective product with good dissolution profile, which becomes the objective of the present invention, for which protection is sought.
Summary of the invention
In line with the above objective, surprisingly, the present inventors have found that the desired controlled and substantially complete release of paracetamol can be obtained using the combination of Povidone and a matrix forming polymer. 3 2016210691 09 Aug 2016
Accordingly, in preferred aspect of the invention there is provided a controlled release layered dosage form of paracetamol comprising a controlled release layer which comprises a combination of matrix forming cellulose polymer and polyvinylpyrrolidone in a ratio of between about 1:1 and 1:3. In some preferred embodiments, there are two layers and the ration is about 1:2.
In another preferred aspect, the present invention provides a controlled release bilayer tablet of paracetamol formulated using the combination of Povidone and a matrix forming polymer, in the controlled release layer. In one preferred embodiment, the matrix forming polymer is Hydroxyethylcellulose.
The formulation thus prepared was found to be bioequivalent with the innovator formulation (Panadol Osteo, Glaxo SmithKline Beecham, Australia).
It is found that by using higher amounts of the povidone i.e., more than 30parts (30 mg), preferably 30 to 35 parts (30 to 35 mg) in the controlled release layer, it is possible to obtain similar dissolution as paracetamol Panadol Osteo. Moreover, the formulation prepared in accordance with the present invention was found to be bioequivalent in both fasting and fed conditions. Further, the formulations of the present invention are easy to manufacture on a commercial scale without requiring complex processing steps. Hydroxyethylcellulose used in the 4 2016210691 09 Aug 2016 invention has good heat stability, insensitive to pH and electrolyte which help to perform sustained action promptly irrespective of pH environment change in in-vivo conditions.
Detailed description of the invention
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
As used herein, the phrases such as “Controlled release, Extended release, Sustained release and Modified release” are used interchangeably throughout the specification and a person skilled in the art would understand as such the use of the above phrases in the context of the disclosure and appreciate the same. ΕΡΌ51 teaches the use of each Povidone and Hydroxyethylcellulose in an amount of 5 - 25 parts, i.e. 5 to 25 mg of povidone and Hydroxyethylcellulose in equal amounts in the sustained release matrix layer. However, it has been surprisingly found that by using higher amounts of the povidone i.e., more than 30 parts i.e. more than 30 mg, in the controlled release layer, it is possible to obtain similar dissolution as paracetamol Panadol Osteo. Moreover, the formulation prepared in accordance with the present invention was found to be bioequivalent in both fasting and fed conditions. Accordingly the present invention utilizes higher amounts of povidone in the range of 30 to 35 parts, i.e., 30 to 35 mg in the controlled release layer. The amount of povidone 5 2016210691 09 Aug 2016 used in the controller release layer of the invention is higher than the amount of Hydroxyethylcellulose used.
Accordingly, the invention provides controlled release multilayer, and preferably bilayer dosage form wherein, the controlled release layer comprises combination of matrix forming cellulose polymer and polyvinylpyrrolidone in a ratio of about between 1:1 to 1:3 and preferably about 1:2. In a preferred embodiment, the invention provides controlled release bilayer dosage form of paracetamol, wherein, the controlled release layer comprises a matrix forming cellulose polymer and polyvinylpyrrolidone (povidone) in a ratio of about 1:2.
In an embodiment, the matrix forming cellulose polymer is selected from the group consisting of hydroxyethylcellulose, hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxmethylcellulose sodium (Sodium CMS), ethylcellulose, methylcellulose and the like.
Accordingly, in an embodiment, the invention provides controlled release bilayer dosage form of paracetamol characterized in that the controlled release layer comprises hydroxyethylcellulose and polyvinylpyrrolidone in a ratio of about 1:2.
According to a preferred embodiment, there is provided a bilayer controlled release dosage form of paracetamol, wherein, the immediate release layer comprises from about 30 to 35% by weight of the total paracetamol; and the controlled release layer comprises 65 to 70% by weight of the 6 2016210691 09 Aug 2016 total paracetamol in the dosage form,wherein, the controlled release layer comprises hydroxyethylcellulose and polyvinylpyrrolidone in a ratio of about 1:2.
Accordingly, in a specific embodiment, the invention provides controlled release bilayer dosage form which comprises a) a controlled release layer has a target weight of 458.85 mg of paracetamol and an immediate release layer has a target weight of 206.15 mg of paracetamol, wherein, the controlled release layer comprises hydroxyethylcellulose and polyvinylpyrrolidone in a ratio of about 1:2.
According to one aspect of the invention, Hydroxyethylcellulose used is 3 to 5% by weight of the paracetamol used in the controlled release layer and polyvinyl pyrrolidone used is 6 to 10% by weight of the paracetamol used in the controlled release layer.
According to another embodiment, the invention provides a controlled release bilayer paracetamol tablet composition which comprises paracetamol and an additional active ingredient in the immediate release layer and paracetamol alone in the sustained release layer. The other active in the immediate release layer may be broadly selected from analgesics, muscle relaxants and non-steroidal anti-inflammatory drugs, for example, ibuprofen, aceclofenac, diclofenac, piroxicam and the like. In one preferred embodiment, Ibuprofen is used in the immediate release layer in addition to paracetamol to formulate the bilayer controlled release dosage form. 7 2016210691 09 Aug 2016
According to another preferred embodiment, the invention provides controlled release bilayer dosage form which comprises Ibuprofen 50 - 400 mg along with paracetamol in immediate release layer and paracetamol alone in controlled release layer.
In yet another embodiment, the controlled release dosage forms of paracetamol have been prepared with hydroxyethylcellulose and without polyvinylpyrrolidone (formulation II) and with polyvinylpyrrolidone and without hydroxyethylcellulose (formulation III) and have been evaluated for the release profiles of the formulations II & III and compared with the formulation I (present formulation) (table 1). According to this table, at the end of 90 mins, 89% and 101% of paracetamol was released from the formulations II and III respectively indicating the dose dumping. However, at the end of 180 mins, 85% of the paracetamol was released from formulation I which indicates the controlled release of the paracetamol in the present formulations, which is prepared with the combined use of hydroxyethylcellulose and polyvinylpyrrolidone in 1:2 ratio.
In yet another embodiment, the invention provides bioequivalent studies of the present formulation I. The bioequivalent studies of the present formulation I was assessed in a pharmacokinetic study in healthy fasted and healthy fed volunteers. The study design was two way crossover involving 12 (fasted) and 28 (healthy fed) volunteers, using paracetamol Panadol Osteo 665 mg tablet of Glaxo SmithKline Consumer Healthcare as a control/reference. The 8 2016210691 09 Aug 2016 comparative pharmacokinetic profiles are shown in table II, which indicates that the present formulation I is bioequivalent with the paracetamol Panadol Osteo 665 mg tablet of Glaxo SmithKline Consumer Healthcare used as a control in this study.
In yet another embodiment, the invention provides a process for preparation of the controlled release compositions that can be achieved by wet granulation or dry granulation and can be formulated by conventional methods of admixture such as granulating, blending, filling and compressing.
For example, the bilayer tablets of the present invention can be produced by a wet granulation process, wherein the immediate release phase and controlled release phase are separately prepared. The active drug substance and excipients are screened and mixed in a high shear mixer granulator or fluid bed dryer, separately, either for the immediate release or controlled release phase. The blend is granulated by the addition of a granulating solution (typically purified water, disintegration agent dissolved/dispersed in purified water, or drug dissolved/dispersed in purified water or a suitable solvent) sprayed into the high shear mixer granulator or fluid bed dryer. If desired, wetting agents such as surfactants can also be added. The resulting granules (optionally pelletised) are dried usually with residual moisture of 1-5 % by tray, fluid bed or microwave drying techniques. The dried granules are milled to produce a uniform particle size and the granules are blended with extragranular excipients as necessary, typically with a lubricant and 9 2016210691 09 Aug 2016 glidant (e.g. magnesium stearate, stearic acid and silicon dioxide). The separately prepared immediate release and controlled release granules can then be compressed together using a rotary tablet press (such as a bilayer tablet press) to obtain a bilayer tablet typically in the weight range of 600 to 1500 mg. The resulting tablets can be coated in a pan coater typically with a 0.05 -1% a aqueous film coat, followed by a wax polishing.
Thus the formulation according to the invention is easy to manufacture on a commercial scale without requiring complex processing steps. Hydroxyethylcellulose as used in the present invention has good heat stability, insensitive to pH and electrolyte which help to perform sustained action promptly irrespective of pH environment change in in-vivo conditions.
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
Example 1
Tablets containing a total of about 665 mg of paracetamol were prepared from the following ingredients:
Ingredients Formula-I(as per Formula-II Formula-Ill present invention) 10 2016210691 09 Aug 2016 mg/tablet % w/w mg/tabl et % w/w mg/table t % w/w IMMEDIATE RELEASE (IR) LAI i/ER Paracetamol 206.150 86.250 206.150 86.25 0 206.150 86.25 0 Maize Starch 3.807 1.590 3.807 1.590 3.807 1.590 Pregelatinized Starch 14.224 5.950 14.224 5.950 14.224 5.950 Sodium Starch Glycolate (Type A) 3.525 1.475 3.525 1.475 3.525 1.475 Povidone K-30 2.371 0.990 2.371 0.990 2.371 0.990 Microcrystalline Cellulose (Type 101) 4.123 1.725 4.123 1.725 4.123 1.725 Stearic Acid (powder) 4.800 2.000 4.800 2.000 4.800 2.000 Total Weight (IR Layer) 239.000 100 239.000 100 239.000 100 CONTROLED RELEASE (CR) LAYER Paracetamol 458.850 82.676 458.850 82.676 458.85 0 82.67 6 Microcrystalline Cellulose (Type 101) 36.269 6.535 66.483 11.979 51.376 9.257 11 2016210691 09 Aug 2016
HydroxyethylCellulose (Natrosol 250 L PH) 15.107 2.722 15.107 2.722 X X Polyvinylpyrrolidone (Povidone K-30) 30.214 5.444 X X 30.214 5.444 Pregelatinized Starch 7.060 1.272 7.060 1.272 7.060 1.272 Magnesium Stearate 7.500 1.351 7.500 1.351 7.500 1.351 Total weight (CR Layer) 555.00 100 555.00 100 555.00 100 Total weight (IR+CR Layer) 794.00 100 794.00 100 794.00 100 FILM COATING & POLISHING Kollicoat IR White 0.400 0.05 0.400 0.05 0.400 0.05 Carnauba Wax (Powder) 0.070 0.01 0.070 0.01 0.070 0.01 Total weight (coated tablet) 794.47 100 794.47 100 794.47 100 * Kollicoat iR White is a commercially available ready mix film coating powder from BASF; Germany contains Kollidon®VA 64; Titanium Dioxide;Kaolin & Sodium lauryl sulfate.
Example 2
The release profiles of test formula I, II and III were characterized using the USP type III apparatus (reciprocating basket) with 250 ml 0.1M HC1 at 37°C set at a cycle speed of 15 strokes / min. All three formulations comprised an immediate release component which released within the first fifteen minutes and a controlled release component that released slowly after 15 minutes as details are in below mentioned table 1. 12 2016210691 09 Aug 2016
Table 1: Dissolution profiles for Paracetamol Extended-Release Tablets, 665 mg Time in minutes % Paracetamol released Formula-I Formula-II Formula-Ill 15 Minutes 33 74 41 60 Minutes 54 86 75 90 Minutes 89 101 180 Minutes 85 nd nd
Example 3
Bioequivalence studies
The formula I (test A) was assessed in a pharmacokinetic study in healthy fasted volunteers. The study design was two way crossover involving 12 volunteers, using paracetamol Panadol Osteo 665 mg tablet of Glaxo SmithKline Consumer Healthcare as a control(reference B). The comparative pharmacokinetic profiles are shown in below table 2.
Table 2: 13 2016210691 09 Aug 2016
Parameters * Geometric mean % Ratio 90% Confidence Interval for Ln-transformed data Test (A) Reference (B) A/B Lower Limit Upper Limit AUCO-t 35842.46 37184.67 96.3904 91.8655 101.1382 Cmax 4301.65 4894.56 87.8863 83.6343 92.3544 *Geometric mean has been taken as the antilog (exponential) of the least square mean of the log transformed data.
The formula I (test A) was assessed in a pharmacokinetic study in healthy fed volunteers also. The study design was two way crossover involving 28 volunteers, using paracetamol Panadol Osteo 665 mg tablet of Glaxo SmithKline Consumer Healthcare as a control (reference B). The comparative pharmacokinetic profiles are shown in below table 3.
Table 3
Parameters * Geometric mean % Ratio 90% Confidence Interval for Ln-transformed data Test (A) Reference (B) A/B Lower Limit Upper Limit 14 AUCO-inf 36307.85 36329.79 99.9396 96.6353 103.3569 Cmax 5505.43 5593.15 98.4316 93.7543 103.3423 * Geometric mean has been taken as the anti og (exponential) of the least square mean of the log 2016210691 09 Aug 2016 transformed data.
Example 4
The tablets containing a total of about 665 mg of paracetamoland ibuprofen 50-400mg were prepared from the following ingredients:
Ingredients Mg/tablet IMMEDIATE RELEASE (IR) LAYER Paracetamol 206.15 Ibuprofen 50-400 Pregelatinized Starch 20-80 Microcrystalline Cellulose 5-40 Croscarmellose Sodium 5-40 Povidone K-30 2-20 Magnesium Stearate 0.2-5 Purified Talc 0.2-5 CONTROLED RELEASE (CR) LAYER Paracetamol 458.850 15
Microcrystalline Cellulose 25-45 HydroxyethylCellulose (Natrosol 250 L PH) 10-20 Polyvinylpyrrolidone (Povidone K-30) 20-40 Pregelatinized Starch 3-12 Magnesium Stearate 3-15 FILM COATING & POLISHING Kollicoat IR White* 0.1-1.0 Carnauba Wax (Powder) 0.01-0.2 * Kollicoat IR White is a commercially available ready mix film coating powder from BASF; Germany contains Kollidon®VA 64; Titanium Dioxide; Kaolin & Sodium lauryl sulfate 2016210691 09 Aug 2016
The total weight of the tablet varies according to the qty used of Ibuprofen in the formulations.
Industrial advantage:
The formulations according to the invention are easy to manufacture on a commercial scale without requiring complex processing steps. Hydroxyethylcellulose is having good heat stability, insensitive to pH and electrolyte which help to perform sustained action promptly irrespective of pH environment change in in-vivo conditions.Also with the higher doses of povidonein the controlled release layer, it is possible to obtain similar dissolution as Panadol Osteo (marketed product). Moreover the formulations of the present invention were found to be bioequivalent in both fasting and fed conditions. 16

Claims (13)

  1. We claim,
    1. A controlled release layered dosage form of paracetamol comprising a controlled release layer which comprises a combination of matrix forming cellulose polymer and polyvinylpyrrolidone in a ratio of between about 1:1 and 1:3.
  2. 2. The dosage form of paracetamol according to claim 1 which comprises a combination of matrix forming cellulose polymer and polyvinylpyrrolidone in a ratio of between about 1:2.
  3. 3. The dosage form of paracetamol according to claim 1, wherein, the matrix forming cellulose polymer is selected from the group consisting of hydroxyethylcellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropylmethylcellulose (HPMC), carboxmethylcellulose sodium (Sodium CMS), ethylcellulose, methylcellulose and the like.
  4. 4. The controlled release dosage form of paracetamol according to claim 2, wherein, the controlled release layer comprises hydroxyethylcellulose and polyvinylpyrrolidone in a ratio of about 1:2.
  5. 5. The controlled release dosage form of paracetamol according to claim 1, wherein the composition comprises paracetamol in immediate release layer and controlled release layer.
  6. 6. The controlled release dosage form of paracetamol according to claim 4, wherein, the immediate release layer comprises from about 30 to 35% by weight of the total paracetamol; and the controlled release layer comprises 65 to 70% by weight of the total paracetamol in the dosage form, wherein, the controlled release layer comprises hydroxyethylcellulose and polyvinylpyrrolidone in a ratio of about 1:2
  7. 7. The controlled release dosage form according to claim 5, comprises a) a controlled release layer has a target weight of 458.85 mg of paracetamol and the immediate release layer has a target weight of 206.15 mg of paracetamol, wherein, the controlled release layer comprises hydroxyethylcellulose and polyvinylpyrrolidone in a ratio of 1:2.
  8. 8. The controlled release dosage form according to claim 6, wherein, the Hydroxyethylcellulose used is 3 to 5% by weight of the paracetamol used in the controlled release layer.
  9. 9. The controlled release dosage form according to claim 6, wherein, the polyvinyl pyrrolidone used is 6 to 10% by weight of the paracetamol used in the controlled release layer.
  10. 10. The controlled release dosage form of paracetamol according to claim 4, wherein the composition comprises optionally comprises an additional active ingredient in the immediate release layer.
  11. 11. The controlled release dosage form of paracetamol according to claim 9, wherein the optional additional active ingredient in the immediate release layer may be broadly selected from analgesics, muscle relaxants and non-steroidal anti-inflammatory drugs, for example, Ibuprofen, aceclofenac, diclofenac, piroxicam and the like.
  12. 12. The controlled release dosage form of paracetamol according to claim 10, wherein, the additional active ingredient in the immediate release layer is ibuprofen 50-400 mg. 12. A controlled release bilayer dosage form, characterized in that,wherein, the controlled release layer comprises hydroxyethylcellulose and polyvinylpyrrolidone in a ratio of about 1:2.
  13. 13. The controlled release dosage form of paracetamol according to claim 1, wherein the dosage form is a bilayer dosage form.
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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114173767A (en) * 2019-06-27 2022-03-11 葛兰素史克消费者健康控股(美国)有限责任公司 Novel combination of ibuprofen and paracetamol

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN114173767A (en) * 2019-06-27 2022-03-11 葛兰素史克消费者健康控股(美国)有限责任公司 Novel combination of ibuprofen and paracetamol

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