Pharmaceutical compositions comprising ibuprofen and paracetamol and relevant excipients

Abstract

The present invention relates to the preperation of pharmaceutical compositions comprising ibuprofen and paracetamole is indicated for temporary relief of acute pain, a binder having viscosity value between 2.0 and 20.0 centipoise(cP) at 2% addition in water at 20°C and a lubricant having a particle size distribution with d90 value of less than 40 µm and larger than 15 µm, wherein the pharmaceutical tablet is prepared by wet granulation.

Description

[0001] PHARMACEUTICAL COMPOSITIONS COMPRISING IBUPROFEN & PARACETAMOL AND RELEVANT EXCIPIENTS

[0002] Field of invention

[0003] The present invention relates to the preperation of pharmaceutical compositions comprising ibuprofen and paracetamole is indicated for temporary relief of acute pain, a binder having viscosity value between 2.0 and 20.0 centipoise(cP) at 2% addition in water at 20°C and a lubricant having a particle size distribution with d90 value of less than 40 pm and larger than 15 pm, wherein the pharmaceutical tablet is prepared by wet granulatiom

[0004] Background of the invention

[0005] Ibuprofen has a chemical name as 2-(4-isobutylphenyl) propionic acid and its chemical structure is shown in the Scheme I. It has molecular weight of 206.28 g / mol, white solid.

[0006] Scheme 1

[0007] Ibuprofen is a member of nonsteroidal antiinflammatory drugs (NSAID). In general, NSAIDs are used for the treatment of acute / chronic conditions attached with pain and inflammation. NSAIDs are generally used for the symptomatic relief of the following conditions; osteoarthritis, rheumatoid arthritis, mild-to-moderate pain due to inflammation and tissue injury, low back pain, inflammatory arthropathies, tennis elbow, headache, migraine, acute gout, Dysmenorrhoea, metastatic bone pain, postoperative pain, muscle stiffness and pain due to Parkinson's disease, pyrexia (fever), ileus, renal colic and etc. Ibuprofen is used for relieving pain, alleviating fever and reducing inflammation. Paracetamol has a chemical name as 4-acetamidophenol and its chemical structure is shown in the Scheme II. It has molecular weight of 151.16 g / mol, an odorless white crystalline solid.

[0008] Scheme II

[0009] Paracetamol (Acetaminophen) is the most commonly taken analgesic worldwide and is recommended as first-line therapy in pain conditions by the World Health Organization (WHO). It is also used for its antipyretic effects, helping to reduce fever.

[0010] In pharmaceutical industry, the oral administration route is prevalent and it has many advantages especially about patient compliance. One of the oral administration way used commonly is tablet form. Tablet form has many advantages like cost-effective, lighter and compact, easiest and cheapest to package, can be masked by coating technique and greatest chemical and microbial stability over all oral dosage forms. Unlikely, tablet dosage form has some disadvantages such as difficulties for children and unconscious patients to swallow, troubles on BE / BA studies for drugs with poor wetting and slow dissolution properties.

[0011] General properties of Tablet dosage forms;

[0012] ■ Tablet should have elegant product without any cracks, discoloration or contamination.

[0013] ■ Mechanical stregnth should be sufficient for production packaging, shipping and dispensing.

[0014] ■ Physical properties shoul maintain the chemical and physical stability.

[0015] ■ Tablet form should have predictable and reproducible manner for releasing the active ingredients.

[0016] Wet granulation is one of the most commonly used methods of developing pharmaceutical products. The advantages of wet granulation method are a narrow particle size distribution (PSD) of the granules, few fine particles that yield little dust, more consistent powder flow, better control of granule size, very good binder homogeneity, and good powder compactability. One of the most important excipient group in a successful wet granulation formulation is the binder. This group’s polymers have different chemistries, mechanical properties, and viscosity ranges. The polymer binder has attracted the attention of formulators in the last decade due to its superior mechanical properties, chemical stability, and multi-functionality.

[0017] Summary of the invention

[0018] The present invention relates to the preparation of pharmaceutical compositions comprising ibuprofen, paracetamol and one or more pharmaceutically acceptable excipients comprising a binder having a viscosity value between 2-20 centipoise at 2% addition in water at 20°C.

[0019] The present invention relates to the preparation of pharmaceutical compositions comprising ibuprofen, paracetamol and one or more pharmaceutically acceptable excipients comprising lubricant having a particle size distribution with d90 value of less than 40 pm and larger than 15 pm.

[0020] The present invention relates to the preparation of pharmaceutical compositions comprising ibuprofen, paracetamol and one or more pharmaceutically acceptable excipients comprising wherein the binder having a viscosity value between 2-20 centipoise at 2% addition in water at 20°C, wherein the lubricant having a particle size distribution with d90 value of less than 40 pm and larger than 15 pm, and the pharmaceutical tablet is prepared by wet granulation.

[0021] Detailed description of the invention

[0022] The present invention relates to the preparation of pharmaceutical compositions comprising ibuprofen, paracetamol and one or more pharmaceutically acceptable carriers or excipients.

[0023] The present invention relates to the preperation of pharmaceutical compositions comprising ibuprofen, paracetamol is indicated for the treatment of acute / chronic conditions attached with pain and inflammation, having a binder having a viscosity value between 2-20 centipoise at 2% addition in water at 20°C.

[0024] The present invention relates to the preperation of pharmaceutical compositions comprising ibuprofen, paracetamol is indicated for the treatment of acute / chronic conditions attached with pain and inflammation, having a lubricant having a particle size distribution with d90 value of less than 40 pm and larger than 15 pm. The present invention provides pharmaceutical compositions comprising ibuprofen, paracetamol formulated for use as tablet dosage form, is prepared by wet granulation.

[0025] In this invention, a pharmaceutical tablet composition comprising ibuprofen, paracetamol and one or more pharmaceutically acceptable excipients, wherein the binder having a viscosity value between 2-20 centipoise at 2% addition in water at 20°C, wherein the lubricant having a particle size distribution with d90 value of less than 40 pm and larger than 15 pm, and the pharmaceutical tablet is prepared by wet granulation.

[0026] In this invention, it is obtained pharmaceutical compositions comprising ibuprofen, paracetamol and the binder with the value of viscosity 2,0 to 20,0 cP at 2% addition in water at 20°C.

[0027] In this invention, it is obtained pharmaceutical compositions comprising ibuprofen, paracetamol and the lubricant having a particle size distribution with d90 value of less than 40 pm and larger than 15 pm.

[0028] The present invention provides pharmaceutical compositions comprising ibuprofen, paracetamol formulated for use as tablet dosage form.

[0029] Viscosity is an essential parameter for process development and solid dosage manufacturing.

[0030] Generally, excipients that is used in tablet dosage form are diluent, binder, disintegrants, lubricant, glidant, viscosity enhancer agent and solvent except active ingredient.

[0031] In this invention, a binder is used in the formulation, the preferred binder is hypromellose.

[0032] In this invention, viscosity value of binder in the pharmaceutical composition are between 2 to 20 cP at 2% addition in water at 20°C.

[0033] In this invention, viscosity value of binder in the pharmaceutical composition are between 2 to 10 cP at 2% addition in water at 20°C.

[0034] In this invention, viscosity value of binder in the pharmaceutical composition are between 2 to 7 cP at 2% addition in water at 20°C. In this invention, viscosity value of binder in the pharmaceutical composition are between 4 to 6 cP at 2% addition in water at 20°C.

[0035] In this invention, particle size distribution with d90 value of lubricant in the pharmaceutical composition are less than 40 pm and larger than 15 pm.

[0036] The term "particle size" as used herein refers to the volume diameter of valsartan particles, as determined by laser light scattering using a Malvern-Mastersizer Apparatus MS 2000.

[0037] Methods of determining the size of particles are well known in the art. For example, Laser Diffraction, Dynamic Light Scattering, Image Particle Analysis, Acoustic Spectroscopy etc.

[0038] The dxvalue indicates that a certain percentage X of the particles has a size below a certain limit, dw means that 90% of particles (V / V) have a higher volume diameter than the indicated value.

[0039] A dw value of less than 10 pm means that 90 % by volume of the particles have a diameter below 10 pm.

[0040] The term "lubricant particle" means a particle that contains lubricant, preferably, a particle that essentially or completely consists of lubricant.

[0041] In the present invention the pharmaceutical compositions of ibuprofen, paracetamol have a lubricant particle size such that dgo is 40 pm.

[0042] In the present invention the pharmaceutical compositions of ibuprofen, paracetamol have a lubricant particle size such that dgo is 35 pm.

[0043] In the present invention the pharmaceutical compositions of ibuprofen, paracetamol have a lubricant particle size such that dgo is 30 pm.

[0044] In the present invention the pharmaceutical compositions of ibuprofen, paracetamol have a lubricant particle size such that dgo is 25 pm.

[0045] In the present invention the pharmaceutical compositions of ibuprofen, paracetamol have a lubricant particle size such that dgo is 20 pm.

[0046] In the present invention the pharmaceutical compositions of ibuprofen, paracetamol have a lubricant particle size such that dgo is 15 pm. In this invention, manufacturing process generally consists of four stages: a) Mixing, b) Granulation, c) Mixing granule with external excipients, d) Tablet compression and Film Coating.

[0047] Table 1: The average PSD results of specific lubricant in pharmaceutical compositions containing ibuprofen, paracetamol.

[0048] In this invention, the formulations preferably contain active ingredient, filler, disintegrant, binder, viscosity enhancer, lubricant and solvent.

[0049] Advantages

[0050] Binder is a critical excipient in the formulation content. The use of suitable binder enabled the product to be obtained in the desired quality and specifications. If binder (for example hypromellose) is not used, the product can not be produced with the desired quality, specification and efficiency.

[0051] Lubricant with the particle size specified in the formulation content (15 microns to 40 microns) is used. Preferably, the use of lubricant with a value in this interval ensured that the product is obtained in the desired quality and specifications. When lubricant with a particle size of less than 15 microns is used, the powder can not compressed, so the product can not be produced in the desired quality, specification and efficiency.

[0052] The active ingredient of Paracetamol (Acetaminophen) has very poor compactability property. In addition to binder and granulation properties, the particle size of the lubricant is very critical for compactability. In the development studies carried out with the product, successful tablet compression performance can not be achieved when the particle size (d90) is below 15 microns.

[0053] For ideal compactability, the particle size (d90) of magnesium stearate used with the binder should be in the range of 15 microns-40 microns. The pharmaceutical compositions of the invention are particularly suited for the oral administration.

[0054] The present invention provides pharmaceutical composition comprising ibuprofen, paracetamol and relevant excipients, characterized by i) A simple and exclusive manufacturing process ii) Stable formulation

[0055] In this invention, a tablet product was obtained by using minimum excipient in the formulation.

[0056] Tablet dosage form is simple, cost-effective, easy and convenient to use, so it has high patient compliance.

[0057] The term "treatment" or "treating" means any treatment of a disease or condition in a subject, such as a mammal, including: 1) preventing or protecting against the disease or condition, that is, causing the clinical symptoms not to develop; 2) inhibiting the disease or condition, that is, arresting or suppressing the development of clinical symptoms; and / or 3) relieving the disease or condition that is, causing the regression of clinical symptoms.

[0058] The term “granulation” as used herein, and as conventionally used in the pharmaceutical industry, refers to the act or process in which primary powder particles are made to adhere to form larger, multiparticle entities called granules. Granules may for example be formed collecting particles together by creating mechanical bonds between them, e.g. by compression or by using a binder. Granulation is extensively used in the manufacturing of tablets.

[0059] The term "oral solid dosage form" as used herein denotes solid preparations (e.g. tablets) for oral administration each containing a single dose of one or more active substances.

[0060] Pharmaceutical composition of the present inventions may comprise one or more pharmaceutically acceptable excipient(s). Pharmaceutically acceptable excipients comprise, but are not limited to, filler, disintegrant, binder, surfactant, lubricant, solvent and the mixtures thereof, to facilitate the physical formulation of various dosage forms for oral administration like tablets.

[0061] Suitable disintegrants according to the present invention include, but are not limited to, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, cross-linked polyvinylpyrrolidone, crospovidone (cross-linked povidone, a synthetic crosslinked homopolymer of N-vinyl-2-pyrrolidone), alginic acid, microcrystalline cellulose (such as refined wood pulp derived from alpha cellulose), hydroxypropyl cellulose, low substituted hydroxypropyl cellulose, polacrillin potassium, sodium alginate, sodium starch glycolate, partially hydrolysed starch, sodium carboxymethyl starch, and starch. The preferred disintegrants is croscarmellose sodium.

[0062] Suitable binders according to the present invention include, but are not limited to, hydroxypropyl cellulose, hypromellose (hydroxypropyl methylcellulose, HPMC), HPMC E5, microcrystalline cellulose, acacia, alginic acid, carboxymethylcellulose, ethylcellulose, methylcellulose, hydroxyethylcellulose, ethylhydroxyethylcellulose, polyvinyl alcohol, polyacrylates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, ethylcellulose, gelatin, liquid glucose, methylcellulose, polyvinyl pyrrolidone and pregelatinized starch. The preferred binder is HPMC E5.

[0063] Suitable lubricants according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearylfumarate, zinc stearate and polyethylene glycol. The preferred lubricant is magnesium stearate.

[0064] Suitable fillers according to the present invention include, but are not limited to, dibasic calcium phosphate, kaolin, microcrystalline cellulose, silicated microcrystalline cellulose, dicalcium phosphate, tricalcium phosphate, magnesium trisilicate, lactose such as example the anhydrous form or the hydrate form such as the monohydrate form, sugars such as dextrose, maltose, saccharose, glucose, fructose or maltodextrine, sugar alcohols such as mannitol, maltitol, sorbitol, xylitol, powdered cellulose, precipitated calcium carbonate, sodium carbonate, sodium phosphate and starch. Fillers which are slightly hygroscopic or non- hygroscopic are preferred, with non-hygroscopic fillers being particularly preferred, in particular when the dosage form is to be used for tropical countries. The preferred fillers is microcrystalline cellulose.

[0065] Suitable viscosity enhancer according to the present invention include, but are not limited to, sodium carboxymethyl cellulose, colloidal silica, acacia, gelatin, methyl cellulose and polyvinyl pyrrolidone. The preferred viscosity enhancer is colloidal silica. Solvents can be selected from the group, but not limited to, ethanol, ethyl alcohol, polyethylene glycol, propylene glycol, isopropyl alcohol, purified water and other materials known to one of ordinary skill in the art and mixtures thereof. The preferred solvent is purified water.

[0066] In another embodiment, a pharmaceutical composition according to invention comprises: Example 1: Ibuprofen & Paracetamol film coated tablet unit formula

[0067] Procedure for composition comprising Ibuprofen&Paracetamol Film Tablet;

[0068] 1. Stage 1 Sieving and Mixing

[0069] Sieving and mixing: ibuprofen, paracetamol, disintegrant and filler. 2. Stage 2 Wet Granulation

[0070] Wet granulation was done with purified water which contains binder into it.

[0071] 3. Stage 3 Sieving and Mixing

[0072] Dried granules were Sieved and mixed with disintegrant, viscosity enhancer, lubricant.

[0073] 4. Stage 4 Tablet compression and Film Coating Tablet compression and Film Coating

[0074] In the present invention, preferably lubricant in the composition is magnesium stearate. The particle size of lubricant can be less than 40 pm and larger than 15 pm. In the present invention, preferably binder in the composition is hypromellose. The viscosity value of binder can be between 2-20 centipoise at 2% addition in water at 20°C.

[0075] In another preferred embodiment, a pharmaceutical composition according to invention comprises:

[0076] Example 2: Ibuprofen&Paracetamol film coated tablet unit formula

[0077] Procedure for composition comprising Ibuprofen&Paracetamol Film Tablet;

[0078] 5. Stage 1 Sieving and Mixing Sieving and mixing: ibuprofen, paracetamol, disintegrant and filler.

[0079] 6. Stage 2 Wet Granulation

[0080] Wet granulation was done with purified water which contains Hypromellose into it.

[0081] 7. Stage 3 Sieving and Mixing

[0082] Dried granules were Sieved and mixed with disintegrant, viscosity enhancer, Magnesium stearate and binder.

[0083] 8. Stage 4 Tablet compression and Film Coating

[0084] Tablet compression and Film Coating In one aspect of present invention, a solid pharmaceutical composition for use in the treatment of temporary relief of acute pain.

[0085] In another aspect of an invention pharmaceutical compositions comprising ibuprofen, paracetamol, hypromellose as a binder and Magnesium stearate as a lubricant for use in the treatment of temporary relief of acute pain.

[0086] In-vitro Tests

[0087] Dissolution results of pharmaceutical compositions comprising the binder having a viscosity value for 5 cp and for 25 cp (at 2% addition in water at 20°C) were compared.

[0088] Table 2: Dissolution results of ibuprofen compositions having a binder with optimum (5 cp) viscosity value at 2% addition in water at 20°C.

[0089] Table 2 shows pharmaceutical product comprising ibuprofen and a binder with optimum (5 cp) viscosity value at 2% addition in water at 20°C. As can be seen, the dissolution of ibuprofen in the compositions with a binder with optimum (5 cp) viscosity value (at 2% addition in water at 20°C) increased above 100% at 10 minutes.

[0090] Table 3 : Dissolution results of ibuprofen compositions having a binder with high (25 cp) viscosity value at 2% addition in water at 20°C

[0091] Table 3 shows pharmaceutical product comprising ibuprofen and a binder with high (25 cp) viscosity value at 2% addition in water at 20°C. the dissolution of ibuprofen in the compositions with a binder with high (25 cp) viscosity value (at 2% addition in water at 20°C) remained below 90% at the end of 1 hour.

[0092] Table 4: Dissolution results of paracetamol compositions having a binder with optimum (5 cp) viscosity value at 2% addition in water at 20°C.

[0093] Table 4 shows pharmaceutical product comprising paracetamol and a binder with optimum (5 cp) viscosity value at 2% addition in water at 20°C. As can be seen, the dissolution of paracetamol in the compositions with a binder with optimum (5 cp) viscosity value (at 2% addition in water at 20°C) increased above 100% at 10 minutes. Table 5: Dissolution results of paracetamol compositions having a binder with high (25 cp) viscosity value at 2% addition in water at 20°C

[0094] Table 5 shows pharmaceutical product comprising paracetamol and a binder with high (25 cp) viscosity value at 2% addition in water at 20°C. the dissolution of paracetamol in the compositions with a binder with high (25 cp) viscosity value (at 2% addition in water at 20°C) remained below 90% at the end of 1 hour.

[0095] As can be seen from the above tables, the desired dissolution values could not be achieved with a pharmaceutical product comprising ibuprofen, paracetamol and a binder with high (25 cp) viscosity value at 2% addition in water at 20°C. The desired values were obtained for a pharmaceutical product comprising ibuprofen, paracetamol and a binder with optimum (5 cp) viscosity value at 2% addition in water at 20°C, which is also described in the scope of the invention.

Claims

Claims1. A pharmaceutical tablet composition prepared by wet granulation, comprising ibuprofen paracetamol a binder and a lubricantwherein the binder has a viscosity value between 2-20 centipoise at 2% addition in water at 20°C, and the lubricant has a particle size distribution with d90 value of less than 40 pm and larger than 15 pm,2. The pharmaceutical composition of claim 1, wherein said binder is Hypromellose3. The pharmaceutical composition of claim 2, Hypromellose has viscosity between 2-20, preferably 2-10 cP at 2% addition in water at 20°C.

4. The pharmaceutical composition of claim 1, wherein the lubricant has particle size distribution with d90 value of less than 30 pm and larger than 20 pm.

6. The pharmaceutical composition according to any one of claims 1 to 5 where the tablet further comprises a film coating material.

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