Solid pharmaceutical compositions comprising ibuprofen and paracetamol

Abstract

The present invention relates to the preparation of pharmaceutical compositions comprising active ingredients of ibuprofen and paracetamol having a particle size distribution with d90 value of less than 150 µm and having a specific ratio of the binder to the total weight of active ingredients, wherein the pharmaceutical tablet is prepared by wet granulation.

Description

[0001] SOLID PHARMACEUTICAL COMPOSITIONS COMPRISING IBUPROFEN AND PARACETAMOL

[0002] Field of invention

[0003] The present invention relates to the preparation of pharmaceutical compositions comprising active ingredients of ibuprofen and paracetamol having a particle size distribution with d90 value of less than 150 pm and having a specific ratio of the binder to the total weight of active ingredients, wherein the pharmaceutical tablet is prepared by wet granulation.

[0004] Background of the invention

[0005] Ibuprofen is a member of nonsteroidal anti-inflammatory drugs (NSA1D), it was first marketed in the UK in 1968. In general, NSAlDs are used for the treatment of acute / chronic conditions attached with pain and inflammation.

[0006] NSAlDs 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, Dysmenorrhea, 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.

[0007] Ibuprofen has a chemical name as 2-(4-isobutylphenyl) propionic acid and its chemical structure is shown in below. It has molecular weight of 206.28 g / mol, white solid.

[0008] Ibuprofen Due to good anti-inflammatory, analgesic and antipyretic effects and few adverse reactions, ibuprofen is considered to be one of the safest nonsteroidal anti-inflammatory drugs (NSAlDs) and has been widely put into clinical use.

[0009] Paracetamol has a chemical name as 4-acetamidophenol and its chemical structure is shown in below. It has molecular weight of 151.16 g / mol, an odorless white crystalline solid.

[0010] Paracetamol

[0011] 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.

[0012] In pharmaceutical industry, the oral administration route is prevalent and it has many advantages especially about patient compliance. One of the oral administration ways 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.

[0013] General properties of tablet dosage forms;

[0014] ■ Tablet should have elegant product without any cracks, discoloration or contamination.

[0015] ■ Mechanical strength should be sufficient for production packaging, shipping and dispensing.

[0016] ■ Physical properties should maintain the chemical and physical stability. ■ Tablet form should have predictable and reproducible manner for releasing the active ingredients.

[0017] 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.

[0018] One of the most important excipient groups 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 multifunctionality.

[0019] In view of the foregoing, there is a need to improve powder flowability and tablet compression in compositions comprising ibuprofen, paracetamol and binder in the state of the art and to produce tablets with wet granulation of a specifically desired quality and dissolution profile. The present invention provides a solution to these problems by providing novel compositions comprising ibuprofen, paracetamol and binder. These solutions will be described in detail.

[0020] Brief Description of The Figures

[0021] Figure 1: Graph of dissolution profile of ibuprofen-optimal amount binder

[0022] Figure 2: Graph of dissolution profile of ibuprofen- excessive amount binder

[0023] Figure 3: Graph of dissolution profile of paracetamol-optimal amount binder Figure 4: Graph of dissolution profile of ibuprofen- excessive amount binder

[0024] Summary of the invention

[0025] The present invention provides a solid pharmaceutical composition comprising ibuprofen wherein the particle size of ibuprofen with d90 value less than 150 pm, paracetamol wherein the particle size of paracetamol with d90 value less than 150 pm, the weight ratio of binder to total weight of active ingredients is from 0.01 to 0.07, wherein the pharmaceutical composition is prepared by wet granulation. The pharmaceutical composition comprises ibuprofen wherein particle size of ibuprofen d90 value can be less than 150 pm and higher than 50 pm.

[0026] The pharmaceutical composition comprises paracetamol wherein particle size of paracetamol with d90 value can be less than 150 pm and higher than 50 pm.

[0027] In other embodiment the weight ratio of binder to total weight of active ingredients can be from 0.02 to 0.05.

[0028] In other embodiment, the pharmaceutical composition comprises Hypromellose as a binder.

[0029] In other aspect of invention, a wet granulation process for manufacturing a pharmaceutical composition wherein the process comprising steps below: a. Sieving and mixing ibuprofen, paracetamol, filler and disintegrant, b. Wet granulation is done with purified water which comprises binder into it, c. Dried granules are sieved and mixed with disintegrant, viscosity enhancer, and lubricant, and d. Tablet compression and film coating.

[0030] In other aspect of invention, a pharmaceutical composition for use in the treatment of temporary relief acute pain.

[0031] Detailed description of the invention

[0032] The aspects and disclosures according to the present invention, in particular the pharmaceutical compositions, methods and uses, refer to the ibuprofen, paracetamol and a binder as defined hereinbefore and hereinafter.

[0033] Excipients used in a formulation may adversely affect physicochemical and pharmacokinetic properties. These excipients can interact with the active ingredient. For this reason, while developing the formulation, the substances to be used in addition to the active substance must be carefully and consciously selected.

[0034] Excipients that are used in tablet dosage form are diluent, binder, disintegrants, lubricant, glidant, viscosity enhancer agent and solvent except active ingredient. The present invention relates to the preparation of pharmaceutical compositions comprising ibuprofen, paracetamol, a binder and one or more pharmaceutically acceptable carriers or excipients.

[0035] 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.

[0036] 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.

[0037] The dxvalue indicates that a certain percentage X of the particles has a size below a certain limit, dgo means that 90% of particles (V / V) have a higher volume diameter than the indicated value.

[0038] The value d90 refers to the 90% value of the distribution measured using a laser diffractometer. For the purposes of the present invention, the d90 value denotes the particle size below which 90% of the quantity of particles is found based on the distribution. In other words, in The D90 describes the diameter where ninety percent of the distribution has a smaller particle size and ten percent has a larger particle size.

[0039] In the present invention the pharmaceutical compositions of ibuprofen, having a particle size distribution with d90 value of less than 150 pm.

[0040] In the present invention, the particle size of ibuprofen can be 50 pm < d90 < 150 pm. More specifically it can be 70 pm< d90 < 100 pm. Even more specifically, the particle size herein may be 70 pm, 75 pm, 80 pm, 85 pm, 90 pm, 95 pm or 100 pm.

[0041] The present invention relates to the preparation of pharmaceutical compositions comprising ibuprofen, paracetamol is indicated for the treatment of acute / chronic conditions attached with pain and inflammation, active ingredient of ibuprofen having a particle size distribution with d90 value of less than 150 pm.

[0042] The present invention relates to the preparation of pharmaceutical compositions comprising ibuprofen, paracetamol is indicated for the treatment of acute / chronic conditions attached with pain and inflammation, active ingredient of paracetamol having a particle size distribution with d90 value of less than 150 pm.

[0043] The present invention relates to the preparation of pharmaceutical compositions comprising ibuprofen, paracetamol is indicated for the treatment of acute / chronic conditions attached with pain and inflammation, wherein the weight ratio of the binder to the total weight of active ingredients can be from 0,01 to 0,07.

[0044] The inventors surprisingly have found that the pharmaceutical composition comprises ibuprofen which has less than 150 d90 value, paracetamol which has less than 150 d90 value, and binder which the weight ratio of binder to total weight of active ingredients 0.01 to 0.07 improves powder blend uniformity, tablet compressibility, dissolution and produces tablets with the desired properties.

[0045] The present invention provides pharmaceutical compositions comprising ibuprofen, paracetamol formulated for use as tablet dosage form, is prepared by wet granulation.

[0046] In this invention, a pharmaceutical composition in the form of a tablet, comprising: a] active ingredient of ibuprofen, having a particle size distribution with d90 value of less than 150 pm, b] active ingredient of paracetamol, having a particle size distribution with d90 value of less than 150 pm, c] the weight ratio of the binder to the total weight of active ingredients is from 0,01 to 0,07. wherein the pharmaceutical product is prepared by wet granulation.

[0047] 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, ethyl cellulose, methylcellulose, hydroxyethyl cellulose, ethylhydroxyethylcellulose, polyvinyl alcohol, polyacrylates, carboxymethylcellulose calcium, carboxymethylcellulose sodium, compressible sugar, ethyl cellulose, gelatin, liquid glucose, methylcellulose, polyvinyl pyrrolidone and pregelatinized starch. The preferred binder is HPMC E5. The present invention provides pharmaceutical compositions comprising ibuprofen, paracetamol formulated for use as tablet dosage form.

[0048] In other embodiment pharmaceutical composition in present invention further comprises lubricant as pharmaceutical excipient.

[0049] Suitable lubricants according to the present invention include, but are not limited to, calcium stearate, magnesium stearate, mineral oil, stearic acid, fumaric acid, sodium stearyl fumarate, zinc stearate and polyethylene glycol. The preferred lubricant is magnesium stearate and / or stearic acid.

[0050] In other embodiment particle size of a lubricant in present invention compositions can be 15 pm to 40 pm. More specifically can be selected from 20 pm to 35 pm. More specifically 20 pm, 21 pm, 22 pm, 23 pm, 24 pm, 25 pm, 26 pm, 27 pm, 28 pm, 29 pm, 30 pm, 31 pm, 32 pm, 33 pm, 34 pm or 35 pm. Even more specifically can be 25 pm.

[0051] Table 1: The average PSD results of lubricant in pharmaceutical compositions comprising ibuprofen, paracetamol.

[0052] Viscosity is an essential parameter for process development and solid dosage manufacturing.

[0053] 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.

[0054] 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.

[0055] 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.

[0056] 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.

[0057] In this invention, manufacturing process comprise of four stages: a) Mixing, b] Granulation, c] Mixing granule with external excipients, d] Tablet compression and Film Coating.

[0058] In this invention, the formulations preferably comprise active ingredients, fillers, disintegrants, binders, viscosity enhancers, lubricants and solvents.

[0059] The present invention provides pharmaceutical composition comprising ibuprofen, paracetamol and relevant excipients, characterized by i] A simple and exclusive manufacturing process ii] Stable formulation

[0060] Table 2: Ibuprofen & Paracetamol film coated tablet unit formula

[0061] Procedure for composition comprising Ibuprofen & Paracetamol Film Tablet;

[0062] 1. Stage 1 Sieving and Mixing

[0063] Sieving and mixing ibuprofen, paracetamol, croscarmellose sodium and microcrystalline cellulose.

[0064] 2. Stage 2 Wet Granulation

[0065] Wet granulation was done with purified water which comprises Hypromellose into it.

[0066] 3. Stage 3 Sieving and Mixing Dried granules were Sieved and mixed with croscarmellose sodium, colloidal silica, stearic acid and magnesium stearate.

[0067] 4. Stage 4 Tablet compression and Film Coating

[0068] Tablet compression and Film Coating

[0069] Invitro Studies

[0070] Ibuprofen

[0071] Dissolution results of present invention compositions comprising different amount of binder were compared.

[0072] For present invention compositions with a binder amount of %3.0 (w / w), which is optimal amount in present invention compositions. Dissolution reached up the range defined in the invention, dissolution reached up to 100% at 10 minutes, and the desired value was achieved (Figure 1).

[0073] Table 3: Dissolution profile of ibuprofen-optimal amount binder

[0074] Other studies on ibuprofen-binder amount, results are different when binder amount goes up %6.0 (w / w). For example, when the amount of binder is 10% by weight, the desired dissolution cannot be achieved (Figure 2).

[0075] Table 4: Dissolution profile of ibuprofen-excessive amount of binder Dissolution reached up to 82% but did not increase further. In other words, the desired dissolution was not achieved.

[0076] Paracetamol

[0077] Dissolution results of present invention compositions comprising different amount of binder were compared.

[0078] For present invention compositions with a binder amount of %3.0 (w / w), which is optimal amount in present invention compositions. Dissolution reached up the range defined in the invention, dissolution reached up to 100% at 15 minutes, and the desired value was achieved (Figure 3).

[0079] Table 5: Dissolution profile of paracetamol-optimal amount binder

[0080] Other studies on paracetamol-binder amount, results are different when binder amount goes up %6.0 (w / w). For example, when the amount of binder is 10% by weight, the desired dissolution cannot be achieved (Figure 4).

[0081] Table 6: Dissolution profile of paracetamol-excessive amount of binder Dissolution reached up to 83% but did not increase further. In other words, the desired dissolution was not achieved.

Claims

Claims1. A pharmaceutical composition prepared by wet granulation in the form of a tablet, comprising; a] ibuprofen, with a particle size distribution of d90 value of less than 150 pm, b] paracetamol, with a particle size distribution of d90 value of less than 150 pm, c] a binder where the weight ratio of the binder to the total weight of ibuprofen and paracetamol is between 0,01 and 0,07,2. The pharmaceutical composition of claim 1, wherein ibuprofen has a particle size distribution of d90 value of less than 150 pm and larger than 50 pm.

3. The pharmaceutical composition of claim 1, wherein paracetamol, has a particle size distribution of d90 value of less than 150 pm and larger than 100 pm.

4. The pharmaceutical composition according to claim 1, wherein the weight ratio of the binder to the total weight of ibuprofen and paracetamol is between 0,02 and 0,05.

5. A pharmaceutical composition according to claim 1, wherein the composition comprises Hypromellose as a binder.

6. A pharmaceutical composition according to any one of the previous claims for use in the treatment of temporary relief of acute pain.

7. A wet granulation process for manufacturing a pharmaceutical composition according to Claim 1, comprising steps of: a. Sieving and mixing ibuprofen, paracetamol, filler and disintegrant, b. Wet granulation is done with purified water which comprises binder c. Dried granules are sieved and mixed with disintegrant, viscosity enhancer, and lubricant, and d. Tablet compression and film coating.

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