EP3727365A2 - Modified release formulations of flurbiprofen - Google Patents

Modified release formulations of flurbiprofen

Info

Publication number
EP3727365A2
EP3727365A2 EP18916470.0A EP18916470A EP3727365A2 EP 3727365 A2 EP3727365 A2 EP 3727365A2 EP 18916470 A EP18916470 A EP 18916470A EP 3727365 A2 EP3727365 A2 EP 3727365A2
Authority
EP
European Patent Office
Prior art keywords
release phase
pharmaceutical formulation
formulation according
sustained release
flurbiprofen
Prior art date
Legal status (The legal status 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 status listed.)
Pending
Application number
EP18916470.0A
Other languages
German (de)
French (fr)
Other versions
EP3727365A4 (en
Inventor
Ali TÜRKYILMAZ
Nur PEHLIVAN AKALIN
Kerim AKKAYA
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Sanovel Ilac Sanayi ve Ticaret AS
Original Assignee
Sanovel Ilac Sanayi ve Ticaret AS
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 Sanovel Ilac Sanayi ve Ticaret AS filed Critical Sanovel Ilac Sanayi ve Ticaret AS
Publication of EP3727365A2 publication Critical patent/EP3727365A2/en
Publication of EP3727365A4 publication Critical patent/EP3727365A4/en
Pending legal-status Critical Current

Links

Classifications

    • 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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5084—Mixtures of one or more drugs in different galenical forms, at least one of which being granules, microcapsules or (coated) microparticles according to A61K9/16 or A61K9/50, e.g. for obtaining a specific release pattern or for combining different drugs
    • 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 

Definitions

  • the present invention relates to pharmaceutical formulations of flurbiprofen or a pharmaceutically acceptable salt thereof comprising an immediate release phase and a sustained release phase.
  • Flurbiprofen is a propionic acid derivative which is an NSAID (non-steroidal anti inflammatory drug), having analgesic and anti-inflammatory activities. Its chemical structure is illustrated with Formula 1 given below.
  • Flurbiprofen is used for alleviating pain in muscle-skeleton system and joint disorders such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis, in soft tissue injuries such as sprains and strains, in postoperative cases, and in painful severe menstruation and migraine. It is in the market under the brandname of ANSAID ® in strength of 50, 100, 200 and 300 mg. It is recommended 2, 3 or 4 times a day dose.
  • the major adverse reactions with flurbiprofen are those affecting the gastrointestinal tract (GIT) including peptic and mucosal ulcer, dyspepsia, gastric bleeding resulting in treatment failures.
  • GIT gastrointestinal tract
  • Non-compliance of patients and its short half-life make it a strong candidate for sustained drug delivery.
  • the application WO 98/52545 relates to pharmaceutical compositions comprising a formulation of flurbiprofen with a therapeutically effective amount of one or more active ingredients selected from an antihistamine, a cough suppressant, a decongestant, an expectorant, a muscle relaxant, a centrally acting analgesic, a local anesthetic, an antibacterial compound, an antiviral compound, an antibiotic compound, an antifungal compound, minerals and vitamins and/or a burn-masking amount of an agent which has a warming effect on the mucosa of the throat.
  • active ingredients selected from an antihistamine, a cough suppressant, a decongestant, an expectorant, a muscle relaxant, a centrally acting analgesic, a local anesthetic, an antibacterial compound, an antiviral compound, an antibiotic compound, an antifungal compound, minerals and vitamins and/or a burn-masking amount of an agent which has a warming effect on the mucosa of the throat.
  • the patent US05807568 discloses a topically-administered formulation comprising flurbiprofen as the active agent.
  • the patent W09523596 discloses a flurbiprofen solution in a C2-4 alcohol.
  • EP2074990 discloses controlled release (CR) flurbiprofen and muscle relaxant combinations for oral administration.
  • flurbiprofen in treating local pains and inflammations may cause a problem especially for those who have gastrointestinal system disorders. Flurbiprofen leads to a complaint in the form of burning sensation in the gastrointestinal system. Preventing the systemic side effects of flurbiprofen is quite important in terms of patient compliance. Various coating processes have been performed to prevent such side effects. The coatings, however, may cause problems in terms of solubility and thus bioavailability. Enhancing the absorption rate both provides ease of application and increases the molecule's efficiency.
  • flurbiprofen Another problem in relation to flurbiprofen is that this molecule is poorly soluble in water. This, in turn, directly effects the bioavailability, and therefore the solubility and dissolution rate have to be increased.
  • the composition should also be very stable because an immediate release due to accidental damaging of capsule of a high dosage form may result in undesired high plasma concentrations, so-called dose dumping, which could cause undesired side effects.
  • the release rate and the release pattern of the active drug substance from the composition should not significantly change during the shelf-life of the composition. Even a minor change in the release rate and/or release pattern may have a significant impact on the in vivo performance of the composition
  • stability problems are frequently encountered in formulations developed with flurbiprofen under the influence of environmental and physical conditions. Flurbiprofen is an active agent that is highly-susceptible to air and humidity conditions. When flurbiprofen is initially exposed to air and humidity, it degrades structurally and develops chemical behavioral changes.
  • the first problem is that the stability of the products developed is not at a desired level and the shelf life thereof is shortened.
  • flurbiprofen may react with the excipients employed in developing those formulations containing the same. This, in turn, causes impurities and unwanted components to be included into the formulation. Thus, it is important to choose excipients and use them in specific amounts that sustain the stability.
  • Flurbiprofen is presented in many capsule and tablet formulations. This active pharmaceutical agent used for treating many diseases, is preferred in pharmaceutical compositions with sustained or immediate release form. Flowever, although there are sustained release compositions of flurbiprofen in the market, none of them have sustained and immediate release phases in one dosage form.
  • modified release formulation of flurbiprofen in a suitable pharmaceutical dosage formulation is needed.
  • a novelty is required in the art of formulations having anti-inflammatory, analgesic, and antipyretic activities due to the aforesaid drawbacks.
  • a formulation has been developed as to combine an immediate release phase and sustained release for flurbiprofen.
  • An object of this present invention is to provide a pharmaceutical formulation making the plasma concentration level stable by maintaining release of flurbiprofen in the blood stream for a longer time period sufficient to justify once daily dosing and thus increases patient compliance.
  • Another object of the present invention is to provide a pharmaceutical formulation maintaining the therapeutic effect due to the sustained release of flurbiprofen over extended period of time that increases patient compliance.
  • An object of this present invention is to provide a pharmaceutical formulation of flurbiprofen or a pharmaceutically acceptable salt thereof comprises an immediate release phase and a sustained release phase.
  • an object of the present invention is to obtain at least one stable formulation with anti-inflammatory, analgesic, and antipyretic activities.
  • Another object of the present invention is to provide a formulation having a desired solubility and dissolution rate, and therefore a desired level of bioavailability, with this formulation comprising flurbiprofen.
  • Another object of the present invention is to obtain a uniform formulation content.
  • a further object of the present invention is to develop a formulation not leading to flowability problems during production.
  • Another object of the present invention is to provide a high disintegration rate for said formulation.
  • the present invention provides flurbiprofen formulations, eliminating all problems referred to above and bringing additional advantages to the relevant prior art.
  • the present invention relates to a pharmaceutical formulation of flurbiprofen or a pharmaceutically acceptable salt thereof comprising an immediate release phase and a sustained release phase that provides such therapeutic relief by releasing flurbiprofen in such a manner that dose dumping is prevented and requisite blood levels are maintained for an extended time period sufficient to justify once daily dosing and thus increase patient compliance.
  • compositions of flurbiprofen or a pharmaceutically acceptable salt thereof comprise an immediate release phase and a sustained release phase, wherein the sustained release phase is in the form of pellets.
  • the sustained release phase is in the form of pellets
  • the release profile of flurbiprofen is almost stable.
  • Selection of pellets as the sustained release phase dosage form enables the sustained release pharmaceutical formulation of flurbiprofen of the present invention to be more advantageous over the prior art and to be successful in achieving the desired release profile of flurbiprofen.
  • the immediate release phase is in the form of powder, tablet, capsule, granule, bead or pellet.
  • the immediate release phase in the form of powder.
  • the pharmaceutical formulation is in the form of capsule.
  • Enclosing the medication within capsule shells provides a tasteless, odourless means of administering medication. Capsules ease to swallow due to the fact that it is smooth, slippery. Combining immediate and sustained release phases in a capsule dosage form increases patient compliance and also prevents the systemic side effects of flurbiprofen without the need for coating process. The coatings in priort art may cause problems in terms of solubility and thus bioavailability.
  • sustained release phase refers to any pharmaceutical formulation that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Sustained release phase is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period.
  • immediate release phase refers to any pharmaceutical formulations that disintegrate rapidly after administration with enhanced rate of dissolution and get dissolved to release the medicaments.
  • the amount of flurbiprofen in the immediate release is between 30.00% and 70.00%, preferably between 40.00% and 60.00%, more preferably between 45.00% and 55.00% by weight of the immediate release phase.
  • the amount of flurbiprofen in the sustained release phase is between 30.00% and 90.00%, preferably between 40.00% and 80.00%, more preferably between 55.00% and 70.00% by weight of the sustained release phase.
  • the ratios of the active agent used in this present invention ensure the required effective doses for the treatment and desired release profiles, which are immediate release and sustained release, for flurbiprofen.
  • the sustained release phase comprises at least one rate controlling polymer which is selected from the group comprises ammonioalkyl methacrylate copolymer dispersion type A, ammonioalkyl methacrylate copolymer dispersion type B polyvinylpyrrolidone, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, dextrin, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, xanthan gum; acrylic acid, carbopol agar, guar gum, psyllium seed gum, gellan gum, ean gum, tara gum, tamarind gum, gum arabic, methylcellulose, chitosan; glycerol, propylene glycol, macrogols, phthalate esters, dibutyl sebacetate, castor oil, acet
  • the sustained release phase comprises at least one rate controlling polymer which is selected from ammonioalkyl methacrylate copolymer dispersion type A, ammonioalkyl methacrylate copolymer dispersion type B or mixtures thereof.
  • the sustained release phase comprises ammonioalkyl methacrylate copolymer dispersion type A and ammonioalkyl methacrylate copolymer dispersion type B as rate controlling polymers.
  • total amount of rate controlling polymers in the sustained release phase is between 1.00% and 40.00%, preferably between 5.00% and 30.00%, more preferably between 10.00% and 20.00% by weight of the sustained release phase.
  • rate controlling polymer refers to an excipient in the final dosage form whose primary function is to modify the duration of release of the active drug substance from the dosage form. Selection of the rate controlling polymers is an important factor for providing an efficient and desired release kinetic. When the rate controlling polymers are used in speceific amounts, the release of flurbiprofen is maintained over a more extended period of time.
  • flurbiprofen or a pharmaceutically acceptable salt thereof is present in an amount of between 10 mg and 300 mg in the formulation.
  • the pharmaceutical formulation releases immediately flurbiprofen to provide sufficient blood concentration in a short time for starting therapeutic effect by means of immediate release phase and it provides release of flurbiprofen for a long duration by means of sustained release phase to maintain required effective blood concentration for the therapeutic effect. Therefore, the sustained release pharmaceutical formulation makes the plasma concentration level stable by maintaining release of flurbiprofen in the blood stream for a longer time period sufficient to justify once daily dosing and this increases patient compliance. Also, reduction of a dose regimen enables fluctuations of the active ingredient concentration in the blood plasma to be prevented.
  • Immediate release phase of said formulation provides rapid release of flurbiprofen after administration to provide sufficient blood concentration in a short time for starting therapeutic effect.
  • Sustained release of flurbiprofen is achieved by the sustained release phase of said formulation to make the plasma concentration level stable by maintaining flurbiprofen in the blood stream for a longer time. Therefore, the release profile of flurbiprofen in sustained release phase is very important to maintain the therapeutic effect.
  • At least one pharmaceutically acceptable excipient which is selected from a group comprising binders, disintegrants, fillers, plasticizers, adsorbents, lubricants and glidants or mixtures thereof.
  • the binder is selected from the group comprising hydroxypropyl cellulose, polyethylene oxide, microcrystalline cellulose (PH 101 , PH 102), polyvinylpyrrolidone, crospovidon, sugars, glycose syrups, natural gums, guar gum, gelatins, pullulan, agar, alginate, sodium alginates, K-Carrageenan, glycyrrhizin, polymetacrylates, collagen, agar, hyaluronic acid, pectin, tragachanti gum, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate and their copolymers, hydroxypropyl methyl cellulose, carboxy methyl cellulose, methyl cellulose, polyvinylalcohol, carrageenan, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers
  • the binder in the immediate release phase is hydroxypropyl cellulose.
  • the amount of binder is between 0.50% and 20.00%, preferably between 1.00% and 15.00%, more preferably between 1 .00% and 10.00% by weight of the immediate release phase.
  • Suitable diluents are selected from the group comprising microcrystalline cellulose, lactose, lactose monohydrate mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
  • the diluent in the sustained release phase is microcrystalline cellulose.
  • the amount of diluent in the sustained release phase is between 10.00% and 40.00%, preferably between 10.00% and 30.00%, more preferably between 15.00% and 25.00% by weight of the sustained release phase.
  • neutral microcrystalline cellulose pellets are used as the diluent in the sustained release phase. Selection of microcrystalline cellulose pellets as the diluent helps to improve the stability of the formulation.
  • the neutral microcrystalline cellulose pellets are coated with a suspension to obtain a sustained release phase in the form of pellets.
  • Coated neutral pellets are obtained by spraying a suspension comprising flurbiprofen into them in a fluid bed dryer.
  • flurbiprofen in the sustained release phase is in a micronized form.
  • the dissolution rate is enhanced by using micronized flurbiprofen.
  • a further advantage of using micronized flurbiprofen is homogeneity of the coating of neutral pellets used herein.
  • the diluent in the immediate release phase is selected from lactose, microcrystalline cellulose or mixtures thereof.
  • the immediate release phase comprises two diluents which are microcrystalline cellulose and lactose.
  • the amount of diluents in the immediate release phase is between 10.00% and 75.00%, preferably between 20.00% and 55.00%, more preferably between 30.00% and 45.00% by weight of the immediate release phase.
  • Suitable disintegrants are selected from the group selected from the group comprising croscarmellose sodium, polyethylene oxide, sodium starch glycolate, microcrystalline cellulose, sodium carboxymethyl starch, soy polysaccharide, cross-linked alginic acid, crospovidone, copovidone, gellan gum, xanthan gum, calcium silicate or ion exchange resins or mixtures thereof.
  • the disintegrant in the immediate release phase is croscarmellose sodium.
  • the amount of the disintegrant in the immediate release phase is between 0.50% and 20.00%, preferably between 1 .00% and 15.00%, more preferably between 1 .00% and 10.00% by weight of the immediate release phase.
  • Suitable plasticizers are selected from a group comprising triethyl citrate, diethyl phthalate, polyethylene glycol, medium chain glycerides, triacetin, acetyltributyl citrate, acetyltriethyl citrate, alpha tocopherol, chlorobutanol, dibutyl sebacate, tributyl citrate or mixtures thereof.
  • the plasticizer in the sustained release phase is triethyl citrate.
  • the amount of plasticizer is between 0.10% and 10.00%, preferably between 0.50% and 7.50%, more preferably between 1.00% and 5.00% by weight of the sustained release phase.
  • Suitable lubricants are selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin or mixtures thereof.
  • the lubricant in the immediate release phase is magnesium stearate.
  • the amount of lubricant is between 0.10% and 10.00%, preferably between 0.10% and 5.00%, more preferably between 0.50% and 1 .00% by weight of the immediate release phase.
  • Suitable glidants are selected from colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.
  • the glidant in the immediate release phase is colloidal silicon dioxide.
  • the amount of glidant is between 0.10% and 10.00%, preferably between 0.10% and 5.00%, more preferably between 0.50% and 1.00% by weight of the immediate release phase.
  • Suitable adsorbents are selected from the group comprising silicon dioxide, talc or mixtures thereof.
  • the adsorbent is silicon dioxide.
  • the amount of the adsorbent is between 0.10% and 10.00%, preferably between 0.20% and 1 .00% by weight of the sustained release phase.
  • the sustained release phase in the form of pellets comprises micronized flurbiprofen as active agent, microcrystalline cellulose as diluent, triethyl citrate as plasticizer, ammonioalkyl methacrylate copolymer dispersion type A and ammonioalkyl methacrylate copolymer dispersion type B as rate controlling polymers, silicon dioxide as adsorbent.
  • the immediate release phase in the form of powder comprises flurbiprofen as active agent, lactose and microcrystalline cellulose as diluent, croscarmellose sodium as disintegrant, hydroxypropyl cellulose as binder, colloidal silicon dioxide as glidant and magnesium stearate as lubricant.
  • the sustained release phase of the formulation comprises;
  • microcrystalline cellulose 10.00% to 40.00%
  • ammonioalkyl methacrylate copolymer dispersion type A 0.50% to 20.00%
  • ammonioalkyl methacrylate copolymer dispersion type B 0.50% to 20.00%
  • silicon dioxide 0.10% to 10.00%
  • the immediate release phase of the formulation comprises;
  • microcrystalline cellulose 15.00% to 50.00%
  • Neutral pellets comprise microcrystalline cellulose.
  • Neutral pellets comprise microcrystalline cellulose.
  • the pharmaceutical formulations mentioned above are prepared by following these steps:
  • ammonioalkyl methacrylate copolymer dispersion type B to the suspension and mixing for 2-3 hours

Abstract

The present invention relates to pharmaceutical formulations of flurbiprofen or a pharmaceutically acceptable salt thereof comprising an immediate release phase and a sustained release phase.

Description

MODIFIED RELEASE FORMULATIONS OF FLURBIPROFEN
Field of Invention
The present invention relates to pharmaceutical formulations of flurbiprofen or a pharmaceutically acceptable salt thereof comprising an immediate release phase and a sustained release phase.
Background of Invention
Flurbiprofen is a propionic acid derivative which is an NSAID (non-steroidal anti inflammatory drug), having analgesic and anti-inflammatory activities. Its chemical structure is illustrated with Formula 1 given below.
Formula 1
Flurbiprofen is used for alleviating pain in muscle-skeleton system and joint disorders such as ankylosing spondylitis, osteoarthritis, and rheumatoid arthritis, in soft tissue injuries such as sprains and strains, in postoperative cases, and in painful severe menstruation and migraine. It is in the market under the brandname of ANSAID® in strength of 50, 100, 200 and 300 mg. It is recommended 2, 3 or 4 times a day dose.
The major adverse reactions with flurbiprofen are those affecting the gastrointestinal tract (GIT) including peptic and mucosal ulcer, dyspepsia, gastric bleeding resulting in treatment failures. Non-compliance of patients and its short half-life make it a strong candidate for sustained drug delivery. The application WO 98/52545 relates to pharmaceutical compositions comprising a formulation of flurbiprofen with a therapeutically effective amount of one or more active ingredients selected from an antihistamine, a cough suppressant, a decongestant, an expectorant, a muscle relaxant, a centrally acting analgesic, a local anesthetic, an antibacterial compound, an antiviral compound, an antibiotic compound, an antifungal compound, minerals and vitamins and/or a burn-masking amount of an agent which has a warming effect on the mucosa of the throat.
The patent US05807568 discloses a topically-administered formulation comprising flurbiprofen as the active agent.
The patent W09523596 discloses a flurbiprofen solution in a C2-4 alcohol.
EP2074990 discloses controlled release (CR) flurbiprofen and muscle relaxant combinations for oral administration.
The use of flurbiprofen in treating local pains and inflammations may cause a problem especially for those who have gastrointestinal system disorders. Flurbiprofen leads to a complaint in the form of burning sensation in the gastrointestinal system. Preventing the systemic side effects of flurbiprofen is quite important in terms of patient compliance. Various coating processes have been performed to prevent such side effects. The coatings, however, may cause problems in terms of solubility and thus bioavailability. Enhancing the absorption rate both provides ease of application and increases the molecule's efficiency.
Another problem in relation to flurbiprofen is that this molecule is poorly soluble in water. This, in turn, directly effects the bioavailability, and therefore the solubility and dissolution rate have to be increased.
The composition should also be very stable because an immediate release due to accidental damaging of capsule of a high dosage form may result in undesired high plasma concentrations, so-called dose dumping, which could cause undesired side effects. The release rate and the release pattern of the active drug substance from the composition should not significantly change during the shelf-life of the composition. Even a minor change in the release rate and/or release pattern may have a significant impact on the in vivo performance of the composition Furthermore, stability problems are frequently encountered in formulations developed with flurbiprofen under the influence of environmental and physical conditions. Flurbiprofen is an active agent that is highly-susceptible to air and humidity conditions. When flurbiprofen is initially exposed to air and humidity, it degrades structurally and develops chemical behavioral changes. As a result of this, two main problems emerge. The first problem is that the stability of the products developed is not at a desired level and the shelf life thereof is shortened. Secondly, flurbiprofen may react with the excipients employed in developing those formulations containing the same. This, in turn, causes impurities and unwanted components to be included into the formulation. Thus, it is important to choose excipients and use them in specific amounts that sustain the stability.
Flurbiprofen is presented in many capsule and tablet formulations. This active pharmaceutical agent used for treating many diseases, is preferred in pharmaceutical compositions with sustained or immediate release form. Flowever, although there are sustained release compositions of flurbiprofen in the market, none of them have sustained and immediate release phases in one dosage form.
Considering all these, modified release formulation of flurbiprofen in a suitable pharmaceutical dosage formulation is needed. In result, a novelty is required in the art of formulations having anti-inflammatory, analgesic, and antipyretic activities due to the aforesaid drawbacks. In this present invention, a formulation has been developed as to combine an immediate release phase and sustained release for flurbiprofen.
Description of Invention
An object of this present invention is to provide a pharmaceutical formulation making the plasma concentration level stable by maintaining release of flurbiprofen in the blood stream for a longer time period sufficient to justify once daily dosing and thus increases patient compliance.
Another object of the present invention is to provide a pharmaceutical formulation maintaining the therapeutic effect due to the sustained release of flurbiprofen over extended period of time that increases patient compliance. An object of this present invention is to provide a pharmaceutical formulation of flurbiprofen or a pharmaceutically acceptable salt thereof comprises an immediate release phase and a sustained release phase.
Accordingly, an object of the present invention is to obtain at least one stable formulation with anti-inflammatory, analgesic, and antipyretic activities.
Another object of the present invention is to provide a formulation having a desired solubility and dissolution rate, and therefore a desired level of bioavailability, with this formulation comprising flurbiprofen.
Another object of the present invention is to obtain a uniform formulation content.
A further object of the present invention is to develop a formulation not leading to flowability problems during production.
Another object of the present invention is to provide a high disintegration rate for said formulation.
The present invention provides flurbiprofen formulations, eliminating all problems referred to above and bringing additional advantages to the relevant prior art.
The present invention relates to a pharmaceutical formulation of flurbiprofen or a pharmaceutically acceptable salt thereof comprising an immediate release phase and a sustained release phase that provides such therapeutic relief by releasing flurbiprofen in such a manner that dose dumping is prevented and requisite blood levels are maintained for an extended time period sufficient to justify once daily dosing and thus increase patient compliance.
In this invention, pharmaceutical formulations of flurbiprofen or a pharmaceutically acceptable salt thereof comprise an immediate release phase and a sustained release phase, wherein the sustained release phase is in the form of pellets.
Surprisingly, it has been found that when the sustained release phase is in the form of pellets, the release profile of flurbiprofen is almost stable. Selection of pellets as the sustained release phase dosage form enables the sustained release pharmaceutical formulation of flurbiprofen of the present invention to be more advantageous over the prior art and to be successful in achieving the desired release profile of flurbiprofen.
In one embodiment, the immediate release phase is in the form of powder, tablet, capsule, granule, bead or pellet.
In one preferred embodiment, the immediate release phase in the form of powder.
In one embodiment, the pharmaceutical formulation is in the form of capsule.
Enclosing the medication within capsule shells provides a tasteless, odourless means of administering medication. Capsules ease to swallow due to the fact that it is smooth, slippery. Combining immediate and sustained release phases in a capsule dosage form increases patient compliance and also prevents the systemic side effects of flurbiprofen without the need for coating process. The coatings in priort art may cause problems in terms of solubility and thus bioavailability.
The term“sustained release phase” refers to any pharmaceutical formulation that maintain constant levels of a drug in the patient's bloodstream by releasing the drug over an extended period of time. Sustained release phase is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period.
The term “immediate release phase” refers to any pharmaceutical formulations that disintegrate rapidly after administration with enhanced rate of dissolution and get dissolved to release the medicaments.
In one embodiment, the amount of flurbiprofen in the immediate release is between 30.00% and 70.00%, preferably between 40.00% and 60.00%, more preferably between 45.00% and 55.00% by weight of the immediate release phase.
In one embodiment, the amount of flurbiprofen in the sustained release phase is between 30.00% and 90.00%, preferably between 40.00% and 80.00%, more preferably between 55.00% and 70.00% by weight of the sustained release phase. According to one embodiment, the ratios of the active agent used in this present invention ensure the required effective doses for the treatment and desired release profiles, which are immediate release and sustained release, for flurbiprofen.
In one embodiment, the sustained release phase comprises at least one rate controlling polymer which is selected from the group comprises ammonioalkyl methacrylate copolymer dispersion type A, ammonioalkyl methacrylate copolymer dispersion type B polyvinylpyrrolidone, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, dextrin, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, xanthan gum; acrylic acid, carbopol agar, guar gum, psyllium seed gum, gellan gum, ean gum, tara gum, tamarind gum, gum arabic, methylcellulose, chitosan; glycerol, propylene glycol, macrogols, phthalate esters, dibutyl sebacetate, castor oil, acetylated monoglycerides, fractionated coconut oil, hydrogenated vegetable oil, hydrogenated castor oil, carnauba wax, candellia wax, beeswax, paraffin wax, glyceryl behenate or a mixtures thereof.
In one preferred embodiment, the sustained release phase comprises at least one rate controlling polymer which is selected from ammonioalkyl methacrylate copolymer dispersion type A, ammonioalkyl methacrylate copolymer dispersion type B or mixtures thereof.
In one embodiment, the sustained release phase comprises ammonioalkyl methacrylate copolymer dispersion type A and ammonioalkyl methacrylate copolymer dispersion type B as rate controlling polymers.
According to this embodiment, total amount of rate controlling polymers in the sustained release phase is between 1.00% and 40.00%, preferably between 5.00% and 30.00%, more preferably between 10.00% and 20.00% by weight of the sustained release phase.
The term“rate controlling polymer” refers to an excipient in the final dosage form whose primary function is to modify the duration of release of the active drug substance from the dosage form. Selection of the rate controlling polymers is an important factor for providing an efficient and desired release kinetic. When the rate controlling polymers are used in speceific amounts, the release of flurbiprofen is maintained over a more extended period of time.
According to one embodiment, flurbiprofen or a pharmaceutically acceptable salt thereof is present in an amount of between 10 mg and 300 mg in the formulation.
According to the present invention, the pharmaceutical formulation releases immediately flurbiprofen to provide sufficient blood concentration in a short time for starting therapeutic effect by means of immediate release phase and it provides release of flurbiprofen for a long duration by means of sustained release phase to maintain required effective blood concentration for the therapeutic effect. Therefore, the sustained release pharmaceutical formulation makes the plasma concentration level stable by maintaining release of flurbiprofen in the blood stream for a longer time period sufficient to justify once daily dosing and this increases patient compliance. Also, reduction of a dose regimen enables fluctuations of the active ingredient concentration in the blood plasma to be prevented.
Immediate release phase of said formulation provides rapid release of flurbiprofen after administration to provide sufficient blood concentration in a short time for starting therapeutic effect. Sustained release of flurbiprofen is achieved by the sustained release phase of said formulation to make the plasma concentration level stable by maintaining flurbiprofen in the blood stream for a longer time. Therefore, the release profile of flurbiprofen in sustained release phase is very important to maintain the therapeutic effect.
According to one embodiment, further comprises at least one pharmaceutically acceptable excipient which is selected from a group comprising binders, disintegrants, fillers, plasticizers, adsorbents, lubricants and glidants or mixtures thereof.
Therefore, it is important to choose excipients and use them in specific amounts that sustain the stability.
In one embodiment, the binder is selected from the group comprising hydroxypropyl cellulose, polyethylene oxide, microcrystalline cellulose (PH 101 , PH 102), polyvinylpyrrolidone, crospovidon, sugars, glycose syrups, natural gums, guar gum, gelatins, pullulan, agar, alginate, sodium alginates, K-Carrageenan, glycyrrhizin, polymetacrylates, collagen, agar, hyaluronic acid, pectin, tragachanti gum, carboxymethyl cellulose, polyethylene glycol, polyvinyl alcohol, polyvinyl acetate and their copolymers, hydroxypropyl methyl cellulose, carboxy methyl cellulose, methyl cellulose, polyvinylalcohol, carrageenan, carbomer, poloxamer, polyacrylamide, aluminum hydroxide, benthonite, laponite, setostearyl alcohol, polyoxyethylene-alkyl ethers, acacia mucilage, polydextrose, xylitol, sucrose stearate or mixtures thereof.
In one preferred embodiment, the binder in the immediate release phase is hydroxypropyl cellulose.
In one embodiment, the amount of binder is between 0.50% and 20.00%, preferably between 1.00% and 15.00%, more preferably between 1 .00% and 10.00% by weight of the immediate release phase.
Suitable diluents are selected from the group comprising microcrystalline cellulose, lactose, lactose monohydrate mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
In one preferred embodiment, the diluent in the sustained release phase is microcrystalline cellulose.
According to these embodiments, the amount of diluent in the sustained release phase is between 10.00% and 40.00%, preferably between 10.00% and 30.00%, more preferably between 15.00% and 25.00% by weight of the sustained release phase.
In one preferred embodiment, neutral microcrystalline cellulose pellets are used as the diluent in the sustained release phase. Selection of microcrystalline cellulose pellets as the diluent helps to improve the stability of the formulation.
According to one embodiment, the neutral microcrystalline cellulose pellets are coated with a suspension to obtain a sustained release phase in the form of pellets. Coated neutral pellets are obtained by spraying a suspension comprising flurbiprofen into them in a fluid bed dryer. In one embodiment, flurbiprofen in the sustained release phase is in a micronized form. The dissolution rate is enhanced by using micronized flurbiprofen. A further advantage of using micronized flurbiprofen is homogeneity of the coating of neutral pellets used herein.
In one preferred embodiment, the diluent in the immediate release phase is selected from lactose, microcrystalline cellulose or mixtures thereof.
In one preferred embodiment, the immediate release phase comprises two diluents which are microcrystalline cellulose and lactose.
According to these embodiments, the amount of diluents in the immediate release phase is between 10.00% and 75.00%, preferably between 20.00% and 55.00%, more preferably between 30.00% and 45.00% by weight of the immediate release phase.
Suitable disintegrants are selected from the group selected from the group comprising croscarmellose sodium, polyethylene oxide, sodium starch glycolate, microcrystalline cellulose, sodium carboxymethyl starch, soy polysaccharide, cross-linked alginic acid, crospovidone, copovidone, gellan gum, xanthan gum, calcium silicate or ion exchange resins or mixtures thereof.
In one preferred embodiment, the disintegrant in the immediate release phase is croscarmellose sodium.
In one embodiment, the amount of the disintegrant in the immediate release phase is between 0.50% and 20.00%, preferably between 1 .00% and 15.00%, more preferably between 1 .00% and 10.00% by weight of the immediate release phase.
In the immediate release phase, high disintegration rate is ensured by the help using the disintegrants in the specific amounts.
Suitable plasticizers are selected from a group comprising triethyl citrate, diethyl phthalate, polyethylene glycol, medium chain glycerides, triacetin, acetyltributyl citrate, acetyltriethyl citrate, alpha tocopherol, chlorobutanol, dibutyl sebacate, tributyl citrate or mixtures thereof. In one preferred embodiment, the plasticizer in the sustained release phase is triethyl citrate.
In one embodiment, the amount of plasticizer is between 0.10% and 10.00%, preferably between 0.50% and 7.50%, more preferably between 1.00% and 5.00% by weight of the sustained release phase.
Suitable lubricants are selected from magnesium stearate, sodium stearyl fumarate, polyethylene glycol, sodium lauryl sulphate, magnesium lauryl sulphate, fumaric acid, glyceryl palmitostearate, hydrogenated natural oils, zinc stearate, calcium stearate, silica, talc, stearic acid, polyethylene glycol, paraffin or mixtures thereof.
In one preferred embodiment, the lubricant in the immediate release phase is magnesium stearate.
In one preferred embodiment, the amount of lubricant is between 0.10% and 10.00%, preferably between 0.10% and 5.00%, more preferably between 0.50% and 1 .00% by weight of the immediate release phase.
Suitable glidants are selected from colloidal silicon dioxide, talc, aluminium silicate or mixtures thereof.
In one preferred embodiment, the glidant in the immediate release phase is colloidal silicon dioxide.
In one embodiment, the amount of glidant is between 0.10% and 10.00%, preferably between 0.10% and 5.00%, more preferably between 0.50% and 1.00% by weight of the immediate release phase.
Suitable adsorbents are selected from the group comprising silicon dioxide, talc or mixtures thereof.
In one preferred embodiment, the adsorbent is silicon dioxide.
According to these embodiments, the amount of the adsorbent is between 0.10% and 10.00%, preferably between 0.20% and 1 .00% by weight of the sustained release phase. In one embodiment, the sustained release phase in the form of pellets comprises micronized flurbiprofen as active agent, microcrystalline cellulose as diluent, triethyl citrate as plasticizer, ammonioalkyl methacrylate copolymer dispersion type A and ammonioalkyl methacrylate copolymer dispersion type B as rate controlling polymers, silicon dioxide as adsorbent. The immediate release phase in the form of powder comprises flurbiprofen as active agent, lactose and microcrystalline cellulose as diluent, croscarmellose sodium as disintegrant, hydroxypropyl cellulose as binder, colloidal silicon dioxide as glidant and magnesium stearate as lubricant.
In one embodiment, the sustained release phase of the formulation comprises;
a. flurbiprofen (micronized) 30.00% to 90.00%
b. microcrystalline cellulose 10.00% to 40.00%
c. triethyl citrate 0.10% to 10.00%
d. ammonioalkyl methacrylate copolymer dispersion, type A 0.50% to 20.00% e. ammonioalkyl methacrylate copolymer dispersion, type B 0.50% to 20.00% f. silicon dioxide 0.10% to 10.00%
by weight of the sustained release phase, and the immediate release phase of the formulation comprises;
g. flurbiprofen 30.00% to 70.00%
h. lactose 1.00% to 25.00%
i. microcrystalline cellulose 15.00% to 50.00%
j. croscarmellose sodium 0.50% to 20.00%
k. hydroxypropyl cellulose 0.50% to 20.00%
L. colloidal silicon dioxide 0.10% to 10.00%
m. magnesium stearate 0.10% to 10.00%
by weight of the immediate release phase
Example 1 :
Neutral pellets comprise microcrystalline cellulose. Example 2:
*Neutral pellets comprise microcrystalline cellulose. The pharmaceutical formulations mentioned above are prepared by following these steps:
I. Preparation of sustained release phase:
a. Mixing water, triethyl citrate and flurbiprofen to form a suspension
b. Adding ammonioalkyl methacrylate copolymer dispersion, type A and
ammonioalkyl methacrylate copolymer dispersion, type B to the suspension and mixing for 2-3 hours
c. Coating neutral pellets by spraying the prepared suspension into them in a fluid bed dryer
d. Stabilization of coated and dried pellets by adding silicon dioxide onto them e. Sieving the pellets
II. Preparation of immediate release phase:
a. Mixing flurbiprofen, lactose, 9/10 of microcrystalline cellulose and colloidal silicon dioxide for 10 minutes
b. Sieving this mixture
c. Adding hydroxypropyl cellulose, croscarmellose sodium, 1/10 of microcrystalline cellulose and mixing for 15 minutes
d. Adding magnesium stearate to the mixture and mixing for 3 minutes
III. Filling sustained release pellets and immediate release powders into capsules

Claims

1. A pharmaceutical formulation of flurbiprofen or a pharmaceutically acceptable salt thereof comprising an immediate release phase and a sustained release phase.
2. A pharmaceutical formulation according to claim 1 , wherein the sustained release phase is in the form of pellets.
3. The pharmaceutical formulation according to claim 1 , wherein the immediate release phase is in the form of powder, tablet, capsule, granule, bead or pellet.
4. The pharmaceutical formulation according to claim 3, wherein the immediate release phase in the form of powder.
5. The pharmaceutical formulation according to claim 4, wherein the amount of flurbiprofen in the immediate release phase is between 30.00% and 70.00% by weight of the immediate release phase.
6. The pharmaceutical formulation according to claim 2, wherein the amount of flurbiprofen in the sustained release phase is between 30.00% and 90.00% by weight of the sustained release phase.
7. The pharmaceutical formulation according to claim 1 , wherein the sustained release phase comprises at least one rate controlling polymer which is selected from the group comprises ammonioalkyl methacrylate copolymer dispersion type A, ammonioalkyl methacrylate copolymer dispersion type B polyvinylpyrrolidone, polyvinyl acetate, hydroxypropyl cellulose, hydroxypropyl methylcellulose, hydroxyethyl cellulose, hydroxymethyl cellulose, gelatin, polyethylene oxide, dextrin, polyhydroxyethylmethacrylate, sodium carboxymethylcellulose, carboxymethyl cellulose, sodium alginate, alginic acid, xanthan gum; acrylic acid, carbopol agar, guar gum, psyllium seed gum, gellan gum, ean gum, tara gum, tamarind gum, gum arabic, methylcellulose, chitosan; glycerol, propylene glycol, macrogols, phthalate esters, dibutyl sebacetate, castor oil, acetylated monoglycerides, fractionated coconut oil, hydrogenated vegetable oil, hydrogenated castor oil, carnauba wax, candellia wax, beeswax, paraffin wax, glyceryl behenate or a mixtures thereof.
8. The pharmaceutical formulation according to claim 7, wherein the sustained release phase comprises at least one rate controlling polymer which is selected from ammonioalkyl methacrylate copolymer dispersion type A, ammonioalkyl methacrylate copolymer dispersion type B or mixtures thereof.
9. The pharmaceutical formulation according to claim 7 or 8, wherein the total amount of rate controlling polymers in the sustained release phase is between 1 .00% and 40.00%, preferably between 5.00% and 30.00%, more preferably between 10.00% and 20.00% by weight of the sustained release phase.
10. The pharmaceutical formulation according to claim 1 , wherein the formulation further comprises at least one pharmaceutically acceptable excipient which is selected from a group comprising binders, disintegrants, fillers, plasticizers, adsorbents, lubricants and glidants or mixtures thereof.
1 1. The pharmaceutical formulation according to claim 10, wherein the diluent is selected from a group comprising microcrystalline cellulose, lactose, lactose monohydrate mannitol, spray-dried mannitol, starch, dextrose, sucrose, fructose, maltose, sorbitol, xylitol, inositol, kaolin, inorganic salts, calcium salts, polysaccharides, dicalcium phosphate, sodium chloride, dextrates, lactitol, maltodextrin, sucrose-maltodextrin mixture, trehalose, sodium carbonate, sodium bicarbonate, calcium carbonate or mixtures thereof.
12. The pharmaceutical formulation according to claim 1 1 , wherein the diluent in the sustained release phase is microcrystalline cellulose.
13. The pharmaceutical formulation according to claim 1 1 or 12, wherein the amount of the diluent in the sustained release phase is between 10.00% and 40.00%, preferably between 10.00% and 30.00%, more preferably between 15.00% and 25.00% by weight of the sustained release phase.
14. The pharmaceutical formulation according to claim 6, wherein said flurbiprofen is in a micronized form.
15. The pharmaceutical formulation according to claim 10, wherein the disintegrant is selected from a group comprising croscarmellose sodium, polyethylene oxide, sodium starch glycolate, microcrystalline cellulose, sodium carboxymethyl starch, soy polysaccharide, cross-linked alginic acid, crospovidone, copovidone, gellan gum, xanthan gum, calcium silicate or ion exchange resins or mixtures thereof.
16. The pharmaceutical formulation according to claim 15, wherein the the disintegrant in the immediate release phase is croscarmellose sodium.
17. The pharmaceutical formulation according to clam 16, wherein the amount of the disintegrant in the immediate release phase is between 0.50% and 20.00%, preferably between 1.00% and 15.00%, more preferably between 1.00% and 10.00% by weight of the immediate release phase.
18. The pharmaceutical formulation according to any of the preceding claims, comprising a. flurbiprofen 30.00% to 90.00%
b. microcrystalline cellulose 10.00% to 40.00%
c. triethyl citrate 0.10% to 10.00%
d. ammonioalkyl methacrylate copolymer dispersion, type A 0.50% to 20.00% e. ammonioalkyl methacrylate copolymer dispersion, type B 0.50% to 20.00% f. silicon dioxide 0.10% to 10.00%
in the sustained release phase, by weight of the sustained release phase, and g. flurbiprofen 30.00% to 70.00%
h. lactose 1.00% to 25.00%
i. microcrystalline cellulose 15.00% to 50.00%
j. croscarmellose sodium 0.50% to 20.00%
k. hydroxypropyl cellulose 0.50% to 20.00%
L. colloidal silicon dioxide 0.10% to 10.00%
m. magnesium stearate 0.10% to 10.00%
in the immediate release phase, by weight of the immediate release phase.
19. The pharmaceutical formulation according to any of the preceding claims, wherein the formulation is in the form of capsule.
EP18916470.0A 2017-12-21 2018-12-20 Modified release formulations of flurbiprofen Pending EP3727365A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2017/21036A TR201721036A2 (en) 2017-12-21 2017-12-21 MODULATED EMISSION FORMULATIONS OF FLURBIPROPHEN
PCT/TR2018/050846 WO2019209217A2 (en) 2017-12-21 2018-12-20 Modified release formulations of flurbiprofen

Publications (2)

Publication Number Publication Date
EP3727365A2 true EP3727365A2 (en) 2020-10-28
EP3727365A4 EP3727365A4 (en) 2021-06-16

Family

ID=67901210

Family Applications (1)

Application Number Title Priority Date Filing Date
EP18916470.0A Pending EP3727365A4 (en) 2017-12-21 2018-12-20 Modified release formulations of flurbiprofen

Country Status (3)

Country Link
EP (1) EP3727365A4 (en)
TR (1) TR201721036A2 (en)
WO (1) WO2019209217A2 (en)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023244502A1 (en) * 2022-06-13 2023-12-21 Soin Therapeutics Llc Methods of using low dose naltrexone to treat chronic pain

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE4140183C2 (en) * 1991-12-05 1995-12-21 Alfatec Pharma Gmbh Retard form for a medicine containing flurbiprofen
DE4140184C2 (en) * 1991-12-05 1995-12-21 Alfatec Pharma Gmbh Acute form for a medicine containing flurbiprofen
EP1064938A1 (en) * 1999-06-28 2001-01-03 Sanofi-Synthelabo Pharmaceutical dosage forms for controlled release producing at least a timed pulse
EP2190418B1 (en) * 2007-08-15 2013-10-02 Mcneil-PPC, Inc Immediate release and sustained release ibuprofen dosing regimen
CA2965237C (en) * 2014-10-21 2023-11-21 Reckitt Benckiser Llc Pharmaceutical capsule containing at least two tablets

Also Published As

Publication number Publication date
EP3727365A4 (en) 2021-06-16
WO2019209217A3 (en) 2020-01-23
TR201721036A2 (en) 2019-07-22
WO2019209217A2 (en) 2019-10-31

Similar Documents

Publication Publication Date Title
ES2606463T3 (en) Combination of levodopa / carbidopa immediate release and controlled release dosage forms
WO2011151708A1 (en) Gastroretentive dosage forms of gaba analogs
KR101156054B1 (en) A stable and control-released pharmaceutical composition comprising eperisone
EP2797584A2 (en) Combinations of diacerein and non-steroidal inflammation drugs
US7303761B2 (en) Stabilised pharmaceutical composition comprising an extended release non-steroidal anti-inflammatory agent and an immediate release prostaglandin
EP3013327A1 (en) Pharmaceutical capsule composite formulation comprising tadalafil and tamsulosin
KR20120033557A (en) Immediate-release and sustained-release pharmaceutical composition comprising levodropropizine
KR20190092805A (en) Pharmaceutical composition comprising Acetylsalicylic acid and Lansoprazole
JP2019532960A (en) Esomeprazole-containing composite capsule and method for producing the same
KR20160076928A (en) A pharmaceutical formulation in the form of mini-tablets containing a fumaric acid ester
EP3727365A2 (en) Modified release formulations of flurbiprofen
JP2010511023A (en) Memantine formulation
WO2013095319A2 (en) Formulations of flurbiprofen and diacerein
EP3238714A1 (en) Extended release formulations of flurbiprofen and tramadol
EP2809305B1 (en) Bilayer tablet formulations of flurbiprofen and glucosamin
KR20160105662A (en) Pharmaceutical composition comprising eperison and pelubiprofen
EP2277511B1 (en) Extended release pharmaceutical compositions of levetiracetam
EP2793856B1 (en) Orally-disintegrating formulations of flurbiprofen
WO2016130094A1 (en) A pharmaceutical composition containing ibuprofen, pseudoephedrine and vitamin c
WO2019212426A2 (en) Delayed release dexketoprofen composition
KR20090107960A (en) Pharmaceutical formulation for treating cardiovascular disease
JP6855387B2 (en) Compression molding formulation
WO2014167439A1 (en) Modified release pharmaceutical compositions of topiramate or salts thereof
EP2797583B1 (en) Combined pharmaceutical formulation containing diacerein
EP2793855A1 (en) Flurbiprofen formulations

Legal Events

Date Code Title Description
STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: THE INTERNATIONAL PUBLICATION HAS BEEN MADE

PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: REQUEST FOR EXAMINATION WAS MADE

17P Request for examination filed

Effective date: 20200718

AK Designated contracting states

Kind code of ref document: A2

Designated state(s): AL AT BE BG CH CY CZ DE DK EE ES FI FR GB GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR

AX Request for extension of the european patent

Extension state: BA ME

DAV Request for validation of the european patent (deleted)
DAX Request for extension of the european patent (deleted)
A4 Supplementary search report drawn up and despatched

Effective date: 20210514

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 31/192 20060101AFI20210508BHEP

Ipc: A61K 9/48 20060101ALI20210508BHEP

Ipc: A61K 9/50 20060101ALI20210508BHEP

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: EXAMINATION IS IN PROGRESS

17Q First examination report despatched

Effective date: 20230629

P01 Opt-out of the competence of the unified patent court (upc) registered

Effective date: 20230708