EP4061370A1 - A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof - Google Patents

A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof

Info

Publication number
EP4061370A1
EP4061370A1 EP20889321.4A EP20889321A EP4061370A1 EP 4061370 A1 EP4061370 A1 EP 4061370A1 EP 20889321 A EP20889321 A EP 20889321A EP 4061370 A1 EP4061370 A1 EP 4061370A1
Authority
EP
European Patent Office
Prior art keywords
pellet
composition according
propiverine
pellet composition
acid
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
EP20889321.4A
Other languages
German (de)
French (fr)
Other versions
EP4061370A4 (en
Inventor
Fatih Sunel
Ediz Yildirim
Gulcin TOK
Bulent DEMIR
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 EP4061370A1 publication Critical patent/EP4061370A1/en
Publication of EP4061370A4 publication Critical patent/EP4061370A4/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
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2072—Pills, tablets, discs, rods characterised by shape, structure or size; Tablets with holes, special break lines or identification marks; Partially coated tablets; Disintegrating flat shaped forms
    • A61K9/2077—Tablets comprising drug-containing microparticles in a substantial amount of supporting matrix; Multiparticulate tablets
    • 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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • 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
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1652—Polysaccharides, e.g. alginate, cellulose derivatives; Cyclodextrin

Definitions

  • the present invention relates to a pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof for oral administration which is formulated as modified release.
  • Overactive bladder (OAB) and the related condition of urge urinary incontinence represent the other major disorder of the storage function. They are characterized by a frequent need to void (frequency), with an intense urge to do so (urgency) and a need to void during the night (nocturia). Contrary to stress urinary incontinence, OAB and urge incontinence are not associated with urethral sphincter control but rather involves disturbances in bladder functions and the regulation thereof.
  • antimuscarinic agents which exert their effects at muscarinic receptors and suppress or diminish the intensity of involuntary detrusor muscle contractions, are the first-choice pharmacotherapy for OAB, and may be the only therapy available whose efficacy is not in question.
  • Propiverine hydrochloride is an extensively studied antimuscarinic and calcium channel blocker agent.
  • Propiverine is one of the most frequently prescribed antimuscarinic drugs used for the treatment of overactive bladder and urinary incontinence.
  • the chemical name of propiverine is (l-methyl-4-piperidyl diphenylpropoxyacetate) and it is a benzylic acid derivative as shown in Formula I.
  • Formula I Propiverine is a BCS (Biopharmaceutical Classification System) Class III drug, which exhibits low permeability and high solubility.
  • typical anticholinergic side effects like and accommodation disorders have to be accepted with a rapid increase in the blood level. Therefore, these side effects limit the amount of the possible unit dose of non-modified, rapidly releasing dosage forms to 10-20 mg.
  • Propiverine in the form of its hydrochloride salt is currently marketed under the trade names Mictonorm® / Detrunorm®/ Proprinorm® by Apogepha Arzneistoff GmbH in two different dosage forms as immediate -release (IR) and modified-release (MR).
  • IR immediate -release
  • MR modified-release
  • TR 2012/11270 patent application discloses an oral pharmaceutical composition comprising propiverine or a pharmaceutically acceptable salt thereof as an anticholinergic active agent.
  • composition comprising propiverine or a pharmaceutically acceptable salt thereof which overcomes the above described problems in the prior art and has additive advantages over them.
  • the main object of the present invention is to provide a composition comprising propiverine or a pharmaceutically acceptable salt thereof having high stability by the help of using a pellet composition.
  • modified release 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. Modified release is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period.
  • propiverine or a pharmaceutically acceptable salt thereof are thus not suitable for the realization of a modified release formulation.
  • propiverine or a pharmaceutically acceptable salt thereof especially propiverine hydrochloride, is sensitive to environmental conditions and excipients used. Therefore, the steps and polymers employed to make modified-release are important in the present invention.
  • Pellets can be blended to deliver incompatible active agents.
  • the reproducibility of the pellet formulations is also much better than the reproducibility of the single-unit dosage forms. They are suitable systems for film coating with respect to the low surface area-volume ratios.
  • one of the advantageous properties of the pellet formulations is being good resistance to external factors such as moisture, air and light.
  • pellets have excellent flow properties. Considering all these advantages, the pellet form is best for use in propiverine-containing formulation.
  • a pellet composition comprises propiverine or a pharmaceutically acceptable salt thereof, wherein the pellet composition is formulated as modified release.
  • propiverine or a pharmaceutically acceptable salt thereof is propiverine hydrochloride.
  • the amount of propiverine hydrochloride is present between 5.0% and 40.0%, 7.0% and 35.0%, 10.0% and 30.0%, 11.0% and 25.0%, 12.0% and 20.0%, 12.0% and 18.0% by weight of the pellet.
  • propiverine hydrochloride is also present outside the pellet.
  • the amount of propiverine hydrochloride is present between 1.0% and 30.0%, 1.0% and 25.0%, 1.0% and 20.0%, 1.0% and 15.0%, 1 .0% and 10.0%, 1.0% and 6.0% by weight of the total composition.
  • the pellets further comprises at least one release modifying agent.
  • Suitable release modifying agent is selected from the group comprising poly(methacrylic acid-co-methylmethacrylate), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), ethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly(methacrylic acid-co- ethylacrylate), polyvinylchloride, polyvinyl acetate phthalate, poly(vinylpyrrolidone-co- vinylacetate), silicone elastomers, shellac, zein, rosin esters or mixtures thereof.
  • the amount of the release modifying agent is between 1.0% and 25.0%, 2.0% and 20.0%, 3.0% and 15.0%, 5.0% and 10.0% by weight of the pellet.
  • the amount of the release modifying agent is between 0.5% and 10.0%, 1.0% and 8.0%, 1.0% and 6.0%, 1.0% and 4.0% by weight of the total composition.
  • the release modifying agent is poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100) or poly(methacrylic acid-co- methylmethacrylate) 1 :1 (Eudragit L 100) or poly(methyl acrylate-co-methyl methacrylate-co- methacrylic acid) 7:3:1 (Eudragit FS 30 D) , they can be used together or separately.
  • the optimum amounts of the excipients for example the composition of the corresponding mixtures depend on several factors, like for example the desired retarding effect, the kind of the release modifying agent having their specific solubility and permeability, and the ratio of acidic substance to active agent propiverine. These parameters vary completely independently from each other and are of essential importance for the controlled and long- lasting, modified release of the propiverine.
  • the preferred dosage forms are tablets or capsules filled with pellets as these are more convenient and easier to administer.
  • the form of the composition is a tablet.
  • Pellet is located within a tablet.
  • the tablet further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, pH adjusters, binders, disintegrants, plasticizers, lubricants, glidants, suspending agents, permeability enhancing agents or mixtures thereof.
  • Suitable fillers are selected from the group comprising neutral microcrystalline cellulose pellets, lactose, microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, isomalt, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, tragacanth, trehalose, polysorbate 80, xylitol or mixtures thereof.
  • the amount of the fillers is between 5.0% and 35.0%, 7.0% and 30.0%, 9.0% and 25.0%, 10.0% and 20.0% by weight of the pellet.
  • the amount of the fillers is between 50.0% and 87.0%, 55.0% and 84.0%, 60.0% and 80.0%, 65.0% and 75.0% by weight of the total composition.
  • the filler is neutral microcrystalline cellulose pellets or lactose or microcrystalline cellulose or mixtures thereof.
  • fillers should be as inert as possible to prevent them from interacting with propiverine hydrochloride, they should serve only as a carrier to enable propiverine hydrochloride.
  • neutral microcrystalline cellulose pellets support the formulation, such as by improving propiverine hydrochloride solubility, improving dissolution and enhancing stability. So, neutral microcrystalline cellulose pellets are used in pellets as fillers.
  • compositions comprise at least one pharmaceutically acceptable organic or inorganic acid having a pKa value of less than 6.65.
  • Acidic compound is used to provide pH-independent solubility of propiverine and the salts thereof by forming aquasiionpair of propiverine and acid, leading to a sufficient release in the whole intestinal tract, independent from the kind of the propiverine salt present.
  • Suitable pH adjusters are selected from the group comprising citric acid, aluminum potassium sulfate, potassium carbonate, anhydrous sodium dihydrogen phosphate, dibasic potassium sulfate, calcium carbonate, nicotinic acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, monobasic potassium phosphate, phosphoric acid, adipic acid, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate dihydrate, tartaric acid, tribasic sodium phosphate or mixtures thereof.
  • the weight ratio of acidic substance (pH adjusters) to propiverine or a pharmaceutically acceptable salt thereof is between 0.1 and 6.0, 0.5 and 5.0, 1.0 and 4.0 or preferably between 1.5 and 3.5.
  • the amount of the pH adjusters is between 30.0% and 60.0%, 32.0% and 50.0%, 35.0% and 45.0% by weight of the pellet.
  • the amount of the pH adjusters is between 1 .0% and 30.0%, 3.0% and 25.0%, 5.0% and 20.0%, 7.0% and 15.0% by weight of the total composition.
  • the pH adjuster is citric acid.
  • Suitable binders are selected from the group comprising polyvinylpyrrolidone, sugars, glycose syrup, natural gums, gelatin, agar, alginates, co-povidone, sodium alginate, guar gum, starch mucilage, acacia mucilage, bentonite, laponit, cetostearyl alcohol, polydextrose, polyethylene oxide, pectin, aluminum hydroxide, hyaluronic acid or mixtures thereof.
  • the amount of the binders is between 1 .0% and 25.0%, 3.0% and 16.0%, 4.0% and 10.0% by weight of the pellet.
  • the amount of the binders is between 1 .0% and 25.0%, 3.0% and 16.0%, 4.0% and 10.0% by weight of the total composition.
  • the binder is polyvinylpyrrolidone.
  • Suitable plasticizers are selected from the group comprising triethyl citrate, polyethylene glycols, triacetin, tributyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols or mixtures thereof.
  • the amount of the plasticizers is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the pellet.
  • the amount of the plasticizers is between 0.01% and 5.0%, 0.05% and 3.0% by weight of the total composition.
  • the plasticizer is triethyl citrate.
  • Suitable disintegrants are selected from the group comprising croscarmellose sodium, carboxymethyl cellulose, sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch or mixtures thereof.
  • the amount of the disintegrants is between 1.0% and 15.0% by weight of the total composition.
  • Suitable lubricants are selected from the group comprising 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 is magnesium stearate.
  • the amount of the lubricants is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the total composition.
  • the lubricant is magnesium stearate.
  • Suitable glidants are selected from the group comprising colloidal silicon dioxide, water soluble excipient, hydrophilic polymers, silicon dioxide or mixtures thereof.
  • the amount of the glidants is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the total composition.
  • the glidant is colloidal silicon dioxide.
  • Suitable suspending agents are selected from the group comprising talc, xanthan gum, guar gum, glycerol, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, cellulose derivatives, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose or mixtures thereof.
  • the suspending agent is talc.
  • the amount of the suspending agents is between 5.0% and 25.0%, 8.0% and 20.0%, 9.0% and 17.0% by weight of the pellet.
  • the amount of the suspending agents is between 0.5% and 10.0%, 1 .0% and 8.0% by weight of the total composition.
  • Suitable permeability enhancing agents are selected from the group comprising ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester, ethanol, isopropyl alcohol, propylene glycol or mixtures thereof.
  • Propiverine is a BCS (Biopharmaceutical Classification System) Class III drug, which exhibits low permeability. So, it is important to permeability enhancing agents used.
  • BCS Biopharmaceutical Classification System
  • the amount of the permeability enhancing agents is between 0.5% and 6.0%, 1 .0% and 4.0% by weight of the pellet.
  • the amount of the permeability enhancing agents is between 0.05% and 4.0%, 0.1% and 2.0% by weight of the total composition.
  • the permeability enhancing agent is ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL) or mixtures thereof.
  • Said pharmaceutical composition is compressed into tablets after direct compression or dry granulation or wet granulation.
  • the tablets may be film-coated in a conventional manner.
  • the pellets comprises;
  • the tablet comprises;
  • Ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL)
  • EXAMPLE 1 A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE
  • EXAMPLE 2 A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE Process for example for 1 or 2;
  • pellet For pellet: a) Adding propiverine hydrochloride, neutral microcrystalline cellulose pellet, citric acid, polyvinylpyrrolidone, lactose, Eudragit RS, Eudragit RL, Eudragit S 100, Eudragit L 100, Eudragit FS 30 D, triethylcitrate, talc, magnesium stearate in homogenizer and mixing, b) Then, obtained pellets with fluidized bed dryer,
  • Steps after obtained pellet c) Granulating granulation solution comprising polyvinylpyrrolidone with microcrystalline cellulose Ph101 , d) Sieving and drying the granules until the humidity is less than 0.3%, e) Again, sieving the granules, f) Adding colloidal silicon dioxide and prepared pellets and mixing g) Adding magnesium stearate and mixing, h) Then, pressing to form tablet, i) Coating tablets with coating agents.
  • EXAMPLE 3 A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE Process for example for 3;
  • pellet For pellet: a) Adding propiverine hydrochloride, neutral microcrystalline cellulose pellet, citric acid, polyvinylpyrrolidone, lactose, Eudragit RS, Eudragit RL, Eudragit S 100, Eudragit L 100, Eudragit FS 30 D, triethylcitrate, talc, magnesium stearate in homogenizer and mixing, b) Then, obtained pellets with fluidized bed dryer,
  • Steps after obtained pellet c) Granulating granulation solution comprising polyvinylpyrrolidone with microcrystalline cellulose Ph101 and croscarmellose sodium and propiverine hydrochloride, d) Sieving and drying the granules until the humidity is less than 0.3%, e) Again, sieving the granules, f) Adding colloidal silicon dioxide and prepared pellets and mixing g) Adding magnesium stearate and mixing, h) Then, pressing to form tablet, i) Coating tablets with coating agents.

Landscapes

  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Urology & Nephrology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)

Abstract

The present invention relates to a pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof for oral administration which is formulated as modified release.

Description

A PELLET COMPOSITION COMPRISING PROPIVERINE OR A PHARMACEUTICALLY
ACCEPTABLE SALT THEREOF
Field of the Invention
The present invention relates to a pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof for oral administration which is formulated as modified release.
Background of the Invention
Overactive bladder (OAB) and the related condition of urge urinary incontinence represent the other major disorder of the storage function. They are characterized by a frequent need to void (frequency), with an intense urge to do so (urgency) and a need to void during the night (nocturia). Contrary to stress urinary incontinence, OAB and urge incontinence are not associated with urethral sphincter control but rather involves disturbances in bladder functions and the regulation thereof.
Several classes of medications have been used to treat and manage overactive bladder, including antimuscarinic agents. Antimuscarinic agents, which exert their effects at muscarinic receptors and suppress or diminish the intensity of involuntary detrusor muscle contractions, are the first-choice pharmacotherapy for OAB, and may be the only therapy available whose efficacy is not in question. Propiverine hydrochloride is an extensively studied antimuscarinic and calcium channel blocker agent.
Propiverine is one of the most frequently prescribed antimuscarinic drugs used for the treatment of overactive bladder and urinary incontinence. The chemical name of propiverine is (l-methyl-4-piperidyl diphenylpropoxyacetate) and it is a benzylic acid derivative as shown in Formula I.
Formula I Propiverine is a BCS (Biopharmaceutical Classification System) Class III drug, which exhibits low permeability and high solubility.
Propiverine in the form of its hydrochloride salt in rapidly releasing oral dosage forms in several preparations, e.g. Mictonorm, has been on the market for years. The dosage used so far of e.g. three times a day of one pill of Mictonorm at 15 mg propiverine-hydrochloride each results in relatively heavily fluctuating blood levels with repeated daily peaks. Because of the anticholinergic effect of propiverine typical anticholinergic side effects like and accommodation disorders have to be accepted with a rapid increase in the blood level. Therefore, these side effects limit the amount of the possible unit dose of non-modified, rapidly releasing dosage forms to 10-20 mg.
Propiverine in the form of its hydrochloride salt is currently marketed under the trade names Mictonorm® / Detrunorm®/ Proprinorm® by Apogepha Arzneimittel GmbH in two different dosage forms as immediate -release (IR) and modified-release (MR).
TR 2012/11270 patent application discloses an oral pharmaceutical composition comprising propiverine or a pharmaceutically acceptable salt thereof as an anticholinergic active agent.
In the prior art, there are also several patents which disclose propiverine or a pharmaceutically acceptable salt thereof in oral pharmaceutical dosage forms. However, many of the formulations in the art rely on a complex formulation which can add to the cost of the manufacture of the drug and it was formed without considering the physicochemical properties of the active substance.
Therefore, there is still need for a composition comprising propiverine or a pharmaceutically acceptable salt thereof which overcomes the above described problems in the prior art and has additive advantages over them.
Detailed Description of the Invention
The main object of the present invention is to provide a composition comprising propiverine or a pharmaceutically acceptable salt thereof having high stability by the help of using a pellet composition.
It is an additional object of the present invention to obtain a modified release dosage formulation for propiverine or a pharmaceutically acceptable salt thereof that can provide continuous and therapeutic levels to the patient in need of such treatment for twenty-four (24h) hour period. More specifically, the present invention relates to an oral dosage form in the form of pellets comprising propiverine or a pharmaceutically acceptable salt thereof wherein the release of the active ingredient is controlled with release modifying agent in the presence of pH adjusters.
The term “modified release” 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. Modified release is formulated to release the active ingredient gradually and predictably over a 12-hour to 24-hour period.
These physicochemical properties of propiverine or a pharmaceutically acceptable salt thereof are thus not suitable for the realization of a modified release formulation. Because propiverine or a pharmaceutically acceptable salt thereof, especially propiverine hydrochloride, is sensitive to environmental conditions and excipients used. Therefore, the steps and polymers employed to make modified-release are important in the present invention.
Pellets can be blended to deliver incompatible active agents. The reproducibility of the pellet formulations is also much better than the reproducibility of the single-unit dosage forms. They are suitable systems for film coating with respect to the low surface area-volume ratios. Also, one of the advantageous properties of the pellet formulations is being good resistance to external factors such as moisture, air and light. Also, pellets have excellent flow properties. Considering all these advantages, the pellet form is best for use in propiverine-containing formulation.
According to one embodiment of the present invention, a pellet composition comprises propiverine or a pharmaceutically acceptable salt thereof, wherein the pellet composition is formulated as modified release.
According to one embodiment of the present invention, propiverine or a pharmaceutically acceptable salt thereof is propiverine hydrochloride.
According to one embodiment of the present invention, the amount of propiverine hydrochloride is present between 5.0% and 40.0%, 7.0% and 35.0%, 10.0% and 30.0%, 11.0% and 25.0%, 12.0% and 20.0%, 12.0% and 18.0% by weight of the pellet.
According to one embodiment of the present invention, propiverine hydrochloride is also present outside the pellet.
According to one embodiment of the present invention, the amount of propiverine hydrochloride is present between 1.0% and 30.0%, 1.0% and 25.0%, 1.0% and 20.0%, 1.0% and 15.0%, 1 .0% and 10.0%, 1.0% and 6.0% by weight of the total composition. According to one embodiment of the present invention, the pellets further comprises at least one release modifying agent.
Suitable release modifying agent is selected from the group comprising poly(methacrylic acid-co-methylmethacrylate), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), ethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly(methacrylic acid-co- ethylacrylate), polyvinylchloride, polyvinyl acetate phthalate, poly(vinylpyrrolidone-co- vinylacetate), silicone elastomers, shellac, zein, rosin esters or mixtures thereof.
According to one embodiment of the present invention, the amount of the release modifying agent is between 1.0% and 25.0%, 2.0% and 20.0%, 3.0% and 15.0%, 5.0% and 10.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the release modifying agent is between 0.5% and 10.0%, 1.0% and 8.0%, 1.0% and 6.0%, 1.0% and 4.0% by weight of the total composition.
An embodiment of this present invention, the release modifying agent is poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100) or poly(methacrylic acid-co- methylmethacrylate) 1 :1 (Eudragit L 100) or poly(methyl acrylate-co-methyl methacrylate-co- methacrylic acid) 7:3:1 (Eudragit FS 30 D) , they can be used together or separately.
The optimum amounts of the excipients, for example the composition of the corresponding mixtures depend on several factors, like for example the desired retarding effect, the kind of the release modifying agent having their specific solubility and permeability, and the ratio of acidic substance to active agent propiverine. These parameters vary completely independently from each other and are of essential importance for the controlled and long- lasting, modified release of the propiverine.
According to one embodiment of the present invention, the preferred dosage forms are tablets or capsules filled with pellets as these are more convenient and easier to administer.
An embodiment of this present invention, the form of the composition is a tablet. Pellet is located within a tablet.
According to one embodiment of the present invention, the tablet further comprises at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, pH adjusters, binders, disintegrants, plasticizers, lubricants, glidants, suspending agents, permeability enhancing agents or mixtures thereof.
Suitable fillers are selected from the group comprising neutral microcrystalline cellulose pellets, lactose, microcrystalline cellulose, ammonium alginate, calcium carbonate, calcium phosphate, calcium phosphate dehydrate, calcium sulfate, cellulose, cellulose acetate, compressible sugar, dextrates, dextrin, dextrose, erythritol, ethylcellulose, fructose, isomalt, mannitol, magnesium carbonate, magnesium oxide, maltodextrin, maltose, medium chain triglycerides, polydextrose, polymethacrylates, sodium alginate, sodium chloride, sorbitol, starch, sucrose, sugar spheres, sulfobutylether beta-cyclodextrin, tragacanth, trehalose, polysorbate 80, xylitol or mixtures thereof.
According to one embodiment of the present invention, the amount of the fillers is between 5.0% and 35.0%, 7.0% and 30.0%, 9.0% and 25.0%, 10.0% and 20.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the fillers is between 50.0% and 87.0%, 55.0% and 84.0%, 60.0% and 80.0%, 65.0% and 75.0% by weight of the total composition.
According to one embodiment of the present invention, the filler is neutral microcrystalline cellulose pellets or lactose or microcrystalline cellulose or mixtures thereof.
According to one embodiment of the present invention, fillers should be as inert as possible to prevent them from interacting with propiverine hydrochloride, they should serve only as a carrier to enable propiverine hydrochloride. Thus, neutral microcrystalline cellulose pellets, support the formulation, such as by improving propiverine hydrochloride solubility, improving dissolution and enhancing stability. So, neutral microcrystalline cellulose pellets are used in pellets as fillers.
The preferred inventive compositions comprise at least one pharmaceutically acceptable organic or inorganic acid having a pKa value of less than 6.65. Acidic compound is used to provide pH-independent solubility of propiverine and the salts thereof by forming aquasiionpair of propiverine and acid, leading to a sufficient release in the whole intestinal tract, independent from the kind of the propiverine salt present.
Suitable pH adjusters are selected from the group comprising citric acid, aluminum potassium sulfate, potassium carbonate, anhydrous sodium dihydrogen phosphate, dibasic potassium sulfate, calcium carbonate, nicotinic acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, monobasic potassium phosphate, phosphoric acid, adipic acid, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate dihydrate, tartaric acid, tribasic sodium phosphate or mixtures thereof.
According to one embodiment of the present invention, the weight ratio of acidic substance (pH adjusters) to propiverine or a pharmaceutically acceptable salt thereof is between 0.1 and 6.0, 0.5 and 5.0, 1.0 and 4.0 or preferably between 1.5 and 3.5.
According to one embodiment of the present invention, the amount of the pH adjusters is between 30.0% and 60.0%, 32.0% and 50.0%, 35.0% and 45.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the pH adjusters is between 1 .0% and 30.0%, 3.0% and 25.0%, 5.0% and 20.0%, 7.0% and 15.0% by weight of the total composition.
According to one embodiment of the present invention, the pH adjuster is citric acid.
Suitable binders are selected from the group comprising polyvinylpyrrolidone, sugars, glycose syrup, natural gums, gelatin, agar, alginates, co-povidone, sodium alginate, guar gum, starch mucilage, acacia mucilage, bentonite, laponit, cetostearyl alcohol, polydextrose, polyethylene oxide, pectin, aluminum hydroxide, hyaluronic acid or mixtures thereof.
According to one embodiment of the present invention, the amount of the binders is between 1 .0% and 25.0%, 3.0% and 16.0%, 4.0% and 10.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the binders is between 1 .0% and 25.0%, 3.0% and 16.0%, 4.0% and 10.0% by weight of the total composition.
According to one embodiment of the present invention, the binder is polyvinylpyrrolidone.
Suitable plasticizers are selected from the group comprising triethyl citrate, polyethylene glycols, triacetin, tributyl citrate, chlorobutanol, dibutyl phthalate, dibutyl sebacate, dimethyl phthalate, glycerin, mannitol, petrolatum and lanolin alcohols or mixtures thereof.
According to one embodiment of the present invention, the amount of the plasticizers is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the plasticizers is between 0.01% and 5.0%, 0.05% and 3.0% by weight of the total composition.
According to one embodiment of the present invention, the plasticizer is triethyl citrate. Suitable disintegrants are selected from the group comprising croscarmellose sodium, carboxymethyl cellulose, sodium carboxymethyl cellulose, crosslinked sodium carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl starch or mixtures thereof.
According to one embodiment of the present invention, the amount of the disintegrants is between 1.0% and 15.0% by weight of the total composition.
Suitable lubricants are selected from the group comprising 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. Preferably, the lubricant is magnesium stearate.
According to one embodiment of the present invention, the amount of the lubricants is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the total composition.
According to one embodiment of the present invention, the lubricant is magnesium stearate.
Suitable glidants are selected from the group comprising colloidal silicon dioxide, water soluble excipient, hydrophilic polymers, silicon dioxide or mixtures thereof.
According to one embodiment of the present invention, the amount of the glidants is between 0.05% and 5.0%, 0.5% and 3.0% by weight of the total composition.
According to one embodiment of the present invention, the glidant is colloidal silicon dioxide.
Suitable suspending agents are selected from the group comprising talc, xanthan gum, guar gum, glycerol, polyvinyl alcohol, polyvinyl pyrrolidone, polyethylene oxide, cellulose derivatives, ethylcellulose, hydroxyethylcellulose, hydroxyethylmethylcellose or mixtures thereof.
According to one embodiment of the present invention, the suspending agent is talc.
According to one embodiment of the present invention, the amount of the suspending agents is between 5.0% and 25.0%, 8.0% and 20.0%, 9.0% and 17.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the suspending agents is between 0.5% and 10.0%, 1 .0% and 8.0% by weight of the total composition. Suitable permeability enhancing agents are selected from the group comprising ethyl acrylate, methyl methacrylate and a low content of methacrylic acid ester, ethanol, isopropyl alcohol, propylene glycol or mixtures thereof.
Propiverine is a BCS (Biopharmaceutical Classification System) Class III drug, which exhibits low permeability. So, it is important to permeability enhancing agents used.
According to one embodiment of the present invention, the amount of the permeability enhancing agents is between 0.5% and 6.0%, 1 .0% and 4.0% by weight of the pellet.
According to one embodiment of the present invention, the amount of the permeability enhancing agents is between 0.05% and 4.0%, 0.1% and 2.0% by weight of the total composition.
According to one embodiment of the present invention, the permeability enhancing agent is ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL) or mixtures thereof.
Said pharmaceutical composition is compressed into tablets after direct compression or dry granulation or wet granulation. The tablets may be film-coated in a conventional manner.
According to one embodiment of the present invention, the pellets comprises;
• Propiverine hydrochloride
• Neutral microcrystalline cellulose pellet
• Citric acid
• Polyvinylpyrrolidone
• Lactose
• Ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL)
• Poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100)
• Poly(methacrylic acid-co-methylmethacrylate) 1 :1 (Eudragit L 100)
• Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (Eudragit FS30D)
• Triethylcitrate
• Talc
• Magnesium stearate According to one embodiment of the present invention, the tablet comprises;
Propiverine hydrochloride
Neutral microcrystalline cellulose pellet
Citric acid
Polyvinylpyrrolidone
Lactose
Ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester (Eudragit RS or Eudragit RL)
Poly(methacrylic acid-co-methylmethacrylate) 1 :2 (Eudragit S 100)
Poly(methacrylic acid-co-methylmethacrylate) 1 :1 (Eudragit L 100)
Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1 (Eudragit FS30D)
Triethylcitrate
Talc
Magnesium stearate Microcrystalline cellulose Ph 101 Colloidal silicone dioxide
EXAMPLE 1 : A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE EXAMPLE 2: A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE Process for example for 1 or 2;
For pellet: a) Adding propiverine hydrochloride, neutral microcrystalline cellulose pellet, citric acid, polyvinylpyrrolidone, lactose, Eudragit RS, Eudragit RL, Eudragit S 100, Eudragit L 100, Eudragit FS 30 D, triethylcitrate, talc, magnesium stearate in homogenizer and mixing, b) Then, obtained pellets with fluidized bed dryer,
Steps after obtained pellet: c) Granulating granulation solution comprising polyvinylpyrrolidone with microcrystalline cellulose Ph101 , d) Sieving and drying the granules until the humidity is less than 0.3%, e) Again, sieving the granules, f) Adding colloidal silicon dioxide and prepared pellets and mixing g) Adding magnesium stearate and mixing, h) Then, pressing to form tablet, i) Coating tablets with coating agents.
EXAMPLE 3: A TABLET COMPRISING PELLETS HAVING PROPIVERINE HYDROCHLORIDE Process for example for 3;
For pellet: a) Adding propiverine hydrochloride, neutral microcrystalline cellulose pellet, citric acid, polyvinylpyrrolidone, lactose, Eudragit RS, Eudragit RL, Eudragit S 100, Eudragit L 100, Eudragit FS 30 D, triethylcitrate, talc, magnesium stearate in homogenizer and mixing, b) Then, obtained pellets with fluidized bed dryer,
Steps after obtained pellet: c) Granulating granulation solution comprising polyvinylpyrrolidone with microcrystalline cellulose Ph101 and croscarmellose sodium and propiverine hydrochloride, d) Sieving and drying the granules until the humidity is less than 0.3%, e) Again, sieving the granules, f) Adding colloidal silicon dioxide and prepared pellets and mixing g) Adding magnesium stearate and mixing, h) Then, pressing to form tablet, i) Coating tablets with coating agents.

Claims

1. A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof, wherein the pellet composition is formulated as modified release.
2. The pellet composition according to claim 1 , wherein propiverine or a pharmaceutically acceptable salt thereof is propiverine hydrochloride.
3. The pellet composition according to claim 2, wherein the amount of propiverine hydrochloride is present between 5.0% and 40.0% by weight of the pellet.
4. The pellet composition according to claim 2, wherein the amount of propiverine hydrochloride is present between 1 .0% and 30.0% by weight of the total composition.
5. The pellet composition according to any preceding claims, wherein the pellets further comprising at least one release modifying agent.
6. The pellet composition according to claim 5, wherein the release modifying agent is selected from the group comprising poly(methacrylic acid-co-methylmethacrylate), poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid), ethyl cellulose, methyl cellulose, hydroxypropylmethylcellulose, cellulose acetate, cellulose acetate phthalate, cellulose acetate trimellitate, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, poly(methacrylic acid-co- ethylacrylate), polyvinylchloride, polyvinyl acetate phthalate, poly(vinylpyrrolidone-co- vinylacetate), silicone elastomers, shellac, zein, rosin esters or mixtures thereof.
7. The pellet composition according to claim 5 or 6, wherein the amount of the release modifying agent is between 1.0% and 25.0% by weight of the pellet.
8. The pellet composition according to claim 5 or 6, wherein the amount of the release modifying agent is between 0.5% and 10.0% by weight of the total composition.
9. The pellet composition according to any preceding claims, wherein the form of the composition is tablet or capsule.
10. The pellet composition according to claim 9, wherein the form of the composition is a tablet.
11. The pellet composition according to claim 10, wherein the tablet further comprising at least one pharmaceutically acceptable excipient which is selected from the group comprising fillers, pH adjusters, binders, disintegrants, plasticizers, lubricants, glidants, suspending agents, permeability enhancing agents or mixtures thereof.
12. The pellet composition according to claim 11 , wherein the amount of the fillers is between 5.0% and 35.0% by weight of the pellet.
13. The pellet composition according to claim 11 , wherein the amount of the fillers is between 50.0% and 87.0% by weight of the total composition.
14. The pellet composition according to claim 11 , wherein pH adjusters are selected from the group comprising citric acid, aluminum potassium sulfate, potassium carbonate, anhydrous sodium dihydrogen phosphate, dibasic potassium sulfate, calcium carbonate, nicotinic acid, dilute hydrochloric acid, glacial acetic acid, lactic acid, maleic acid, monobasic potassium phosphate, phosphoric acid, adipic acid, sodium acetate, sodium bicarbonate, sodium carbonate, sodium citrate, sodium dihydrogen phosphate dihydrate, tartaric acid, tribasic sodium phosphate or mixtures thereof.
15. The pellet composition according to claim 14, wherein the weight ratio of acidic substance (pH adjusters) to propiverine or a pharmaceutically acceptable salt thereof is between 0.1 and 6.0, 0.5 and 5.0, 1 .0 and 4.0 or preferably between 1 .5 and 3.5.
16. The pellet composition according to claim 14, wherein the amount of the pH adjusters is between 30.0% and 60.0% by weight of the pellet.
17. The pellet composition according to claim 14, wherein the amount of the pH adjusters is between 1 .0% and 30.0% by weight of the total composition.
18. The pellet composition according to claim 10, wherein the pellets comprising; -Propiverine hydrochloride
-Neutral microcrystalline cellulose pellet -Citric acid - Polyvinylpyrrolidone -Lactose
-Ethyl acrylate or methyl methacrylate or a low content of methacrylic acid ester
-Poly(methacrylic acid-co-methylmethacrylate) 1 :2
-Poly(methacrylic acid-co-methylmethacrylate) 1 :1
-Poly(methyl acrylate-co-methyl methacrylate-co-methacrylic acid) 7:3:1
-Triethylcitrate
-Talc
EP20889321.4A 2019-11-19 2020-10-27 COMPOSITION OF GRANULES COMPRISING PROPIVERINE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF Pending EP4061370A4 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2019/18013A TR201918013A2 (en) 2019-11-19 2019-11-19 PELLET COMPOSITION CONTAINING PROPIVERIN OR A PHARMACEUTICALLY ACCEPTABLE SALT OF PROPIVERIN
PCT/TR2020/050998 WO2021101481A1 (en) 2019-11-19 2020-10-27 A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof

Publications (2)

Publication Number Publication Date
EP4061370A1 true EP4061370A1 (en) 2022-09-28
EP4061370A4 EP4061370A4 (en) 2023-08-02

Family

ID=75980701

Family Applications (1)

Application Number Title Priority Date Filing Date
EP20889321.4A Pending EP4061370A4 (en) 2019-11-19 2020-10-27 COMPOSITION OF GRANULES COMPRISING PROPIVERINE OR A PHARMACEUTICALLY ACCEPTABLE SALT THEREOF

Country Status (4)

Country Link
EP (1) EP4061370A4 (en)
CA (1) CA3162408C (en)
TR (2) TR201918013A2 (en)
WO (1) WO2021101481A1 (en)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2023080856A1 (en) * 2021-11-03 2023-05-11 Santa Farma Ilac Sanayii A.S. Enteric coated pharmaceutical composition of propiverine hydrochloride
WO2023128906A1 (en) * 2021-12-30 2023-07-06 Santa Farma Ilac Sanayii A.S. Release of propiverine compositions in gastric conditions

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE10149674A1 (en) * 2001-10-09 2003-04-24 Apogepha Arzneimittel Gmbh Orally administered composition for sustained release of propiverine, useful for treatment of hypertonic bladder disorders, especially by once-daily administration
ITMI20061024A1 (en) * 2006-05-25 2007-11-26 Eurand Pharmaceuticals Ltd PELLETS BASED ON LIPOIC ACID
TWI519322B (en) * 2008-04-15 2016-02-01 愛戴爾製藥股份有限公司 Compositions comprising weakly basic drugs and controlled-release dosage forms
CN102579404A (en) 2012-01-17 2012-07-18 广州科的信医药技术有限公司 Sustained-release capsule containing propiverine hydrochloride and preparation method of sustained-release capsule

Also Published As

Publication number Publication date
EP4061370A4 (en) 2023-08-02
CA3162408C (en) 2024-11-05
TR201918013A2 (en) 2021-06-21
WO2021101481A1 (en) 2021-05-27
CA3162408A1 (en) 2021-05-27
TR202016210A2 (en) 2021-06-21

Similar Documents

Publication Publication Date Title
CA2595033C (en) Gastroresistant pharmaceutical formulations containing rifaximin
CN100353935C (en) Pharmaceutical formulation contg. tolterodine and its use
US20250120919A1 (en) Compositions of midodrine and methods of using the same
US9011912B2 (en) Extended-release oral dosage forms for poorly soluble amine drugs
JP2011513391A (en) Sustained release pharmaceutical composition containing mycophenolate and method thereof
US20210220281A1 (en) Oral pharmaceutical compositions of mesalazine
KR20090029830A (en) Oral pharmaceutical preparations with controlled release of active ingredient in small intestine and preparation method thereof
WO2006011159A2 (en) Stabilized pharmaceutical composition containing rabeprazole sodium with improved bioavailability
US6270799B1 (en) Medicament formulation with a controlled release of an active agent
RU2010109408A (en) COMPOSITIONS WITH PROLONGED RELEASE, INCLUDING SODIUM MYCOPHENOLS, AND THEIR ACTIONS
KR20210109480A (en) Pharmaceutical composition comprising benzimidazole derivative compound
CA3162408C (en) A pellet composition comprising propiverine or a pharmaceutically acceptable salt thereof
CA3021066C (en) Oral pharmaceutical compositions of nicotinamide
US9132092B1 (en) Pharmaceutical composition of doxycycline
KR20090086128A (en) Memantine pharmaceutical composition
KR101990951B1 (en) A sustained releasing Pharmaceutical Composition comprising Rivastigmine
CN118265524A (en) Controlled release preparation of flavoxate and preparation method thereof
WO2024162929A1 (en) A controlled release formulation of propiverine
JP2009525953A (en) Sustained release formulation of divalproic acid and its derivatives
CA2902665A1 (en) Pharmaceutical compositions of donepezil having specific in vitro dissolution profile or pharmacokinetics parameters
WO2015150943A1 (en) Pharmaceutical composition of nsaid and ppi or salt thereof

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: 20220517

AK Designated contracting states

Kind code of ref document: A1

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

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: 20230703

RIC1 Information provided on ipc code assigned before grant

Ipc: A61K 9/22 20060101ALI20230627BHEP

Ipc: A61K 9/20 20060101ALI20230627BHEP

Ipc: A61K 9/16 20060101ALI20230627BHEP

Ipc: A61K 9/50 20060101ALI20230627BHEP

Ipc: A61K 47/38 20060101ALI20230627BHEP

Ipc: A61P 13/10 20060101ALI20230627BHEP

Ipc: A61P 13/00 20060101ALI20230627BHEP

Ipc: A61K 31/445 20060101AFI20230627BHEP

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

Effective date: 20230708

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: 20240314

RAP3 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOVEL ILAC SANAYI VE TICARET ANONIM SIRKETI

RAP3 Party data changed (applicant data changed or rights of an application transferred)

Owner name: SANOVEL ILAC SANAYI VE TICARET A.S.