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WO2023096615A2 - Forme posologique orale solide comprimée comprenant du pinavérium et du médazépam - Google Patents

Forme posologique orale solide comprimée comprenant du pinavérium et du médazépam Download PDF

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Publication number
WO2023096615A2
WO2023096615A2 PCT/TR2022/051250 TR2022051250W WO2023096615A2 WO 2023096615 A2 WO2023096615 A2 WO 2023096615A2 TR 2022051250 W TR2022051250 W TR 2022051250W WO 2023096615 A2 WO2023096615 A2 WO 2023096615A2
Authority
WO
WIPO (PCT)
Prior art keywords
pinaverium
dosage form
medazepam
oral dosage
layer
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.)
Ceased
Application number
PCT/TR2022/051250
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English (en)
Other versions
WO2023096615A3 (fr
Inventor
Cigdem CETIN ALUC
Ali Osman Sarikaya
Udaya Kumar DUDE
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.)
Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Original Assignee
Abdi Ibrahim 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
Priority claimed from TR2021/018486 external-priority patent/TR2021018486A2/tr
Application filed by Abdi Ibrahim Ilac Sanayi Ve Ticaret AS filed Critical Abdi Ibrahim Ilac Sanayi Ve Ticaret AS
Publication of WO2023096615A2 publication Critical patent/WO2023096615A2/fr
Publication of WO2023096615A3 publication Critical patent/WO2023096615A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • 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
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A61K31/551—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole having two nitrogen atoms, e.g. dilazep
    • A61K31/5513—1,4-Benzodiazepines, e.g. diazepam or clozapine

Definitions

  • the present invention relates to a compressed solid oral dosage form comprising Pinaverium or a pharmaceutically acceptable salt thereof and Medazepam or a pharmaceuticall accetable salt thereof and process for the preparation of the same.
  • the invention further relates to use of this dosage form as medicament in the treatment of Irritable Bowel Syndrome.
  • Pinaverium Bromide is a derivative of the quaternary ammonium of chemical name 4-(6-bromoveratril)-4- ⁇ 2-[2-(6,6 dimethyl-2-norpinil)etoxyl]- ethyljmorfolinium bromide, whose chemical formula is: C26H4iBr2NO4 and its molecular weight is: 591 .4. And whose structural formula is the following:
  • Pinaverium Bromide is a non-atrophic, anticholinergic, antispasmodic agent with a potent musculotropic action and is a very weak neurotropic component.
  • Pinaverium Bromide is a calcium channel blocker with selective action on the smooth muscle fiber of the gastrointestinal tract which achieves the relief of abdominal pain and correction of the altered gastrointestinal passage. It is also able to decrease the quantity of acid without modifying the volume of gastric secretion and accelerating evacuation of stomach. Due to the quaternary ammonium group contained in its chemical structure, Pinaverium Bromide has a high polarity, so its passage through lipid membranes is limited.
  • Pinaverium was registered by Solvay Pharmaceuticals in 1975 as pinaverium bromide and is marketed under the brands Dicetel® and Eldicet®.
  • Medazepam is a benzodiazepine derivative. As a result of metabolism, diazepam is formed first and then it is transformed into desmethyldiazepam and oxazepam. By acting on the alpha subunit (GABA-A) of gamma amino butyric acid (GABA) in the nervous system, it increases the entry of chloride ions through the chloride channels in the nerve cell membrane, causing hyperpolarization in the neuron. Thus, it helps to reduce or eliminate the restlessness, anxiety and tension that exist in the patient.
  • GABA-A alpha subunit
  • GABA gamma amino butyric acid
  • Medazepam is disclosed by document US 3243427 and is marketed under the brand name Tranko-Buskas® in combination with the Rudotel® brand in the market. Its chemical name is 7-chloro-1 -methyl-5-phenyl-2,3- dihydro-1 H-1 ,4-benzodiazepine and whose structural formula is the following.
  • EP 0900084 B1 patent discloses use of pinaverium bromide for the preparation of a medication intended for the prevention or treatment of an excessive proliferation of cells of the hepatodigestive tract, that are cells of the stomach, intestines, colon or liver.
  • TR 2016/01803 discloses a composition comprising combination of pinaverium bromide and medazepam for the treatment of Irritable Bowel Syndrome.
  • TR 2018/19752 discloses a stable pharmaceutical composition comprising pinaverium, medazepam and at least one pharmaceutically acceptable excipient.
  • Inventors of TR 2018/19752 has solved the problem of color and impurity by employing the specific kind of coating material comprising acrylic acid or its deriviative.
  • the dissolution profile of monolayer tablet prepared according to TR 2018/19752 has been checked w.r.t. the reference product, it has been observed that dissolution profile of one active has not found satisfactory.
  • pinaverium and medazepam i.e. pinaverium belong to BCS class III (high solubility, low permeability), whereas medazepam belongs to BCS II (low solubility, high permeability), it is challenging to develop a pharmaceutical composition, in which the dissolution of said medazepam occurs independently of said pinaverium.
  • Inventors of the present invention have been surprisingly found that a development of bilayer composition comprising pinaverium and medazepam in different layers with specific amount allows better dissolution profile of medazepam, which is independent of pinaverium.
  • the main object of the present invention is to provide a compressed solid oral dosage form comprising two i.e.: pinaverium and medazepam in two different layers in such a way so that dissolution of said medazepam occurs independently of said pinaverium.
  • Another object of the present invention is to provide a process for the preparation of said compressed oral solid dosage form, which a cost competitive and feasible at commercial scale.
  • Yet another object of the present invention is to provide a said compressed oral solid dosage form, which satisfy the stability criteria as per the regulatory guideline.
  • the present invention provides a compressed solid oral dosage form comprising a first layer and a second layer, wherein: a) the first layer comprises at least 50% of pinaverium or a pharmaceutically acceptable salt thereof, b) the second layer comprises at least 50% medazepam or a pharmaceutically acceptable salt thereof, and c) said first layer and said second layer are in a side-by-side arrangement such that dissolution of said medazepam occurs independently of said pinaverium.
  • the present invention provides a compressed solid oral dosage form comprising a first layer and a second layer, wherein: a) the first layer comprises at least 70% of pinaverium or a pharmaceutically acceptable salt thereof, b) the second layer comprises at least 70% medazepam or a pharmaceutically acceptable salt thereof, and c) said first layer and said second layer are in a side-by-side arrangement such that dissolution of said medazepam occurs independently of said pinaverium.
  • the present invention provides a compressed solid oral dosage form comprising a first layer and a second layer, wherein: a) the first layer comprises at least 90% of pinaverium or a pharmaceutically acceptable salt thereof, b) the second layer comprises at least 90% medazepam or a pharmaceutically acceptable salt thereof, and c) said first layer and said second layer are in a side-by-side arrangement such that dissolution of said medazepam occurs independently of said pinaverium.
  • the present invention provides a compressed solid oral dosage form comprising a first layer and a second layer, wherein: a) the first layer comprises substantially all amount of pinaverium or a pharmaceutically acceptable salt thereof, b) the second layer comprises substantially all amount of medazepam or a pharmaceutically acceptable salt thereof, and c) said first layer and said second layer are in a side-by-side arrangement such that dissolution of said medazepam occurs independently of said pinaverium.
  • the present invention provides a process to prepare said compressed solid oral dosage form in the form of bilayer composition by conventional processes.
  • the present invention provides a use of said compressed solid oral dosage form as medicament in the treatment of irretable bowel syndrome.
  • compressed dosage form refers to a dosage form comprising a compressed powder.
  • a compressed tablet may be formed using a rotary tablet press or other similar machinery known to one of skill in the art.
  • bilayer compressed dosage form refers to a single compressed dosage form comprising two layers.
  • a bilayer compressed dosage form can be made in a single compression step.
  • wet granulation refers to a process known in the pharmaceutical arts that involves forming granules by the addition of a liquid, such as purified water, alcohol, or a binder solution.
  • the term "substantially all” indicates that at least 95%, and preferably greater than 98%, of the total therapeutic agent present in the tablet is included within one distinct layer.
  • the layers should be arranged such that the individual therapeutic agents dissolve independently of one another, i.e., dissolution should occur at approximately the same rate as would occur if the drugs were given separately.
  • pinaverium refers to pinaverium, pharmaceutically acceptable salt thereof. Preferably, it is pinaverium bromide. Pinaverium bromide can be in crystalline and amorphous form. Present invention contains 10-500 mg of pinaverium bromide, preferably 50 mg and 100 mg.
  • Medazepam refers to medazepam, pharmaceutically acceptable salt thereof.
  • Present invention contains 5-100 mg of medazepam, preferably 10 mg and 20 mg.
  • the present invention provides a compressed solid oral dosage form comprising a first layer and a second layer, wherein: d) the first layer comprises at least 50% of pinaverium or a pharmaceutically acceptable salt thereof, e) the second layer comprises at least 50% of medazepam or a pharmaceutically acceptable salt thereof, and f) said first layer and said second layer are in a side-by-side arrangement such that dissolution of said medazepam occurs independently of said pinaverium.
  • the first layer comprises at least 50% of pinaverium or preferably at least 70% of pinaverium or preferably at least 90% of pinaverium or substantially all amount of pinaverium or a pharmaceutically acceptable salt thereof. More preferably the first layer comprises substantially all amount of pinaverium or a pharmaceutically acceptable salt thereof.
  • the second layer comprises at least 50% of medazepam or preferably at least 70% of medazepam or preferably at least 90% of medazepam or substantially all amount of medazepam or a pharmaceutically acceptable salt thereof. More preferably the second layer comprises substantillay all amount of medazepam or a pharmaceutically acceptable salt thereof.
  • pinaverium as used in the present invention is in micronized form.
  • Mean particle size distribution (dso) is preferably 15 pm or less, more preferably is in the range of 3-10 pm.
  • the value of dgo is preferably 20 pm or less, more preferably is in the range of I Q- 15 pm.
  • dso particle size used herein to average particle size of the particles and refers to average particle diameter by volume
  • dgo particle size refers to a particle size of 90% of particles by volume
  • dso and dgo values can be measured by using a known measuring device such as the instrument measuring particle distribution by laser diffraction (e.g. Malvern MasterSizer). The measurements can be done by wet or dry method in laser diffraction instrument.
  • the compressed solid oral dosage comprising pinaverium and medazepam in two different layers can be manufactured by conventional methods like direct compression, direct mix, wet granulation, dry granulation, fluid bed granulation, spray drying.
  • direct compression direct compression
  • wet granulation dry granulation
  • fluid bed granulation fluid bed granulation
  • spray drying spray drying.
  • combination of direct mix and wet granulation are used in the invention.
  • layer comprising specific amount pinaverium can be obtained by direct mix and layer comprising specific amount medazepam can be obtained by wet granulation.
  • the term bilayer composition refers to bilayer tablet, granulation and/or coating of active ingredients in/producing separate layers. Preferably, it is bilayer tablet.
  • the present invention is directed to bilayer tablet composition
  • bilayer tablet composition comprising pinaverium and its pharmaceutically acceptable salt thereof and medazepam and its pharmaceutically acceptable salt thereof in which these therapeutic agents are in specific amounts.
  • Specific amount of pinaverium is found in one layer of the tablet and specific amount of medazepam is found in a second, separate layer.
  • pharmaceutically acceptable excipients comprise at least one filler (diluent), at least one disintegrant, at least one binder, at least one lubricant, at least one glidant, and combination thereof.
  • one layer of tablet comprises pinaverium or its pharmaceutically acceptable salts, at least one filler (diluent), at least one disintegrant, at least one lubricant, at least one glidant.
  • Another layer of the tablet comprises medazepam or its pharmaceutically acceptable salt, at least one filler (diluent), at least one binder, at least one disintegrant and at least one lubricant.
  • filler refers to at least one of lactose monohydrate, anhydrate lactose, microcrystalline cellulose, silicified microcrystalline cellulose, calcium hydrogene phosphate, calcium phosphate and mannitol or mixtures thereof and is not limited thereto. Preferably, they are lactose and silicified microcrystalline cellulose.
  • disintegrant refers to at least one of croscarmellose sodium, sodium starch glycolate, crospovidone, microcrystalline cellulose, low substituted hydroxypropyl cellulose, povidone, starch, pregelatinized starch, sodium or calcium alginate, methyl cellulose, agar, alginic acid or mixtures thereof and is not limited thereto. Preferably, they are pregelatinized starch and crospovidone.
  • lubricant used herein refers to at least one of magnesium stearate, sodium stearyl fumarate, hydrogenated vegetable oil, talc or mixtures thereof and is not limited thereto. Preferably, they are magnesium stearate and talc.
  • glidant refers to at least one of colloidal silicon dioxide, aluminum silicate, magnesium silicate, cellulose powder, talc, tribasic calcium phosphate or combinations thereof. Preferably, it is colloidal silicone dioxide.
  • binder refers to at least one of hydroxypropyl methyl cellulose, methyl cellulose, hydroxyethylcellulose, hydroxyethylmethylcellulose, hydroxypropyl cellulose, polyvinylpyrrolidone (povidone), polyvinyl alcohol, copovidone, gelatine and pregelatinized starch or mixtures thereof and is not limited thereto. Preferably, it is gelatine.
  • the compressed solid oral dosage form of the present invention can be prepared by any conventional processes well known in the art of pharmaceutical sciences (Rubinstein, M.H. In Pharmaceutics: The Science of Dosage Form Design; Bandelin, In Pharmaceutical Dosage Forms: Tablets, Lieberman, et al. eds., Marcel Dekker, Inc., New York, 1989, p. 131 -193; and Carstensen, J.T. In Pharmaceutics of Solids and Solid Dosage Forms, John Wiley & Sons: New York, 1977).
  • step (iii) adding disintegrant & second filler into the mixture obtained in step (ii) in stepwise manner and mixed all, and
  • step (iv) mixing lubricants into the mixture obtained in step (iii) and obtained the final blend.
  • step (iii) drying the granules obtained in step (ii) and sieved them, and
  • step (iv) adding the lubricants in granule obtained in step (iii) and mixed well.
  • the “solvent” as used in above mentioned step (ii) of medazepam layer is selected from water, organic solvents like ethanol, methanol, isopropanol, acetone, dichloromethane, dimethylsulphoxide or combinations thereof and mixtures of water and one or more organic solvent.
  • the solvent is water.
  • the above mentioned compressed solid oral dosage form such as bilayer oral dosage form may be made by compressing a first layer composition, such as a first layer blend as described above, and a second layer composition, such as a second layer blend as described above.
  • the first and second layer blends may be compressed into a bilayer solid oral dosage form, e.g., a bilayer tablet, in a single compression step.
  • compression can be carried out using bilayer tabletting machines, e.g. a Cadmach bilayer press (Cadmach Machinery Co. PVT. Ltd., India) or a tablet press with displacement monitoring such as the Courtoy- R292F (Courtroy, nv, Belgium).
  • the dosage forms can be made into any desired shape, such as an oval shape, using suitable punches, such as oval punches.
  • the dosage form may also be of any other appropriate shape, such as round, cubic, cylindrical, spherical.
  • the dosage form can be any suitable size.
  • the size of the compressed tablets may range from about 1 mm to about 6 mm.
  • the dose form comprises a first layer comprising a first planar surface and a second layer comprising a second planar surface, wherein the first planar surface of the first layer is adjacent the second planar surface of the second layer.
  • oral dosage forms of the present invention can be formulated to have any desired hardness. Hardness can be assessed by means commonly used in the art, for example, using commercially available hardness testers that are routinely used for assessing the hardness of pharmaceutical dosage forms.
  • the solid oral dosage form such as tablets may be coated or there may be a barrier or coating layer between layers containing active agents.
  • Typical coating components include a polymer (e.g., hydroxypropylmethyl cellulose), a plasticizer (e.g., polyethylene glycol or polysorbate 80) and a coloring agent (e.g., titanium dioxide).
  • First layer Blend a) reproduced and sieved spray dried lactose and aerosil were taken into a container, b) compacted and sieved pinaverium bromide was added into the above obtained mixture and mixed well, c) pregelatinized starch & silicified microcrystalline cellulose were added into the above obtained mixture and mixed, and d) finally, talc and magnesium stearate were added into container and mixed.
  • Second layer Blend a) medazepam and lactose monohydrate were mixed in container, b) gelatine solution in hot water was prepared and added into the mixture of step a) and granulation was performed, and c) the obtained granules were dried and sieved, and d) finally, talc and magnesium stearate were added and mixed.
  • Production method a) reproduced and sieved lactose, spray dried and crospovidone, pregelatinized starch were taken into a container, b) medazepam and compacted and sieved pinaverium bromide were added into the mixture of step a), c) talc was sieved and taken into the container and mixed well, and d) magnesium stearate was sieved and taken into the container and mixed, and e) obtained blend compressed into the tablet.
  • Example-3 Dissolution Profile Analysis Dissolution analyses of bilayer tablet of Example-1 and monolayer tablet of Example-2 were performed in three media pH 6.8 phosphate buffer, 0.1 N HCI and pH 4.5 acetate buffer in 900 ml at 50 rpm in paddle. Obtained dissolution profiles of the examples were compared to currently available reference products Rutodel® and Dicetel® of medazepam and pinaverium respectively as depicted in below table-1 & table-2 respectively.

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Abstract

La présente invention concerne une forme posologique orale solide comprimée comprenant du pinavérium ou un sel pharmaceutiquement acceptable de celui-ci et du madazépam ou un sel pharmaceutiquement acceptable de celui-ci et un procédé pour la préparation de celle-ci. L'invention concerne en outre l'utilisation de cette forme posologique en tant que médicament dans le traitement du syndrome du côlon irritable.
PCT/TR2022/051250 2021-11-25 2022-11-07 Forme posologique orale solide comprimée comprenant du pinavérium et du médazépam Ceased WO2023096615A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
TR2021/018486 TR2021018486A2 (tr) 2021-11-25 Pinaveryum ve medazepam içeren sıkıştırılmış katı oral dozaj formları.
TR2021018486 2021-11-25

Publications (2)

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WO2023096615A2 true WO2023096615A2 (fr) 2023-06-01
WO2023096615A3 WO2023096615A3 (fr) 2023-07-06

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PCT/TR2022/051250 Ceased WO2023096615A2 (fr) 2021-11-25 2022-11-07 Forme posologique orale solide comprimée comprenant du pinavérium et du médazépam

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117717531A (zh) * 2023-11-21 2024-03-19 广州仁恒医药科技股份有限公司 一种匹维溴铵片及其制备方法

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2006009825A1 (fr) * 2004-06-17 2006-01-26 Virun, Inc. Compositions comprenant une protéine adhérant aux muqueuses et principe actif pour la délivrance d'agents dans des muqueuses
TR201601803A2 (tr) * 2016-02-11 2017-09-21 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Ibs tedavi̇si̇ i̇çi̇n pi̇naveryum bromür ve medazepam kombi̇nasyonu
TR201819752A2 (tr) * 2018-12-18 2020-07-21 Abdi Ibrahim Ilac Sanayi Ve Ticaret Anonim Sirketi Pi̇naveryum ve medazepam i̇çeren kati farmasöti̇k bi̇leşi̇m

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN117717531A (zh) * 2023-11-21 2024-03-19 广州仁恒医药科技股份有限公司 一种匹维溴铵片及其制备方法

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