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WO2015027303A1 - Procédé de fabrication d'une combinaison pharmaceutique contenant un agent analgésique et un agent anti-spasmodique et combinaison pharmaceutique - Google Patents

Procédé de fabrication d'une combinaison pharmaceutique contenant un agent analgésique et un agent anti-spasmodique et combinaison pharmaceutique Download PDF

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Publication number
WO2015027303A1
WO2015027303A1 PCT/BR2014/000214 BR2014000214W WO2015027303A1 WO 2015027303 A1 WO2015027303 A1 WO 2015027303A1 BR 2014000214 W BR2014000214 W BR 2014000214W WO 2015027303 A1 WO2015027303 A1 WO 2015027303A1
Authority
WO
WIPO (PCT)
Prior art keywords
microgranules
weight
talc
pvp
povidone
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/BR2014/000214
Other languages
English (en)
Portuguese (pt)
Inventor
Jaime ABRAMOWICZ
Fernando Rafael De Souza
Carlos Antonio Martins
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.)
DIFFUCAP CHEMOBRAS QUIMICA E FARMACEUTICA Ltda
Original Assignee
DIFFUCAP CHEMOBRAS QUIMICA E FARMACEUTICA Ltda
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 BR102013021950-9A external-priority patent/BR102013021950B1/pt
Application filed by DIFFUCAP CHEMOBRAS QUIMICA E FARMACEUTICA Ltda filed Critical DIFFUCAP CHEMOBRAS QUIMICA E FARMACEUTICA Ltda
Publication of WO2015027303A1 publication Critical patent/WO2015027303A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • 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
    • A61K31/46—8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
    • 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
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/216—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acids having aromatic rings, e.g. benactizyne, clofibrate
    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/407—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with other heterocyclic ring systems, e.g. ketorolac, physostigmine
    • 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
    • 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
    • A61K9/167—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface
    • A61K9/1676—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction with an outer layer or coating comprising drug; with chemically bound drugs or non-active substances on their surface having a drug-free core with discrete complete coating layer containing drug
    • 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
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4866—Organic macromolecular compounds
    • 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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/06—Anti-spasmodics, e.g. drugs for colics, esophagic dyskinesia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]

Definitions

  • the present patent application has as its main object a manufacturing procedure for a new pharmaceutical combination and the obtained pharmaceutical combination, composed of an analgesic, Tromethamine Ketorolac (5-Benzoyl-2,3-dihydro-1H-pyrrolysin-1 1-earboxylic acid, 2-amino-2-hydroxymethyl-1,3-propanediol), in antiospasmodic type of Hioscin or Pargeverine.
  • analgesic Tromethamine Ketorolac
  • Tromethamine Ketorolac 5-Benzoyl-2,3-dihydro-1H-pyrrolysin-1 1-earboxylic acid, 2-amino-2-hydroxymethyl-1,3-propanediol
  • the present application relates to a new pharmaceutical combination procedure of the specified type, which has been designed and developed as a result of experience in dosing the Tromethamine Ketorolac analgesic and a Hioscin or Pargeverine antispasmodic .
  • the procedure of the present patent application allows to obtain microgranules of each active ingredient separately in order to avoid contact incompatibility between the analgesic agent and the antispasmodic agent, which form the new invention obtained by the procedure described and claimed. in the present invention patent application.
  • Etor Tromethamine Ketorolac is a non-steroidal anti-inflammatory with analgesic, anti-inflammatory and antipyretic action, whose mechanism of action It is related to its ability to inhibit prostaglandin synthesis and a peripheral analgesic effect.
  • Hyoscine is an alkaloid synthesized by certain plants that produces an anticholinergic effect exerting an antispasmodic action on the smooth muscle of the gastrointestinal, biliary and genitourinary tract.
  • ⁇ Pargeverine is a moderate and non-selective antispasmodic antagonist of muscarinic receptors that acts directly on visceral smooth muscle, ie, it inhibits the activity of muscarinic receptors located mostly in the smooth muscle of some organs and glands.
  • Ketorolac has been known since 1978 from Belgian Patent Nos. 856,681 and U.S. Patent No. 4,089,969, which are mentioned as prior art to the present inventive development in the field of pharmacology.
  • Ketorolac is a prostaglandin synthesis inhibitor with peripheral analgesic effect, of which no effect on opioid receptors has been demonstrated.
  • hyoscine (C17H21NO4) differs from atropine only in that it has an oxygen bridge between carbon atoms 6 and 7, which gives it the possibility of penetration into the blood-brain barrier, although the N-Butylbromuro derivative used in this patent application. of invention do not cross it.
  • Pargeverine has a dual effect on the smooth muscle of the hollow viscera. On the one hand, the most important is its potent musculotropic effect, 96 times greater than that of Papaverine (the head drug of the musculotropic antispasmodic group), which is probably due to a blockage of calcium intake from the muscle cell. On the other hand, it exerts a mild neurotropic (anticholinergic) action by competing with acetylcholine for its muscarinic receptor, but with 17 times less potency than atropine. In this way Pargeverine quickly nullifies the painful spasm and allows the smooth muscle to regain its normal tone.
  • the subject-matter of this application relates to a manufacturing procedure for a novel pharmaceutical combination and the pharmaceutical combination obtained which comprises in its formulation immediate release microgranules containing the analgesic Tretoramine Ketorolac (5-Benzoyl-2,3-dihydro-1H-pyrrolysin-1-carboxylic acid , 2-amino-2-hydroxymethyl-1,3-propanediol), and scheduled release microgranules containing an antispasmodic agent such as hyoscine or pargeverine.
  • analgesic Tretoramine Ketorolac 5-Benzoyl-2,3-dihydro-1H-pyrrolysin-1-carboxylic acid , 2-amino-2-hydroxymethyl-1,3-propanediol
  • an antispasmodic agent such as hyoscine or pargeverine.
  • composition of this new combination has been designed to avoid the interaction of the active ingredients both during manufacture and in vivo once ingested by the patient.
  • microgranules containing each active ingredient are manufactured.
  • the microgranules containing the active ingredient Ketorolac of Tromethamine are designed to be immediate release, being made with nuclei composed of sugar and starch, to which the micronized active principle is incorporated by means of binder polymers.
  • high plasma analgesic concentrations are rapidly achieved.
  • microgranules containing the antispasmodic active ingredient Hioscin or Pargeverine are designed to be of. scheduled release, to which coating polymers are added to them to achieve the appropriate release profile. In this way the gradual release in the organism is achieved, in times and different areas of the analgesic.
  • the manufacturing procedure for a batch of 46,000 doses of each active agent comprises the following steps:
  • Step 1) Manufacture of the immediate release microgranules of the Tromethamine Ketorolac analgesic comprising the following substeps:
  • the weight of the final product will be from 3,680 kg to 5,520 kg, preferably 4,600 kg.
  • Step 2) Manufacture of the antiospasmodic release granules of the antiospasmodic Hioscin or Pargeverine comprising the following substeps:
  • talc and colorants Dry the mixture obtained in 2.3) at a temperature of 45 ⁇ 5 ° C for 8 to 16 hours, preferably 12 hours.
  • 0 weight of this mixture of talc and colorants will be of 0,402 kg to 0,602 kg, preferably 0.502 kg.
  • Povidone (PVP K30) solution by dissolving with stirring to a clear solution of 0.080 Kg to 0.120 Kg, preferably 0.100 Kg of Povidone (PVP K30) with 0.700 Kg to 1200 Kg, preferably 0.900 kg of isopropyl alcohol, obtaining from 0.780 kg to 1.320 kg, preferably 1.000 kg of 10% Povidone solution (PVP K30).
  • the formula or composition for a batch of 46,000 doses each containing microgranules of the Tromethamine Ketorolac analgesic is as follows:
  • Tromethamine Ketorolac from 0.300 kg to 0.700 kg, preferably 0.500 kg
  • Core from 2,800 kg to 4,200 kg, preferably 3,498 kg
  • Purified Water and Alcohol Isopropyl compounds are not present because they are volatile components.
  • the formula or composition for a batch of 46,000 doses each containing microgranules of the antiospasmodic Hioscin or Pargeverine is as follows:
  • Hyoscine or Pargeverine from 0.400 kg to 0.600 kg, preferably 0.500 kg;
  • Tartrazine Yellow Dye from 1,000 g to 1,525g, preferably 1,271g;
  • Bright Blue Dye 0.990. g to 1.490 g, preferably 1.241g;
  • Core from 2,800 kg to 4,200 kg, preferably 3,498 kg;
  • Purified water and isopropyl alcohol are not present as they are volatile components.
  • Tromethamine Ketorolac 2.5% to 15% by weight
  • Hyoscine or Pargeverine 2 : 5% to 15% by weight
  • Coating Polymers 1% to 5% by weight
  • the sum of the weight percentages of each component should be 100%.

Landscapes

  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Animal Behavior & Ethology (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Medicinal Chemistry (AREA)
  • Veterinary Medicine (AREA)
  • Public Health (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Organic Chemistry (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • General Chemical & Material Sciences (AREA)
  • Emergency Medicine (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé de fabrication d'une combinaison pharmaceutique contenant un agent analgésique et un agent anti-spasmodique et une combinaison pharmaceutique, et notamment un procédé de fabrication d'une nouvelle combinaison pharmaceutique contenant un agent analgésique, ou kétorolac de trométhamine, et un agent anti-spasmodique, du type hyoscine ou pargévérine, chacun de ces agents actifs étant fabriqué sous forme de microgranules, à libération immédiate pour le kétorolac et à libération programmée pour l'hyoscine ou la pargévérine, avec ajout à ces derniers de polymères d'enrobage en vue de l'obtention du profil de libération approprié, les microgranules étant incorporés dans une capsule en différentes proportions. Le procédé comprend les étapes suivantes : 1) : Fabrication des microgranules à libération immédiate de l'analgésique kétorolac de trométhamine avec un total de dix sous-étapes; 2) : Fabrication des microgranules à libération programmée de l'anti-spasmodique hyoscine ou pargévérine avec un total de dix sous-étapes. La composition du contenu de chaque capsule avec les microgranules à libération immédiate de l'analgésique kétorolac de trométhamine et les microgranules à libération programmée de l'anti-spasmodique hyoscine ou pargévérine est la suivante : kétorolac de trométhamine : 2,5% à 15% en poids, hyoscine ou pargévérine : 2,5% à 15% en poids, povidone (PVP K30) : 1% à 5% en poids, talc blanc : 5% à 30% en poids, colorants (jaune + vert) : 0,03% à 0,06% en poids, noyau (sucre et amidon) : 87,97% à 29,94% en poids, polymères d'enrobage : 1% à 5% en poids.
PCT/BR2014/000214 2013-08-28 2014-06-30 Procédé de fabrication d'une combinaison pharmaceutique contenant un agent analgésique et un agent anti-spasmodique et combinaison pharmaceutique Ceased WO2015027303A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
BR102013021950-9A BR102013021950B1 (pt) 2012-10-04 2013-08-28 procedimento de fabricação de combinação farmacêutica contendo agente analgésico e agente antiespasmódico e combinação farmacêutica
BRBR1020130219509 2013-08-28

Publications (1)

Publication Number Publication Date
WO2015027303A1 true WO2015027303A1 (fr) 2015-03-05

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PCT/BR2014/000214 Ceased WO2015027303A1 (fr) 2013-08-28 2014-06-30 Procédé de fabrication d'une combinaison pharmaceutique contenant un agent analgésique et un agent anti-spasmodique et combinaison pharmaceutique

Country Status (1)

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016041036A1 (fr) * 2014-09-19 2016-03-24 Diffucap Chemobras Química E Farmacéutical Ltda Combinaison pharmaceutique contenant un agent analgésique et un agent antispasmodique

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033448A1 (fr) * 1997-12-23 1999-07-08 Merck Patent Gmbh Comprime a liberation instantanee et prolongee d'un ou de plusieurs principes actifs
WO2014075155A1 (fr) * 2012-11-14 2014-05-22 Diffucap Chemobras Química E Farmacêutica Ltda Combinaison pharmaceutique contenant un agent analgésique et un agent antispasmodique

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1999033448A1 (fr) * 1997-12-23 1999-07-08 Merck Patent Gmbh Comprime a liberation instantanee et prolongee d'un ou de plusieurs principes actifs
WO2014075155A1 (fr) * 2012-11-14 2014-05-22 Diffucap Chemobras Química E Farmacêutica Ltda Combinaison pharmaceutique contenant un agent analgésique et un agent antispasmodique

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DEL VALLE-LAISEQUILLA, CF ET AL.: "Ketorolac tromethamine improves the analgesic effect of hyoscine butylbromide in patients with intense cramping pain from gastrointestinal or genitourinary origin.", ARZNEIMITTEL-FORSCHUNG DRUG RESEARCH, vol. 62, no. 12, 23 December 2012 (2012-12-23), pages 603 - 8 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2016041036A1 (fr) * 2014-09-19 2016-03-24 Diffucap Chemobras Química E Farmacéutical Ltda Combinaison pharmaceutique contenant un agent analgésique et un agent antispasmodique

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