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
  • A61K9/14—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
  • A61K9/1617—Organic compounds, e.g. phospholipids, fats
  • A61K9/1623—Sugars or sugar alcohols, e.g. lactose; Derivatives thereof; Homeopathic globules
• • 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
  • A61K31/235—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group
  • A61K31/24—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids having an aromatic ring attached to a carboxyl group having an amino or nitro group
• • 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
  • A61K9/5005—Wall or coating material
  • A61K9/5021—Organic macromolecular compounds
  • A61K9/5052—Proteins, e.g. albumin

Definitions

• the present invention relates to modified release formulations comprising an antispasmodic as the active agent and their areas of use.
• Mebeverine is an antispasmodic active agent having the chemical name (&S)-4-(ethyl[l-(4- methoxyphenyl)propan-2-yl]amino)butyl 3 ,4-dimethoxybenzoate.
• the active agent is in dragee (100 mg), modified release capsule (200 mg) and liquid (10 mg/ml) dosage forms.
• These pharmaceutical formulations comprising the active agent are used in the treatment of irritable bowel syndrome, chronic irritable colon, spastic constipation, mucous colitis, spastic colitis and similar diseases and for symptoms of abdominal pain and spasms related to these diseases, persistent diarrhea with or without constipation and bloating in stomach and bowels.
• Bioavailability of the active agent is pretty low and this requires intake of more than one dose daily in order to observe therapeutic effect.
• dragee form is suggested to be taken four times daily in the treatment of said diseases.
• liquid dosage forms are used three times a day.
• the active agent is preferred to act directly in bowels.
• Mebeverine which already has a pretty low bioavailability, is metabolized until reaching to the bowels when taken by the oral route and the required therapeutic activity cannot be provided.
• dosage forms of the active agent that can directly be applied into the bowels such as suppository can be developed.
• these dosage forms cause serious limitations in terms of patient adaptation. Patients express that they do not feel comfortable during and after use of the dosage form and they do not want to use the dosage form.
• Formulations comprising the active agent are formulated in form of modified release capsules for use twice a day in the prior art. Decreasing the frequency of administration of the active agent provides advantages such as improving the efficiency, decreasing undesired effects, reducing fluctuations on pharmacokinetic criteria therefore on clinical effect, improving adaptation of patients and increasing treatment costs.
• modified release dosage forms of the active agent There exist various studies on modified release dosage forms of the active agent. For instance, in a study published by P. M. Dandagi et. al.*, formulations which are formulated in form of modified release microspheres are disclosed. Formulations according to this study are prepared by emulsifying a polymer solution composed of mebeverine and methacrylic group polymers and obtaining modified release microspheres from this emulsion (*pH-Sensitive Mebeverine Microspheres for Colon Delivery, Indian J Pharm Sci. 2009 Jul-Aug; 71(4): 464- 468).
• microsphere formulations produced according to the method given in this study pose various difficulties.
• the method given in the study is a considerably difficult method to apply in which emulsion conditions (environment, temperature etc.) have to be adjusted in earnest.
• the microspheres are washed with petroleum ether or n-hexane at a temperature in the range of 40 °C and 60 °C and dried at room temperature for at least 3 hours.
• These process steps carry significant risks in terms of leading to chemical degradation in the formulations.
• Formulating a formulation using minimum number of chemical processes is preferable in terms of pharmaceutical technology.
• particle size has to be adjusted sensitively in the microspheres obtained by this method.
• desired release properties cannot be provided in the final dosage form and efficiency of the treatment decreases.
• formulations comprising mebeverine there appears a need for new approaches which can provide perfect patient adaptation, can be produced easily and have high bioavailability by means of providing appropriate release properties.
• formulations of the present invention are that they can be produced more easily than the modified release dosage forms in the prior art and they have more stable release properties.
• the present invention relates to modified release pellet formulations of mebeverine.
• a characteristic feature of the formulations of the present invention is that the formulations comprise mebeverine as the active agent and they are in modified release pellet form.
• mebeverine used herein refers to mebeverine and/or pharmaceutically acceptable solvates, hydrates, enantiomers, racemates, organic salts, inorganic salts, polymorphs, crystalline and amorphous forms of mebeverine or combinations thereof.
• modified release mebeverine pellet formulations of the present invention comprise the active agent at more than 70%, preferably in the range of 70% and 95%, more preferably in the range of 70% and 90% by weight.
• the active agent used in the modified release pellet formulations of the present invention comprising mebeverine is preferably mebeverine hydrochloride.
• the formulations of the present invention are formulated so as to dissolve in basic intestine pH for improving therapeutic effect.
• the modified release formulations of the present invention dissolve in a pH value in the range of 6-7.
• modified release pellet form refers to pellet formulations which dissolve in the range of 30% and 55% at the end of 2 hours; in the range of 50% and 80% at the end of 6 hours; at minimum70%, preferably in the range of 70% and 99% at the end of 12 hours in a pH value in the range of 6-7.
• modified release pellet formulations of the present invention dissolve in the range of 30% and 55% at the end of 2 hours; in the range of 50% and 80% at the end of 6 hours; at minimum70%, preferably in the range of 70% and 99% at the end of 12 hours in basic pH range (pH:6-7). Highest bioavailability and thus therapeutic effect could be obtained with pellet formulations of the present invention which enable the formulations to release in this profile.
• the modified release pellet formulations of the present invention comprising mebeverine comprise at least one pharmaceutically acceptable excipient in addition to the active agent mebeverine.
• the excipients that can be used in the modified release pellet formulations of the present invention comprising mebeverine are selected from a group comprising disintegrant, diluent, solvent, lubricant, glidant, binder, coloring agent, pH regulating agent, surfactant, stabilizing agent, sweetener and/or taste regulating agent, flavoring agent, plasticizers, rate controlling agents and filling agents or combinations thereof.
• the diluents that can be used in the modified release pellet formulations of the present invention comprising mebeverine are selected from a group comprising calcium carbonate, dibasic calcium phosphate, tribasic calcium phosphate, calcium sulfate, microcrystalline cellulose, dextrose, fructose, lactitol, lactose, magnesium carbonate, magnesium oxide, maltitol, maltodextrin, maltose, mannitol, simethicone, sorbitol, starch, sodium chloride, sucrose, talc, xylitol or combinations thereof.
• the diluent used in the modified release pellet formulations of the present invention comprising mebeverine is preferably sucrose.
• Particle size of the diluent used in the formulations is a significant parameter when preparing the formulations in pellet form as they provide easy processing. According to this, average particle size of sucrose used in the modified release pellet formulations of the present invention comprising mebeverine is larger than 250 ⁇ , preferably larger than 350 ⁇ , more preferably in the range of 450 ⁇ and 700 ⁇ .
• binders that can be used in the modified release pellet formulations of the present invention comprising mebeverine are selected from a group comprising starches such as potato starch, corn starch, wheat starch; sugars such as sucrose, glucose, dextrose, lactose, maltodextrin; natural and synthetic gums; gelatine; cellulose derivatives such as macrocrystalline cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, carboxymethyl cellulose, methyl cellulose, ethyl cellulose; polyvinylpyrrolidone (povidone); polyethylene glycol (PEG); waxes; calcium carbonate; calcium phosphate; alcohols such as dibasic calcium phosphate, sorbitol, xylitol, mannitol and water or a combination thereof.
• starches such as potato starch, corn starch, wheat starch
• sugars such as sucrose, glucose, dextrose, lactose, mal
• plasticizers that can be used in the modified release pellet formulations of the present invention comprising mebeverine are selected from a group comprising dibutyl sebacate, diethyl phthalate, castor oil, propylene glycol, glycerol, polyethylene glycols, liquid sorbitol and/or combinations thereof.
• the lubricants that can be in the modified release pellet formulations of the present invention comprising mebeverine are selected from a group comprising calcium stearate, magnesium stearate, polyethylene glycol, sodium benzoate, potassium benzoate, sodium lauryl sulfate, talc, stearic acid, zinc stearate or combinations thereof.
• the pellet formulations of the present invention comprising mebeverine are coated with a coating comprising at least one pharmaceutically acceptable rate controlling agent and at least another excipient in order to provide release property.
• the rate controlling agents that can be used to coat the modified release pellet formulations of the present invention comprising mebeverine can be selected from a group comprising cellulose derivatives such as ethyl cellulose, cellulose acetate, hydroxypropyl cellulose, hydroxymethyl cellulose, methyl cellulose; alginic acid or pharmaceutically acceptable salts of alginic acid (for example sodium alginate), vinyl acetate copolymers, polysaccharides, polyethylene oxide or combinations thereof.
• methacrylic acid or its derivates for example metal methacrylate
• pellet formulations of the present invention are coated with a coating comprising a cellulose derivative rate controlling agent at least at 2%, preferably in the range of 2% and 6%, more preferably in the range of 2% and 5% by weight in proportion to total dosage form weight and at least another excipient.
• the rate controlling agents here can be ethyl cellulose, cellulose acetate, hydroxypropyl cellulose, hydroxymethyl cellulose and/or methyl cellulose.
• the present invention further discloses a production method for modified release pellet formulations comprising mebeverine.
• the modified release pellet formulations of the present invention comprising mebeverine are prepared by preparing pellet formulations , comprising mebeverine and at least another excipient; coating the prepared formulations with a coating comprising ethyl cellulose, cellulose acetate, hydroxypropyl cellulose, hydroxymethyl cellulose and/or methyl cellulose and at least another excipient in order to provide modified release property.
• Pellets of the present invention are prepared by the method of spraying a pharmaceutically acceptable solvent or solvent mixture on the mixture composed of active agent and at least one excipient.
• modified release pellet formulations of mebeverine of the present invention are prepared according to the method comprising the steps of;
• pellet formulations of the present invention can optionally be compressed in tablet form or filled into capsules.
• modified release dosage forms of the present invention comprising mebeverine are presented as filled into a capsule made of preferably hard or soft gelatin.
• modified release pellet formulations of the present invention comprising mebeverine are prepared in capsule dosage form.
• Mebeverine hydrochloride is sieved
• the sieved active agent and sucrose- are prepared in pellet form with a binder solution composed of the binder and optionally at least one solvent,
• Dry pellets are coated with a coating solution comprising ethyl cellulose, plasticizer and lubricant,

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Citations (1)

• 2013
  • 2013-07-02 WO PCT/TR2013/000204 patent/WO2014007776A1/fr not_active Ceased

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