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WO2016137266A2 - Composition pharmaceutique contenant de l'épérisone et du pélubiprofène - Google Patents

Composition pharmaceutique contenant de l'épérisone et du pélubiprofène Download PDF

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Publication number
WO2016137266A2
WO2016137266A2 PCT/KR2016/001911 KR2016001911W WO2016137266A2 WO 2016137266 A2 WO2016137266 A2 WO 2016137266A2 KR 2016001911 W KR2016001911 W KR 2016001911W WO 2016137266 A2 WO2016137266 A2 WO 2016137266A2
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WIPO (PCT)
Prior art keywords
release
pelubiprofen
mixed
combined
water
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/KR2016/001911
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English (en)
Korean (ko)
Other versions
WO2016137266A3 (fr
Inventor
채보람
이경민
김정률
황한준
송세현
손세일
이홍우
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.)
DAE WON PHARMACEUTICAL CO LTD
Daewoong Pharmaceutical Co Ltd
Original Assignee
DAE WON PHARMACEUTICAL CO LTD
Daewoong Pharmaceutical Co Ltd
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Publication of WO2016137266A2 publication Critical patent/WO2016137266A2/fr
Publication of WO2016137266A3 publication Critical patent/WO2016137266A3/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
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
    • A61K31/19—Carboxylic acids, e.g. valproic acid
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic acid 
    • 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
    • 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
    • A61K31/4453—Non condensed piperidines, e.g. piperocaine only substituted in position 1, e.g. propipocaine, diperodon
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/44—Oils, fats or waxes according to two or more groups of A61K47/02-A61K47/42; Natural or modified natural oils, fats or waxes, e.g. castor oil, polyethoxylated castor oil, montan wax, lignite, shellac, rosin, beeswax or lanolin
    • 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
    • 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
    • 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
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants

Definitions

  • the present invention relates to a pharmaceutical composition containing eferison and pelubiprofen. More specifically, the present invention relates to a formulation characterized in that the release pattern of pelubiprofen and the release pattern of eferison are different from each other. Furthermore, the present invention relates to a pharmaceutical composition characterized by slowing the release of pelubiprofen, inhibiting elution in the gastrointestinal tract, and causing major elution in the small intestine.
  • Pelubiprofen is a nonsteroidal anti-inflammatory drug (NSAID) developed by the applicant as the 12th domestic new drug and is a drug used for pain treatment.
  • NSAID nonsteroidal anti-inflammatory drug
  • Pelubiprofen is a cyclogenase inhibitor and is used for the treatment of osteoarthritis, rheumatoid arthritis, low back pain and the like.
  • Eperisone acts as a relaxant in musculoskeletal smooth muscle and vascular smooth muscle, and is used to treat painful muscular spasms associated with musculoskeletal disorders and spastic paralysis caused by neurological diseases.
  • Drugs and muscle relaxants of the NSAID family are currently available in the form of immediate release. Eperisone is taken three times a day, and most NSAID drugs are taken several times a day.
  • immediate release drugs are to be taken several times a day, so the fluctuation of drug concentration in the blood is large, so there is a high possibility of side effects.
  • the immediate release agent is low in the ease of taking the medication compliance of the patient is lowered, thereby reducing the effect of the drug because the blood drug concentration does not maintain the treatment area. Therefore, the use of such immediate release preparation causes problems such as an increase in the therapeutic effect and duration of treatment, and efforts have been made to develop the immediate release preparation as a controlled release preparation.
  • NSAID drugs In particular, in the case of NSAID drugs, the frequency of exposure in the gastrointestinal tract is increased by taking several times a day, thereby increasing the incidence of gastrointestinal side effects. In order to improve the gastrointestinal side effects, attempts have been made to prepare NSAID drugs as enteric preparations to reduce gastric exposure and to be administered with NSAIDs and gastritis treatments, and controlled release agents that reduce the daily dose. ought.
  • Korean Laid-Open Patent Publication No. 2014-0118412 discloses a sustained-release preparation composition containing eferison as an active ingredient, wherein the eferison pharmaceutical composition having storage and pH stability is 50 to 90% by weight; 1-20% by weight of hydroxypropylmethylcellulose (HPMC) as a release controlling agent; And a sustained release formulation composition containing epheryson as an active ingredient comprising 5 to 45% by weight of controlled release polymer.
  • 2012-52080 relates to an epherizone-containing sustained-release tablet and a method for preparing the same, wherein the eperison includes polyvinylacetate, vinylpyrrolidone-vinylacetate copolymer, and hydroxypropylmethylcellulose.
  • the eperison includes polyvinylacetate, vinylpyrrolidone-vinylacetate copolymer, and hydroxypropylmethylcellulose.
  • Compositions in sustained-release form are disclosed.
  • the formulations disclosed in the preceding patent literature on the basis of the known fact that epherisone is unstable in the alkaline region, lower the ambient pH environment of epherisone in the formulation (e.g. 5.6 or less), and therefore, it does not relate to a technique for preferably expressing the dissolution pattern of eferison.
  • it is important that the release of eferison from the formulation is mostly in the gastrointestinal tract, but no prior formulations have been disclosed.
  • Korean Patent Publication No. 922519 which was previously filed by the present applicant, includes felrubiprofen having an average particle diameter of 1 to 30 ⁇ m as an active ingredient.
  • a pharmaceutical preparation for oral administration for anti-inflammatory analgesics which has a dissolution rate and stability, containing an excipient such as lactose and the like, is improved.
  • pelubiprofen is a drug with a short half-life, so it needs to be taken several times a day to effectively control pain.
  • NSAIDs such as pelubiprofen have low medication compliance when taken several times a day and increase the frequency of drug exposure to the gastrointestinal tract, thereby increasing the incidence of gastrointestinal side effects. Therefore, if the number of doses can be reduced as a pharmaceutical formulation containing pelubiprofen as an active ingredient, it is expected that the ease of taking and the side effects of the gastrointestinal tract will be reduced. .
  • Korean Laid-Open Patent Publication No. 2008-39400 discloses a sustained-release pharmaceutical composition of a high water-soluble drug containing an active ingredient having a short half-life and a hydrophilic polymer.
  • Korean Patent Publication No. 167078 discloses a sustained release oral dosage form comprising ibuprofen and the like as an active ingredient, comprising a plurality of drug particles dispersed in a hydrophilic, water-swellable polymer.
  • sustained release formulations disclosed so far have merely focused on delaying the release of the drug from the formulation and have not been in mind with the reduction of gastrointestinal side effects of pelubiprofen.
  • the present invention provides a novel sustained-release formulation for reducing the gastrointestinal side effects while slowing the release of felubiprofen in a novel pharmaceutical formulation comprising felubiprofen and eperison. do.
  • the administration of pelubiprofen and epherisone once or twice a day can have an analgesic effect for 12 hours or 24 hours, and the treatment is provided by providing the ease of administration to the patient by reducing the frequency of drug administration. Increasing effectiveness and reducing gastrointestinal side effects.
  • One aspect of the present invention may be a double tablet consisting of a first layer containing felubipropene and a second layer containing eferison, but is not limited thereto, and may be embodied in conventional formulations such as nuclear tablets or capsules. have.
  • the preparation of the present invention contains pelubiprofen and epherisone as active ingredients, and the following characteristics exist in formulating and sustaining-release each of these active ingredients.
  • felubiprofen since felrubiprofen has a half-life within 6 hours, a plurality of daily administrations are necessary to effectively control pain. Therefore, sustained release of pelubiprofen is advantageous in terms of dose compliance, but in order to prevent gastrointestinal side effects, it is additionally required to suppress drug release in the gastrointestinal tract and to continue drug release in the small intestine region as much as possible. do.
  • sustained release means used in the prior art utilizes the technical idea of forming a gel layer to prolong the erosion of the formulation and slow the diffusion of the drug when the formulation is in contact with body fluids, generally a hydrogel such as a cellulose polymer or It is usually selected from water soluble polymers such as polyethylene oxide or methacrylate polymers.
  • the present inventors earnestly studied the sustained-release pharmaceutical formulation containing felubiprofen, surprisingly, when containing the felubiprofen and the water-insoluble polymer as the release control polymer, the release of the drug in the gastrointestinal tract
  • the present invention has been completed by finding that the sustained release is limited in the small intestine region.
  • the dissolution rate of pelubiprofen in the gastrointestinal region is minimized to reduce the gastrointestinal exposure of the drug to reduce gastrointestinal side effects, and the bioavailability is maximized in the small intestine region, which is the main absorption site of the drug. Increase the treatment effect.
  • the sustained release of pelubiprofen using a water-insoluble polymer in the release control polymer it is possible to minimize the release in the gastrointestinal region and to maximize the release in the small intestine region, unlike other conventional NSAID drugs. It's an amazing discovery in that it's another unusual phenomenon.
  • the water-insoluble polymer include carbomer, calcium carboxymethyl cellulose, cellulose acetate phthalate, methyl cellulose and ethyl cellulose.
  • cellulose derivatives selected from hydroxypropylmethyl cellulose phthalate, waxes such as microcrystalline lead, white lead, carnauba lead, light lead, lead emulsion, methacrylate copolymer, polyvinylacetate, collidone SL and mixtures thereof
  • waxes such as microcrystalline lead, white lead, carnauba lead, light lead, lead emulsion, methacrylate copolymer, polyvinylacetate, collidone SL and mixtures thereof
  • methacrylate copolymer polyvinylacetate, collidone SL and mixtures thereof
  • eferison another active ingredient of the present invention, unlike pelubiprofen, rather, most of the release is preferably performed in the gastrointestinal tract, which is easily broken down into the piperidine ring in an alkaline environment. This is because it has very unstable characteristics. In other words, since the efericone is decomposed due to the low stability when released in the small intestine region, which is an alkaline environment, the controlled release of the efericone should be designed to be mostly released in the gastrointestinal region.
  • the inventors of the present invention when the sustained release of the pelubiprofen using the water-insoluble polymer, and at the same time to release the eferison using a water-soluble or non-aqueous polymer, the eferison is different from the pelubiprofen Otherwise, most of the shapes released in the gastrointestinal tract were found.
  • a water-insoluble polymer for controlled release of pelubipropene may be used, and as the water-soluble polymer for controlled release of efericone, hydroxypropylmethyl cellulose, hydroxypropyl cellulose, hydride Cellulose derivatives selected from hydroxymethylcellulose, hydroxyethylcellulose, methylcellulose, carboxymethylcellulose sodium, hydroxypropylmethylcellulose acetate succinate, hydroxyethylmethylcellulose, guar gum, locust bean gum, tragacanta, carrageenan, Gums selected from acacia gum, gum arabic, gellan gum, xanthan gum, polyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl acetal diethylamino acetate, and the like.
  • the dissolution rate of pelubiprofen in the gastrointestinal area for 2 hours is less than 30%. This means that the release of felubiprofen in the gastrointestinal tract is extremely limited, and in the case of using a conventional sustained release material, a large amount of felubiprofen is released in the gastrointestinal tract, which is a characteristic of the present invention. Configure.
  • the drug release in the gastrointestinal tract is suppressed by the combination of pelubiprofen and the water-insoluble polymer, because for other active ingredients belonging to the NSAID, for example, ketoprofen or roxof Lofen and the like do not reduce drug release in the gastrointestinal tract even when combined with a water-insoluble polymer.
  • the drug release in the gastrointestinal tract is lowered by the combination with the water-insoluble polymer and the expression of adverse gastrointestinal side effects is a unique characteristic achieved by the combination of the pelubiprofen and the water-insoluble polymer.
  • the dissolution rate of felubiprofen in the small intestine region during 2 hours is 50% or more. This means that felubiprofen is continuously released in the small intestine area, thus, it is possible to achieve a release pattern that exhibits the efficacy of the drug while reducing the frequency of administration.
  • drug release in the gastrointestinal and small intestine regions is based on pH 1.2 eluate and pH 6.8 eluate.
  • compositions of the present invention can be prepared in various forms of formulations, such as single tablets, double tablets or capsules.
  • a water-soluble or non-aqueous polymer is included in the first layer containing felubiprofen, and the water-soluble or non-aqueous polymer is included in the second layer containing epherizone to form a bilayer tablet.
  • felubiprofen a water-soluble or non-aqueous polymer is included in the first layer containing felubiprofen
  • the water-soluble or non-aqueous polymer is included in the second layer containing epherizone to form a bilayer tablet.
  • the content of the water-insoluble polymer in the double tablet may be included in an amount of 1% by weight to 50% by weight based on the total weight of the composition constituting each layer, based on the felubipropene layer and the eferison layer, The content may be included in an amount of 10% by weight to 60% by weight, and the content of epherisone in an amount of 20% by weight to 60% by weight.
  • the preparation according to the present invention is prepared by mixing pelubiprofen or epherisone with an excipient and a binder, and then using a suitable solvent, followed by drying to prepare tableting granules or filling granules. Then, it can be prepared by adding pharmaceutically acceptable excipients such as water-insoluble polymers and lubricants. Alternatively, other assembly methods commonly known in the art may be used.
  • lactose, calcium hydrogen phosphate, starch, polyol may be used, and mannitol, isomalt, xylitol may be used as the polyol;
  • binder hydroxypropyl cellulose, polysaccharide may be used, and as the polysaccharide, xanthan gum and carrageenan may be used;
  • disintegrant carboxymethyl cellulose calcium, low-substituted hydroxypropyl cellulose, starch can be used;
  • lubricant magnesium stearate and talc can be used.
  • the content of the additives can be appropriately used by those skilled in the art according to a specific prescription, 10 to 50% by weight of excipient, 1 to 25% by weight of binder, 1 to 25% by weight of disintegrant, lubricant It may be included in 0.5 to 10% by weight.
  • the form of the pharmaceutical preparation for oral administration according to the present invention is preferably double tablets.
  • preferred examples are provided to aid in understanding the present invention.
  • the following examples are merely provided to more easily understand the present invention, and the technical spirit of the present invention should not be construed as being limited thereto.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • pelubiprofen 90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of ethyl cellulose and 4.6 g of magnesium stearate were added to the sieved material to prepare a pelubiprofen mixture.
  • eferison hydrochloride 150 g of eferison hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were mixed, combined with ethanol, and dried. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • eferison hydrochloride 150 g of eferison hydrochloride, 120 g of lactose hydrate, and 4 g of hydroxypropyl cellulose were mixed and then combined with ethanol, followed by drying. 50 g of hydroxypropyl cellulose, 60 g of prosolve, and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • eferison hydrochloride 150 g of eferison hydrochloride, 120 g of lactose hydrate, and 4 g of hydroxypropyl cellulose were mixed and then combined with ethanol, followed by drying. 40 g of carbomer, 60 g of prosolve, and 3 g of magnesium stearate were added to the sieved material, and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 4 g of hydroxypropyl cellulose, and 100 g of eudragitacese were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, and 4 g of hydroxypropyl cellulose were mixed and then combined with ethanol, followed by drying. 100 g of collidone AL, 60 g of prosolve, and 3 g of magnesium stearate were added to the sieved material, and the mixture was mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • eferison hydrochloride 150 g of eferison hydrochloride, 120 g of lactose hydrate, 4 g of hydroxypropyl cellulose, and 50 g of hypromellose were mixed and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • eferison hydrochloride 150 g of eferison hydrochloride, 120 g of lactose hydrate, 4 g of hydroxypropyl cellulose, and 50 g of hypromellose were mixed and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • eferison hydrochloride 150 g of eferison hydrochloride, 120 g of lactose hydrate, 4 g of hydroxypropyl cellulose, and 50 g of hypromellose were mixed and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Magnesium stearate was added to each of the two prepared mixtures and mixed to prepare a mixture, which was then compressed into a single tablet.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve was added to the formulation and mixed to prepare an eferison hydrochloride mixture. Magnesium stearate was added to each of the two prepared mixtures and mixed to prepare a mixture, which was then compressed into a single tablet.
  • pelubiprofen 90 g of pelubiprofen, 90 g of lactose, and 4.6 g of hydroxypropyl cellulose were mixed, combined with water, and dried to form. 25 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material to prepare a pelubiprofen mixture, which was compressed into tablets.
  • eferison hydrochloride 150 g of eferison hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined, and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture.
  • the inner core tablet was prepared using the core tablet obtained from the pelubipropene mixture as the inner core, and the inner core tablet was prepared using an inner core tablet press machine together with the eferison hydrochloride mixture.
  • eferison hydrochloride 150 g of eferison hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined, and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture, which was compressed using a tablet press equipped with a fine tablet punch. The micro tablets corresponding to each dose were filled into capsules using a suitable capsule filling machine.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material, and mixed to prepare a mixture of the eferison hydrochloride layer. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • ketoprofen 90 g of ketoprofen, 90 g of lactose monohydrate, and 4.6 g of hydroxypropyl cellulose were mixed and then combined with water, followed by drying and sizing. 25 g of collidone AL and 4.6 g of magnesium stearate were added to the sieved material and mixed to prepare a ketopropene mixture.
  • epherisone hydrochloride 150 g of epherisone hydrochloride, 120 g of lactose hydrate, 50 g of hypromellose, and 4 g of hydroxypropyl cellulose were combined and then combined with ethanol, followed by drying. 60 g of prosolve and 3 g of magnesium stearate were added to the sieved material and mixed to prepare an eferison hydrochloride mixture. Double tablets were prepared using a tableting machine using the two mixtures prepared respectively.
  • the dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour and 2 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)
  • Example 1 pH pH 1.2 pH 6.8 time 1 hours 2 hours 1 hours 2 hours 4 hours
  • Example 1 1.8 4.9 37.7 83.5 98.7
  • Example 2 1.3 8.3 21.3 55.4 78.4
  • Example 3 0.3 2.1 18.4 57.1 72.5
  • Example 4 1.5 3.3 77.8 98.8 99.7
  • Example 5 1.9 16.3 88.2 95.3 96.4
  • Example 6 13.5 21.3 16.3 55.8 77.8
  • Example 7 1.8 5.3 38.8 69.8 98.3 Comparative Example 1 33.8 54.6 32.8 59.3 85.1 Comparative Example 2 42.8 63.8 33.2 63.2 82.9
  • the dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour and 2 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)
  • the dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour, 2 hours and 4 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)
  • the dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour, 2 hours and 4 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)
  • the dissolution test was conducted in accordance with the Dissolution Test Method 1 (rotational sample method) of the Korean Pharmacopoeia General Test Method. After 1 hour, 2 hours and 4 hours after the start of the test, the eluate was collected, filtered and analyzed by HPLC. (unit %)
  • composition of the present invention through the combination of pelubiprofen and the water-insoluble polymer, the release of pelubiprofen in the gastrointestinal tract.
  • active ingredients belonging to the NSAID for example, ketoprofen or loxoprofen was confirmed that drug release is not reduced in the gastrointestinal tract even when combined with a water-insoluble polymer.
  • composition of the present invention is made of a combination of felubiprofen and a water-insoluble polymer
  • felubiprofen release is limited in the gastrointestinal tract and maximization of the release of eperison, It can be seen that the release is continuous.

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Abstract

L'invention concerne une composition pharmaceutique contenant du pélubiprofène, de l'épérisone et un polymère insoluble dans l'eau.
PCT/KR2016/001911 2015-02-27 2016-02-26 Composition pharmaceutique contenant de l'épérisone et du pélubiprofène Ceased WO2016137266A2 (fr)

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KR10-2015-0028626 2015-02-27
KR1020150028626A KR20160105662A (ko) 2015-02-27 2015-02-27 에페리손과 펠루비프로펜을 함유하는 약제학적 조성물

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KR101856911B1 (ko) * 2017-12-13 2018-05-10 동국대학교 산학협력단 펠루비프로펜의 서방성 고체분산체 제제 및 이의 제조방법
KR102462607B1 (ko) * 2020-11-11 2022-11-03 대원제약주식회사 펠루비프로펜 신규 염을 주성분으로 하는 안정성이 증가된 약학적 조성물

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US5007790A (en) 1989-04-11 1991-04-16 Depomed Systems, Inc. Sustained-release oral drug dosage form
US8007827B2 (en) * 2004-04-02 2011-08-30 Impax Laboratories, Inc. Pharmaceutical dosage forms having immediate release and/or controlled release properties
KR20050114921A (ko) * 2004-06-02 2005-12-07 씨제이 주식회사 방출제어형 약제학적 조성물
CN101257894A (zh) 2005-07-07 2008-09-03 法纳姆公司 高水溶性药物的缓释药物组合物
KR101230731B1 (ko) * 2008-04-29 2013-02-07 한올바이오파마주식회사 약제학적 제제
KR20100053424A (ko) * 2009-07-06 2010-05-20 대원제약주식회사 펠루비프로펜을 함유하는 용출률 및 안정성이 개선된 경구투여용 약제학적 제제
KR101497354B1 (ko) 2013-03-29 2015-03-02 초당약품공업 주식회사 활성 성분으로 에페리손을 함유하는 서방성 제제 조성물

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