WO1993000891A1 - Preparation enterique sensible aux enzymes destinee a une administration orale - Google Patents

Preparation enterique sensible aux enzymes destinee a une administration orale Download PDF

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Publication number
WO1993000891A1
WO1993000891A1 PCT/US1992/005245 US9205245W WO9300891A1 WO 1993000891 A1 WO1993000891 A1 WO 1993000891A1 US 9205245 W US9205245 W US 9205245W WO 9300891 A1 WO9300891 A1 WO 9300891A1
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Prior art keywords
preparation
medicine
fatty acid
acid ester
solution
Prior art date
Application number
PCT/US1992/005245
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English (en)
Inventor
Toshiaki Nishihata
Mayumi Narita
Ken Yamamoto
Original Assignee
The Upjohn Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by The Upjohn Company filed Critical The Upjohn Company
Publication of WO1993000891A1 publication Critical patent/WO1993000891A1/fr

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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
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841—Filling excipients; Inactive ingredients
    • A61K9/4858—Organic compounds
    • 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
    • A61K31/403—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 carbocyclic rings, e.g. carbazole
    • A61K31/404—Indoles, e.g. pindolol
    • A61K31/405—Indole-alkanecarboxylic acids; Derivatives thereof, e.g. tryptophan, indomethacin
    • 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
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • 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
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • 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

Definitions

  • the present invention provides a new means for administering pharmaceutical compounds orally.
  • the present invention relates to an enzyme-sensitive enteric pharmaceutical preparation for oral administration. More particularly, it relates to an enzyme-sensitive enteric pharmaceutical preparation which, after administered, releases a medicine in the small intestine by degradation of an oily vehicle (liquid carrier in a capsule, or pellet) by a pancreatic lipase or esterase.
  • an oily vehicle liquid carrier in a capsule, or pellet
  • enteric pharmaceutical preparations which are presently marketed are those depending upon (or is sensitive to) pH. That is, since pH in the stomach is generally in acidic range and pH in the small intestine is neutral range, the preparations are therefore obtained by coating on tablets or granules with polymers which degrade in neutral pH range but not in acidic pH range (e.g., celluloselose derivative or Eudragit) [see I.Mharaj et al., J.Pharam.Sci. , volume 73, page 59, 1988; S. Y.Lin et al., Pharm.Res., volume 4, page 70, 1987].
  • enteric preparations wherein small particles or granules disintegrate by a pancreatic lipase and thereby a medicine is released
  • this kind of dosage forms are fundamentally similar to those of triglyceride suppositories. Therefore, they have similar defects to those of the triglyceride suppositories. That is, firstly, since a medicine is in a suspended state, uniformity of a medicine in the preparation requires speci processes. Secondly, sometimes, storage in cold places is required for preservation.
  • the object of the present invention is to solve the problem of the above-described proposal and provide a pharmaceutical preparation which is enzyme- sensitive rather than pH-sensitive and is improved in enteric specificity.
  • the second object of the present invention is to provide a preparation wherein a medicine is dispersed uniformly therein, particularly in a fashion of monomolecular dispersion, because such the dispersion leads to improvement in absorbability and productivity of a very slightly soluble medicine.
  • a preparation wherein triglyceride having extremely low potency as a solubilizer can not accomplish this object.
  • the object of the present invention is t provide an enzyme-sensitive pharmaceutical preparation having excellent storage stability.
  • the present inventors have tried various methods. As a result, it has been unexpectedly found that the above object can be accomplished by firstly selecting oils of fatty acid esters which are easily degraded by an esterase in addition to pancreatic lipase having higher activity in the small intestine, and then selecting oils (solubilizers) which have higher potency for solubilizing a medicine, and further selecting oils which have higher partition coefficient from the selected oils.
  • the present invention provides an enzyme sensitive enteric pharmaceutical preparation for oral administration characterized in that a medicine is dissolve in a vehicle containing one or more fatty acid esters selected form a group consisting of glycerol fatty acid ester ( onoester, diester), polyoxyethylene sorbitan fatty acid ester, propylene glycol fatty acid ester, polyethylene glycol fatty acid ester, ethylene glycol fatty acid ester and decaglycerol fatty acid ester.
  • glycerol fatty acid ester onoester, diester
  • polyoxyethylene sorbitan fatty acid ester propylene glycol fatty acid ester
  • polyethylene glycol fatty acid ester polyethylene glycol fatty acid ester
  • ethylene glycol fatty acid ester ethylene glycol fatty acid ester
  • decaglycerol fatty acid ester decaglycerol fatty acid ester
  • the medicines to be contained in the pharmaceutical preparation of the present invention are not specifically limited.
  • a medicine having influence on stomach disorder a medicine which is unstable in gastric solution (including ones having unstable fundamental structure, or a medicine of which properties changes by desalting from a salt of the compound) can be contained.
  • nonsteroidal antiphlogistic and analgesic agents indomethacin, sodium diclofenac, aspirin
  • general aromatic halogenated compound indomethacin, sodium diclofenac, aspirin
  • antianxiety agents ⁇ -78875 (merchandise number of THE UPJOHN COMPANY)
  • thrombolytic agents initazigrel
  • anti-malignant tumor agents menogaril, bropyrimine
  • vitamins vitamin A palmitate, vitamin 1(3, tocopherol, ubiquinone, coenzyme-type vitamin B 12 , biotin
  • the above medicine are contained in the preparation by dissolving them in a particular solubilizer.
  • a solubilizer those having higher sensitivity to pancreatic lipase or esterase which is an enzyme having higher activity in small intestine are used. This time, it has been found that, by using such the enzyme-sensitive solubilizer, the specific properties for releasing a medicine in small intestine is improved.
  • fatty acid esters which are known as a nonionic surfactant, that is, glycerol mono-fatty acid ester (glycerol mono-caprate, glycerol mono-myristate, glycerol mono-stearate, glycerol mono-oleate etc.), glycerol di-fat acid ester (glycerol di-caprylate, glycerol di-myristate, glycerol di-stearate, glycerol di-oleate etc.), polyoxyethylene sorbitan fatty acid ester (polyoxyethylene sorbitan mono-oleate (polysorbate 80), polyoxyethylene sorbitan mono-stearate, polyoxyethylene sorbitan mono- palmitate etc.), propylene glycol fatty acid ester (propylene glycol mono-caprylate, propylene glycol ono-is octanate, propylene glycol di-cap
  • polysorbate 80 glycerol mono-caprylate, glycerol mono- stearate, polyethylene glycol mono-stearate are preferable.
  • solubilizers may be also appropriately used as a mixture of more than one of them.
  • the amount of the solubilizer to be used can be appropriately selected depending upon the kind of a particular solubilizer, a particular medicine to be dissolved, purpose of the use and the like. In any event. the solubilizer is used in an amount to dissolve the medicine.
  • the production can be conducted according to the conventional method. For example, a predetermined amount of the medicine and a sufficient amount of the above-described enzyme-sensitive solubilizer to dissolve the medicine are mixed well using an aquamizer (manufactured by Hosokawa Micron Ltd.) to dissolve the medicine completely, then the mixture is filled into a soft capsule or a hard capsule with an encapsulating machine. On the other hand, pellets are produced using a pelletizer.
  • the amount of the medicine in the pharmaceutical preparation can be appropriately selected depending upon a particular medicine, the usa purpose and the like.
  • other ingredients which are conventionally used in production of the pharmaceutical preparations may be optionally added.
  • An enzyme-sensitive enteric pharmaceutical preparation of the present invention thus obtained can be orally administered.
  • An oily vehicle of the pharmaceutical preparation which has been administered holds the medicine therein in gastric solution even if it should be dispersed, which results in no release of the medicine.
  • this administered oily vehicle reaches duodenum, it is degraded by pancreatic lipase or esterase, and the medicine contained in it is released by disintegration of the dosage form.
  • the medicine Since the medicine is in the monomolecularly dispersed (dissolved) state, the medicine which is released after dedradation of the oily vehicle is rapidly absorbed from small intestine even if the medicine is very slightly soluble. As a result, reprecipitation dose not occur and the absorbability becomes excellent.
  • a pellet dosage form holds its own form in gastric solution after administration, and when it reaches duodenum, it is dedraded by pancreatic lipase or esterase and the medicine is released by disintegration of the dosage form.
  • Degradation by lipase or esterase of a fatty acid ester which is an enzyme-sensitive oily solubilizer was examined as follows. To 100 ml of 0.05 M phosphate buffer (pH 6.8) containing bovine pancreatic lipase (4yg/ml) or esterase (10 ⁇ g/ml) and sodium taurocholate (24 mM) added 500 mg of a test solubilizer, and temperature was kept at 37 °C in water bath while shaking. A sample solution for measuring the degradation was collected at 15, 30 and 60 min., and free fatty acid in the collected sample which had been produced by degradation was quantitated using a commercially available free fatty acid measuring kit (NEFA- Test, manufacture by ako Junyaku).
  • NEFA- Test manufacture by ako Junyaku
  • Fig 1 shows degradation by pancreatic lipase or esterase of glycerol mono-caprylate, propylene glycol di- caprylate, polysorbate 80, polyethylene glycol mono- stearate, glycerol mono-stearate and a mixed oily solubilizer. It can be understood from Fig 1 that, although degrading velocity differs depending upon a kind of oily solubilizer and sensitivity relative to lipase or esterase, the velocity of the tested solubilizers is high.
  • Solubility of a medicine in an enzyme-sensitive oily solubilizer was measured at room temperature, 40 °C, 5 °C and 60 °C. This was done based on the melting point of solubilizer because one which is solid at room temperature is used to dissolve a medicine at the temperature above its melting point. The measuring was carried out according to the conventional method [see Toshiaki NISHIHATA et al., Chem.Pharm.Bull, volume 39, pages 509-511, 1991]. Table 1 shows solubility of a medicine such as itazigrel, • indomethacin, U-78875 etc. in various oily solubilizers.
  • glycerol mono-caprylate and polysorbate 80 are excellent solubilizers and the solubility properties of propylene glycol di-caprylate significantly differs depending upon a particular medicine to be used.
  • Polyethylene glycol mono-stearate and glycerol mono-stearate are semisolid at room temperature. But they can dissolve a medicine therein after they have been melted, and disperse a medicine in the monomolecular state, so they can be adopted as an oily solubilizer in the present preparation.
  • these two oily solubilizers having the higher melting point can be used as an additive for keeping the melting point of a solubilizing vehicle for a medicine having relatively not good partition coefficient at the temperature slightly above bodily temperature as shown in the below Experiment.
  • volume of water phase and oil phase were selected as follows. That is, water phase was used in an amount of 100 g while oil phase was used in an amount of 0.25g, and the test was carried out at 37 °C while shaking.
  • Oil-water partition coefficient (oil phase/water phase) (37 °C)
  • indomethacin 2 g was dissolved in 100 g of glycerol mono- caprylate, and each 250 mg of the solution was filled into a hard capsule or soft capsule as a support to obtain 400 preparations of the present invention, respectively .
  • indomethacin 5 g was dissolved in 100 g of polysorbate 80, and each 250 mg of the solution was filled into a hard capsule or soft capsule to obtain 400 preparations of the present invention, respectively.
  • indomethacin 5 g was dissolved in a mixture solution of 50 g of glycerol mono-caprylate and 50 g of glycerol mono-stearate which had been warmed to 60 °C, then 50 mg pellets were made by a pelletizer at room temperature.
  • indomethacin 5 g was dissolved in a mixture solution of 50 g of glycerol mono-caprylate and 50 g of glycerol mono-stearate which had been warmed to 60 °C, then 50 mg pellets were made by a pelletizer at room temperature.
  • release test was carried out using liquid oily vehicles. Release test from a liquid oily vehicle was carried out by putting each one capsule from Examples 1 to 6 into a conical tube filled with 50 ml of test solution. As the test solution. Solution 1 and Solution 2 of Disintegration Test in Japanese Pharmacopoeia as well as the same containing pancreatic lipase or esterase were used. Fig 2 or Fig 3 shows the results when itazigrel or indomethacin was used as a medicine, respectively.
  • Fig 3 shows release behavior of indomethacin from indomethacin pharmaceutical preparation using glycerol mono- caprylate or polysorbate 80 as an oily vehicle. Release of indomethacin was not observed at all in Solution 1, but a few % of release from glycerol mono-caprylate within 1 hour and about 10 % of release from polysorbate 80 were observed in Solution 2. When lipase was contained in these two Solutions, about 90 % of release of indomethacin from glycerol mono-caprylate vehicle was observed at 15 min., and from this, it can be understood that the pharmaceutical preparation of Example 2 is a good lipase-sensitive enteric preparation. Further, polysorbate 80 vehicle showed remarkably increased release in Solution 2 containing esterase. From this, it can be understood that the pharmaceutical preparation of Example 5 is a good esterase- sensitive enteric preparation.
  • test sample 3 25 g of Sudan II was dissolved in 1 kg of polysorbate 80 to obtain a test sample preparation.
  • Table 3 Stained state of membrana mucosa of gastrointestinal tract at 1.5 hours after administration of the preparation containing Sudan II and recovery rate of Sudan II from contents in gastrointestinal tract Preparation Stained state Recovery rate
  • the recovery rate of Sudan II from contents in cavity of gastrointestinal tract was about 100%.
  • a liquid vehicle preparation of test sample 1 was orally administered, the stained state of gastric membrana mucosa was not recognized at all, but the remarkably stained state of small intestinal membrana mucosa (in particular, duodenal membrana mucosa) was recognized.
  • This result shows that the preparation of test sample 1 dose not release Sudan II in stomach and remarkably releases Sudan II in duodenum, therefore the preparation is an enteric preparation.
  • the recovery rate of Sudan II from the gastrointestinal tract is about 35% at 1.5 hours, it is shown that absorption of Sudan II from small intestine is remarkable after administration of this preparation in comparison with the case of suspension.
  • this preparation is an enzyme-sensitive enteric preparation in the animal test.
  • a liquid vehicle preparation of test sample 2 was orally administered, the stained state of gastric membrana mucosa was not recognized at all or slightly even if recognized.
  • small intestinal membrana mucosa the remarkably stained state was recognized.
  • This result shows that the preparation of test sample 2 dose not release Sudan II in stomach or slightly even if it releases the pigment while it releases much in small intestine, and further that the recovery rate of Sudan II from the gastrointestinal tract at 1.5 hours after administration is about 45 % and absorption of Sudan II from small intestine after administration of the preparation is remarkable in comparison with the case of suspension. Therefore, it was confirmed in the animal test that this preparation is an enzyme-sensitive enteric preparation, and it was found at the same time that the preparation has also the properties to improve absorbability of very slightly soluble material.
  • an enzyme-sensitive enteric preparation which is not pH-sensitive and has improved specificity for releasing a medicine by being degraded in small intestine.
  • Such the preparation of the present invention is of type that a medicine is dissolved, it has uniform dispersion of a medicine and good absorbability of a very slightly soluble medicine. And, since the present preparation requires no special processes to obtain uniformity, it is excellent in productivity of the preparation.
  • Fig 1 is a graph showing degradation behavior when sample oily solubilizers were degraded by lipase or esterase.
  • Fig 1 (A) is the case where the fatty acid ester is glycerol mono-caprylate or propylene glycol di-caprylate.
  • Fig 1 (B) is the case where the fatty acid ester is polysorbate 80 or polyethylene glycol mono-stearate, and Fig 1
  • fatty acid ester is glycerol mono-stearate, a mixture of glycerol mono-stearate and polysorbate 80, or a mixture of glycerol mono-caprylate and glycerol mono-stearate.
  • Fig 2 is a graph showing the releasing behavior of itazigrel from the preparation obtained in Examples, and Fig
  • Fig 2 (A) is the case of the preparation of Example 1 and Fig 2 (B) is the case of the preparation of Example 4.
  • Fig 3 is a graph showing the releasing behavior of indomethacin from the preparations obtained in Examples, and Fig 3 (A) is the case of the preparation of Example 2 and Fig 3 (B) is the case of the preparation of Example 5.
  • Fig 4 is a graph showing the releasing behavior of itazigrel from the preparations obtained Examples, and Fig 4
  • Fig 5 is a graph showing the releasing behavior of indomethacin from the preparations obtained in Examples, and Fig 5 (A) is the case of the preparation of Example 8 and Fig 5 (B) is the case of the preparation of Example 11.
  • Fig 6 is a graph showing the releasing behavior of U-78875 from the preparations obtained in Examples, and Fig 6 (A) is the case of the preparation of Example 9 and Fig 6 (B) is the case of the preparation of Example 12.
  • Fig.1(A) O and ⁇ glycerol monocaprylate
  • ⁇ and A propylene glycol di-caprylate
  • Fig. KB O and ⁇ , polysorbate 80; ⁇ and A, polyethylene glycol mono-stearate
  • SymbolsO, ⁇ and D designate the results when lipase is present, and ⁇ , A and ⁇ designate the results when esterase is present.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Medicinal Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Molecular Biology (AREA)
  • Medicinal Preparation (AREA)

Abstract

Cette invention se rapporte à une préparation entérique qui presente une spécificité élevée et qui est sensible par rapport aux enzymes. La préparation comprend un médicament dissous dans un véhicule contenant au moins un acide gras choisi dans le groupe composé de l'ester d'acide gras de glycérol, l'ester d'acide gras de sorbitan de polyoxyéthylène, l'ester d'acide gras de propylèneglycol, l'ester d'acide gras de polyéthylèneglycol, l'ester d'acide gras d'éthylèneglycol et l'ester d'acide gras de décaglycérol.
PCT/US1992/005245 1991-07-01 1992-06-26 Preparation enterique sensible aux enzymes destinee a une administration orale WO1993000891A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP16043791A JPH0525037A (ja) 1991-07-01 1991-07-01 経口投与酵素感受性腸溶製剤
JP160437/1991 1991-07-01

Publications (1)

Publication Number Publication Date
WO1993000891A1 true WO1993000891A1 (fr) 1993-01-21

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Application Number Title Priority Date Filing Date
PCT/US1992/005245 WO1993000891A1 (fr) 1991-07-01 1992-06-26 Preparation enterique sensible aux enzymes destinee a une administration orale

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JP (1) JPH0525037A (fr)
AU (1) AU2293892A (fr)
WO (1) WO1993000891A1 (fr)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014423A1 (fr) * 1992-12-18 1994-07-07 R.P. Scherer Corporation Solutions pharmaceutiques avec solubilite amelioree
WO1995001786A1 (fr) * 1993-07-08 1995-01-19 Ciba-Geigy Ag Preparations pharmaceutiques pour principes actifs difficilement solubles
EP2143428A1 (fr) * 2007-03-30 2010-01-13 TMRC Co., Ltd. Préparation de capsules de tamibarotène
US8231896B2 (en) 2004-11-08 2012-07-31 R.P. Scherer Technologies, Llc Non-gelatin soft capsule system
WO2015045037A1 (fr) * 2013-09-25 2015-04-02 テムリック株式会社 Préparation en capsule
WO2024098160A1 (fr) * 2022-11-10 2024-05-16 Allen Greenspoon Formulation administrable par voie orale

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4614258B2 (ja) * 2001-06-12 2011-01-19 森下仁丹株式会社 崩壊性が改良されたソフトカプセル
JP4718414B2 (ja) * 2006-10-26 2011-07-06 アスモ株式会社 埋込磁石型モータ
JP2013199458A (ja) * 2012-03-26 2013-10-03 Tmrc Co Ltd カプセル製剤
US10716761B2 (en) 2017-07-24 2020-07-21 Alcresta Therapeutics, Inc. Ingestible medical delivery devices

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3374146A (en) * 1966-04-18 1968-03-19 American Cyanamid Co Sustained release encapsulation
DE2439538A1 (de) * 1974-08-17 1976-03-04 Heumann Ludwig & Co Gmbh Verfahren zur retardierung von arzneimitteln
EP0274870A2 (fr) * 1986-12-18 1988-07-20 Cortecs Limited Micelles contenant des agents anti-inflammatoires non-stéroidiques
EP0320136A2 (fr) * 1987-12-08 1989-06-14 Novo Nordisk A/S Composés d'imidazoquinoxaline, leur préparation et utilisation

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3374146A (en) * 1966-04-18 1968-03-19 American Cyanamid Co Sustained release encapsulation
DE2439538A1 (de) * 1974-08-17 1976-03-04 Heumann Ludwig & Co Gmbh Verfahren zur retardierung von arzneimitteln
EP0274870A2 (fr) * 1986-12-18 1988-07-20 Cortecs Limited Micelles contenant des agents anti-inflammatoires non-stéroidiques
EP0320136A2 (fr) * 1987-12-08 1989-06-14 Novo Nordisk A/S Composés d'imidazoquinoxaline, leur préparation et utilisation

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994014423A1 (fr) * 1992-12-18 1994-07-07 R.P. Scherer Corporation Solutions pharmaceutiques avec solubilite amelioree
US5376688A (en) * 1992-12-18 1994-12-27 R. P. Scherer Corporation Enhanced solubility pharmaceutical solutions
WO1995001786A1 (fr) * 1993-07-08 1995-01-19 Ciba-Geigy Ag Preparations pharmaceutiques pour principes actifs difficilement solubles
US8231896B2 (en) 2004-11-08 2012-07-31 R.P. Scherer Technologies, Llc Non-gelatin soft capsule system
US8377470B2 (en) 2004-11-08 2013-02-19 R.P. Scherer Technologies, Llc Non-gelatin soft capsule system
EP2143428A1 (fr) * 2007-03-30 2010-01-13 TMRC Co., Ltd. Préparation de capsules de tamibarotène
EP2143428A4 (fr) * 2007-03-30 2012-02-22 Tmrc Co Ltd Préparation de capsules de tamibarotène
US8252837B2 (en) 2007-03-30 2012-08-28 Tmrc Co., Ltd. Tamibarotene capsule preparation
WO2015045037A1 (fr) * 2013-09-25 2015-04-02 テムリック株式会社 Préparation en capsule
WO2024098160A1 (fr) * 2022-11-10 2024-05-16 Allen Greenspoon Formulation administrable par voie orale

Also Published As

Publication number Publication date
AU2293892A (en) 1993-02-11
JPH0525037A (ja) 1993-02-02

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