WO2013147452A1 - Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt - Google Patents

Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt Download PDF

Info

Publication number
WO2013147452A1
WO2013147452A1 PCT/KR2013/002316 KR2013002316W WO2013147452A1 WO 2013147452 A1 WO2013147452 A1 WO 2013147452A1 KR 2013002316 W KR2013002316 W KR 2013002316W WO 2013147452 A1 WO2013147452 A1 WO 2013147452A1
Authority
WO
WIPO (PCT)
Prior art keywords
revaprazan
pharmaceutical composition
salt
polyoxylglyceride
surfactant
Prior art date
Application number
PCT/KR2013/002316
Other languages
French (fr)
Inventor
Byoung-Moo Lee
Chang-Keun Hyun
Yoong-Sik Park
Original Assignee
Yuhan Corporation
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 Yuhan Corporation filed Critical Yuhan Corporation
Publication of WO2013147452A1 publication Critical patent/WO2013147452A1/en

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
    • A61K31/495—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
    • A61K31/505—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim
    • A61K31/506—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim not condensed and containing further heterocyclic rings
    • 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
    • A61K47/06—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite
    • A61K47/08—Organic compounds, e.g. natural or synthetic hydrocarbons, polyolefins, mineral oil, petrolatum or ozokerite containing oxygen, e.g. ethers, acetals, ketones, quinones, aldehydes, peroxides
    • A61K47/14—Esters of carboxylic acids, e.g. fatty acid monoglycerides, medium-chain triglycerides, parabens or PEG fatty acid esters
    • 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
    • A61K9/0087—Galenical forms not covered by A61K9/02 - A61K9/7023
    • A61K9/0095—Drinks; Beverages; Syrups; Compositions for reconstitution thereof, e.g. powders or tablets to be dispersed in a glass of water; Veterinary drenches
    • 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
    • A61K9/08—Solutions
    • 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
    • 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

Definitions

  • the present invention relates to a pharmaceutical composition for oral administration in a form of non-aqueous liquid (i.e., non-aqueous liquid formulation) comprising revaprazan or its salt.
  • Revaprazan whose chemical name is 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine, is represented by the following Formula 1.
  • Revaprazan can be used in a form of an acid addition salt, including e.g., HCl salt (see International Publication No. WO1996/05177, WO1997/042186, and WO1998/018784).
  • Revaprazan or its salt is reversibly bound to a H + /K + exchange site of a proton pump (H + /K + ATPase) existing in a gastric parietal cell so that secretion of H + into the gastric lumen is competitively inhibited.
  • Revaprazan or its salt is also bound to a specific site of H + /K + ATPase, thereby inhibiting transport of H + and suppressing an acid secretion to the gastric lumen, which results in increasing the intragastric pH.
  • irreversible proton pump inhibitors e.g., omeprazole
  • revaprazan or its salt is not dependent upon acid activation of a drug in a stomach or secretion status of a proton pump. Therefore, based on the mechanism different from irreversible proton pump inhibitors, such as omeprazole, revaprazan or its salt is classified into an acid pump antagonist (APA).
  • APA acid pump antagonist
  • Revaprazan has very low water-solubility, i.e. less than 0.2 mg/mL, and even lower solubility in a buffer solution having pH 1 to 12. And also, revaprazan has very low intrinsic dissolution rate, i.e., about 0.0086 mg/min/cm 2 . Due to such a low solubility and intrinsic dissolution rate, its dissolution in the gastrointestinal tract is also very low. Therefore, when revaprazan is orally administered, its absorption rate is relatively low. Revaprazan also has strong adhesion and agglutination properties, and thus, when revaprazan is formulated into a capsule or a tablet, it may be stuck to a punch or a die, thereby showing low formulation processability.
  • WO 2008/078922 has disclosed a pharmaceutical composition for oral administration comprising a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof.
  • a pharmaceutical composition for oral administration comprising a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof.
  • the bioavailability thereof is still unsatisfactory.
  • the present inventors performed various researches for developing revaprazan or its salt-containing pharmaceutical formulations for oral administration, which has excellent bioavailability.
  • the present inventors designed various formulations that can provide efficient absorption of revaprazan in the gastrointestinal tract.
  • the present inventors designed a non-aqueous liquid formulation containing revaprazan or its salt along with a certain oil and a surfactant, the formulation being able to exist in a form of emulsion in the gastrointestinal tract through self-emulsifying.
  • a pharmaceutical composition for oral administration in a form of non-aqueous liquid comprising revaprazan or its salt; a certain oil; and a surfactant.
  • a pharmaceutical composition for oral administration in a form of non-aqueous liquid comprising revaprazan or its salt; an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and a surfactant.
  • the surfactant may be selected from the group consisting of sorbitan ester, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, polyethylene glycol-15-hydroxystearate, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, alpha-tocopheryl polyethylene glycol succinate, polyoxyethylene alkyl ester, fatty acid macrogol glyceride, polyglyceryl fatty acid ester, bile acid, sodium lauryl sulfate, lecithin, glyceryl fatty acid ester, polyethylene glycol stearate, and a mixture thereof.
  • the surfactant may be selected from the group consisting of sucrose fatty acid ester, alpha-tocopheryl polyethylene glycol succinate, polyethylene glycol-15-hydroxystearate, and a mixture thereof.
  • the oil may be present in an amount ranging from 4 to 20 parts by weight, based on 1 part by weight of revaprazan or its salt.
  • the surfactant may be present in an amount ranging from 0.2 to 10 parts by weight, based on 1 part by weight of revaprazan or its salt.
  • a process for preparing a pharmaceutical composition for oral administration in a form of non-aqueous liquid comprising (a) melting an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and (b) dissolving or dispersing revaprazan or its salt and a surfactant in the melt obtained in the step (a).
  • a capsule comprising the pharmaceutical composition.
  • the pharmaceutical composition in a form of non-aqueous liquid according to the present invention contains a certain oil along with a surfactant, thereby not only increasing solubility and dissolution rate of revaprazan remarkably but also exhibiting excellent stability without phase separation. And also, through excellent solubilizing effects, the pharmaceutical composition according to the present invention can be suitably applied to production of capsules containing a therapeutically effective amount of revaprazan. That is, the pharmaceutical composition in a form of non-aqueous liquid according to the present invention can be easily filled into a capsule, thereby exhibiting excellent formulation processability.
  • the pharmaceutical composition in a form of non-aqueous liquid according to the present invention is maintained in a form of emulsion (where revaprazan is dissolved or dispersed through self-emulsifying) in the gastrointestinal tract, which leads to high gastrointestinal absorption rate, thereby being able to accomplish remarkably excellent bioavailability.
  • the process for preparing the pharmaceutical composition according to the present invention is simple and therefore can be easily applied to industrial mass production.
  • the present invention provides a pharmaceutical composition for oral administration in a form of non-aqueous liquid (i.e., non-aqueous liquid formulation), comprising revaprazan or its salt; an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and a surfactant.
  • glyceryl monolinoleate glyceryl monooleate
  • propylene glycol monocaprylate diethylene glycol monoethyl ether
  • caprylocaproyl polyoxylglyceride oleoyl polyoxylglyceride
  • linoleoyl polyoxylglyceride linoleoyl polyoxyl
  • the present inventors designed a non-aqueous liquid formulation that can exist in a form of emulsion in the gastrointestinal tract through self-emulsifying.
  • the present inventors performed researches on various systems containing oil(s) and surfactant(s) that can dissolve or disperse revaprazan.
  • a certain oil e.g., glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, and/or linoleoyl polyoxylglyceride
  • a certain oil e.g., glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, and/or linoleoyl polyoxylglyceride
  • the pharmaceutical composition according to the present invention can be suitably applied to production of capsules containing a therapeutically effective amount (for example, about 10 to 500 mg) of revaprazan. That is, the pharmaceutical composition in a form of non-aqueous liquid according to the present invention can be easily filled into a capsule, thereby exhibiting excellent formulation processability.
  • the pharmaceutical composition in a form of non-aqueous liquid according to the present invention is maintained in a form of emulsion (where revaprazan is dissolved or dispersed through self-emulsifying) in the gastrointestinal tract, which leads to high gastrointestinal absorption rate, thereby being able to accomplish remarkably excellent bioavailability.
  • the process for preparing the pharmaceutical composition according to the present invention is simple and therefore can be easily applied to industrial mass production.
  • revaprazan or its salt may be used in a therapeutically effect amount, for example in range of 10 to 500 mg in a unit dosage form of capsule, but not limited thereto.
  • the pharmaceutically acceptable salt of revaprazan may be an acid addition salt, including revaprazan hydrochloride, revaprazan sulfate, revaprazan phosphate, revaprazan nitrate, revaprazan camphorsulfonate (i.e., revaprazan camsylate), revaprazan thiocyanate, and the like.
  • the salt of revaprazan is revaprazan hydrochloride.
  • the oil used as a medium in the pharmaceutical composition of the present invention includes glyceryl monolinoleate (for example, Maisine TM , etc.), glyceryl monooleate (for example, Peceol TM , etc.), propylene glycol monocaprylate (for example, Capryol TM 90, Capryol PGMC TM , etc.), diethylene glycol monoethyl ether (for example, Transcutol P TM , etc.), caprylocaproyl polyoxylglyceride (for example, Labrasol TM , etc.), oleoyl polyoxylglyceride (for example, Labrafil M 1944 TM , etc.), linoleoyl polyoxylglyceride (for example, Labrafil M 2125 TM , etc.), and a mixture thereof.
  • glyceryl monolinoleate for example, Maisine TM , etc.
  • glyceryl monooleate for
  • the oil may be present in an amount ranging from 4 to 20 parts by weight, preferably from 6 to 10 parts by weight, based on 1 part by weight of revaprazan or its salt. When the oil is present below 4 parts by weight, it may become difficult to form a composition capable of providing sufficient self-emulsification of revaprazan. When the oil is present above 20 parts by weight, it may become difficult to perform capsule-filling.
  • the surfactant includes any surfactants conventionally used in the field of pharmaceutics.
  • the surfactant include sorbitan ester (for example, Span TM , etc.), polyoxyethylene sorbitan fatty acid ester (for example, Tween TM , etc.), sucrose fatty acid ester (for example, Ryoto Ester L 1695 TM , etc.), polyethylene glycol-15-hydroxystearate (for example, Solutol HS15 TM , etc.), polyoxyethylene glycolated natural or hydrogenated castor oil (for example, Cremophor RH 40 TM , etc.), polyoxyethylene-polyoxypropylene copolymer (for example, Poloxamer TM , etc.), alpha-tocopheryl polyethylene glycol succinate, polyoxyethylene alkyl ester (for example, Brij 52 TM , etc.), fatty acid macrogol glyceride (for example, Gelucire 44/14 TM , etc.), polygly
  • a surfactant selected from the group consisting of sucrose fatty acid ester, alpha-tocopheryl polyethylene glycol succinate, polyethylene glycol-15-hydroxystearate, and a mixture thereof.
  • the surfactant may be present in an amount ranging from 0.2 to 10 parts by weight, preferably from 0.5 to 4 parts by weight, based on 1 part by weight of revaprazan or its salt. When the surfactant is present below 0.2 parts by weight, it may become difficult to obtain sufficient solubilizing effect of revaprazan. When the surfactant is present above 10 parts by weight, phase separation may occur.
  • the present invention also provides a process for preparing a pharmaceutical composition for oral administration in a form of non-aqueous liquid, the process comprising (a) melting an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and (b) dissolving or dispersing revaprazan or its salt and a surfactant in the melt obtained in the step (a).
  • an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglycer
  • the melting in step (a) may be performed by heating the oil to about 40 to 80 °C, preferably about 50 to 60 °C, under stirring.
  • the dissolving or dispersing in step (b) may be performed by simultaneously or sequentially adding the surfactant and revaprazan or its salt to the melt obtained in the step (a), under stirring.
  • the present invention also provides a capsule comprising the pharmaceutical composition in a form of non-aqueous liquid.
  • the capsule may be prepared by filling a hard or soft capsule with the above-described non-aqueous liquid (i.e., non-aqueous liquid formulation), according to conventional methods.
  • the non-aqueous liquid formulations were prepared according to the components and amounts shown in Table 1.
  • the oil was melted by heating to about 50 to 60 °C under stirring. While stirring the resulting melt, the surfactant was dissolved therein; and then revaprazan was dissolved or dispersed therein to obtain each non-aqueous liquid formulation.
  • non-aqueous liquid formulations were prepared by using the same procedures of Examples 1 to 21, according to the components and amounts shown in Table 2.
  • non-aqueous liquid formulations were prepared by using the same procedures of Examples 1 to 21, according to the components and amounts shown in Table 3.
  • Glyceryl monolinoleate (Maisine TM , 346.2 g) was melted by heating to about 50 to 60 °C under stirring. While stirring the resulting melt, revaprazan (50 g) was added thereto. The resulting product was obtained in an inhomogeneous dispersion form, where revaprazan was not completely dispersed.
  • each aliquot i.e., non-aqueous liquid formulation
  • a hard capsule i.e., void capsule
  • the dissolution test of each resulting capsule was performed according to the 'Dissolution Test 2 (Paddle Method)' of the Korean Pharmacopeia.
  • 900 ml of a pH1.2 buffer was used as a dissolution medium and the dissolution test was performed at 37 ⁇ 0.5 °C and at the paddle rotation rate of 50 rpm.
  • Example Dissolution rate (60 min.) Example Dissolution rate (60 min.) 1 22 % 16 30 % 2 31 % 17 40 % 3 25 % 18 39 % 4 28 % 19 26 % 5 24 % 20 41 % 6 35 % 21 42 % 7 34 % 22 38 % 8 33 % 23 37 % 9 26 % 24 34 % 10 36 % 25 29 % 11 46 % 26 28 % 12 43 % 27 34 % 13 49 % 28 31 % 14 55 % Comparative Example 1 14 % 15 34 % Revanex TM 19 %
  • the capsules obtained from the non-aqueous liquid formulations according to the present invention exhibited remarkably increased dissolution rates, showing maximum 250% of high dissolution rate in comparison with the tablet of Revanex TM .
  • mice Male rats (body weight: about 200 g, 7 weeks old) fasted for 16 hours were subject to endotracheal intubation and then divided into 4 groups, each group having 3 rats.
  • the rats of each groups were orally administered with the non-aqueous liquid formulations obtained in Examples 17, 20, or 21 and the control (i.e., the 0.5 % MC suspension of revaprazan) in a dose of 20 mg/whole body, respectively.
  • the blood sample was collected at the time of 0, 0.5, 1, 1.5, 2, 3, 5, and 7 hours after the administration and then centrifuged to obtain the serum.
  • the concentration of revaprazan in the serum was analyzed with LC/MS/MS under the following conditions.
  • the standard material i.e., revaprazan (m/z 363.1 > 245.1)
  • the internal standard material i.e., oxybutynin (m/z 358.2 > 142.1)
  • Example 17 Example 20
  • Example 21 0.5% MC suspension Cmax(ng/mL) 3343 ⁇ 383.6 3033.3 ⁇ 269.3 2793.0 ⁇ 230.6 750.5 ⁇ 63.9
  • Tmax(hour) 5.0 ⁇ 1.2 3.0 ⁇ 0.0 3.7 ⁇ 0.7 1.8 ⁇ 0.2
  • the non-aqueous liquid formulations prepared according to the present invention exhibited remarkably increased AUC, thereby being able to accomplish high bioavailability. It is thought that these results are originated from the mechanism that, when orally administered, the formulations according to the present invention are maintained in a form of absorption-facilitated emulsion (where revaprazan is solubilzed through self-emulsifying) in the gastrointestinal tract, which leads to high gastrointestinal absorption rate.

Abstract

The present invention provides a pharmaceutical composition for oral administration in a form of non-aqueous liquid, comprising revaprazan or its salt; an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and a surfactant. The present invention also provides a process for preparing the pharmaceutical composition for oral administration in a form of non-aqueous liquid and a capsule comprising the same.

Description

PHARMACEUTICAL COMPOSITION IN FORM OF NON-AQUEOUS LIQUID COMPRISING REVAPRAZAN OR ITS SALT
The present invention relates to a pharmaceutical composition for oral administration in a form of non-aqueous liquid (i.e., non-aqueous liquid formulation) comprising revaprazan or its salt.
Revaprazan, whose chemical name is 5,6-dimethyl-2-(4-fluorophenylamino)-4-(1-methyl-1,2,3,4-tetrahydroisoquinolin-2-yl)pyrimidine, is represented by the following Formula 1. Revaprazan can be used in a form of an acid addition salt, including e.g., HCl salt (see International Publication No. WO1996/05177, WO1997/042186, and WO1998/018784).
Formula 1
Figure PCTKR2013002316-appb-I000001
Revaprazan or its salt is reversibly bound to a H+/K+ exchange site of a proton pump (H+/K+ ATPase) existing in a gastric parietal cell so that secretion of H+ into the gastric lumen is competitively inhibited. Revaprazan or its salt is also bound to a specific site of H+/K+ ATPase, thereby inhibiting transport of H+ and suppressing an acid secretion to the gastric lumen, which results in increasing the intragastric pH. Unlike irreversible proton pump inhibitors, e.g., omeprazole, revaprazan or its salt is not dependent upon acid activation of a drug in a stomach or secretion status of a proton pump. Therefore, based on the mechanism different from irreversible proton pump inhibitors, such as omeprazole, revaprazan or its salt is classified into an acid pump antagonist (APA).
Revaprazan has very low water-solubility, i.e. less than 0.2 mg/mL, and even lower solubility in a buffer solution having pH 1 to 12. And also, revaprazan has very low intrinsic dissolution rate, i.e., about 0.0086 mg/min/cm2. Due to such a low solubility and intrinsic dissolution rate, its dissolution in the gastrointestinal tract is also very low. Therefore, when revaprazan is orally administered, its absorption rate is relatively low. Revaprazan also has strong adhesion and agglutination properties, and thus, when revaprazan is formulated into a capsule or a tablet, it may be stuck to a punch or a die, thereby showing low formulation processability. In order to address these problems, WO 2008/078922 has disclosed a pharmaceutical composition for oral administration comprising a solid dispersion in which revaprazan particles are surface-modified with a water-soluble polymer, a water-soluble saccharide, a surfactant, or a mixture thereof. However, the bioavailability thereof is still unsatisfactory.
The present inventors performed various researches for developing revaprazan or its salt-containing pharmaceutical formulations for oral administration, which has excellent bioavailability. The present inventors designed various formulations that can provide efficient absorption of revaprazan in the gastrointestinal tract. Especially, the present inventors designed a non-aqueous liquid formulation containing revaprazan or its salt along with a certain oil and a surfactant, the formulation being able to exist in a form of emulsion in the gastrointestinal tract through self-emulsifying.
Therefore, it is an object of the present invention to provide a pharmaceutical composition for oral administration in a form of non-aqueous liquid, comprising revaprazan or its salt; a certain oil; and a surfactant.
And also, it is another object of the present invention to provide a process for preparing the pharmaceutical composition; and a capsule (soft or hard capsule) comprising the pharmaceutical composition.
In accordance with an aspect of the present invention, there is provided a pharmaceutical composition for oral administration in a form of non-aqueous liquid, comprising revaprazan or its salt; an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and a surfactant.
In the pharmaceutical composition of the present invention, the surfactant may be selected from the group consisting of sorbitan ester, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, polyethylene glycol-15-hydroxystearate, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, alpha-tocopheryl polyethylene glycol succinate, polyoxyethylene alkyl ester, fatty acid macrogol glyceride, polyglyceryl fatty acid ester, bile acid, sodium lauryl sulfate, lecithin, glyceryl fatty acid ester, polyethylene glycol stearate, and a mixture thereof. Preferably, the surfactant may be selected from the group consisting of sucrose fatty acid ester, alpha-tocopheryl polyethylene glycol succinate, polyethylene glycol-15-hydroxystearate, and a mixture thereof.
The oil may be present in an amount ranging from 4 to 20 parts by weight, based on 1 part by weight of revaprazan or its salt. The surfactant may be present in an amount ranging from 0.2 to 10 parts by weight, based on 1 part by weight of revaprazan or its salt.
In accordance with another aspect of the present invention, there is provided a process for preparing a pharmaceutical composition for oral administration in a form of non-aqueous liquid, the process comprising (a) melting an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and (b) dissolving or dispersing revaprazan or its salt and a surfactant in the melt obtained in the step (a).
In accordance with still another aspect of the present invention, there is provided a capsule comprising the pharmaceutical composition.
The pharmaceutical composition in a form of non-aqueous liquid according to the present invention contains a certain oil along with a surfactant, thereby not only increasing solubility and dissolution rate of revaprazan remarkably but also exhibiting excellent stability without phase separation. And also, through excellent solubilizing effects, the pharmaceutical composition according to the present invention can be suitably applied to production of capsules containing a therapeutically effective amount of revaprazan. That is, the pharmaceutical composition in a form of non-aqueous liquid according to the present invention can be easily filled into a capsule, thereby exhibiting excellent formulation processability. Especially, when orally administered, the pharmaceutical composition in a form of non-aqueous liquid according to the present invention is maintained in a form of emulsion (where revaprazan is dissolved or dispersed through self-emulsifying) in the gastrointestinal tract, which leads to high gastrointestinal absorption rate, thereby being able to accomplish remarkably excellent bioavailability. In addition, the process for preparing the pharmaceutical composition according to the present invention is simple and therefore can be easily applied to industrial mass production.
The present invention provides a pharmaceutical composition for oral administration in a form of non-aqueous liquid (i.e., non-aqueous liquid formulation), comprising revaprazan or its salt; an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and a surfactant.
The present inventors designed a non-aqueous liquid formulation that can exist in a form of emulsion in the gastrointestinal tract through self-emulsifying. The present inventors performed researches on various systems containing oil(s) and surfactant(s) that can dissolve or disperse revaprazan. As a result thereof, we found that the use of a certain oil (e.g., glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, and/or linoleoyl polyoxylglyceride) as a dispersing medium resulted in increasing solubility and dissolution rate of revaprazan remarkably as well as forming a stable system without phase separation. And also, we found that the use of said oil as a medium made it possible to obtain a solution having a volume suitable for capsule-filling, through excellent solubilizing effects thereof. Therefore, the pharmaceutical composition according to the present invention can be suitably applied to production of capsules containing a therapeutically effective amount (for example, about 10 to 500 mg) of revaprazan. That is, the pharmaceutical composition in a form of non-aqueous liquid according to the present invention can be easily filled into a capsule, thereby exhibiting excellent formulation processability. Especially, when orally administered, the pharmaceutical composition in a form of non-aqueous liquid according to the present invention is maintained in a form of emulsion (where revaprazan is dissolved or dispersed through self-emulsifying) in the gastrointestinal tract, which leads to high gastrointestinal absorption rate, thereby being able to accomplish remarkably excellent bioavailability. In addition, the process for preparing the pharmaceutical composition according to the present invention is simple and therefore can be easily applied to industrial mass production.
In the pharmaceutical composition of the present invention, revaprazan or its salt may be used in a therapeutically effect amount, for example in range of 10 to 500 mg in a unit dosage form of capsule, but not limited thereto. The pharmaceutically acceptable salt of revaprazan may be an acid addition salt, including revaprazan hydrochloride, revaprazan sulfate, revaprazan phosphate, revaprazan nitrate, revaprazan camphorsulfonate (i.e., revaprazan camsylate), revaprazan thiocyanate, and the like. Preferably, the salt of revaprazan is revaprazan hydrochloride.
The oil used as a medium in the pharmaceutical composition of the present invention includes glyceryl monolinoleate (for example, MaisineTM, etc.), glyceryl monooleate (for example, PeceolTM, etc.), propylene glycol monocaprylate (for example, CapryolTM 90, Capryol PGMCTM, etc.), diethylene glycol monoethyl ether (for example, Transcutol PTM, etc.), caprylocaproyl polyoxylglyceride (for example, LabrasolTM, etc.), oleoyl polyoxylglyceride (for example, Labrafil M 1944TM, etc.), linoleoyl polyoxylglyceride (for example, Labrafil M 2125TM, etc.), and a mixture thereof. The oil may be present in an amount ranging from 4 to 20 parts by weight, preferably from 6 to 10 parts by weight, based on 1 part by weight of revaprazan or its salt. When the oil is present below 4 parts by weight, it may become difficult to form a composition capable of providing sufficient self-emulsification of revaprazan. When the oil is present above 20 parts by weight, it may become difficult to perform capsule-filling.
The surfactant includes any surfactants conventionally used in the field of pharmaceutics. Examples of the surfactant include sorbitan ester (for example, SpanTM, etc.), polyoxyethylene sorbitan fatty acid ester (for example, TweenTM, etc.), sucrose fatty acid ester (for example, Ryoto Ester L 1695TM, etc.), polyethylene glycol-15-hydroxystearate (for example, Solutol HS15TM, etc.), polyoxyethylene glycolated natural or hydrogenated castor oil (for example, Cremophor RH 40TM, etc.), polyoxyethylene-polyoxypropylene copolymer (for example, PoloxamerTM, etc.), alpha-tocopheryl polyethylene glycol succinate, polyoxyethylene alkyl ester (for example, Brij 52 TM, etc.), fatty acid macrogol glyceride (for example, Gelucire 44/14 TM, etc.), polyglyceryl fatty acid ester (for example, Plurol oleique TM, etc.), bile acid, sodium lauryl sulfate, lecithin, glyceryl fatty acid ester, polyethylene glycol stearate, and the like. In terms of solubilization of revaprazan and inhibition of phase separation, it is preferable to use a surfactant selected from the group consisting of sucrose fatty acid ester, alpha-tocopheryl polyethylene glycol succinate, polyethylene glycol-15-hydroxystearate, and a mixture thereof. The surfactant may be present in an amount ranging from 0.2 to 10 parts by weight, preferably from 0.5 to 4 parts by weight, based on 1 part by weight of revaprazan or its salt. When the surfactant is present below 0.2 parts by weight, it may become difficult to obtain sufficient solubilizing effect of revaprazan. When the surfactant is present above 10 parts by weight, phase separation may occur.
The present invention also provides a process for preparing a pharmaceutical composition for oral administration in a form of non-aqueous liquid, the process comprising (a) melting an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and (b) dissolving or dispersing revaprazan or its salt and a surfactant in the melt obtained in the step (a).
The melting in step (a) may be performed by heating the oil to about 40 to 80 ℃, preferably about 50 to 60 ℃, under stirring. And also, the dissolving or dispersing in step (b) may be performed by simultaneously or sequentially adding the surfactant and revaprazan or its salt to the melt obtained in the step (a), under stirring.
The present invention also provides a capsule comprising the pharmaceutical composition in a form of non-aqueous liquid. The capsule may be prepared by filling a hard or soft capsule with the above-described non-aqueous liquid (i.e., non-aqueous liquid formulation), according to conventional methods.
The present invention will be described in further detail with reference to the following examples. These examples are for illustrative purposes only and are not intended to limit the scope of the present invention.
Examples 1 to 21
The non-aqueous liquid formulations were prepared according to the components and amounts shown in Table 1. The oil was melted by heating to about 50 to 60 ℃ under stirring. While stirring the resulting melt, the surfactant was dissolved therein; and then revaprazan was dissolved or dispersed therein to obtain each non-aqueous liquid formulation.
Table 1
Example Revaprazan Oil Surfactant
MaisineTM PeceolTM TPGS* Ryoto Ester L 1695TM Solutol HS 15TM
1 50 g 350 g - 100 g - -
2 50 g 350 g - - 100 g -
3 50 g 350 g - - - 100 g
4 50 g 350 g - 50 g 50 g -
5 50 g 350 g - 50 g - 50 g
6 50 g 350 g - - 50 g 50 g
7 50 g 350 g - 33 g 33 g 33 g
8 50 g 200 g - 30 g 30 g 30 g
9 50 g 350 g - 3 g 3 g 3 g
10 50 g 350 g - 30 g 30 g 30 g
11 50 g 350 g - 150 g 150 g 150 g
12 50 g 500 g - 30 g 30 g 30 g
13 50 g 1000 g - 30 g 30 g 30 g
14 50 g 1000 g - 150 g 150 g 150 g
15 50 g 346.2 g - 34.6 g 69.2 g -
16 50 g - 321.4 g 96.4 g 32.1 g -
17 50 g 346.2 g - 34.6 g 34.6 g 34.6 g
18 50 g - 346.2 g 34.6 g 34.6 g 34.6 g
19 50 g 346.2 g - 34.6 g - 69.2 g
20 50 g 321.4 g - 32.1 g 64.3 g 32.1 g
21 50 g - 321.4 g 32.1 g 64.3 g 32.1 g
* TPGS: alpha-tocopheryl polyethylene glycol succinate
All of the formulations obtained in Examples 1 to 21 existed in the liquid form where revaprazan is dissolved or dispersed. All of the formulations maintained a complete liquid formulation form without phase separation, even after placing at room temperature (about 20 to 25 ℃) for 24 hours. And also, all of the resulting liquid formulations were suitable for preparing a capsule containing a therapeutically effective amount (for example, about 200 mg) of revaprazan.
Examples 22 to 26
The non-aqueous liquid formulations were prepared by using the same procedures of Examples 1 to 21, according to the components and amounts shown in Table 2.
Table 2
Example Revaprazan Oil Surfactant
Capryol 90TM Transcutol PTM LabrasolTM Labrafil M 1944TM Labrafil M 2125TM TPGS* Ryoto Ester L 1695TM Solutol HS 15TM
22 50 g 346.2 g - - - - 34.6 g 34.6 g 34.6 g
23 50 g - 346.2 g - - - 34.6 g 34.6 g 34.6 g
24 50 g - - 346.2 g - - 34.6 g 34.6 g 34.6 g
25 50 g - - - 346.2 g - 34.6 g 34.6 g 34.6 g
26 50 g - - - - 346.2 g 32.1 g 64.3 g 32.1 g
* TPGS: alpha-tocopheryl polyethylene glycol succinate
All of the liquid formulations obtained in Examples 22 to 26 also existed in the liquid form where revaprazan is dissolved or dispersed. All of the formulations maintained a complete liquid formulation form without phase separation, even after placing at room temperature (about 20 to 25 ℃) for 24 hours. And also, all of the resulting liquid formulations were suitable for preparing a capsule containing a therapeutically effective amount (for example, about 200 mg) of revaprazan.
Examples 27 and 28
The non-aqueous liquid formulations were prepared by using the same procedures of Examples 1 to 21, according to the components and amounts shown in Table 3.
Table 3
Example Revaprazan Oil Surfactant
MaisineTM PeceolTM CapryolTM 90 TPGS* Ryoto Ester L 1695TM Solutol HS 15TM
27 50 g 173.1 g 173.1 g - 34.6 g 34.6 g 34.6 g
28 50 g 115.4 g 115.4 g 115.4 g 34.6 g 34.6 g 34.6 g
* TPGS: alpha-tocopheryl polyethylene glycol succinate
All of the formulations obtained in Examples 27 and 28 also existed in the liquid form where revaprazan is dissolved or dispersed. All of the formulations maintained a complete liquid formulation form without phase separation, even after placing at room temperature (about 20 to 25 ℃) for 24 hours. And also, all of the resulting liquid formulations were suitable for preparing a capsule containing a therapeutically effective amount (for example, about 200 mg) of revaprazan.
Comparative Example 1
Glyceryl monolinoleate (MaisineTM, 346.2 g) was melted by heating to about 50 to 60 ℃ under stirring. While stirring the resulting melt, revaprazan (50 g) was added thereto. The resulting product was obtained in an inhomogeneous dispersion form, where revaprazan was not completely dispersed.
Experimental Example 1: Evaluation of dissolution rate
From the non-aqueous liquid formulations obtained in Examples 1 to 28, each aliquot (i.e., non-aqueous liquid formulation) was taken in an amount corresponding to 200 mg of revaprazan. Each aliquot was filled in a hard capsule (i.e., void capsule) to obtain a capsule. The dissolution test of each resulting capsule was performed according to the 'Dissolution Test 2 (Paddle Method)' of the Korean Pharmacopeia. 900 ml of a pH1.2 buffer was used as a dissolution medium and the dissolution test was performed at 37 ± 0.5 ℃ and at the paddle rotation rate of 50 rpm. Each sample was taken from the dissolution medium after 60 minutes and then the absorbance at 268 nm thereof was measured with UV to obtain the dissolution rate. For comparison, the dissolution rates of the dispersion of Comparative Example 1 and the tablet of RevanexTM 200 mg (Yuhan Corporation) were also measured according to the same method. The results are presented in the following Table 4.
Table 4
Example Dissolution rate (60 min.) Example Dissolution rate (60 min.)
1 22 % 16 30 %
2 31 % 17 40 %
3 25 % 18 39 %
4 28 % 19 26 %
5 24 % 20 41 %
6 35 % 21 42 %
7 34 % 22 38 %
8 33 % 23 37 %
9 26 % 24 34 %
10 36 % 25 29 %
11 46 % 26 28 %
12 43 % 27 34 %
13 49 % 28 31 %
14 55 % Comparative Example 1 14 %
15 34 % RevanexTM 19 %
As shown in Table 4, the capsules obtained from the non-aqueous liquid formulations according to the present invention exhibited remarkably increased dissolution rates, showing maximum 250% of high dissolution rate in comparison with the tablet of RevanexTM.
Experimental Example 2: Pharmacokinetic study
Pharmacokinetic studies of the non-aqueous liquid formulations obtained in Examples 17, 20, and 21 were performed. For comparison, the suspension obtained by dispersing revaprazan in a 0.5 wt/wt% aqueous solution of methyl cellulose (MC) was used as a control.
Male rats (body weight: about 200 g, 7 weeks old) fasted for 16 hours were subject to endotracheal intubation and then divided into 4 groups, each group having 3 rats. The rats of each groups were orally administered with the non-aqueous liquid formulations obtained in Examples 17, 20, or 21 and the control (i.e., the 0.5 % MC suspension of revaprazan) in a dose of 20 mg/whole body, respectively. The blood sample was collected at the time of 0, 0.5, 1, 1.5, 2, 3, 5, and 7 hours after the administration and then centrifuged to obtain the serum. The concentration of revaprazan in the serum was analyzed with LC/MS/MS under the following conditions.
<LC/MS/MS condition >
Using a triple quadrupole mass spectrometer, the standard material [i.e., revaprazan (m/z 363.1 > 245.1)] and the internal standard material [i.e., oxybutynin (m/z 358.2 > 142.1)] were detected according to the MRM (Multiple Reaction Monitoring) method.
< HPLC condition >
- HPLC system: Waters alliance 2695 HPLC system (Waters, USA)
- Column: Xterra Phenyl (2.1 x 50 mm, 3.5 ㎛)
- Guard cartridge: Phenomenex C18 (4.0 X 2.0 mm I.D)
- Column temperature: 40 ℃
- Autosampler temperature: 10 ℃
- Mobile phase: 10 mM ammonium formate (pH 7.4):acetonitrile = 25:75 (v/v)
- Flow rate: 300 μL/min
- Injection volume: 5 μL
- Run time: 2 minutes
< MS condition >
- MS system: Agilent 6410 mass spectrometer (Agilent, USA)
- Scan type: MRM (Multiple Reaction Monitoring) mode
- Polarity: Positive
- Ion source: Electrospray ionization
- Resolution Q1 : unit
- Resolution Q3 : unit
- Dwell time: 0.2 sec.
The pharmacokinetic parameters obtained from the above conditions are presented in Table 5 below.
Table 5
Example 17 Example 20 Example 21 0.5% MC suspension
Cmax(ng/mL) 3343 ± 383.6 3033.3 ± 269.3 2793.0 ± 230.6 750.5 ± 63.9
Tmax(hour) 5.0 ± 1.2 3.0 ±0.0 3.7 ± 0.7 1.8 ± 0.2
AUClast(ng*hr/mL) 16151.2 ±2388.4 15368.0 ± 1258.3 12383.8 ± 1657.8 2602.4 ± 247.6
As shown in Table 5, the non-aqueous liquid formulations prepared according to the present invention exhibited remarkably increased AUC, thereby being able to accomplish high bioavailability. It is thought that these results are originated from the mechanism that, when orally administered, the formulations according to the present invention are maintained in a form of absorption-facilitated emulsion (where revaprazan is solubilzed through self-emulsifying) in the gastrointestinal tract, which leads to high gastrointestinal absorption rate.

Claims (7)

  1. A pharmaceutical composition for oral administration in a form of non-aqueous liquid, comprising revaprazan or its salt; an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and a surfactant.
  2. The pharmaceutical composition according to claim 1, wherein the surfactant is selected from the group consisting of sorbitan ester, polyoxyethylene sorbitan fatty acid ester, sucrose fatty acid ester, polyethylene glycol-15-hydroxystearate, polyoxyethylene glycolated natural or hydrogenated castor oil, polyoxyethylene-polyoxypropylene copolymer, alpha-tocopheryl polyethylene glycol succinate, polyoxyethylene alkyl ester, fatty acid macrogol glyceride, polyglyceryl fatty acid ester, bile acid, sodium lauryl sulfate, lecithin, glyceryl fatty acid ester, polyethylene glycol stearate, and a mixture thereof.
  3. The pharmaceutical composition according to claim 1, wherein the surfactant is selected from the group consisting of sucrose fatty acid ester, alpha-tocopheryl polyethylene glycol succinate, polyethylene glycol-15-hydroxystearate, and a mixture thereof.
  4. The pharmaceutical composition according to claim 1, wherein the oil is present in an amount ranging from 4 to 20 parts by weight, based on 1 part by weight of revaprazan or its salt.
  5. The pharmaceutical composition according to claim 1, wherein the surfactant is present in an amount ranging from 0.2 to 10 parts by weight, based on 1 part by weight of revaprazan or its salt.
  6. A process for preparing a pharmaceutical composition for oral administration in a form of non-aqueous liquid, the process comprising (a) melting an oil selected from the group consisting of glyceryl monolinoleate, glyceryl monooleate, propylene glycol monocaprylate, diethylene glycol monoethyl ether, caprylocaproyl polyoxylglyceride, oleoyl polyoxylglyceride, linoleoyl polyoxylglyceride, and a mixture thereof; and (b) dissolving or dispersing revaprazan or its salt and a surfactant in the melt obtained in the step (a).
  7. A capsule comprising the pharmaceutical composition according to any one of claims 1 to 5.
PCT/KR2013/002316 2012-03-28 2013-03-21 Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt WO2013147452A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR10-2012-0031411 2012-03-28
KR1020120031411A KR101739820B1 (en) 2012-03-28 2012-03-28 Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt

Publications (1)

Publication Number Publication Date
WO2013147452A1 true WO2013147452A1 (en) 2013-10-03

Family

ID=49260644

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2013/002316 WO2013147452A1 (en) 2012-03-28 2013-03-21 Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt

Country Status (2)

Country Link
KR (1) KR101739820B1 (en)
WO (1) WO2013147452A1 (en)

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170319698A1 (en) * 2014-10-29 2017-11-09 Jagotec Ag Gastroretentive gel formulations
WO2020053662A3 (en) * 2018-09-13 2020-07-30 Ftf Pharma Private Limited Non-aqueous solutions for oral dosage
WO2022259205A1 (en) * 2021-06-11 2022-12-15 Universidade Da Beira Interior Self-emulsifying composition, production methods and uses thereof
US11767328B2 (en) 2018-03-14 2023-09-26 KaNDy Therapeutics Limited Method of treatment of symptoms of menopause

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR102327750B1 (en) * 2018-12-19 2021-11-18 대화제약 주식회사 Pharmaceutical composition for oral administration comprising GLP-1 agonist

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060165797A1 (en) * 2005-01-12 2006-07-27 Pozen Inc. Dosage form for treating gastrointestinal disorders
US20080050428A1 (en) * 2004-10-05 2008-02-28 Altana Pharma Ag Oral Pharmaceutical Preparation Comprising a Proton Pump Antagonist and a Basic Excipient
US20080102133A1 (en) * 2004-10-05 2008-05-01 Antje Brueck-Scheffler Oral Pharmaceutical Preparation for Proton Pump Antagonists
US20100041688A1 (en) * 2006-12-22 2010-02-18 Yuhan Corporation Revaprazan-containing solid dispersion and process for the preparation thereof
WO2010122583A2 (en) * 2009-04-24 2010-10-28 Rubicon Research Private Limited Oral pharmaceutical compositions of acid labile substances

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR101739815B1 (en) 2010-12-01 2017-05-26 주식회사유한양행 Injectable liquid composition containing revaprazan or its salt

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080050428A1 (en) * 2004-10-05 2008-02-28 Altana Pharma Ag Oral Pharmaceutical Preparation Comprising a Proton Pump Antagonist and a Basic Excipient
US20080102133A1 (en) * 2004-10-05 2008-05-01 Antje Brueck-Scheffler Oral Pharmaceutical Preparation for Proton Pump Antagonists
US20060165797A1 (en) * 2005-01-12 2006-07-27 Pozen Inc. Dosage form for treating gastrointestinal disorders
US20100041688A1 (en) * 2006-12-22 2010-02-18 Yuhan Corporation Revaprazan-containing solid dispersion and process for the preparation thereof
WO2010122583A2 (en) * 2009-04-24 2010-10-28 Rubicon Research Private Limited Oral pharmaceutical compositions of acid labile substances

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20170319698A1 (en) * 2014-10-29 2017-11-09 Jagotec Ag Gastroretentive gel formulations
US11767328B2 (en) 2018-03-14 2023-09-26 KaNDy Therapeutics Limited Method of treatment of symptoms of menopause
US11787820B2 (en) 2018-03-14 2023-10-17 KaNDy Therapeutics Limited Method of treating certain sex hormone-dependent diseases administering a soft gelatin capsule comprising NK1 and NK3 receptors antagonists
WO2020053662A3 (en) * 2018-09-13 2020-07-30 Ftf Pharma Private Limited Non-aqueous solutions for oral dosage
GB2596184A (en) * 2018-09-13 2021-12-22 Ftf Pharma Private Ltd Non-aqueous solutions for oral dosage
WO2022259205A1 (en) * 2021-06-11 2022-12-15 Universidade Da Beira Interior Self-emulsifying composition, production methods and uses thereof

Also Published As

Publication number Publication date
KR20130109570A (en) 2013-10-08
KR101739820B1 (en) 2017-05-25

Similar Documents

Publication Publication Date Title
WO2017196148A1 (en) Composite formulation of dutasteride and tadalafil comprising glycerol fatty acid ester derivative or propylene glycol fatty acid ester derivative and oral capsule formulation comprising the same
US9504656B2 (en) Pharmaceutical compositions for poorly soluble active ingredients
WO2013147452A1 (en) Pharmaceutical composition in form of non-aqueous liquid comprising revaprazan or its salt
WO2013032207A1 (en) Sustained-release lipid pre-concentrate of pharmacologically active substance and pharmaceutical composition comprising the same
WO2017116190A1 (en) Pharmaceutical composition comprising dutasteride and propylene glycol monolaurate and preparation method of the same
EP1474172A1 (en) Pharmaceutical compositions for hepatitis c viral protease inhibitors
SG177569A1 (en) Pharmaceutical composition for a hepatitis c viral protease inhibitor
BRPI0715423A2 (en) formulations for benzimidazolyl pyridyl ethers
BRPI0008228B1 (en) pharmaceutical composition containing n-benzoyl staurosporine and solubilizing agents
US20150132388A1 (en) Complexes of fulvestrant and its derivatives, process for the preparation thereof and pharmaceutical compositions containing them
WO2012074244A2 (en) Injectable liquid composition or injectable dried powder containing revaprazan or its salt
WO2019045501A1 (en) Solid preparation comprising dutasteride and method for preparing same
CN112220748A (en) Desloratadine oral liquid preparation and preparation method thereof
WO2017043913A1 (en) Pharmaceutical composition including dutasteride and capsule formulation comprising the same
US20230321249A1 (en) Drug-clay mineral complex containing phospholipid and oral administration composition including same
WO2016126058A2 (en) Solid dispersion containing dutasteride, and composition containing same
WO2016017993A1 (en) Pharmaceutical formulation comprising amorphous or thermodynamically metastable rivaroxaban
WO2019245309A1 (en) A sustained release pharmaceutical preparation comprising tacrolimus
WO2015163689A1 (en) Active ingredient (i) containing composition and method for preparing same
WO2020256349A1 (en) Pharmaceutical composition comprising irinotecan free base for oral administration
WO2007018710A1 (en) Controlled release of hypnotic agents
WO2017069533A1 (en) Oral liquid formulation of tadalafil
WO2020080875A1 (en) Oral composition containing aprepitant
WO2019124789A1 (en) Pharmaceutical composition containing irinotecan or pharmaceutically acceptable salt thereof for oral administration
WO2018203636A1 (en) Composition having improved water solubility and bioavailability

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 13768873

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

32PN Ep: public notification in the ep bulletin as address of the adressee cannot be established

Free format text: NOTING OF LOSS OF RIGHTS PURSUANT TO RULE 112(1) EPC (EPO FORM 1205A DATED 30/01/2015

122 Ep: pct application non-entry in european phase

Ref document number: 13768873

Country of ref document: EP

Kind code of ref document: A1