WO2015130083A1 - Composition pharmaceutique à usage amélioré contenant de l'entécavir - Google Patents

Composition pharmaceutique à usage amélioré contenant de l'entécavir Download PDF

Info

Publication number
WO2015130083A1
WO2015130083A1 PCT/KR2015/001839 KR2015001839W WO2015130083A1 WO 2015130083 A1 WO2015130083 A1 WO 2015130083A1 KR 2015001839 W KR2015001839 W KR 2015001839W WO 2015130083 A1 WO2015130083 A1 WO 2015130083A1
Authority
WO
WIPO (PCT)
Prior art keywords
pharmaceutical composition
entecavir
chain fatty
group
dietary
Prior art date
Application number
PCT/KR2015/001839
Other languages
English (en)
Korean (ko)
Inventor
김순회
손미원
장선우
박찬웅
김정수
마경완
이상진
Original Assignee
동아에스티 주식회사
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 동아에스티 주식회사 filed Critical 동아에스티 주식회사
Priority claimed from KR1020150026453A external-priority patent/KR101633292B1/ko
Publication of WO2015130083A1 publication Critical patent/WO2015130083A1/fr

Links

Images

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
    • A61K31/519—Pyrimidines; Hydrogenated pyrimidines, e.g. trimethoprim ortho- or peri-condensed with heterocyclic rings
    • A61K31/52—Purines, e.g. adenine
    • A61K31/522—Purines, e.g. adenine having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1635—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/16—Agglomerates; Granulates; Microbeadlets ; Microspheres; Pellets; Solid products obtained by spray drying, spray freeze drying, spray congealing,(multiple) emulsion solvent evaporation or extraction
    • A61K9/1605—Excipients; Inactive ingredients
    • A61K9/1629—Organic macromolecular compounds
    • A61K9/1641—Organic macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, poloxamers
    • 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
    • A61K9/28—Dragees; Coated pills or tablets, e.g. with film or compression coating
    • A61K9/2886—Dragees; Coated pills or tablets, e.g. with film or compression coating having two or more different drug-free coatings; Tablets of the type inert core-drug layer-inactive layer

Definitions

  • the present invention relates to a pharmaceutical composition containing entecavir, and relates to a composition containing entecavir by maximizing bioavailability and enabling patients to take entecavir with or without meals.
  • Entecavir is [1S- (1 ⁇ , 3 ⁇ , 4 ⁇ )]-2-amino-1,9-dihydro-9- [4-hydroxy-3- (hydroxymethyl) -2- of Formula 1 Methylenecyclopentyl] -6H-purin-6-one, a guanosine nucleoside analog approved in March 2005 by the US FDA, and through animal and human mechanisms that inhibit the three-step process of viral replication. It is used as a treatment for chronic hepatitis B by showing antiviral activity in.
  • Entercavir is described in US Pat. No. 5,206,244 for the use of a therapeutic agent for hepatitis B virus, wherein the patent assumes an effective dosage of an antiviral agent for oral or parenteral administration in the range of about 1.0 to 50 mg / kg body weight, with preferred administration. Amounts and appropriate intervals are disclosed.
  • Korean Patent No. 10-0757155 discloses a composition containing a low dose of entercavir administered daily to treat hepatitis B virus infection and co-infection.
  • the patent also provides formulations for oral administration of low doses of entercavir.
  • BARACLUDE ® tablet is manufactured, marketed in accordance with the Republic of Korea Patent (Baraclude information ®, Bristol-Myers Squibb) is a widely used product for the treatment of chronic hepatitis B.
  • the dosage and dosage of the barracrud tablets is limited to fasting (2 hours after meal or at least 2 hours before) administration, causing a lot of discomfort in patients with chronic hepatitis B who need to take a long time.
  • Cmax is reduced by about 44% and AUC by about 20% when taken with low-fat meals, while Cmax is about 46% when taken with high-fat meals, and AUC. Is indicated to be reduced by about 18%.
  • a study published in the journal Arzneistoffforschung in 2010 compared the fasting and post-entak entecavir bioavailability in 12 Chinese subjects. Reported a decrease of about 22%.
  • entecavir is limited to fasting doses, and this limited dosage regimen may reduce the compliance of entecavir and cause incomplete treatment effects.
  • the present inventors conducted various studies to identify the cause and solve the problem of the problem of the pharmaceutical composition containing entecavir, in particular, to reduce the bioavailability when taken with meals. As a result, by minimizing the dietary effect of entecavir, a pharmaceutical composition containing entecavir, which exhibits stable bioavailability regardless of food intake, has been invented.
  • the present invention is to provide an enticavir-containing pharmaceutical composition exhibiting a stable bioavailability regardless of food intake by minimizing the dietary effect of entecavir when taking an enticavir-containing preparation with a meal.
  • the present invention provides a pharmaceutical composition comprising entecavir and a dietary effect remover.
  • the dietary effect remover is a substance selected from the group consisting of the heavy chain fatty acids and salts thereof, the heavy chain fatty acid derivatives, the organic acids, and the cationic polymers described below, and the role of enticavir in the active ingredient enticavir is increased and It plays a role of increasing the time to stay in the urinary tract at high concentration, and when entecavir-containing preparation is taken with a meal, it means that it shows stable bioavailability regardless of food intake by minimizing the dietary effect of entecavir.
  • medium chain fatty acids and salts thereof are salts of medium chain fatty acids and medium chain fatty acids having a carbon chain length of 6 to 20 carbon atoms, and the medium chain fatty acid derivatives are glyceryl caprylate / caprate.
  • organic acids are lactinic acid, maleic acid, citric acid, phytic acid, cationic polymers may include chitosan, dimethylaminoethyl methacrylate copolymer, polyvinyl acetal diethylaminoacetate, one of them The above can be selected.
  • the present invention provides a method for preparing entericavir tablets comprising the steps of preparing a particle comprising the active ingredient enticavir and a dietary scavenger, preparing a tablet by mixing a pharmaceutically acceptable excipient and coating the tablet. It can manufacture.
  • the pharmaceutical composition comprising enticavir and a dietary effect remover of the present invention can maximize the bioavailability stably regardless of food intake by minimizing the dietary effect of entecavir, and the dietary effect of reducing the bioavailability when taken with meals. This can solve the problem causing discomfort in the patient when taking, and improve the patient's compliance with the medication.
  • Figure 1 shows the results of the dissolution test of the tablets of Examples 4, 5 and 6 of the present invention and the commercial formulation of Comparative Example 1 according to the USP dissolution test method 2 (paddle method).
  • Figure 2 shows the results of the dissolution test of the enteric coated tablets prepared in Examples 7, 8 and 9 of the present invention according to the USP dissolution test method 2 (paddle method).
  • entecavir monohydrate (1 mg as enticavir) and 24 mg of citric acid are added to 1 g of distilled water and dissolved therein, and 60 mg of dimethylaminoethyl methacrylate copolymer is added to dissolve completely.
  • To the solution was added 35 mg of caprylocapryl polyoxy-8 glyceride, 50 mg of glyceryl dicaprate / dikiprilate and 5 mg of sodium lauryl sulfate, followed by stirring and dispersing 40 mg of calcium silicate and 100 mg of lactose. Let's do it.
  • the obtained solution was spray-dried (inlet temperature 115-125 degreeC, outlet temperature 65-75 degreeC) using the spray dryer, and solid particle
  • entecavir monohydrate (1 mg as entecavir) and 24 mg of citric acid are added to 1 g of distilled water and dissolved, and 60 mg of polyvinyl acetal diethylaminoacetate is added to dissolve completely.
  • To the solution was added 35 mg of caprylocapryl polyoxy-8 glyceride, 50 mg of glyceryl dicaprate / dikiprilate and 5 mg of sodium lauryl sulfate, followed by stirring and dispersing 40 mg of calcium silicate and 100 mg of lactose. Let's do it.
  • the obtained solution was spray-dried (inlet temperature 115-125 degreeC, outlet temperature 65-75 degreeC) using the spray dryer, and solid particle
  • entecavir monohydrate (1 mg as entecavir) and 40 mg of citric acid are added to 1 g of distilled water and dissolved, and 100 mg of polyvinyl acetal diethylamino acetate is added to dissolve completely.
  • To the solution was added 35 mg of caprylocapryl polyoxy-8 glyceride, 50 mg of glyceryl dicaprate / dikiprilate and 5 mg of sodium lauryl sulfate, followed by stirring and dispersing 40 mg of calcium silicate and 100 mg of lactose. Let's do it.
  • the obtained solution was spray-dried (inlet temperature 115-125 degreeC, outlet temperature 65-75 degreeC) using the spray dryer, and solid particle
  • Example 1 315.06 mg of the particles prepared in Example 1 were mixed with 60 mg of crospovidone, 60 mg of croscarmellose sodium, 50 mg of colloidal silicon dioxide, and 3 mg of magnesium stearate, followed by tableting with a single tableting machine to prepare tablets containing 1 mg of entacavir. It was.
  • Example 2 315.06 mg of the particles prepared in Example 2 were mixed with 60 mg of crospovidone, 60 mg of croscarmellose sodium, 50 mg of colloidal silicon dioxide, and 3 mg of magnesium stearate, followed by tableting with a single tableting machine to prepare tablets containing 1 mg of entacavir. It was.
  • Example 3 371.06 mg of the particles prepared in Example 3 were mixed with 60 mg of crospovidone, 60 mg of croscarmellose sodium, 50 mg of colloidal silicon dioxide, and 3 mg of magnesium stearate, followed by tableting with a single tableting machine to prepare tablets containing 1 mg of entacavir. It was.
  • Example 4 The tablets prepared in Example 4 were sprayed with a 7% hydroxypropylmethylcellulose ethanol solution using a coater to prepare tablets subcoated with about 3% HPMC. 20% of the enteric coating solution (methacrylate copolymer solution) was sprayed onto the obtained tablet to prepare a tablet coated with about 10% of the enteric base.
  • enteric coating solution methacrylate copolymer solution
  • Example 5 The tablets prepared in Example 5 were sprayed with 7% hydroxypropylmethylcellulose ethanol solution using a coater to prepare tablets subcoated with about 3% HPMC. 20% of the enteric coating solution (methacrylate copolymer solution) was sprayed onto the obtained tablet to prepare a tablet coated with about 10% of the enteric base.
  • enteric coating solution methacrylate copolymer solution
  • Tablets prepared in Example 6 were sprayed with 7% hydroxypropylmethylcellulose ethanol solution using a coater to prepare tablets subcoated with about 3% HPMC. 20% of the enteric coating solution (methacrylate copolymer solution) was sprayed onto the obtained tablet to prepare a tablet coated with about 10% of the enteric base.
  • enteric coating solution methacrylate copolymer solution
  • the tablets prepared in Examples 4, 5 and 6 and the commercially available formulations of Comparative Example 1 were subjected to a dissolution test in accordance with USP Dissolution Test Method 2 (paddle method).
  • the dissolution test solution was 900 ml of the first solution, the temperature of the test solution was set to 37 ⁇ 0.5 °C, the paddle rotation speed was set to 50 rpm. 5, 10, 15, 30, 45, and 60 minutes after the start of the test, 5 ml of the elution test solution was taken out and filtered through a 0.45 ⁇ m syringe filter. The filtrate was analyzed by HPLC and the results are shown in FIG. 1.
  • the tablets prepared in Examples 7, 8 and 9 were subjected to dissolution test in accordance with USP Dissolution Test Method 2 (paddle method).
  • USP Dissolution Test Method 2 (paddle method).
  • 750 ml of 0.1N hydrochloric acid was used as an acidic test solution, and after 2 hours, 250 ml of 0.2M sodium triphosphate solution was added to pH 6.8 test solution to convert the pH of the eluate to pH 6.8.
  • the temperature of the test solution was set at 37 ⁇ 0.5 ° C., and the paddle rotation speed was 50 rpm.
  • Comparative Example 1 In order to confirm the dietary effect of the formulation of Comparative Example 1, the bioavailability was evaluated in the fasted and fed state using a beagle dog.
  • the formulation of Comparative Example 1 used a commercially available barracrud 1 mg tablet ® (Bristol- Mayers Squibb).
  • the fasting group was orally administered to five beagle dogs fasted for 12 hours at fasting, and the feeding group was orally administered 200 ml of diet to 5 beagle dogs fasting for 12 hours and orally after 30 minutes. After administration, blood was drawn with a heparinized syringe after 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hours.
  • the collected blood was centrifuged at 4000 rpm for 10 minutes, and the separated plasma was taken and stored frozen at -70 ° C until analysis.
  • the concentration of entecavir in plasma was quantified using LC / MS, and the PK parameters obtained from the blood concentration profile are shown in Table 1 below.
  • Comparative Example 1 Baraclude 1mg tablet ® ), which is a commercially available product, can be confirmed that the bioavailability is reduced when taken with a diet.
  • Bioavailability of the tablets prepared in Examples 4, 5, and 6 according to the present invention was evaluated using beagle dogs. Comparative evaluation with a commercially available formulation of BARACLUDE 1mg tablet ® (Bristol-Mayers Squibb Co.) was orally administered to the fasting beagles targeting the 5 weight of about 8kg were fasted for 12 hours. As a test evaluation, the tablets prepared in Examples 4, 5 and 6 were orally administered to fasting groups of 5 beagle dogs fasted for 12 hours, and the feeding group of 5 beagle dogs fasted for 12 hours. 200 ml of diet was forced orally and 30 minutes later.
  • the fasting group of the comparative evaluation group and the test evaluation group had 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hours later, and the feeding group of the test evaluation group had 1, 1.5, 2 , 2.5, 3, 3.5, 4, 5, 6, 8, 12 hours later, blood was collected with a heparinized syringe.
  • the collected blood was centrifuged at 4000 rpm for 10 minutes, and the separated plasma was taken and stored frozen at -70 ° C until analysis.
  • the concentration of entecavir in plasma was quantified using LC / MS, and the PK parameters obtained from the blood concentration profile are shown in Table 2 below.
  • the tablet according to the present invention exhibited a similar degree to AUC and Cmax in fasting state of Comparative Example 1 (Baraclude 1mg tablet ® ) in fasting and wet state, which is commercially available, so that the entecavir-containing formulation is taken with the meal. It can be seen that by minimizing the dietary effect of entecavir shows a stable bioavailability regardless of food intake.
  • the bioavailability of the coatings prepared in Examples 7, 8, and 9 according to the present invention was evaluated using beagle dogs. Comparative evaluation with a commercially available formulation of BARACLUDE 1mg tablet ® (Bristol-Mayers Squibb Co.) was orally administered to the fasting beagles targeting the 5 weight of about 8kg were fasted for 12 hours. In the evaluation of the test, the coatings prepared in Examples 7, 8 and 9 were orally administered to fasting groups of 5 beagle dogs fasted for 12 hours, and the feeding group of 5 beagle dogs fasting for 12 hours. 200 ml of diet was forced orally and 30 minutes later.
  • the fasting group of the comparative evaluation group and the test evaluation group had 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, 8, 12 hours later, and the feeding group of the test evaluation group had 1, 1.5, 2 , 2.5, 3, 3.5, 4, 5, 6, 8, 12 hours later, blood was collected with a heparinized syringe.
  • the collected blood was centrifuged at 4000 rpm for 10 minutes, and the separated plasma was taken and stored frozen at -70 ° C until analysis.
  • the concentration of entecavir in plasma was quantified using LC / MS, and the PK parameters obtained from the blood concentration profile are shown in Table 3 below.
  • the enteric coating agent according to the present invention exhibits a similar degree to AUC and Cmax in the fasting state of Comparative Example 1 (Baraclude 1mg tablet ® ) in the fasting and wet state of commercially available preparations, so that the preparation containing entecavir with a meal When taken, it can be seen that it shows stable bioavailability regardless of food intake by minimizing the dietary effect of entecavir.
  • Comparative Example 1 Baraclude 1mg tablets ®
  • AUC and Cmax in the fed state was reduced by about 10% and C60 was reduced by about 60% compared to AUC and Cmax in the fasting state, but the bioavailability was lowered.
  • Tablets and enteric coatings of the present invention exhibit a high bioavailability even in the fed state, it is possible to take the formulation containing entecavir regardless of the meal to improve the patient's ease of taking.

Landscapes

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

Abstract

La présente invention concerne une composition pharmaceutique contenant de l'entécavir en tant qu'ingrédient actif et un suppresseur d'effet diététique. La composition pharmaceutique selon la présente invention présente un comportement in vivo stable indépendamment de la prise alimentaire, en réduisant à un minimum un effet diététique présenté lors de la prise d'entécavir, c'est-à-dire la diminution de la biodisponibilité, qui se produit lors de la prise d'entécavir avec les repas. Par conséquent, la présente invention peut maximiser la biodisponibilité de l'entécavir indépendamment de la prise alimentaire et améliorer l'observance thérapeutique chez les patients souffrant d'hépatite B chronique et prenant l'entécavir et, de ce fait, l'amélioration de l'effet thérapeutique peut être anticipée.
PCT/KR2015/001839 2014-02-25 2015-02-25 Composition pharmaceutique à usage amélioré contenant de l'entécavir WO2015130083A1 (fr)

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
KR10-2014-0021939 2014-02-25
KR20140021939 2014-02-25
KR10-2015-0026453 2015-02-25
KR1020150026453A KR101633292B1 (ko) 2014-02-25 2015-02-25 용법이 개선된 엔테카비어를 함유하는 약학적 조성물

Publications (1)

Publication Number Publication Date
WO2015130083A1 true WO2015130083A1 (fr) 2015-09-03

Family

ID=54009338

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/KR2015/001839 WO2015130083A1 (fr) 2014-02-25 2015-02-25 Composition pharmaceutique à usage amélioré contenant de l'entécavir

Country Status (1)

Country Link
WO (1) WO2015130083A1 (fr)

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080044486A1 (en) * 2003-11-25 2008-02-21 Goran Nilsson Controlled Food Effect Composition
US20110311594A1 (en) * 2010-06-22 2011-12-22 Shou-Chiung Chen Controlled release compositions with reduced food effect
CN101224211B (zh) * 2008-01-25 2012-05-30 杨喜鸿 恩替卡韦的固体分散体、药物组合物及其制备方法和药物应用
WO2012174082A1 (fr) * 2011-06-14 2012-12-20 Novartis Ag Libération modifiée de 4-méthyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-5-(4-méthyl-1h-imidazol-1-yl)-3-(trifluorométhyl)phényl] benzamide solubilisé à l'aide d'acides organiques
US20130142877A1 (en) * 2010-05-10 2013-06-06 Evonik Roehm Gmbh Pharmaceutical dosage form comprising one or more antiretroviral active ingredients

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20080044486A1 (en) * 2003-11-25 2008-02-21 Goran Nilsson Controlled Food Effect Composition
CN101224211B (zh) * 2008-01-25 2012-05-30 杨喜鸿 恩替卡韦的固体分散体、药物组合物及其制备方法和药物应用
US20130142877A1 (en) * 2010-05-10 2013-06-06 Evonik Roehm Gmbh Pharmaceutical dosage form comprising one or more antiretroviral active ingredients
US20110311594A1 (en) * 2010-06-22 2011-12-22 Shou-Chiung Chen Controlled release compositions with reduced food effect
WO2012174082A1 (fr) * 2011-06-14 2012-12-20 Novartis Ag Libération modifiée de 4-méthyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-n-5-(4-méthyl-1h-imidazol-1-yl)-3-(trifluorométhyl)phényl] benzamide solubilisé à l'aide d'acides organiques

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
LI, L. ET AL.: "Polymer-and lipid-based nanoparticle therapeutics for the treatment of liver diseases", NANO TODAY, vol. 5, no. 4, 2010, pages 296 - 312, XP027196108 *

Similar Documents

Publication Publication Date Title
US6627224B2 (en) Low dose entecavir formulation and use
US20210244714A1 (en) Pharmaceutical formulations containing rifaximin, processes for their obtainment and method of treating intestinal disease
WO2013157754A1 (fr) Procédé de préparation d'une formulation d'entécavir faiblement dosée à administrer par voie orale
EP0078079B1 (fr) Forme de dosage du nitrofurantoine
EP0643967A2 (fr) Composition pharmaceutique contenant un analgésique opiacé, e.g. morphine, et un laxative, e.g. bisacodyl
KR100366130B1 (ko) 항과혈당증작용을지닌약제
WO2020171404A1 (fr) Composition pharmaceutique
KR101633292B1 (ko) 용법이 개선된 엔테카비어를 함유하는 약학적 조성물
WO2015130083A1 (fr) Composition pharmaceutique à usage amélioré contenant de l'entécavir
AU2018303109B2 (en) Use of aminoalkylbenzothiazepine derivatives
WO2022075760A1 (fr) Composition pharmaceutique comprenant de l'aprémilast
JP5386477B2 (ja) 脊髄損傷を治療するための４−シクロプロピルメトキシ−ｎ−（３，５−ジクロロ−１−オキシドピリジン−４−イル）−５−（メトキシ）ピリジン−２−カルボキサミドの使用
WO2019160243A1 (fr) Composition pharmaceutique à libération prolongée contenant du lacosamide
KR100192534B1 (ko) 소마토스타틴 분비증가제와 분비저하 억제제
AU705751B2 (en) An agent for inhibiting carcinogenesis
AU2003217704A1 (en) Diphenhydramine tannate compositions and methods of use
WO2021112548A1 (fr) Composition pharmaceutique
WO2018203636A1 (fr) Composition ayant une solubilité dans l'eau et une biodisponibilité améliorées
WO2019107986A1 (fr) Composition pharmaceutique comprenant du fimasartan
WO2007036947A1 (fr) Composition anti-paludéenne à libération retardée
WO2016195377A2 (fr) Composition de préparation solide contenant du pranlukast à biodisponibilité améliorée et procédé pour sa préparation
WO2015056956A1 (fr) Composition pharmaceutique à libération contrôlée à base d'acide propionique
WO2013032310A1 (fr) Comprimés de mégestrol à dissolution rapide et leur procédé de fabrication
TW202110444A (zh) 一種西達本胺藥物組合物及其製備方法和用途
JP2702284B2 (ja) ソマトスタチン増加用またはソマトスタチン低下抑制用薬剤

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: 15755103

Country of ref document: EP

Kind code of ref document: A1

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 15755103

Country of ref document: EP

Kind code of ref document: A1