WO2013179305A1 - Ibandronate sodium solid dispersion - Google Patents

Ibandronate sodium solid dispersion Download PDF

Info

Publication number
WO2013179305A1
WO2013179305A1 PCT/IN2013/000327 IN2013000327W WO2013179305A1 WO 2013179305 A1 WO2013179305 A1 WO 2013179305A1 IN 2013000327 W IN2013000327 W IN 2013000327W WO 2013179305 A1 WO2013179305 A1 WO 2013179305A1
Authority
WO
WIPO (PCT)
Prior art keywords
solid dispersion
ibandronate sodium
pharmaceutically acceptable
substantially amorphous
amorphous solid
Prior art date
Application number
PCT/IN2013/000327
Other languages
French (fr)
Inventor
Bandi Parthasaradhi Reddy
Kura Rathnakar Reddy
Dasari Muralidhara Reddy
Kesireddy Subash Chander Reddy
Bandi Vamsi Krishna
Original Assignee
Hetero Research Foundation
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 Hetero Research Foundation filed Critical Hetero Research Foundation
Publication of WO2013179305A1 publication Critical patent/WO2013179305A1/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
    • A61K31/66—Phosphorus compounds
    • A61K31/662—Phosphorus acids or esters thereof having P—C bonds, e.g. foscarnet, trichlorfon
    • A61K31/663—Compounds having two or more phosphorus acid groups or esters thereof, e.g. clodronic acid, pamidronic acid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/32—Macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. carbomers, poly(meth)acrylates, or polyvinyl pyrrolidone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/34—Macromolecular compounds obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyesters, polyamino acids, polysiloxanes, polyphosphazines, copolymers of polyalkylene glycol or poloxamers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/30—Macromolecular organic or inorganic compounds, e.g. inorganic polyphosphates
    • A61K47/36—Polysaccharides; Derivatives thereof, e.g. gums, starch, alginate, dextrin, hyaluronic acid, chitosan, inulin, agar or pectin
    • A61K47/38—Cellulose; Derivatives thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions

Definitions

  • the present invention provides a novel substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • Ibandronate sodium is chemically, [ l-hydroxy-3-
  • Ibandronate sodium is a potent bisphosphonate drug used in the prevention and treatment of osteoporosis. It may also be used to treat hypercalcemia (elevated blood calcium levels). It is marketed under the brand name Boniva ® by GlaxoSmithKline.
  • Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice.
  • polymorphs are different crystalline structures of the same pure substance in which the molecules have d ifferent arrangements and/or different configurations of the molecules.
  • Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph.
  • Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
  • XRD X-ray diffraction
  • DSC Differential Scanning Calorimetry
  • IR Infrared spectrometry
  • Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
  • Ibandronate and its sodium salt can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
  • Monohydrate crystalline Form 1 and Form II of ibandronate sodium were disclosed in International patent publication no. WO 2007/074475.
  • European patent publication no. 1966227 disclosed crystalline Form V, Form W and Form L of ibandronate sodium.
  • substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
  • the substantially amorphous solid dispersion of ibandronate sodium is stable, reproducible and so, the substantially amorphous solid dispersion of ibandronate sodium is suitable for formulating ibandronate sodium.
  • Normally amorphous Forms are hygroscopic.
  • Substantially amorphous solid dispersion of ibandronate sodium is found to be non- hygroscopic.
  • an object of the present invention is to provide substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
  • the present invention provides substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
  • the present invention there is provided a process for the preparation of substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier, which comprises:
  • the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of substantially amorphous solid dispersion of ibandronate sodium along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
  • Figure 1 is a powder X-ray diffractogram patterns of substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
  • Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffracto meter having a copper- ⁇ radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.
  • room temperature refers to temperature at about 25 to 35°C.
  • substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier there is provided substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
  • the powdered x-ray diffractogram (PXRD) of substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier is shown in figure 1 .
  • Substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier is found to be stable.
  • the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span 20 or soluplus.
  • a process for the preparation of substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier which comprises:
  • Ibandronate sodium used in step (a) may preferably be ibandronate sodium obtained by the known process.
  • the solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide and ethanol.
  • the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus, span 20 or hydroxypropyl methylcellulose.
  • the solvent may be removed from the solution in step (b) by known methods, for example, distillation or spray drying.
  • the distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure.
  • the distillation may preferably be carried out until the solvent is almost completely distilled off.
  • reduced pressure refers to a pressure of less than 100 mmHg.
  • pharmaceutical compositions comprising a therapeutically effective amount of substantially amorphous solid dispersion of ibandronate sodium along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
  • the substantially amorphous solid dispersion of ibandronate sodium may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
  • the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or luricants.
  • pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or luricants.
  • binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
  • diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol* starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.
  • Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monol
  • disintegrants include low-substituted hydro xypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
  • lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
  • Coloring agents include any FDA approved colors for oral use.
  • Phosphorous acid 60 gm was added to 3-(N-Methyl-N- pentylamino)propionicacid hydrochloride ( 100 gm) and then heated to 60 to 65°C.
  • phosphorous trichloride 19 gm was added slowly for 1 hour 30 minutes at 60 to 65°C and then heated to 80 to 85°C.
  • the reaction mass was then cooled to room temperature and added a solution of hydrochloric acid (330 ml) in water (330 ml) slowly for 45 minutes. The contents were heated to reflux and stirred for 9 hours.
  • the reaction mass was then cooled to room temperature and pH of the reaction mass was adjusted to 4.3 to 4.5 with sodium hydroxide solution.
  • the reaction mass was stirred for 30 minutes at room temperature, and then treated with carbon and filtered through hi-flow bed.
  • To the filtrate thus obtained was added ethanol (450 ml) and stirred for 1 1 hours at room temperature.
  • the separated solid was filtered and then dried to provide 145 gm of ibandronate sodium.
  • Ibandronate sodium (20 gm) as obtained in example 1 was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added copovidone (20 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 39 gm of substantially amorphous ibandronate sodium solid dispersion with copovidone.
  • Example 3 Example 3:
  • Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 15 minutes at room temperature to provide a clear solution. To the solution was added copovidone (30 gm) and water (300 ml), with stirring for 30 minutes. To the solution was added span 20 (4 gm) and then heated to reflux. The solution was stirred for 1 hour at reflux and then cooled to 60 to 65°C. The water was distilled off under reduced pressure at below 65°C to provide 52 gm of substantially amorphous ibandronate sodium solid dispersion with copovidone.
  • Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added copovidone (20 gm) and water (300 ml), with stirring for 30 minutes. To the solution was added span 20 (4 gm) and ethanol (50 ml) with stirring for 1 hour. The ethanol solvent and water was distilled off under reduced pressure at below 65°C to provide 43 gm of substantially amorphous ibandronate sodium solid dispersion with copovidone.
  • Example 4 was repeated using, dimethylformamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with copovidone.
  • Example 4 Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone
  • Example 4 was repeated using dimethylacetamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with copovidone.
  • Example 7
  • Example 4 was repeated using dimethylformamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with copovidone.
  • Example 4 was repeated using methanol solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with copovidone.
  • Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added hydroxypropyl methylcellulose (20 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 38 gm of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
  • Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 15 minutes at room temperature to provide a clear solution. To the solution was added hydroxypropyl methylcellulose (20 gm) and water (300 ml), with stirring for 30 minutes. To the solution was added span 20 (4 gm) and ethanol (50 ml) with stirring for 1 hour. The ethanol solvent and water was distilled off under reduced pressure at below 65°C to provide 42 gm of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
  • Example 12 Example 12:
  • Example 1 1 was repeated using dimethylformamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
  • Example 1 1 Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose
  • Example 1 1 was repeated using dimethylacetamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
  • Example 1 1 was repeated using dimethylformamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
  • Example 1 1 was repeated using methanol solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
  • Ibandronate sodium (10 gm) was dissolved in water (200 ml) and stirred for 15 minutes at room temperature to provide a clear solution. To the solution was added soluplus (20 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 26 gm of substantially amorphous ibandronate sodium solid dispersion with soluplus.
  • Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added ethyl cellulose (20 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 37 gm of substantially amorphous ibandronate sodium solid dispersion with ethyl cellulose.
  • Phosphorous acid 60 gm was added to 3-(N-Methyl-N- pentylamino)propionicacid hydrochloride (100 gm) and then heated to 60 to 65°C.
  • phosphorous trichloride 1 92 gm was slowly for 1 hour 30 minutes at 60 to 65°C and then heated to 80 to 85°C.
  • the reaction mass was then cooled to room temperature and added a solution of hydrochloric acid (330 ml) in water (330 ml) slowly for 45 minutes. The contents were heated to reflux and stirred for 9 hours.
  • the reaction mass was then cooled to room temperature and pH of the reaction mass was adjusted to 4.3 to 4.5 with sodium hydroxide solution.
  • Phosphorous acid 60 gm was added to 3-(N-Methyl-N- pentylamino)propionicacid hydrochloride (100 gm) and then heated to 60 to 65°C.
  • phosphorous trichloride 19 gm was added slowly for 1 hour 30 minutes at 60 to 65°C and then heated to 80 to 85°C.
  • the reaction mass was then cooled to room temperature and added a solution of hydrochloric acid (330 ml) in water (330 ml) slowly for 45 minutes. The contents were heated to reflux and stirred for 9 hours.
  • the reaction mass was then cooled to room temperature and pH of the reaction mass was adjusted to 4.3 to 4.5 with sodium hydroxide solution.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Inorganic Chemistry (AREA)
  • Dispersion Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Preparation (AREA)

Abstract

The present invention provides a novel substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it. In a preferred embodiment the process for the preparation of amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier comprises: preparing a solution comprising a mixture of ibandronate sodium and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span 20 or soluplus in a solvent, water or mixture thereof; and removing the solvent or water to obtain substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.

Description

IBANDRONATE SODIUM SOLID DISPERSION
This application claims the benefit of Indian Provisional Patent Application No. 2204/CHE/2012, filed on June 01 , 2012, which is incorporated herein by reference.
Filed of the Invention
The present invention provides a novel substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it.
Background of the Invention
Ibandronate sodium is chemically, [ l-hydroxy-3-
(methylpentylamino)propylidene]bisphosphonic acid sodium and has the structure formula:
Figure imgf000003_0001
Ibandronate sodium is a potent bisphosphonate drug used in the prevention and treatment of osteoporosis. It may also be used to treat hypercalcemia (elevated blood calcium levels). It is marketed under the brand name Boniva® by GlaxoSmithKline.
Ibandronate and its salts were disclosed in U.S. patent no. 4,927,814.
Polymorphism is defined as "the ability of a substance to exist as two or more crystalline phases that have different arrangement and/or conformations of the molecules in the crystal Lattice. Thus, in the strict sense, polymorphs are different crystalline structures of the same pure substance in which the molecules have d ifferent arrangements and/or different configurations of the molecules". Different polymorphs may differ in their physical properties such as melting point, solubility, X-ray diffraction patterns, etc. Although those differences disappear once the compound is dissolved, they can appreciably influence pharmaceutically relevant properties of the solid form, such as handling properties, dissolution rate and stability. Such properties can significantly influence the processing, shelf life, and commercial acceptance of a polymorph. It is therefore important to investigate all solid forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. Polymorphic forms of a compound can be distinguished in the laboratory by analytical methods such as X-ray diffraction (XRD), Differential Scanning Calorimetry (DSC) and Infrared spectrometry (IR).
Solvent medium and mode of crystallization play very important role in obtaining one polymorphic Form over the other.
Ibandronate and its sodium salt can exist in different polymorphic Forms, which may differ from each other in terms of stability, physical properties, spectral data and methods of preparation.
International patent publication no. WO 2006/024024 described crystalline Form C, Form D, Form E, Form F, Form G, Form H, Form J, Form K, Form 2, Form K3, Form Q, Form Ql ; Form Q2, Form Q3, Form Q4, Form Q5, Form Q6, Form QQ, Form R, Form S, Form T and amorphous Form of ibandronate sodium.
onohydrate crystalline Form A of ibandronate sodium was disclosed in International patent publication no. WO 2006/081 963.
International patent publication no. WO 2006/081962 disclosed monohydrate crystalline Form B of ibandronate sodium.
Monohydrate crystalline Form 1 and Form II of ibandronate sodium were disclosed in International patent publication no. WO 2007/074475.
European patent publication no. 1966227 disclosed crystalline Form V, Form W and Form L of ibandronate sodium.
International patent publication no. WO 2008/131 160 disclosed in crystalline Form I, Form II, Form III, Form IV, Form VI, Form VII, Form VIII, Form IX, Form X, Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, Form XVI r, Form XVIII, Form XIX, Form XX, Form XXI, Form XXII, Form XXIII, Form XXIV, Form XXV, Form XXVI, Form XXVII, Form XXVIII, Form XXIX, Form XXX, Form XXXI, Form a and Form β of ibandronate sodium.
International patent publication no. WO 2009/020483 disclosed Form C2, Form a and Form β of ibandronate sodium. It was observed that the crystalline Forms and amorphous Form of ibandronate sodium either not reproducible or not stable.
We have found a novel substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier. The substantially amorphous solid dispersion of ibandronate sodium is stable, reproducible and so, the substantially amorphous solid dispersion of ibandronate sodium is suitable for formulating ibandronate sodium. Normally amorphous Forms are hygroscopic. Substantially amorphous solid dispersion of ibandronate sodium is found to be non- hygroscopic.
Thus, an object of the present invention is to provide substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier, process for its preparation and pharmaceutical compositions comprising it. Summary of the Invention
Γη one aspect, the present invention provides substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
In another aspect, the present invention there is provided a process for the preparation of substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of ibandronate sodium and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span 20 or soluplus in a solvent, water or mixture thereof; and
b) removing the solvent or water to obtain substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier. Yet in another aspect, the present invention provides pharmaceutical compositions comprising a therapeutically effective amount of substantially amorphous solid dispersion of ibandronate sodium along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. Brief Description of the Drawing
Figure 1 is a powder X-ray diffractogram patterns of substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
Powder X-ray diffraction spectrum was measured on a bruker AXS D8 advance powder X-ray diffracto meter having a copper-Κα radiation. Approximately 500 mg of sample was gently flattered on a sample holder and scanned from 2 to 50 degrees two- theta, at 0.020 degrees two theta per step and a step time of 1 second. The sample was simply placed on the sample holder. The sample was rotated at 30 rpm at a voltage 40 kV and current 35 mA.
Detailed Description of the Invention
The term "room temperature" refers to temperature at about 25 to 35°C.
According to one aspect of the present invention, there is provided substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
The powdered x-ray diffractogram (PXRD) of substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier is shown in figure 1 .
Substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier is found to be stable.
Preferably the pharmaceutically acceptable carriers may be one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span 20 or soluplus.
According to another aspect of the present invention, there is provided a process for the preparation of substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier, which comprises:
a) preparing a solution comprising a mixture of ibandronate sodium and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span 20 or soluplus in a solvent, water or mixture thereof; and
b) removing the solvent or water to obtain substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier. Ibandronate sodium used in step (a) may preferably be ibandronate sodium obtained by the known process.
The solvent used in step (a) may preferably be a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol, and more preferably the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide and ethanol.
Preferably the pharmaceutically acceptable carriers used in step (a) may be selected from copovidone, soluplus, span 20 or hydroxypropyl methylcellulose.
The solvent may be removed from the solution in step (b) by known methods, for example, distillation or spray drying. The distillation of the solvent may be carried out at atmospheric pressure or at reduced pressure. The distillation may preferably be carried out until the solvent is almost completely distilled off.
As used herein, "reduced pressure" refers to a pressure of less than 100 mmHg. According to another aspect of the present invention, there is provided pharmaceutical compositions comprising a therapeutically effective amount of substantially amorphous solid dispersion of ibandronate sodium along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient. The substantially amorphous solid dispersion of ibandronate sodium may preferably be formulated into tablets, capsules, suspensions, dispersions, injectables or other pharmaceutical forms.
Preferably the present invention provides a pharmaceutical composition containing said solid dispersion along with the pharmaceutically acceptable excipients such as diluents, chelating agents, disintegrant, glidant, binders, surfactants, coloring agents and/or luricants.
Specific examples of binders include methyl cellulose, hydroxypropyl cellulose, hydroxypropyl methylcellulose, polyvinylpyrrolidone, gelatin, gum Arabic, ethyl cellulose, polyvinyl alcohol, pullulan, pregelatinized starch, agar, tragacanth, sodium alginate, propylene glycol, and the like.
Specific examples of diluents include calcium carbonate, calcium phosphate- dibasic, calcium phosphate-tribasic, calcium sulfate, microcrystalline cellulose, cellulose powdered, dextrates, dextrins, dextrose excipients, fructose, kaolin, lactitol, lactose, mannitol, sorbitol* starch, starch pregelatinized, sucrose, sugar compressible, sugar confectioners, and the like and mixtures thereof.
Surfactants include both non-ionic and ionic (cationic, anionic and zwitterionic) surfactants suitable for use in pharmaceutical dosage forms. These include polyethoxylated fatty acids and its derivatives, for example, polyethylene glycol 400 distearate, polyethylene glycol-20 dioleate, polyethylene glycol 4 - 150 mono dilaurate, and polyethylene glycol - 20 glyceryl stearate; alcohol - oil transesterification products, for example, polyethylene glycol - 6 corn oil; polyglycerized fatty acids, for example, polyglyceryl - 6 pentaoleate; propylene glycol fatty acid esters, for example, propylene glycol monocaprylate; mono and diglycerides, for example, glyceryl ricinoleate; sterol and sterol derivatives; sorbitan fatty acid esters and its derivatives, for example, polyethylene glycol - 20 sorbitan monooleate and sorbitan monolaurate; polyethylene glycol alkyl ether or phenols, for example, polyethylene glycol - 20 cetyl ether and polyethylene glycol - 10 - 100 nonyl phenol; sugar esters, for example, sucrose monopalmitate; polyoxyethylene - polyoxypropylene block copolymers known as "poloxamer"; -ionic surfactants, for example, sodium caproate, sodium glycocholate, soy lecithin, sodium stearyl fumarate, propylene glycol alginate, octyl sulfosuccinate disodium, and palmitoyl carnitine; and the like and mixtures thereof.
Specific examples of disintegrants include low-substituted hydro xypropylcellulose (L-HPC), sodium starch glycollate, carboxymethyl cellulose, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, croscarmellose sodium A-type (Ac-di-sol), starch, crystalline cellulose, hydroxypropyl starch, pregelatinized starch, and the like and mixtures thereof.
Specific examples of lubricants/glidants include colloidal silicon dioxide, stearic acid, magnesium stearate, calcium stearate, talc, hydrogenated castor oil, sucrose esters of fatty acid, microcrystalline wax, yellow beeswax, white beeswax, and the like and mixtures thereof.
Coloring agents include any FDA approved colors for oral use.
The invention will now be further described by the following examples, which are illustrative rather than limiting.
Examples
Example 1 :
Preparation of ibandronate sodium
Phosphorous acid (60 gm) was added to 3-(N-Methyl-N- pentylamino)propionicacid hydrochloride ( 100 gm) and then heated to 60 to 65°C. To the mixture was added phosphorous trichloride (192 gm) slowly for 1 hour 30 minutes at 60 to 65°C and then heated to 80 to 85°C. The reaction mass was then cooled to room temperature and added a solution of hydrochloric acid (330 ml) in water (330 ml) slowly for 45 minutes. The contents were heated to reflux and stirred for 9 hours. The reaction mass was then cooled to room temperature and pH of the reaction mass was adjusted to 4.3 to 4.5 with sodium hydroxide solution. The reaction mass was stirred for 30 minutes at room temperature, and then treated with carbon and filtered through hi-flow bed. To the filtrate thus obtained was added ethanol (450 ml) and stirred for 1 1 hours at room temperature. The separated solid was filtered and then dried to provide 145 gm of ibandronate sodium.
Example 2:
Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone
Ibandronate sodium (20 gm) as obtained in example 1 was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added copovidone (20 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 39 gm of substantially amorphous ibandronate sodium solid dispersion with copovidone. Example 3:
Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone
Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 15 minutes at room temperature to provide a clear solution. To the solution was added copovidone (30 gm) and water (300 ml), with stirring for 30 minutes. To the solution was added span 20 (4 gm) and then heated to reflux. The solution was stirred for 1 hour at reflux and then cooled to 60 to 65°C. The water was distilled off under reduced pressure at below 65°C to provide 52 gm of substantially amorphous ibandronate sodium solid dispersion with copovidone.
Example 4:
Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone
Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added copovidone (20 gm) and water (300 ml), with stirring for 30 minutes. To the solution was added span 20 (4 gm) and ethanol (50 ml) with stirring for 1 hour. The ethanol solvent and water was distilled off under reduced pressure at below 65°C to provide 43 gm of substantially amorphous ibandronate sodium solid dispersion with copovidone.
Example 5:
Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone
Example 4 was repeated using, dimethylformamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with copovidone.
Example 6:
Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone Example 4 was repeated using dimethylacetamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with copovidone. Example 7:
Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone
Example 4 was repeated using dimethylformamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with copovidone.
Example 8:
Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone
Example 4 was repeated using methanol solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with copovidone.
Example 9:
Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose
Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added hydroxypropyl methylcellulose (20 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 38 gm of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
Example 10:
Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 15 minutes at room temperature to provide a clear solution. To the solution was added hydroxypropyl methylcellulose (40 gm) and water (300 ml), with stirring for 30 minutes. To the solution was added span 20 (4 gm) and then heated to reflux. The solution was stirred for 1 hour at reflux and then cooled to 60 to 65°C. The water was distilled off under reduced pressure at below 65°C to provide 62 gm of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
Example 1 1 :
Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose
Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 15 minutes at room temperature to provide a clear solution. To the solution was added hydroxypropyl methylcellulose (20 gm) and water (300 ml), with stirring for 30 minutes. To the solution was added span 20 (4 gm) and ethanol (50 ml) with stirring for 1 hour. The ethanol solvent and water was distilled off under reduced pressure at below 65°C to provide 42 gm of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose. Example 12:
Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose
Example 1 1 was repeated using dimethylformamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
Example 13 :
Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose Example 1 1 was repeated using dimethylacetamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose. Example 14:
Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose
Example 1 1 was repeated using dimethylformamide solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
Example 15 :
Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose
Example 1 1 was repeated using methanol solvent instead of ethanol solvent to obtain substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.
Example 16:
Preparation of substantially amorphous ibandronate sodium solid dispersion with soluplus
Ibandronate sodium (10 gm) was dissolved in water (200 ml) and stirred for 15 minutes at room temperature to provide a clear solution. To the solution was added soluplus (20 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 26 gm of substantially amorphous ibandronate sodium solid dispersion with soluplus.
Example 17:
Preparation of substantially amorphous ibandronate sodium solid dispersion with polyethylene glycol Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added polyethylene glycol (10 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 25 gm of substantially amorphous ibandronate sodium solid dispersion with polyethylene glycol:
Example 18:
Preparation of substantially amorphous ibandronate sodium solid dispersion with ethyl cellulose
Ibandronate sodium (20 gm) was dissolved in water (200 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added ethyl cellulose (20 gm) and water (300 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 37 gm of substantially amorphous ibandronate sodium solid dispersion with ethyl cellulose.
Example 19:
Preparation of substantially amorphous ibandronate sodium solid dispersion with copovidone
Phosphorous acid (60 gm) was added to 3-(N-Methyl-N- pentylamino)propionicacid hydrochloride (100 gm) and then heated to 60 to 65°C. To the mixture was added phosphorous trichloride (1 92 gm) slowly for 1 hour 30 minutes at 60 to 65°C and then heated to 80 to 85°C. The reaction mass was then cooled to room temperature and added a solution of hydrochloric acid (330 ml) in water (330 ml) slowly for 45 minutes. The contents were heated to reflux and stirred for 9 hours. The reaction mass was then cooled to room temperature and pH of the reaction mass was adjusted to 4.3 to 4.5 with sodium hydroxide solution. The reaction mass was stirred for 30 minutes at room temperature, and then treated with carbon and filtered through hi-flow bed. To the filtrate thus obtained was added ethanol (450 ml), with stirring for 1 1 hours at room temperature and then added water (1400 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added copovidone (145 gm) and water (2000 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65 C to provide 280 gm of substantially amorphous ibandronate sodium solid dispersion with copovidone.
Example 20:
Preparation of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose
Phosphorous acid (60 gm) was added to 3-(N-Methyl-N- pentylamino)propionicacid hydrochloride (100 gm) and then heated to 60 to 65°C. To the mixture was added phosphorous trichloride (192 gm) slowly for 1 hour 30 minutes at 60 to 65°C and then heated to 80 to 85°C. The reaction mass was then cooled to room temperature and added a solution of hydrochloric acid (330 ml) in water (330 ml) slowly for 45 minutes. The contents were heated to reflux and stirred for 9 hours. The reaction mass was then cooled to room temperature and pH of the reaction mass was adjusted to 4.3 to 4.5 with sodium hydroxide solution. The reaction mass was stirred for 30 minutes at room temperature, and then treated with carbon and filtered through hi-flow bed. To the filtrate thus obtained was added ethanol (450 ml), with stirring for 1 1 hours at room temperature and then added water (1400 ml) and stirred for 20 minutes at room temperature to provide a clear solution. To the solution was added hydroxypropyl methylcellulose (145 gm) and water (2000 ml), with stirring for 1 hour. The water was distilled off under reduced pressure at below 65°C to provide 275 gm of substantially amorphous ibandronate sodium solid dispersion with hydroxypropyl methylcellulose.

Claims

We claim:
1. An amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
2. The amorphous solid dispersion of claim 1 , wherein the pharmaceutically acceptable carrier comprises one or more of copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span 20 or soluplus.
3. The amorphous solid dispersion of claim 1 , having a powder X-ray diffractogram as shown in figure 1.
4. A process for the preparation of amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier of claim 1 , which comprises: a. preparing a solution comprising a mixture of ibandronate sodium and one or more pharmaceutically acceptable carriers selected from copovidone, ethyl cellulose, hydroxypropyl methylcellulose, polyethylene glycol, span 20 or soluplus in a solvent, water or mixture thereof; and
b. removing the solvent Or water to obtain substantially amorphous solid dispersion of ibandronate sodium in combination with a pharmaceutically acceptable carrier.
5. The process as claimed in claim 4, wherein the solvent used in step (a) is a solvent or a mixture of solvents selected from dimethyl sulfoxide, dimethylacetamide, dimethylformamide, methanol, ethanol, isopropanol, n-butanol and n-pentanol. .
6. The process as claimed in claim 5, wherein the solvents are dimethyl sulfoxide, dimethylacetamide, dimethylformamide and ethanol.
7. The process as claimed in claim 4, wherein the pharmaceutically acceptable carriers used in step (a) is selected from copovidone, soluplus, span 20 or hydroxypropyl methylcellulose.
8. Pharmaceutical compositions comprising a therapeutically effective amount of amorphous solid dispersion of ibandronate sodium along with a pharmaceutically acceptable carrier, and at least one pharmaceutically acceptable excipient.
9. The pharmaceutical composition as claimed in claim 8, wherein the amorphous solid dispersion of ibandronate sodium is formulated into tablets, capsules, suspensions, dispersions or injectables.
PCT/IN2013/000327 2012-06-01 2013-05-21 Ibandronate sodium solid dispersion WO2013179305A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
ININ2204/CHE/2012 2012-06-01
IN2204CH2012 2012-06-01

Publications (1)

Publication Number Publication Date
WO2013179305A1 true WO2013179305A1 (en) 2013-12-05

Family

ID=49672585

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/IN2013/000327 WO2013179305A1 (en) 2012-06-01 2013-05-21 Ibandronate sodium solid dispersion

Country Status (1)

Country Link
WO (1) WO2013179305A1 (en)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2007074475A2 (en) * 2005-12-27 2007-07-05 Natco Pharma Limited Novel polymorphic forms of ibandronate
US20070179119A1 (en) * 2004-08-23 2007-08-02 Revital Lifshitz-Liron Solid and crystalline ibandronate sodium and processes for preparation thereof
US20080139514A1 (en) * 2006-11-29 2008-06-12 Subhash Pandurang Gore Diphosphonic acid pharmaceutical compositions
US20100125149A1 (en) * 2007-04-19 2010-05-20 Dr. Reddy's Laboratories Ltd. Ibandronate sodium polymorphs

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070179119A1 (en) * 2004-08-23 2007-08-02 Revital Lifshitz-Liron Solid and crystalline ibandronate sodium and processes for preparation thereof
WO2007074475A2 (en) * 2005-12-27 2007-07-05 Natco Pharma Limited Novel polymorphic forms of ibandronate
US20080139514A1 (en) * 2006-11-29 2008-06-12 Subhash Pandurang Gore Diphosphonic acid pharmaceutical compositions
US20100125149A1 (en) * 2007-04-19 2010-05-20 Dr. Reddy's Laboratories Ltd. Ibandronate sodium polymorphs

Similar Documents

Publication Publication Date Title
EP1713489B1 (en) Crystalline form of ibandronate sodium and processes for preparation thereof
WO2014076712A2 (en) Lurasidone hydrochloride solid dispersion
WO2014118808A2 (en) Ticagrelor solid dispersion
KR100333215B1 (en) Mesylate dihydrate salts of 5-(2-(4-(1,2-benzisothiazol-3-yl)-1-piperazinyl)-ethyl)-6-chloro-1,3-dihydro-2(1h)-indol-2-one(=ziprasidone), its preparation and its use as dopamine d2 antagonist
ES2966924T3 (en) Procedure for the preparation of a dual-acting neprilysin-angiotensin receptor inhibitor compound
US9624172B2 (en) Polymorphs of lomitapide and its salts
WO2013160916A1 (en) Sunitinib malate solid dispersion
JP2012246316A (en) Process for preparation of crystalline modification for use in preparation of esomeperazole sodium salt
KR20070083679A (en) Use of purified donepezil maleate for preparing pharmaceutically pure amorphous donepezil hydrochloride
US20170296570A1 (en) High Drug Load Tablets Comprising Sofosbuvir
JP6887980B2 (en) Solid form of pharmaceutically active compound
WO2014115169A2 (en) Crizotinib solid dispersion
WO2013179305A1 (en) Ibandronate sodium solid dispersion
WO2013171766A2 (en) Saxagliptin solid dispersion
US20090012047A1 (en) Crystalline forms of ibandronate sodium
US20090118239A1 (en) Amorphous and crystalline forms of ibandronate disodium
RU2663617C1 (en) Novel crystalline form of 5-chloro-n-({(5s)-2-oxo-3-[4-(5,6-dihydro-4h-[1,2,4]triazin-1-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene-2-carboxamide methanesulphonate and pharmaceutical composition containing same
WO2014108921A2 (en) Carvedilol phosphate solid dispersion
WO2014174529A2 (en) Polymorphs of avanafil
WO2014102832A2 (en) Saxagliptin hydrochloride solid dispersion
US20150141457A1 (en) Elvitegravir solid dispersion
WO2013164857A1 (en) Desvenlafaxine succinate solid dispersion
EA035894B1 (en) Novel polymorphic form of n-[2-(6-fluoro-1h-indol-3-yl)ethyl]-3-(2,2,3,3-tetrafluoropropoxy)benzylamine hydrochloride for the treatment of alzheimer's disease
KR20100091127A (en) Novel salts of adefovir dipivoxil and method for the preparation of the same
WO2015107545A1 (en) Water soluble salts of dasatinib hydrate

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: 13796406

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: 13796406

Country of ref document: EP

Kind code of ref document: A1