AP285A - Pharmaceutical composition comprising a particular pysical form of a heterocyclic amide derivative. - Google Patents

Pharmaceutical composition comprising a particular pysical form of a heterocyclic amide derivative. Download PDF

Info

Publication number
AP285A
AP285A APAP/P/1991/000340A AP9100340A AP285A AP 285 A AP285 A AP 285A AP 9100340 A AP9100340 A AP 9100340A AP 285 A AP285 A AP 285A
Authority
AP
ARIPO
Prior art keywords
vhich
physical form
methyl
amino
composition
Prior art date
Application number
APAP/P/1991/000340A
Other versions
AP9100340A0 (en
Inventor
James Joseph Holohan
Ieuan John Edwards
Robert Joseph Timko
Randy John Bradway
Arlene Clements
Original Assignee
Zeneca Ltd
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
Family has litigation
First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=26298105&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=AP285(A) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.
Priority claimed from GB909027014A external-priority patent/GB9027014D0/en
Priority claimed from GB919115107A external-priority patent/GB9115107D0/en
Application filed by Zeneca Ltd filed Critical Zeneca Ltd
Publication of AP9100340A0 publication Critical patent/AP9100340A0/en
Application granted granted Critical
Publication of AP285A publication Critical patent/AP285A/en

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • 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
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/20—Pills, tablets, discs, rods
    • A61K9/2004—Excipients; Inactive ingredients
    • A61K9/2022—Organic macromolecular compounds
    • A61K9/2027—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
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P11/00—Drugs for disorders of the respiratory system
    • A61P11/06—Antiasthmatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicinal Chemistry (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Pulmonology (AREA)
  • Inorganic Chemistry (AREA)
  • Dermatology (AREA)
  • Pain & Pain Management (AREA)
  • Rheumatology (AREA)
  • Immunology (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Medicinal Preparation (AREA)
  • Indole Compounds (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

The invention provides a pharmaceutical physical form of n-(4=(5-(cyclopentyloxy carbonyl)amino-1-methylindol-3-yl-methyl)-3-methoxybenzoyl)-2-methyl benzenesulphonamide and polyvinypyrrolidone. It also provides methods for preparing this physical form, and another physical form of n-(4-(5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-yl-methyl)-3-methoxybenzoyl)-2-methylbenzesulphonamide useful in the prepatation of the first mentioned physical form. The compositions are useful in the treatment of diseases in which leukotrienes are implicated, for example asthma

Description

PHARMACEUTICAL AGENTS
The present invention relates to pharmaceutical agents.
More particularly, it relates to a pharmaceutical composition comprising a particular physical fora of a heterocyclic amide derivative, to processes for the preparation of this physical form, and to another physical form of the heterocyclic amide useful in the preparation of the first-mentioned physical form.
European patent application publication number EP-A2-0199543 discloses certain heterocyclic amide derivatives vhich antagonise the pharmacological actions of one or more of the arachidonic acid metabolites knovn as leukotrienes, for example C^, D^, and/or E^, vhich are knovn to be powerful spasmogens (particularly in the lung), to increase vascular permeability and have been implicated in the pathogenesis of asthma and inflammation (see J. L. Marx, Science,
1982, 215, 1380-1383) as veil as of endotoxic shock (see J. A. Cook, et al., J. Pharmacol. Exp. Ther., 1985, 235, 470) and traumatic shock (see C, Denzlinger, et al., Science, 1985, 230, 330). The compounds are thus useful in the treatment of diseases in vhich leukotrienes are implicated and in vhich antagonism of their action is desired. , Such diseases include, for example, allergic pulmonary disorders such as asthma, hay fever and allergic rhinitis and certain inflammatory diseases such as bronchitis, ectopic and atopic eczema, psoriasis, as veil as vasospastic cardiovascular disease, and endotoxic and traumatic shock conditions.
One of the heterocyclic amice derivatives disclosed in EP-A2-0199543 is N-[4-[5-( cyclopentyloxycarbony1)amino-1-methylindol-3-ylmethyl]-3-me thoxybenzoyl]-2-methylbenzenesulphonamide. This compound is described in Example 105 of the patent specification, and vill be referred to hereinafter as compound 1.
BADORIGINAL ti
PH.36076
- 2 In recent clinical trials compound 1 has been found to be effective in the treatment of asthma vhen administered orally to asthmatic patients. This ability of compound 1 to be effective vhen administered orally is unusual and highly desirable.
The pharmaceutical composition used in the aforementioned clinical trials vas not entirely satisfactory, and an improved formulation has been sought. As vill be described in more detail hereinbelow, a number of technical problems needed to be solved in order for such a composition to be obtained.
Compound 1 has been found to possess relatively poor solubility in vater. There has therefore been a need for a pharmaceutical composition suitable for oral administration vhich comprises compound 1 in the solid state.
It has been found that compound 1 can be obtained in the solid state as a material having a range of different physical properties, depending upon the vay in vhich it has been isolated and subsequently treated. This ability has been found to be due to the fact that compound 1 can exist in more than one physical form, at least one of vhich has poor physical stability, and vhich physical forms can be obtained in mixtures. It has also been found that different samples of compound 1 in the solid state have different bioavailabilities.
It is unattractive to develop a formulation containing a •nix':ure of physical forms of a compound tha’ hae different bioavailabilities, especially vhere one is physically unstable, because the effective dose of the compound cannot be properly controlled. There has therefore been a need to find methods for preparing physical forms of compound 1 substantially free of other physical forms.
BAO OBlGlNAt §j
AP Ο Ο Ο 2 8 5
PH.36076
- 3 Methods for preparing three physical forms of compound 1 substantially free of other physical forms have been found, and the physical stability and bioavailability of these three forms have been investigated. Tvo of these forms, referred to hereinafter as forms B and X, have been found to be physically stable, but to have relatively poor bioavailability. The third of the three forms, referred to hereinafter as form A, has been found to have relatively good bioavailability. However, it has been found that this physical form tends to convert into form B in the presence of water. This property is disadvantageous for a material which is intended to be formulated in a solid composition, because granulation involves the use of water as an adjuvant in the mixing process. Indeed the tablets used in the aforementioned clinical trials were prepared by the wet granulation method from form A, and were found to contain form B in an amount varying from about 25 to about 302 by weight, based on the weight of compound 1.
There is therefore a need for a pharmaceutical composition suitable for oral administration which comprises compound 1 in one physical form, substantially free of other physical forms, which composition. is physically stable, can be prepared reproducibly and has good bioavailability.
Surprisingly, it has now been found that pharmaceutical compositions meeting these requirements may be obtained by selecting form A as the active ingredient and polyvinylpyrrolidone as a co-ingredient.
Accordingly the present invention provides a pharmaceutical composition, which comprises, as active ingredient, a physical form of N-[4-[5-(cyclopentyloxycarbony1)amino-1-methylindol-3-ylmethyl]-3-methoxybenzoyl 1 -2-methylbenzenesuIphonamide (hereinbefore referred to as form A) substantially free of other physical forms vhich physical form has an infra-red spectrum (0.52 in KBr) having sharp peaks at 1690, 1530, 1490, 1420. 1155, 1060, 862 and 550cm'1, and polyvinylpyrrolidone.
bad original
PH.36076
Form A has an X-ray povder diffraction pattern having no discernable peaks, and is therefore amorphous.
It has been found that compositions according to the invention have acceptable physical stability, can be prepared reproducibly and have surprisingly high bioavailability.
Where reference is made in this specification to form A substantially free of other physical forms, it preferably means that at least 902 by veight of the compound 1 present is in that physical form, more preferably at least 952, for example at least 962, 972, 982 or 992.
The composition according to the invention may be in any conventional form suitable for oral administration, for example in the form of a tablet, capsule, beadlet or povder. Preferably it is in the form of a tablet.
In the composition according to the invention, the active ingredient is conveniently present in an amount of from 1 to 902 by veight, based upon the total veight of the composition, for example from 10 to 502 by veight.
The polyvinylpyrrolidone is conveniently present in an amount of at least 1Z by veight, based on the total veight of the composition. It may, together vith the active ingredient, account for the total veight of the composition. Hovever. the composition viii more usually further comprise at least on5 pnarmareutically acceptable carrier. For example, the polyvinylpyrrolidone may be present in an amount of from 1 to 202 by veight based on the total veight of the composition, preferably from 2 to 62 by veight.
Examples of suitable pharmaceutically acceptable carriers include, for example, sugar derivatives such as mannitol, lactose, sorbitol, glucose, sucrose, dextrose, fructose and xylitol, and cellulose derivatives such as microcrystalline cellulose, povdered
bad origin*1·
AP Ο Ο Ο 2 8 5
PH.36076
- 5 cellulose and hydroxypropylmethylcellulose. Preferably the composition comprises a sugar derivative, especially lactose, and a cellulose derivative, especially microcrystalline cellulose. The amount of sugar derivative present may, for example be in the range of from 10 to 30X by weight based upon the total weight of the composition. The amount of cellulose derivative present may, for example, be in the range of from 25 to 70X by weight, based upon the total weight of the composition.
The composition may further comprise one or more processing adjuvants such as disintegrants, for example croscarmellose sodium, sodium starch glycolate and starch, and lubricants, for example magnesium stearate, stearic acid, talc and powdered vegetable stearine. The amount of disintegrant present may, for example, be in the range of from 1 to 10X by weight based upon the total weight of the composition. The amount of lubricant present may, for example, be in the range of from 0.25 to 2X by weight, based upon the total weight of the composition.
The composition may be prepared by mixing the ingredients according to a conventional method, for example by a granulation process.
According to another aspect, therefore, the invention provides a process for preparing a pharmaceutical composition which comprises mixing form A substantially free of other physical forms with polyvinylpyrrolidone and water, and ir'-'ine the resultant mixture.
The quantity of water used will depend upon the type of pharmaceutical composition required (eg a tablet, capsule, powder or beadlet) and the nature of any other ingredient to be incorporated in the composition. Conveniently t.he weight ratio of water to form A used will be on the range of from 0.1 to 100:1.
When the composition is in the form of a tablet, the weight of the tablet may conveniently be in the range of from 25 to 500 mg,
BAD ORIGINAL
PH.36076
- 6 such as from 50 to 250 mg, for example from 100 to 200 mg. The tablet may be uncoated or coated. The coating may be a conventional coating and may be applied by a conventional method.
According to another aspect, the invention provides methods for preparing form A substantially free of other physical forms of compound 1.
Accordingly, the invention provides a process for preparing form A substantially free of other physical forms, vhich comprises heating another physical form of N-[4-[5-(cyclopentyloxycarbonyl)amino-l-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide (hereinbefore referred to as form B) substantially free of other crystalline forms, vhich physical form is a monohydrate of N-[4-[5-(cyclopentyloxycarbony1)amino-1-methylindol-3-y1-methyl]-3methoxybenzoyl]-2-methylbenzenesulphonamide vhich is crystalline, has an infra-red spectrum (0.5Z in KBr) having sharp peaks at 3560, 1690, 1660, 1540, 1440, 1165, 380 and 353cm’^, and an X-ray povder diffraction pattern having peaks at 2Θ = 10.0, 11.2, 14.6, 19.8 and 23.0°, at a temperature in the range of from 90 to 125’C under reduced pressure.
The dehydration of form B is preferably conducted at a temperature in the range of from 115 to 122 °C.
The pressure during the dehydration of form B is preferably not more than 100 mbara. more preferably net more than 50 mbara. For example, the pressure may be in tne range -: trim : :q 5·' moara.
Form B may be prepared substantially free of other crystalline forms by crystallisation from hot aqueous acetone. In particular, it may be prepared by dissolving a source of compound 1 in aqueous acetone at an elevated temperature, adding more vater, and allowing the resultant mixture to cool. Preferably the vater is added bad
ORIGIN^- S
AP Ο Ο Ο 2 8 5
ΡΗ.36076
- 7 rapidly so that the compound 1 initially separates out as an oil. Material prepared in this vay has been found to afford form A in a particularily high state of morphological putity.
The crystalline product may be dried at an elevated temperature, for example at about 60°C or below. If it is desired to start from an impure source of compound 1, it has been found advantageous to triturate this impure source vith hot toluene/ethyl acetate prior to crystallisation.
It vill be appreciated that if form B is dried at a high temperature, for example at above 60°C, then some conversion to form A may occur. Material prepared by drying form B at a temperature of about 60°C or below has been found to be substantially free of any other physical forms of compound 1.
Form B is believed to be novel. The invention therefore also provides form B substantially free of other crystalline forms.
The invention also provides another process for preparing form A substantially free of other physical forms of compound 1, vhich comprises rapidly evaporating the solvent from a solution of compound 1. For example, it may be prepared by spray drying a solution of compound 1.
The solvent may be any liquid substance capable of dissolving compound 1 and of evaporation ar a temperature belov the melting point of form A. Examples of solents include ketones, such as acetone, and nitriles such as acetonitrile, optionally in admixture vith vater. Aqueous acetone has been found to be a particularily suitable solvent.
The temperature at vhich the solvent is evaporated should be belov the melting point of form A. Conveniently it is belov 125°C, preferably belov 120°C. when using acetone as the solvent, it has been found that a significant amount of crystalline material is
BAD ORIGINAL
PH.36076
- 8 obtained if the temperature is belov 100°C. Hence, for example, the temperature at vhich the solvent is evaporated may be in the range of from 100 to 125’C.
The solution of compound 1 is conveniently prepared by dissolving a crystalline form of compound 1, such as form B, in the solvent. A solution prepared in this vay vill contain a minimum amount of non-volatile impurities.
It vill be appreciated from the foregoing that aqueous acetone is a particularly advantageous solvent for use in the preparation of form A substantially free of other physical forms.
Indeed it has also been found that the organic solvent content of form A produced via form B using this solution is very lov. According to a another aspect therefore, the invention provides a solution of compound 1 in aqueous acetone. The solution may comprise, for example, from 5 to 15X veight of compound 1, preferably from 6 to 13 X. The solvent may comprise, for example, from 3 to 9Z by veight of vater, preferably from 4 to 8/X.
The advantageous nature of the compositions according to the invention may be demonstrated by comparing their properties vith corresponding compositions in vhich form A has been replaced vith form B or form X, and vith a composition comprising form A vhich contains no polyvinylpyrrolidone.
Form X is a physical form of ccmDound 1 vhich is cry's tall ine, has an X-ray pcvder diffra:* :·.·η pattern vith spectiic peaks occuring at 29 = 3.1. 12.7. 16.-*. 20.5 and 23.73 and an infra-red spectrum (0.zZ in KBr) having sharp peaks at 2370, io7Q,
1525. 1490. 1280, 890. 370 and 550cm'1.
Form X may be prepared substantially free of other physical forms by a process vhich comprises dissolving a source of compound 1 in hot aqueous acetone, reducing the volume of the resultant solution by evaporation, adding toluene and further reducing the volume by badowoinm. J?
AP Ο Ο Ο 2 8 5
ΡΗ.36076
- 9 evaporation. If it is desired to employ material vhich is a relatively impure source of compound 1, such material may advantageously be triturated vith hot toluene/ethyl acetate prior to the crystallisation step.
Each of the forms A, B and X may conveniently be characterised, for example, by their X-ray povder diffraction pattern alone, or their infra-red pattern alone.
In this specification, infra-red spectra vere determined using a 0.5X dispersion of sample material in a potassium bromide disk over the vave number range 4000 to 400 cnT^. Examples of infra-red spectra for each of forms X, A and B are given in Figures 1, 2 and 3 hereinafter.
X-ray povder diffraction spectra vere determined using 2g of sample material mounted in a Philips standard deep pack holder over the scanning range of 4-40° 2Θ counting for 4 seconds per point at 0.02° intervals to produce a trace of spacings against intensity for this range. Examples of X-ray povder diffraction spectra for each of forms X, A and B are given in Figures 4, 5 and 6 hereinafter.
The melting points of each of the forms A, B and X generally depend upon their level of purity. Typically, form X has been found to have a melting point of above 190 °C, for example about 200 °C; form A betveen 115 and 140 °C, for example about 124 to 132 °C; and form 3 about 140 to 160 9C. for example from 145 to Iff 9C. Form 3 has' been observed to lose vater at a temperature above about 60 3C. and may not shov a sharp melting point.
As stated hereinabove, form A is acceptably stable in the compositions according to the invention. Hovever, under conditions of high relative humidity and elevated temperatures, conversion of form A into form B has been found to occur. Accordingly, it may in certain circumstances be desirable to keep pharmaceutical formulations comprising form A in the presence of a suitable desiccant, such as
SAD ORIGINAL d
PH.36076
- 10 silica gel. It nay also be desirable to keep them in an airtight container, such as a blister pack.
The dose of compound 1 to be administered to a patient in a composition according to the invention will depend upon the severity of the condition to be treated, the age and the size of the patient. In general, the compound vill be administered in a dose in the range of from 0.1 to 10 mg/kg, for example from 0.2 to 5 mg/kg.
Acute toxicity studies have been conducted on compound 1 in order to obtain Ι2\θ values. For example, in mice and rats it has been found that the LDRq value for compound 1 is >500 mg/kg.
The following non-limiting Examples illustrate the invention.
Example 1
Preparation of Form A
a) Preparation of an impure source of compound 1
Methyl 3-me thoxy-4-(1-methy1-5-ni troindol-3-yImethyl)benzoate (prepared as described in Example 4 of EP-A2-0199543) vas converted into the free acid by treatment with aqueous sodium hydroxide. The free acid vas then converted into the acid chloride by treatment vith thionyl chloride in dichloromethane. The acid chloride vas then reacted vith o-toluenesulphonamide in dichloromethane in the presence of 2.3 equivalents of a-dimethyla-tnopvr:di.-.e to afford tne dimethylaminopyridine salt of 4-(l-methyl-5-nitroindoi-3-ylmethyl)-3-me thoxybenzoyl-2-me thylbenzenesulphonamide
A solution of the dimethylaminopyridine salt of
4-(1-me thy1-5-nitroindo1-3-yImethyl)-3-methoxybenzoyl-2-methylbenzenesulphonamide (30 g) in 2-methoxyethanol (130 ml) and concentrated sodium hydroxide liquor (3.2 ml) vas charged to a nitrogen-purged flask containing 10X palladium on charcoal (3.3 g of a 60.9% vater-vet
AP Ο Ο Ο 2 8 5
ΡΗ.36076
- 11 paste). The fixture vas then stirred under a hydrogen atmosphere at a pressure of 3 bar for 2.5 hours. The mixture vas then filtered through diatomaceous earth, and vashed through vith 2-methoxyethanol (37.5 ml). To the combined liquors vas added cyclopentyl chloroformate (9.2 ml), and the mixture alloved to stir under an atmosphere of nitrogen overnight. The temperature vas then adjusted to 30-33 °C, and 0.8 M hydrochloric acid (68 ml) vas added over 20 minutes vith vigorous agitation. The mixture vas then cooled to 15-20 ’C and stirred for one hour. The crude crystalline product vas then filtered off, vashed vith vater and dried at 50 °C. It vas then used in the next step.
b) Trituration of impure compound 1 g (0.101 gmol) of the product of step a), toluene 240 ml (4 volumes) and ethyl acetate 150 ml (2.5 volumes) vere slovly heated to reflux and 30 ml (0.5 volumes) of distillate vere collected to remove most of the released vater. The mixture vas heated under reflux for one hour (88-90 °C) and vas then cooled to 10-15 °C. After stirring for three hours at 10-15 °C, the solid vas filtered through a glass sinter and vashed vith a 2:1 mixture of toluene (80 ml) and ethyl acetate (40 ml). The product vas then dried to constant veight on the sinter to afford 53.2 g of dry compound 1 (yield 91.5%).
c) Preparation of Form B
30.0 g of the product of step b), 210 ml acetone and 12 ml vater vere charged to a 500 ml reaction flask. The mixture vas then heated under reflux for 15 minutes, and vas then screened at 45-50 °C through a diatomaceous earth pad on a glass sinter directly into a 500 ml reaction flask. The flask and sinter vere vashed vith a mixture of acetone (60 ml) and vater (3 ml). The combined liquids vere then stirred in a vater bath at approximately 40 9C and vater (120 ml) vas added over five minutes. The mixture oiled out at first, but then rapidly crystallised. The mixture vas then cooled to 20 °C over one hour, stirred for tvo hours at 15-20 9C and then filtered. The product vas vashed vith vater (60 ml), dried as far as possible on the
BAD ORIGINAL
PH.36076
- 12 sinter and then dried in an air oven at 60 °C (max.). The yield of form B was 30.0 g (97%).
d) Preparation of Form A
The product of step c) (15.0 g) vas placed in a 500 ml round bottomed flask which vas then evacuated on a rotary evaporator at 20 mbar. The flask and contents were then immersed in an oil bath preheated to 118 °C, and slowly rotated at this temperature for 6 hours. The mass vas broken up on cooling to afford form A as a white powder.
For large scale preparations, form A may be prepared as follows:
kg of the product of step c) is spread evenly onto metal 2 trays and heated at 120 °C under vacuum in 7m vacuum oven for up to 24 hours. Typically the pressure is about 20 mbara. On cooling (to 40 °C or below), the material is discharged from the oven and milled to afford the desired form A.
If desired, the -form A may be micronised prior to use.
Preparation of Form X
The product of step b) (30.0 g, 0.0521 g mol) vas dissolved in .acetone (150 ml) and water (i.7 ml) by gentle heating to reflux, and the solution screened through a sintered glass funnel. The filtrate was heated to boiling and 90 ml distillate collected.
Toluene (120 ml) was added and a further 75 ml distillate collected. More toluene (120 ml) was added and an additional 75 ml distillate collected. After heating for a further hour at reflux, the mixture vas cooled to 15-20 °C, and the product collected and washed vith toluene (2x30 ml). The yield after drying on the sinter funnel vas 29.5 g (98.3%).
AP Ο Ο Ο 2 8 5
PH.36076
- 13 Example 2
Alternative Preparation of Form A
Form B (vhich may be obtained as described in Example 1) vas dissolved in aqueous acetone to produce an 8% v/v solution of compound 1 in 6% v/v aqueous acetone. This solution vas then spray dried using a Niro Laboratory Minor spray drier (obtainable from A/S Niro Atomizer, Gladsaxevej 305, DK-2860 Soeborg, Denmark.). The solution vas atomised at a flow rate of 2 kg/h vith nitrogen at a flow rate of
6.6 kg/h using a tvo fluid nozzle atomiser. The drying gas used vas nitrogen vith a flow rate of 70 kg/h and inlet/outlet temperatures respectively of 215/12O°C. The form A produced vas collected on a bag filter.
Example 3
Tablet Formulation of Form A
Granulating Material mg/tablet mg/tablet mg/tablet
Active ingredient 2 20 50
Croscarmellose sodium NF 6 5 5
Polyvinylpyrrolidone USP 7 4 8
Microcrystalline cellulose NF 54 74 40
Lactose NF 54 50 40
Purified Vater USP 80 98 62
Final Blend Material
Dried milled granulation 123 153 143
Lactose NF - 20 -
Croscarmellose sodium NF 6 5 7
Microcrystalline cellulose NF 69 20 48
Magnesium stearate NF 2 2 2
The ingredients of the granulating material vere vet granulated. The granules vere then dried and milled. The dried milled granulation vas ^JDORIGINAL
PH.36076
- 14 then blended vith the other ingredients of the final blend mixture and compressed into tablets.
The percentage by weight of form B present, based upon the weight of compound 1 present, vas determined by X-ray analysis. For the 20mg tablet, this vas found to be <82. For the 50mg tablet more sensitive X-ray methods were used. The percentage by weight of form B before formulation vas found to be 32, and after formulation vas found to be <3.22.
Note: In each of the examples herein, the polyvinylpyrrolidone used had a K value of 29 - 32. It is believed that any pharmaceutical grade polyvinylpyrrolidone, for example, that having a K value in the range 10 to 100, vill be suitable.
Example 4
Short Term Stability Test
Tablets prepared according to the method of Example 3 and containing 20mg of form A vere stored under various conditions for 1, and'3 months. The tablets vere then studied by X-rAy diffraction to determine hov much of the active ingredient had been converted into form B. The results are summarised in Table 1 belov.
bad
AP Ο Ο Ο 2 8 5
PH.36076
- 15 - Table 1
Stability tests on tablet formulation containing form A
Storage conditions X conversion to form B
initial none detectable
1 month, room temp. none detectable
2 months, room temp. none detectable
3 months, room temp. none detectable
3 months, 50 °C none detectable
1 month, 40 °C, 80X Rfl 87
2 months, 40 °C, 80X Rfl 91
3 months, 40 °C, 80X Rfl 82
Rfl = relative humidity
The tablets stored at room temperature and 50 °C were in white high density polyethylene bottles with metal caps.
The tablets stored at 80X Rfl were exposed to the air.
BAD°^Nal
PH.36076
- 16 Comparative Example 1
Tablet formulation of form A containing no polyvinylpyrrolidone.
Granulating Material mg/tablet
Active ingredient 50.0
Pregelatinised starch NF 20.0
Lactose NF 34.55
Sodium starch glycolate NF 2.0
Microcrystalline cellulose NF 34.95
Sodium lauryl sulphate NF 0.5
Purified Water USP 100.0
Final Blend Material
Dried milled granulation 142.0 Sodium starch glycolate NF 6.0 Microcrystalline cellulose NF 50.0 Magnesium stearate NF 2.0
The ingredients of the granulating material vere vet granulated. The granules vere then dried and milled. The dried milled granulation vas then blended vith the other ingredients of the final blend mixture and compressed into tablets.
The percentage of compound 1 present as form B vas determined by X-ray analysis before and after granulation. Before granulation it vas found that <1.52 of the compound 1 vas present as form B. Hovever, after granulation 282 of the compound 1 vas found to be present as form B.
These results clearly demonstrate the improved stability of form A in the compositions according to the invention.
bad ow
AP Ο Ο Ο 2 8 5
ΡΗ.36076
- 17 Example 5
Capsule Formulation mg/capsule
Active Ingredient 20
Polyvinylpyrrolidone 20
Lactose 177.25
Microcrystalline cellulose 177.25
Colloidal silicon dioxide 0.5
Magnesium stearate 5
Size 0 gelatin Capsule
Mix the active ingredient, polyvinylpyrrolidone, lactose and microcrystalline cellulose in a suitable mixer, mix vith purified vater to proper consistency, dry, size through a suitable milling operation. Mix vith the colloidal silicon dioxide and magnesium stearate Encapsulate vith size 0 tvo piece gelatin capules.
Beadlets (spheroids) mg/capsule '
Active ingredient 10 sugar spheres 200 Polyvinylpyrrolidone 10
Prepare a 10% dispersion of the polyvinylpyrrolidone in purified vater. Add the active ingredient and mix until uniformly dispersed; spray onto the sugar spheres using suitable equipment. The beadlets can be filled into size 1 tvo piece capsules or dispensed in a suitable sachet.
bad original
PH.36076
Powder Formulation mg/povder
Active Ingredient
Polyvinylpyrrolidone
Mannitol
Flavour
364.6
0.4
Mix the active ingredient, polyvinylpyrrolidone and mannitol in a suitable mixer. Mix to a suitable consistency vith purified vater, dry, and pass through a suitable sizeing operation.
Comparative Example 2
Comparison of the bioavailability of compound 1 in compositions prepared from form A vith and vithout polyvinylpyrrolidone.
healthy male human volunteers vere randomly assigned to treatment groups. One treatment vas a single 50mg tablet prepared as described in Example 3, and another a single 50mg tablet prepared as described in Comparative Example 1. During the course of the study each volunteer received both preparations. During each treatment period, blood samples vere periodically obtained and the concentration of compound 1 vas determined.
BAD ORIGINAL
AP Ο Ο Ο 2 8 5
ΡΒ.36076
- 19 -
Product of Product of
Example 3 Comparative Example 1
Mean standard Mean standard
figure enor (I) figure enor (I)
Maximum concentration of compound 1 (ng/mL) 588 54 223 28
Time to maximum concentration (hours) 2.6 0.3 3.7 0.3
Half-life 9.0 0.5 8.2 0.7
Area under the curve (ng.h/mL) 2268 220 970 126
These results clearly demonstrate the improved bioavailability of
compound 1 in the compositions according to the invention.
sad
PH.36076
- 20 Comparison Example 3
Comparison of the bioavailability of compound 1 in compositions prepared vith polyvinylpyrrolidone and forms A, B and X.
Tablets containing 20mg form A, form B or form C vere prepared according to the following recipee.
Granulating material mg/tablet
Active Ingredient 20 Croscarmellose sodium NF 6 Polyvinylpyrrolidone USP 7 Microcrystalline Cellulose NF 45 Lactose NF 45
Final 31end Material
Croscarmellose sodium NF 6
Microcrystalline Cellulose NF Magnesium stearate NF
Using a balanced crossover design, 8 dogs each received each of the three tablet forms. During each study period, blood samples vere periodically obtained from each animal and the concentration of compound 1 determined. The results are summarised belov.
Active ingredient Maximum Half-life Area under curve
concentration (Ug.h/mL)
(ug/ml) (hours)
Form A 1.004 5.398 4.028
Form B 0.105 3.524 0.773
Form X 0.314 3.590 1.307
AP Ο Ο Ο 2 8 5
ΡΗ.36076
- 21 These results clearly demonstrate the superior bioavailability of compositions according to the invention, compared vith.compositions containing form B or form X.

Claims (17)

1. A pharmaceutical composition, vhich comprises, as active ingredient, a physical form of N-(4-[5-(cyclopentyloxycarbonyl)amino-l-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide substantially free of other physical forms, vhich physical form has an infra-red spectrum (0.52 in KBr) having sharp peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550cm'1, and polyvinylpyrrolidone.
2. A composition as claimed in claim 1, vhich further comprises a pharmaceutically acceptable carrier.
3. A composition as claimed in claim 1 or claim 2, in vhich the active ingredient is present in an amount of from 1 to 902 by veight, based upon the total veight of the composition.
4. A composition as claimed in any one of claims 1 to 3, in vhich the polyvinylpyrrolidone is present in an amount of from 1 to
202 by veight, based upon the total veight of· the composition.
5. A composition as claimed in any one of claims 1 to 4, in vhich the pharmaceutically acceptable carrier is selected from mannitol, lactose, sorbitol, glucose, sucrose, dextrose, fructose, xylitol, microcrystalline cellulose, powdered cellulose and hydroxypropyimethylcellulose.
6. A composition as claimed in any one of claims 1 to 5, vhich further comprises a processing adjuvant selected from croscar.mellose sodium, sodium starch glycolate, starch, magnesium stearate, stearic acid, talc and powdered vegetable stearine.
7. A composition as claimed in any one of claims 1 to 6, vhich is in the form of a tablet.
AP Ο Ο Ο 2
8 5
ΡΗ.36076
- 23 8. A process for the preparation of a pharmaceutical composition as claimed in claim 1 vhich comprises mixing a physical form of N-(4-[5-(cyclopentyloxycarbonyl)amino-1-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methyibenzenesulphonamide substantially free of other physical forms, vhich physical form has an infra-red spectrum (0.5% in KBr) having sharp peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550cm~^ vith polyvinylpyrrolidone and vater, and drying the resultant mixture.
9. A process for preparing a physical form of
N-(4-(5-(cyclopentyloxycarbonyl)amino-l-methylindol-3-yl-methyl]-3methoxybenzoyl]-2-mechylbenzenesulphonamide substantially free of other physical forms vhich physical form has an infra-red spectrum (0.5% in KBr) having sharp peaks at 1690, 1530, 1490, 1420, 1155,
1060, 862 and 550cm-^, vhich comprises heating another physical form of N-(4-[5-(cyclopentyloxycarbonyl)amino-l-methylindol-3-yl-methyl]-3methoxybenzoyl]-2-methylbenzenesulphonamide substantially free of other crystalline forms vhich physical form is a monohydrate of N-[4-[5-(cyclopentyloxycarbony1)amino-1-methylindol-3-y1-methyl]-3methoxybenzoylJ-2-methylbenzenesulphonamide vhich is crystalline, has an infra-red spectrum (0.5% in KBr) having sharp peaks at 3560, 1690, 1660, 1540, 1440, 1165, 880 and 858cm_\ and an X-ray povder diffraction pattern having peaks at 20 »
10.0,
11.2, 14.6, 19.8 and 23.0°, at a temperature in the range of from 90 to 125°C under reduced pressure.
10._ A process as claimed in claim 9, in vhich the pressure is in the range of from 5 to 50mbara. 11. A process as claimed in claim 9 or claim 10, in vhich the
monohydrate physical form has been prepared by crystallisation from hot aqueous acetone.
12. A process as claimed in claim 11, in vhich the crystallisation has been performed by rapidly adding vater so that the compound 1 initially separates out as an oil.
PH.36076
- 24
13. A physical form of N-[4-[5-(cyclopentyloxycarbonyl)amino-lmethylindol-3-yl-methyl J-3-methoxybenzoyl]-2-methylbenzenesulphonamide substantially free of other physical forms, vhich physical form has an infra-red spectrum (0.5% in KBr) having sharp peaks at 1690, 1530,
1490, 1420, 1155, 1060, 862 and 550cm-1, vhen prepared by a process as claimed in any one of claims 7 to 10.
14. A physical form of N-[4-[5-(cyclopentyloxycarbonyl)amino-lmethylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide substantially free of other crystalline forms, vhich physical form is a monohydrate of N-[4-[5-(cyclopentyloxycarbonyl)amino-l-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide vhich is crystalline, has an infra-red spectrum (0.5% in KBr) having sharp peaks at 3560, 1690, 1660, 1540, 1440, 1165, 880 and 858cm 1, and an X-ray povder diffraction pattern having peaks at 29 = 10.0, 11.2,
14.6, 19.8 and 23.0°.
15. A process for preparing a physical form of N-[4-[5-(cyclopentyloxycarbony1) amino-1-methylindol-3-yl-methylJ-3-methoxybenzoyl]-2-methylbenzenesulphonamide substantially free of other physical forms vhich physical form has an infra-red spectrum (0.5% in KBr) having· sharp peaks at 1690, 1530, 1490, 1420, 1155, 1060, 862 and 550cm- , vhich comprises spray drying a solution of N-[4-[5-(cyclopentyloxycarbonyl)amiino-l-methylindol-3-yl-methyl]-3-methoxybenzoyl]-2 -methylbenzenesulphonamide.
16., A process as claimed in claim 15, in vhich an aqueous acetone solution is used.
17. A physical form of N-[4-(5-(cyclopentyloxycarbonyl)amino-lmethylindol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide substantially free of other physical forms, vhich physical form has an infra-red spectrum (0.5% in K3r) having sharp peaks at 1690, 1530,
1490, 1420, 1155, 1060, 862 and 550cm-1, vhen prepared by a process as claimed in claim 14 or claim 15. o
AP Ο Ο Ο 2 8 5
ΡΗ.36076
- 25 18. A solution of N-(4-[5-(cyclopentyloxycarbonyl).amino-lmethy1indol-3-yl-methyl]-3-methoxybenzoyl]-2-methylbenzenesulphonamide in aqueous acetone.
APAP/P/1991/000340A 1990-12-12 1991-12-11 Pharmaceutical composition comprising a particular pysical form of a heterocyclic amide derivative. AP285A (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB909027014A GB9027014D0 (en) 1990-12-12 1990-12-12 Pharmaceutical agents
GB919115107A GB9115107D0 (en) 1991-07-12 1991-07-12 Pharmaceutical agents

Publications (2)

Publication Number Publication Date
AP9100340A0 AP9100340A0 (en) 1992-01-31
AP285A true AP285A (en) 1993-09-23

Family

ID=26298105

Family Applications (1)

Application Number Title Priority Date Filing Date
APAP/P/1991/000340A AP285A (en) 1990-12-12 1991-12-11 Pharmaceutical composition comprising a particular pysical form of a heterocyclic amide derivative.

Country Status (30)

Country Link
US (6) US5319097A (en)
EP (1) EP0490648B1 (en)
JP (1) JP2585495B2 (en)
KR (2) KR0183027B1 (en)
CN (2) CN1043405C (en)
AP (1) AP285A (en)
AT (1) ATE131048T1 (en)
AU (1) AU656157B2 (en)
BE (1) BE1004229A5 (en)
CA (2) CA2319308C (en)
CZ (1) CZ283181B6 (en)
DE (2) DE4140858A1 (en)
DK (1) DK0490648T3 (en)
ES (1) ES2079589T3 (en)
FI (1) FI101193B (en)
FR (1) FR2670488B1 (en)
GB (2) GB2280606B (en)
GR (1) GR3018318T3 (en)
HK (2) HK81597A (en)
HU (2) HU213211B (en)
IE (1) IE75348B1 (en)
IL (1) IL100091A (en)
IT (1) IT1256282B (en)
MX (1) MX9102473A (en)
MY (1) MY106315A (en)
NZ (1) NZ240939A (en)
PH (1) PH30928A (en)
RU (1) RU2106140C1 (en)
SK (2) SK279813B6 (en)
TW (1) TW276181B (en)

Families Citing this family (48)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL100091A (en) * 1990-12-12 1998-08-16 Zeneca Ltd Pharmaceutical compositions containing a physical form of n-[4-[5-(cyclopentyloxycarbonyl)amino-1-methyl indol-3-yl-methyl]-2-methylbenzenesulpho-namide and process for their preparation
GB9119001D0 (en) * 1991-09-05 1991-10-23 Ici Plc Pharmaceutical agents
GR1001368B (en) * 1992-10-08 1993-10-29 Ici Plc Pharmaceutical agents.
DE4235133A1 (en) * 1992-10-19 1994-04-21 Bayer Ag Crystalline (R) - (-) - 2-cycloheptyl-N-methylsulfonyl- [4- (2-quinolinyl-methoxy) phenyl] acetamide
DE9410461U1 (en) * 1994-07-01 1994-09-22 Merck Patent Gmbh, 64293 Darmstadt X-ray fluorescence analysis media
US6279736B1 (en) 1995-04-19 2001-08-28 Capitol Specialty Plastics, Inc. Barrier pack having an absorbing agent applied to the interior of the pack
IN182496B (en) * 1996-02-20 1999-04-17 Reddy Research Foundation
US6630496B1 (en) 1996-08-26 2003-10-07 Genetics Institute Llc Inhibitors of phospholipase enzymes
USRE43932E1 (en) 1997-07-18 2013-01-15 Novartis Ag Crystal modification of a N-phenyl-2-pyrimidineamine derivative, processes for its manufacture and its use
GB9723985D0 (en) 1997-11-14 1998-01-14 Zeneca Ltd Pharmaceutical compositions
GB9726735D0 (en) * 1997-12-18 1998-02-18 Zeneca Ltd Pharmaceutical compositions
US6828344B1 (en) 1998-02-25 2004-12-07 Genetics Institute, Llc Inhibitors of phospholipase enzymes
US6916841B2 (en) * 1998-02-25 2005-07-12 Genetics Institute, Llc Inhibitors of phospholipase enzymes
US6500853B1 (en) 1998-02-28 2002-12-31 Genetics Institute, Llc Inhibitors of phospholipase enzymes
US6224907B1 (en) 1998-03-06 2001-05-01 Alza Corporation Anti-asthma therapy
KR100283682B1 (en) * 1998-07-14 2001-03-02 조정래 Hot wind drying apparatur
US6253463B1 (en) 1999-04-26 2001-07-03 Niro A/S Method of spray drying
IN191496B (en) 1999-07-30 2003-12-06 Ranbaxy Lab Ltd
WO2001021211A2 (en) * 1999-09-20 2001-03-29 Alza Corporation Process for lessening polymorphic conversion of a drug
IL139243A0 (en) * 2000-10-24 2001-11-25 Internat Specialty Products Is Ethanolate of zafirlukast, process for manufacture and pharmaceutical compositions thereof
IL140096A0 (en) * 2000-12-05 2002-02-10 Internat Specialty Products Is Process for preparation of zafirlukast
US6982251B2 (en) 2000-12-20 2006-01-03 Schering Corporation Substituted 2-azetidinones useful as hypocholesterolemic agents
US20060287254A1 (en) * 2001-01-26 2006-12-21 Schering Corporation Use of substituted azetidinone compounds for the treatment of sitosterolemia
SK287988B6 (en) * 2001-01-26 2012-09-03 Schering Corporation Composition, oral dosage form and use thereof
EP1406880A1 (en) * 2001-07-10 2004-04-14 PHARMACIA &amp; UPJOHN COMPANY Crystalline thiazine oxazolidinones
CN100439360C (en) 2001-08-15 2008-12-03 法玛西雅厄普约翰美国公司 Crystals including a malic acid salt of a 3-pyrrole substituted 2-indolinone, and compositions thereof
MXPA04002573A (en) * 2001-09-21 2004-06-18 Schering Corp Treatment of xanthoma with azetidinone derivatives as sterol absorption inhibitors.
US7053080B2 (en) * 2001-09-21 2006-05-30 Schering Corporation Methods and therapeutic combinations for the treatment of obesity using sterol absorption inhibitors
AR040588A1 (en) * 2002-07-26 2005-04-13 Schering Corp PHARMACEUTICAL FORMULATION INCLUDING AN INHIBITOR OF CHOLESTEROL ABSORPTION AND AN INHIBITOR OF A HMGCO TO REDUCTASE
US7459442B2 (en) * 2003-03-07 2008-12-02 Schering Corporation Substituted azetidinone compounds, processes for preparing the same, formulations and uses thereof
ATE406364T1 (en) 2003-03-07 2008-09-15 Schering Corp SUBSTITUTED AZETIDINONE DERIVATIVES, THEIR PHARMACEUTICAL FORMULATIONS AND THEIR USE IN THE TREATMENT OF HYPERCHOLESTEROLEMIA
JP4589919B2 (en) * 2003-03-07 2010-12-01 シェーリング コーポレイション Substituted azetidinone compounds, their formulations and uses for the treatment of hypercholesterolemia
US20090317476A1 (en) * 2003-07-31 2009-12-24 Robinson Cynthia B Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease
US20050026882A1 (en) * 2003-07-31 2005-02-03 Robinson Cynthia B. Combination of dehydroepiandrosterone or dehydroepiandrosterone-sulfate with a leukotriene receptor antagonist for treatment of asthma or chronic obstructive pulmonary disease
US20050113410A1 (en) * 2003-11-03 2005-05-26 Mark Tawa Pharmaceutical salts of zafirlukast
ITMI20041032A1 (en) * 2004-05-24 2004-08-24 Neuroscienze S C A R L PHARMACEUTICAL COMPOSITES
CA2598288A1 (en) * 2005-03-03 2006-09-14 Elan Pharma International Limited Nanoparticulate compositions of heterocyclic amide derivatives
US20070197467A1 (en) * 2006-02-06 2007-08-23 Srinivasulu Rangineni Zafirlukast compositions
US20090012146A1 (en) * 2007-07-02 2009-01-08 Giridhar Reddy Buggana Solubility-enhanced pharmaceutical compositions comprising zafirlukast
CN101835749A (en) * 2007-07-30 2010-09-15 奥斯拜客斯制药有限公司 The indoles that replaces
US20090149662A1 (en) * 2007-12-05 2009-06-11 Raghupathi Reddy Anumula Processes for preparing zafirlukast
WO2014012954A1 (en) 2012-07-18 2014-01-23 Takeda Gmbh Treatment of partly controlled or uncontrolled severe asthma
US20160339010A1 (en) 2014-01-22 2016-11-24 Takeda Gmbh Treatment of Partly Controlled or Uncontrolled Severe Asthma
PT109030B (en) * 2015-12-15 2019-09-25 Hovione Farmaciência, S.A. PREPARATION OF ZAFIRLUCAST INHALABLE PARTICULES
WO2018140858A1 (en) 2017-01-30 2018-08-02 Western New England University Thiol isomerases inhibitors and use thereof
WO2019130334A1 (en) 2017-12-28 2019-07-04 Council Of Scientific & Industrial Research Process for the preparation of zafirlukast and analogs thereof
CA3219671A1 (en) 2021-05-19 2022-11-24 Thomas Christian Lines Quercetin-containing compositions for use in treating amyotrophic lateral sclerosis
WO2023214391A1 (en) 2022-05-06 2023-11-09 Quercis Pharma AG Method for treating cancers and neurological diseases using quercetin-containing compositions

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB8607294D0 (en) * 1985-04-17 1986-04-30 Ici America Inc Heterocyclic amide derivatives
IL100091A (en) * 1990-12-12 1998-08-16 Zeneca Ltd Pharmaceutical compositions containing a physical form of n-[4-[5-(cyclopentyloxycarbonyl)amino-1-methyl indol-3-yl-methyl]-2-methylbenzenesulpho-namide and process for their preparation
GB9027018D0 (en) * 1990-12-12 1991-01-30 Ici Plc Heterocyclic compounds

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
NONE *

Also Published As

Publication number Publication date
PH30928A (en) 1997-12-23
CS375691A3 (en) 1992-06-17
US5482963A (en) 1996-01-09
GB2280606A (en) 1995-02-08
AU656157B2 (en) 1995-01-27
AP9100340A0 (en) 1992-01-31
HUT61281A (en) 1992-12-28
CN1105705C (en) 2003-04-16
IL100091A (en) 1998-08-16
FI101193B1 (en) 1998-05-15
BE1004229A5 (en) 1992-10-13
FI915826A0 (en) 1991-12-11
SK279813B6 (en) 1999-04-13
KR0183027B1 (en) 1999-05-01
US5319097A (en) 1994-06-07
FR2670488A1 (en) 1992-06-19
US5612367A (en) 1997-03-18
ATE131048T1 (en) 1995-12-15
NZ240939A (en) 1994-05-26
HK81397A (en) 1997-06-27
GB2280606B (en) 1995-05-17
IE914310A1 (en) 1992-06-17
HU211126A9 (en) 1995-10-30
CN1043405C (en) 1999-05-19
HU913865D0 (en) 1992-02-28
JPH04266824A (en) 1992-09-22
IL100091A0 (en) 1992-08-18
CA2056066C (en) 2002-04-02
DE69115229D1 (en) 1996-01-18
SK279814B6 (en) 1999-04-13
EP0490648B1 (en) 1995-12-06
GR3018318T3 (en) 1996-03-31
IT1256282B (en) 1995-11-29
CA2319308C (en) 2001-08-21
US6143775A (en) 2000-11-07
KR920011493A (en) 1992-07-24
KR100207802B1 (en) 1999-07-15
MY106315A (en) 1995-04-29
GB9418154D0 (en) 1994-10-26
CN1243827A (en) 2000-02-09
GB2251791A (en) 1992-07-22
HU213211B (en) 1997-03-28
ITMI913324A1 (en) 1993-06-11
ITMI913324A0 (en) 1991-12-11
CA2319308A1 (en) 1992-06-13
CZ283181B6 (en) 1998-01-14
DK0490648T3 (en) 1996-05-06
FR2670488B1 (en) 1994-01-28
JP2585495B2 (en) 1997-02-26
MX9102473A (en) 1992-06-01
DE4140858A1 (en) 1992-06-17
FI101193B (en) 1998-05-15
CA2056066A1 (en) 1992-06-13
AU8899491A (en) 1992-06-18
GB9126354D0 (en) 1992-02-12
DE69115229T2 (en) 1996-05-09
CN1062291A (en) 1992-07-01
EP0490648A1 (en) 1992-06-17
TW276181B (en) 1996-05-21
FI915826A (en) 1992-03-31
US5504216A (en) 1996-04-02
ES2079589T3 (en) 1996-01-16
RU2106140C1 (en) 1998-03-10
GB2251791B (en) 1995-05-17
KR970005014A (en) 1997-01-29
US5993859A (en) 1999-11-30
HK81597A (en) 1997-06-27
IE75348B1 (en) 1997-08-27

Similar Documents

Publication Publication Date Title
AP285A (en) Pharmaceutical composition comprising a particular pysical form of a heterocyclic amide derivative.
JP4282092B2 (en) Polymorphic compound
CA2056067C (en) A physical form of n-¬4-¬5-(cyclopentyloxcarbony)-amino-1-methylindol-3-yl-methyi|-3-methoxybenzoy1|-2-methyibezenesulphonanide, processes for its preparation and compositions containing it
AU3095600A (en) New pharmaceutical formulation
JP3995414B2 (en) Stable pharmaceutical composition
CA2532351A1 (en) Stable modifications of tegaserod hydrogen maleate
FI106021B (en) Process for preparing a physical form of N-[4-[5- (cyclopentyloxycarbonyl)amino-1-methylindol-3-ylmethyl]-3- methoxybenzoyl]-2-methylbenzenesulphonamide
WO2021097650A1 (en) Cocrystal of orlistat and amino acid, and pharmaceutical composition comprising same
NO179575B (en) Pharmaceutical preparation containing a physical form of the compound N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl-3-methoxybenzoyl] -2-methylbenzenesulfonamide
PT100508B (en) PHARMACEUTICAL COMPOSITIONS AND PROCESS FOR THEIR PREPARATION
SK7362002A3 (en) Solid pharmaceutical preparation
HU220769B1 (en) New physical modification of n-[4-(5-/cyclopentyl-oxy-carbonyl-amino/-1-methyl-indol-3-yl-methyl)-3-methoxy-benzoyl]-2-methyl-benzene-sulfonamide and process for producing it
NO179248B (en) Physical form of N- [4- [5- (cyclopentyloxycarbonyl) amino-1-methylindol-3-ylmethyl] -3-methoxybenzoylA-2-methylbenzenesulfonamide and process for the preparation thereof