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WO1997033579A1 - Medicaments comprising 5ht1-like receptor agonists with an increased absorption - Google Patents

Medicaments comprising 5ht1-like receptor agonists with an increased absorption Download PDF

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Publication number
WO1997033579A1
WO1997033579A1 PCT/GB1997/000663 GB9700663W WO9733579A1 WO 1997033579 A1 WO1997033579 A1 WO 1997033579A1 GB 9700663 W GB9700663 W GB 9700663W WO 9733579 A1 WO9733579 A1 WO 9733579A1
Authority
WO
WIPO (PCT)
Prior art keywords
paracellular
receptor agonist
absoφtion
naratriptan
δht
Prior art date
Application number
PCT/GB1997/000663
Other languages
French (fr)
Inventor
Jeremy Bharat Desai
Laurence Francis Lacey
Sheila Irene Schwartz
Original Assignee
Glaxo Group Limited
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
Priority claimed from GBGB9605328.5A external-priority patent/GB9605328D0/en
Priority claimed from GBGB9605329.3A external-priority patent/GB9605329D0/en
Application filed by Glaxo Group Limited filed Critical Glaxo Group Limited
Priority to AU21040/97A priority Critical patent/AU2104097A/en
Publication of WO1997033579A1 publication Critical patent/WO1997033579A1/en

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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
    • A61K31/70—Carbohydrates; Sugars; Derivatives thereof
    • A61K31/7004—Monosaccharides having only carbon, hydrogen and oxygen atoms
    • 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
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/42—Oxazoles
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom

Definitions

  • the present invention relates to a method for improving the abso ⁇ tion of compounds which act as agonists at ⁇ HT-j-like receptors, e.g. sumatriptan and naratriptan 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S) oxazolidin-2-one following oral or intranasal administration. More specifically, the present invention provides pharmaceutical compositions of 5HT " ⁇ -like receptor agonists, particularly compositions for oral or intranasal administration.
  • 5-HT-j-like receptors are located, for example, in the dog saphenous vein and the 5-HT ⁇ -like receptor agonists with which the present invention is concerned contract the dog saphenous vein.
  • Such compounds may therefore be identified by their contractile effect on the dog isolated saphenous vein strip as described, for example, by Apperiey et al.. Br. J. Pharmacol, 68, 215-224 (1980).
  • Compounds which are selective 5-HT ⁇ -like receptor agonists have also been found to selectively constrict the carotid arterial bed of the anaesthetised dog.
  • a particular compound for use in the instant invention is 3-[2- (dimethylamino)ethyl]-N-methyl-1 H-indole-5-methanesulphonamide and physiologically acceptable salts and solvates thereof as disclosed in GB2162522.
  • This compound is also known as sumatriptan.
  • “Sumatriptan” when used hereinafter means the compound 3-[2-(Dimethylamino)ethyl]-N-methyl-1H-indole- 5-methanesulphonamide and its physblogically acceptable salts and solvates thereof.
  • Another particular compound for use in the instant invention is (N-methyl-3-(1- methyl-4-piperidinyl)-1 H-indole-5-ethanesulphonamide and physiologically acceptable salts and solvates thereof as disclosed in GB2208646.
  • This compound is also known as naratriptan.
  • “Naratriptan” when used hereinafter means the compound (N-methyl-3-(1-met yl-4-piperidinyl)-1H-indole-5- ethanesulphonamide and its physiologically acceptable salts and solvates thereof.
  • An additional specific compound which acts as an agonist at 5HT ⁇ -like receptors and is of use in the instant invention is 4-[3-(trans-3-dimethylaminocyclobutyl)- 1H-indol-5-yimethyl]-(4S) oxazolidin-2-one (described in WO95/20588).
  • 5HT ⁇ -like receptor agonists means sumatriptan, naratriptan, 4-[3-(trans-3-dimethylaminocyclobutyl)-1 H-indol-5-ylmethyl]-(4S) oxazolidin-2-one, the compounds generically and specifically disclosed in the patent specifications listed hereinbefore and physiologically acceptable salts and solvates thereof.
  • Compounds which act as agonists at 5HT ⁇ -like receptors exhibit selective vasoconstrictor activity. They are useful in the treatment of cephalic pain resulting from dilation of the cranial vasculature, in particular migraine.
  • the compounds are also useful in the treatment of other conditions associated with cephalic pain such as cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or their withdrawal (for example drug withdrawal) and tension headache. Also, the compounds are useful in the treatment of elevated intraocular pressure, in particular glaucoma e.g. high tension glaucoma and low tension glaucoma.
  • -like receptor agonists may be administered orally and, following oral administration, it is believed that they are absorbed paracellularly (i.e. through the tight junctions between cells of the intestinal mucosa). It is also believed that, following intranasal administration, 5HT ⁇ -like receptor agonists are absorbed paracellularly.
  • 5HT ⁇ -like receptor agonists such as sumatriptan and naratriptan are sufficiently well-absorbed following oral or intranasal administration to effect treatment, enhancement of drug abso ⁇ tion would be advantageous since this would enable lower doses to be effective (enhanced extent of abso ⁇ tion) and would provide more rapid relief from symptoms (enhanced rate of abso ⁇ tion).
  • -like receptor agonists following oral or intranasal administration involves administration of the 5HT-
  • these further compounds are hereinafter referred to as "paracellular absorption enhancers".
  • paracellular absorption enhancers the present invention provides, in one aspect, the use of a 5HT ⁇ -like receptor agonist and one or more paracellular abso ⁇ tion enhancers in the manufacture of medicaments for simultaneous, separate or sequential use for the treatment of cephalic pain, e.g. migraine, and elevated intraocular pressure.
  • the 5HT ⁇ -like receptor agonist is sumatriptan, naratriptan or 4-[3-(ttans- 3-dimethylaminocyclobutyl)-1 H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one.
  • the 5HT-j-like receptor agonist is sumatriptan or naratriptan, with naratriptan being particularly preferred.
  • the present invention provides the use of a 5HT-
  • the use of sumatriptan or naratriptan, particularly naratriptan is preferred.
  • the invention provides a method of treatment of cephalic pain, e.g. migraine, and elevated intraocular pressure, comprising orally or intranasally administering to a sufferer an effective amount of a pharmaceutical composition comprising a 5HT-
  • a pharmaceutical composition comprising a 5HT-
  • sumatriptan, naratriptan or 4-[3-(trans-3- dimethylaminocyclobutyl)-1H-indol-5-ylmethyl ⁇ -(4S)-oxazolidin-2-one is administered, with sumatriptan and naratriptan being preferred.
  • Intranasal administration of naratriptan is particularly preferred.
  • paracellular abso ⁇ tion enhancer encompasses any compound which is believed to enhance paracellular absorption.
  • suitable paracellular abso ⁇ tion enhancers are those which occur naturally in nutrients.
  • Paracellular abso ⁇ tion enhancers include carbohydrates such as monosaccharides, e.g.
  • the monosaccharides may be employed in either their D- or L- forms. Where the monosaccharide is naturally occuring, the naturally occuring form is preferred.
  • Preferred paracellular abso ⁇ tion enhancers include glucose, e.g. D-glucose.
  • a further preferred group of paracellular abso ⁇ tion enhancers includes galactose, e.g. D-galactose, mannose, e.g. D-mannose, 3-0-methyl glucose, e.g 3-0-methyl D-glucose, xylose, e.g. D-xylose.
  • paracellular absorption enhancer(s) employed in the instant invention will be of the reversible type i.e. one whose abso ⁇ tion enhancement effect rapidly diminishes when it is no longer present at the site of action. All of the paracellular abso ⁇ tion enhancers specifically mentioned above are of the reversible type.
  • the paracellular abso ⁇ tion enhancers may be used alone or in combination.
  • the 5HT ⁇ -like receptor agonists e.g. sumatriptan or naratriptan
  • the compositions according to the invention in the form of a physiologically acceptable salt.
  • such salts include salts of inorganic or organic acids such as hydrochloride, hydrobromide, sulphate, nitrate, phosphate, formate, mesylate, citrate, benzoate, fumarate, maieate and succinate salts.
  • sumatriptan (3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole- 5-methanesulphonamide) will be employed in the compositions according to the invention in the form of its succinate (1 :1) salt.
  • sumatriptan will most preferably be employed in the compositions according to the invention in the form of its sulphate salt (2:1) as described in International Patent Application No. WO92/10477 which is incorporated herein by reference.
  • Naratriptan is preferably in the form of its hydrochloride salt for oral administration.
  • the hydrochloride salt of naratriptan is also preferred for intranasal administration.
  • Another preferred salt of naratriptan for intranasal administration is the aspartate.
  • the maieate salt of naratriptan is particularly preferred for intranasal administration.
  • paracellular abso ⁇ tion enhancers enhance abso ⁇ tion of the 5HT ⁇
  • paracellular abso ⁇ tion enhancers have been found to significantly enhance the absorption of 5HT ⁇ -like receptor agonists following oral or intranasal administration. Su ⁇ risingly, both the extent and rate of abso ⁇ tion are enhanced. In the case of sumatriptan, and especially naratriptan, the extent and rate of absorption are enhanced to an unexpected, surprisingly large degree.
  • the present invention provides a method of significantly enhancing the rate of absorption of a 5HT ⁇
  • the ⁇ HT-j-like receptor agonist and one or more paracellular abso ⁇ tion enhancers may be co-administered in the form of separate pharmaceutical compositions for simultaneous and/or sequential use.
  • the ⁇ HT-j-like receptor agonist and paracellular abso ⁇ tion enhancer(s) are administered as a single pharmaceutical composition for oral or intranasal use comprising effective amounts of the active ingredient.
  • the invention provides a pharmaceutical composition for oral or intranasal use comprising a receptor agonist and one or more paracellular abso ⁇ tion enhancers.
  • Suitable compositions comprise, sumatriptan, naratriptan or 4-[3-(trans-3-dimethylaminocyclobutyl)-1H- indol- ⁇ -ylmethyl]-(4S) oxazolidin-2-one.
  • Compositions comprising sumatriptan or naratriptan are preferred.
  • compositions for intranasal use are particularly preferred.
  • the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate).
  • binding agents e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose
  • fillers e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate
  • lubricants e.g. magnesium stearate, talc or silica
  • disintegrants e.g. potato starch or sodium starch glycollate
  • Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use.
  • Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p- hydroxybenzoates or sorbic acid).
  • the preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
  • Suitable methods of formulation are known in the art and include those methods described in UK patent Specification Nos 2250917 (effervescent tablets), 2254784 (film-coated tablet), International Patent Specification Nos WO93/24116 (chewable capsules), and French Patent Specification No 9306435 (non- effervescent granules), which are inco ⁇ orated herein by reference.
  • the pharmaceutical formulations may take the form of, for example, a liquid in the form of, for example, a solution, suspension or emulsion, presented in the form of a spray or drops, or as a powder.
  • the preparation for intranasal administration is delivered in the form of a spray or aerosol from an insufflator or from a pressurised pack or nebuliser with the use of a suitable propeliant.
  • Suitable methods of formulation are known in the art and include those methods described in International Patent Specification No WO92/10477 (intranasal sumatriptan formulation) which is incorporated herein by reference.
  • the paracellular abso ⁇ tion enhancer(s) may be inco ⁇ orated into the above- mentioned formulations according to conventional procedures.
  • 5HT ⁇ -like receptor agonists and paracellular abso ⁇ tion enhancer(s) may, if desired, be administered in combination with one or more other therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art.
  • the 5HT ⁇ t-like receptor agonist and paracellular abso ⁇ tion enhancer(s) may be administered in combination with an anti-emetic.
  • a suitable formulation of this is described in European Patent Specification No EP0433043.
  • the paracellular absorption enhancer(s) may be inco ⁇ orated into the above-mentioned formulations according to conventional procedures.
  • the ratio of 5HT ⁇ j-like receptor agonist to paracellular abso ⁇ tion enhancer(s) used in the method or compositions according to the invention is in the range of 1:1 to 1:1000 (by weight), such as 1 :1 to 1 :50 or 1 :150 (by weight), for example 1 : 5 (by weight).
  • the amount of paracellular abso ⁇ tion enhancer used in the oral formulations according to the instant invention is in the range of 1 to 10g, e.g. 1 to 3g, per dosage unit.
  • the amount of 5HT ⁇ -like receptor agonist used in the oral formulations according to the instant invention is preferably in the range of 0.5 to 250mg per dosage unit.
  • the amount of sumatriptan in the composition is preferably in the range of 1 to 200mg, more preferably 5 to 100mg, such as 10 to 50mg expressed as the weight of free base.
  • the amount of naratriptan in the composition is preferably in the range of 0.1 to 50mg, such as 5 to 20mg, e.g. 0.25 to 2.5mg expressed as the weight of free base.
  • the unit dose (for example contained in one tablet according to the invention) may be administered for example, 1 to 4 times a day, preferably once or twice a day.
  • a convenient unit dose contains the active ingredient in an amount from 0.05mg to 100mg, preferably in the range of 1 to 60mg, most preferably 2 to 40mg, which may be administered to either one or both nostrils.
  • the active ingredient is sumatriptan sulphate (2:1), 2.5mg to 25mg of the active ingredient is administered in a single dose to one nostril.
  • the active ingredient is naratriptan hydrochloride, naratriptan aspartate or naratriptan maieate, preferably 0.1 mg to 1mg of the active ingredient is administered in a single dose to one nostril.
  • Granules for Oral Administration Unit dose 0 (mg per sachet)
  • the active ingredient and D-glucose are mixed together and granulated by the 0 addition of purified water.
  • the granules obtained after mixing are dried and passed through a screen, and the resulting granules are then mixed with the aspartame.
  • the mixture is filled into aluminium foil sachets which are sealed in conventional manner.
  • Powder for Oral Administration Unit dose (mg per sachet)
  • the ingredients are thoroughly mixed together in a suitable blender under 0 anhydrous conditions and filled into an aluminium foil sachet.
  • the sachet is sealed after filling in conventional manner.
  • the active ingredient and lactose are mixed together and granulated by the addition of purified water.
  • the granules obtained after mixing are dried and passed through a screen, and the resulting granules are then mixed with the aspartame.
  • the mixture is filled into aluminium foil sachets and sealed in conventional manner.
  • the contents of the sachet are dissolved in a glass of drinking water immediately ⁇ prior to oral administration.
  • the active ingredient, anhydrous monosodium citrate, sodium bicarbonate and aspartame are mixed together and granulated by the addition of a solution of the ⁇ polyvinylpyrrolidone in the alcohol.
  • the granules obtained after mixing are dried and passed through a calibrator, and the resulting granules are then mixed with the D-galactose, sodium benzoate and flavourings.
  • the granulated material is compressed into tablets using an alternative machine fitted with 20mm punches. A rotative machine fitted with 20mm punches may also be used for tabletting.
  • the active compound and D-glucose is dissolved in the sulphuric acid previously diluted with water.
  • the solution is made up to approximately 90% volume.
  • the 5 solution pH is adjusted to ⁇ . ⁇ with sodium hydroxide solution and the solution finally made up to volume.
  • the solution pH is remeasured and adjusted if necessary.
  • the solution may be packaged for intranasal administration, for example by filling 0 into vials, sealing and sterilising the vials by autoclaving at 121 * C for not less than 1 ⁇ minutes.
  • the active compound and D-glucose is dissolved in the sulphuric acid previously diluted with water. Phenylethyl alcohol and benzalkonium chloride are added and the solution is made up to approximately 90% of volume.
  • the solution pH is adjusted to ⁇ . ⁇ with sodium hydroxide solution and the solution finally made up to 0 volume. The solution pH is remeasured and adjusted if necessary.
  • Formulations are administered in unit dose volumes of 100 ⁇ l to either one or both nostrils of patients suffering from a moderate or severe migraine attack to deliver a dose of 1 , ⁇ , 10, 20 or 40mg of the active compound.
  • Example 8 Sterile Formulation for Intranasal Administration
  • the glucose level may be used in the range from 10-1 OOmg (1-10% w/v).
  • the rate of abso ⁇ tion of naratriptan in an intranasal formulation containing a ⁇ paracellular absorption enhancer was compared with the rate of abso ⁇ tion of an aqueous formulation of naratriptan in dogs.

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  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
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Abstract

The invention relates to a method improving the absorption of compounds which act as 5HT1-like receptor agonists following oral or intranasal administration. The invention also provides pharmaceutical compositions for oral or intranasal administration of 5HT1-like receptor agonists and paracellular absorption enhancers. The paracellular absorption enhancers increase the rate of absorption of the 5HT1-like receptor agonist. Suitable 5HT1-like receptor agonists for use in the invention include sumatriptan, naratriptan and 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S) oxazolidin-2-one.

Description

MEDICAMENTS COMPRISING 5HT1-LIKE RECEPTOR AGONISTS WITH AN
INCREASED ABSORPTION
The present invention relates to a method for improving the absoφtion of compounds which act as agonists at δHT-j-like receptors, e.g. sumatriptan and naratriptan 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S) oxazolidin-2-one following oral or intranasal administration. More specifically, the present invention provides pharmaceutical compositions of 5HT"ι-like receptor agonists, particularly compositions for oral or intranasal administration.
5-HT-j-like receptors are located, for example, in the dog saphenous vein and the 5-HTτ-like receptor agonists with which the present invention is concerned contract the dog saphenous vein. Such compounds may therefore be identified by their contractile effect on the dog isolated saphenous vein strip as described, for example, by Apperiey et al.. Br. J. Pharmacol, 68, 215-224 (1980). Compounds which are selective 5-HTη-like receptor agonists have also been found to selectively constrict the carotid arterial bed of the anaesthetised dog.
A variety of compounds which selectively constrict the dog isolated saphenous vein strip and which constrict the carotid arterial bed of the anaesthetised dog have been described in the art. These include indole derivatives such as those disclosed inter alia in published British Patent Specifications Nos. 2082175, 2081717, 2083463, 2124210. 2150932, 2162522. 2168347, 2168973, 2185020, 2186874, 2191488, 2208646, published European Patent Specifications Nos. 147107, 237678, 242939, 244085, 225726, 254433, 303506, 313397, 354777, 382570, 464558, 506363, 506369, 450238, 451022, 451008, 478954, 438230, 494774, 497512, 501568 and published International patent application Nos. WO92/11013, W092/11014, WO92/06973, WO93/00086, WO92/13856, WO93/00094, WO91/18897, WO93/00333 and WO94/02477 which specifications are incorporated herein by reference.
A particular compound for use in the instant invention is 3-[2- (dimethylamino)ethyl]-N-methyl-1 H-indole-5-methanesulphonamide and physiologically acceptable salts and solvates thereof as disclosed in GB2162522. This compound is also known as sumatriptan. "Sumatriptan" when used hereinafter means the compound 3-[2-(Dimethylamino)ethyl]-N-methyl-1H-indole- 5-methanesulphonamide and its physblogically acceptable salts and solvates thereof.
Another particular compound for use in the instant invention is (N-methyl-3-(1- methyl-4-piperidinyl)-1 H-indole-5-ethanesulphonamide and physiologically acceptable salts and solvates thereof as disclosed in GB2208646. This compound is also known as naratriptan. "Naratriptan" when used hereinafter means the compound (N-methyl-3-(1-met yl-4-piperidinyl)-1H-indole-5- ethanesulphonamide and its physiologically acceptable salts and solvates thereof.
An additional specific compound which acts as an agonist at 5HTι-like receptors and is of use in the instant invention is 4-[3-(trans-3-dimethylaminocyclobutyl)- 1H-indol-5-yimethyl]-(4S) oxazolidin-2-one (described in WO95/20588).
Reference hereinafter to "5HTη-like receptor agonists" means sumatriptan, naratriptan, 4-[3-(trans-3-dimethylaminocyclobutyl)-1 H-indol-5-ylmethyl]-(4S) oxazolidin-2-one, the compounds generically and specifically disclosed in the patent specifications listed hereinbefore and physiologically acceptable salts and solvates thereof. Compounds which act as agonists at 5HTη-like receptors exhibit selective vasoconstrictor activity. They are useful in the treatment of cephalic pain resulting from dilation of the cranial vasculature, in particular migraine. The compounds are also useful in the treatment of other conditions associated with cephalic pain such as cluster headache, chronic paroxysmal hemicrania, headache associated with vascular disorders, headache associated with substances or their withdrawal (for example drug withdrawal) and tension headache. Also, the compounds are useful in the treatment of elevated intraocular pressure, in particular glaucoma e.g. high tension glaucoma and low tension glaucoma.
5HT-|-like receptor agonists may be administered orally and, following oral administration, it is believed that they are absorbed paracellularly (i.e. through the tight junctions between cells of the intestinal mucosa). It is also believed that, following intranasal administration, 5HTπ-like receptor agonists are absorbed paracellularly. Although 5HTη-like receptor agonists such as sumatriptan and naratriptan are sufficiently well-absorbed following oral or intranasal administration to effect treatment, enhancement of drug absoφtion would be advantageous since this would enable lower doses to be effective (enhanced extent of absoφtion) and would provide more rapid relief from symptoms (enhanced rate of absoφtion).
A method of significantly enhancing the absoφtion of 5HT-|-like receptor agonists following oral or intranasal administration has now been found. This method involves administration of the 5HT-|-like receptor agonist together with one or more further compounds which, without wishing to be bound by theory, are believed to increase paracellular absoφtion. These further compounds are hereinafter referred to as "paracellular absorption enhancers". Thus the present invention provides, in one aspect, the use of a 5HTπ-like receptor agonist and one or more paracellular absoφtion enhancers in the manufacture of medicaments for simultaneous, separate or sequential use for the treatment of cephalic pain, e.g. migraine, and elevated intraocular pressure. Suitably the 5HTι-like receptor agonist is sumatriptan, naratriptan or 4-[3-(ttans- 3-dimethylaminocyclobutyl)-1 H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one. In a preferred embodiment the 5HT-j-like receptor agonist is sumatriptan or naratriptan, with naratriptan being particularly preferred.
In a further aspect, the present invention provides the use of a 5HT-|-like receptor agonist, for example sumatriptan, naratriptan or 4-[3-(tιans-3- dimethylaminocyclobutyl)-1H-indol-5-ylmethyl]-(4S)-oxazolidin-2-one, and one or more paracellular absoφtion enhancers in the manufacture of medicaments for simultaneous, separate or sequential use for the treatment of cephalic pain, e.g. migraine, and elevated intraocular pressure, characterised in that the paracellular absorption enhancer(s) significantly enhances the absorption of the 5HTπ-like receptor agonist. The use of sumatriptan or naratriptan, particularly naratriptan, is preferred.
In a further aspect, the invention provides a method of treatment of cephalic pain, e.g. migraine, and elevated intraocular pressure, comprising orally or intranasally administering to a sufferer an effective amount of a pharmaceutical composition comprising a 5HT-|-like receptor agonist, or a physiologically acceptable salt thereof, and one or more paracellular absoφtion enhancers, wherein the paracellular absoφtion enhancer significantly enhances the absoφtion of the 5HTπ-like receptor agonist. Suitably, sumatriptan, naratriptan or 4-[3-(trans-3- dimethylaminocyclobutyl)-1H-indol-5-ylmethyl}-(4S)-oxazolidin-2-one is administered, with sumatriptan and naratriptan being preferred. Intranasal administration of naratriptan is particularly preferred. The term "paracellular absoφtion enhancer" as used herein encompasses any compound which is believed to enhance paracellular absorption. For example, suitable paracellular absoφtion enhancers are those which occur naturally in nutrients. Paracellular absoφtion enhancers include carbohydrates such as monosaccharides, e.g. glucose, galactose, mannose, 3-0-methyl glucose, xylose, ribose, arabinose, ribulose, fructose and sorbose. The monosaccharides may be employed in either their D- or L- forms. Where the monosaccharide is naturally occuring, the naturally occuring form is preferred.
Preferred paracellular absoφtion enhancers include glucose, e.g. D-glucose. A further preferred group of paracellular absoφtion enhancers includes galactose, e.g. D-galactose, mannose, e.g. D-mannose, 3-0-methyl glucose, e.g 3-0-methyl D-glucose, xylose, e.g. D-xylose.
It will be appreciated that the paracellular absorption enhancer(s) employed in the instant invention will be of the reversible type i.e. one whose absoφtion enhancement effect rapidly diminishes when it is no longer present at the site of action. All of the paracellular absoφtion enhancers specifically mentioned above are of the reversible type.
The paracellular absoφtion enhancers may be used alone or in combination.
It will be appreciated that reference to treatment is intended to include prophylaxis as well as the alleviation of established symptoms.
It is preferred that the 5HTη-like receptor agonists, e.g. sumatriptan or naratriptan, should be employed in the compositions according to the invention in the form of a physiologically acceptable salt. In the case of sumatriptan and naratriptan such salts include salts of inorganic or organic acids such as hydrochloride, hydrobromide, sulphate, nitrate, phosphate, formate, mesylate, citrate, benzoate, fumarate, maieate and succinate salts. Most preferably, for oral administration, sumatriptan (3-[2-(dimethylamino)ethyl]-N-methyl-1H-indole- 5-methanesulphonamide) will be employed in the compositions according to the invention in the form of its succinate (1 :1) salt. For intranasal administration, sumatriptan will most preferably be employed in the compositions according to the invention in the form of its sulphate salt (2:1) as described in International Patent Application No. WO92/10477 which is incorporated herein by reference. Naratriptan is preferably in the form of its hydrochloride salt for oral administration. The hydrochloride salt of naratriptan is also preferred for intranasal administration. Another preferred salt of naratriptan for intranasal administration is the aspartate. The maieate salt of naratriptan is particularly preferred for intranasal administration.
It will be appreciated that the paracellular absoφtion enhancers enhance absoφtion of the 5HT<|-!ike receptor agonists following dissociation from their salts.
As mentioned hereinbefore, paracellular absoφtion enhancers have been found to significantly enhance the absorption of 5HTπ-like receptor agonists following oral or intranasal administration. Suφrisingly, both the extent and rate of absoφtion are enhanced. In the case of sumatriptan, and especially naratriptan, the extent and rate of absorption are enhanced to an unexpected, surprisingly large degree.
Thus, according to a further aspect, the present invention provides a method of significantly enhancing the rate of absorption of a 5HT<|-like receptor agonist, for example sumatriptan, naratriptan or 4-[3-(trans-3-dimethylaminocyclobutyl)-1H- indol-5-ylmethyl]-(4S) oxazolidin-2-one or a physiologically acceptable salt thereof, following oral or intranasal administration by simultaneous, separate or sequential administration of the 5HT<j-like receptor agonist with one or more paracellular absoφtion enhancers. Intranasal administration of naratriptan is particularly preferred.
The δHT-j-like receptor agonist and one or more paracellular absoφtion enhancers may be co-administered in the form of separate pharmaceutical compositions for simultaneous and/or sequential use. Preferably, the δHT-j-like receptor agonist and paracellular absoφtion enhancer(s) are administered as a single pharmaceutical composition for oral or intranasal use comprising effective amounts of the active ingredient.
Thus, according to a further aspect, the invention provides a pharmaceutical composition for oral or intranasal use comprising a
Figure imgf000009_0001
receptor agonist and one or more paracellular absoφtion enhancers. Suitable compositions comprise, sumatriptan, naratriptan or 4-[3-(trans-3-dimethylaminocyclobutyl)-1H- indol-δ-ylmethyl]-(4S) oxazolidin-2-one. Compositions comprising sumatriptan or naratriptan are preferred.
In the case of naratriptan, pharmaceutical compositions for intranasal use are particularly preferred.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g. pregelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g. lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g. magnesium stearate, talc or silica); disintegrants (e.g. potato starch or sodium starch glycollate); or wetting agents (e.g. sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g. sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g. lecithin or acacia); non-aqueous vehicles (e.g. almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g. methyl or propyl-p- hydroxybenzoates or sorbic acid). The preparations may also contain buffer salts, flavouring, colouring and sweetening agents as appropriate.
Suitable methods of formulation are known in the art and include those methods described in UK patent Specification Nos 2250917 (effervescent tablets), 2254784 (film-coated tablet), International Patent Specification Nos WO93/24116 (chewable capsules), and French Patent Specification No 9306435 (non- effervescent granules), which are incoπ orated herein by reference.
For intranasal administration the pharmaceutical formulations may take the form of, for example, a liquid in the form of, for example, a solution, suspension or emulsion, presented in the form of a spray or drops, or as a powder. Preferably the preparation for intranasal administration is delivered in the form of a spray or aerosol from an insufflator or from a pressurised pack or nebuliser with the use of a suitable propeliant. Suitable methods of formulation are known in the art and include those methods described in International Patent Specification No WO92/10477 (intranasal sumatriptan formulation) which is incorporated herein by reference. The paracellular absoφtion enhancer(s) may be incoφorated into the above- mentioned formulations according to conventional procedures.
5HTι-like receptor agonists and paracellular absoφtion enhancer(s) may, if desired, be administered in combination with one or more other therapeutic agents and formulated for administration by any convenient route in a conventional manner. Appropriate doses will be readily appreciated by those skilled in the art. For example, the 5HT<t-like receptor agonist and paracellular absoφtion enhancer(s) may be administered in combination with an anti-emetic. For example, a suitable formulation of this is described in European Patent Specification No EP0433043. The paracellular absorption enhancer(s) may be incoφorated into the above-mentioned formulations according to conventional procedures.
The ratio of 5HT<j-like receptor agonist to paracellular absoφtion enhancer(s) used in the method or compositions according to the invention is in the range of 1:1 to 1:1000 (by weight), such as 1 :1 to 1 :50 or 1 :150 (by weight), for example 1 : 5 (by weight).
The amount of paracellular absoφtion enhancer used in the oral formulations according to the instant invention is in the range of 1 to 10g, e.g. 1 to 3g, per dosage unit.
The amount of 5HTη-like receptor agonist used in the oral formulations according to the instant invention is preferably in the range of 0.5 to 250mg per dosage unit. For example, the amount of sumatriptan in the composition is preferably in the range of 1 to 200mg, more preferably 5 to 100mg, such as 10 to 50mg expressed as the weight of free base. The amount of naratriptan in the composition is preferably in the range of 0.1 to 50mg, such as 5 to 20mg, e.g. 0.25 to 2.5mg expressed as the weight of free base.
The unit dose (for example contained in one tablet according to the invention) may be administered for example, 1 to 4 times a day, preferably once or twice a day.
For intranasal administration, a convenient unit dose contains the active ingredient in an amount from 0.05mg to 100mg, preferably in the range of 1 to 60mg, most preferably 2 to 40mg, which may be administered to either one or both nostrils. Most preferably, when the active ingredient is sumatriptan sulphate (2:1), 2.5mg to 25mg of the active ingredient is administered in a single dose to one nostril. When the active ingredient is naratriptan hydrochloride, naratriptan aspartate or naratriptan maieate, preferably 0.1 mg to 1mg of the active ingredient is administered in a single dose to one nostril.
The following are illustrations of non-limiting examples of pharmaceutical compositions according to the invention.
Example 1
Powder for Oral Administration Unit dose
(mg per sachet)
3[2-(Dimethylamino)ethyl]-N-methyl-1H-indole-δ- methanesulphonamide(1 : 1) succinate 140*
D-Glucose 1000
Aspartame 40
Flavour 16
*Equivalent to 100mg base The ingredients are thoroughly mixed together in a suitable blender under anhydrous conditions and filled into an aluminium foil sachet. The sachet is sealed after filling in conventional manner.
δ The contents of the sachet are dissolved in a glass of drinking water immediately prior to oral administration.
Example 2
Granules for Oral Administration Unit dose 0 (mg per sachet)
3[2-(Dimethylamino)ethyl]-N-methyl-1H-indole-δ- methanesulphonamide(1 : 1 ) succinate 3δ*
D-Glucose 3000
Aspartame 10 δ Purified water q.s.+
*Equivalent to 2δmg base +The water does not appear in the final product
The active ingredient and D-glucose are mixed together and granulated by the 0 addition of purified water. The granules obtained after mixing are dried and passed through a screen, and the resulting granules are then mixed with the aspartame. The mixture is filled into aluminium foil sachets which are sealed in conventional manner.
5 The contents of the sachet are dissolved in a glass of drinking water immediately prior to oral administration.
Example 3
Powder for Oral Administration Unit dose (mg per sachet)
N-Methyl-3-(1 -methyl-4-piperidinyl)-1 H-indole-δ- ethanesulphonamide hydrochloride 22.2*
D-glucose 1000
Aspartame 40
Flavour 16
•Equivalent to 20mg base
The ingredients are thoroughly mixed together in a suitable blender under 0 anhydrous conditions and filled into an aluminium foil sachet. The sachet is sealed after filling in conventional manner.
The contents of the sachet are dissolved in a glass of drinking water immediately prior to oral administration. δ
Example 4
Granules for Oral Administration Unit dose
(mg per sachet)
N-Methyl-3-(1 -methyl-4-piperidinyl)-1 H-indole-δ- δ.δδ* 0 ethanesulphonamide hydrochloride
D-glucose 3000
Aspartame 10
Purified water q.s.+
•Equivalent to δmg base δ +The water does not appear in the final product
The active ingredient and lactose are mixed together and granulated by the addition of purified water. The granules obtained after mixing are dried and passed through a screen, and the resulting granules are then mixed with the aspartame. The mixture is filled into aluminium foil sachets and sealed in conventional manner.
The contents of the sachet are dissolved in a glass of drinking water immediately δ prior to oral administration.
Example 5
Effervescent Table Unit dose
(mg per sachet) 0 3[2-(Dimethylamino)ethyl]-N-methyl-1H-indole-δ- methanesulphonamide(1 : 1) succinate 140.0*
Sodium bicarbonate 6δ6.4
Monosodium citrate anhydrous 6δ9.δ
D-galactose 3000 δ Aspartame 40.0
Polyvinylpyrrolidone 32.0
Sodium benzoate 48.0
Orange flavour IFF 29G44 16.0
Lemon flavour IFF 29M194 8.0 0 Absolute alcohol for granulation
•Equivalent to 100mg base
The active ingredient, anhydrous monosodium citrate, sodium bicarbonate and aspartame are mixed together and granulated by the addition of a solution of the δ polyvinylpyrrolidone in the alcohol. The granules obtained after mixing are dried and passed through a calibrator, and the resulting granules are then mixed with the D-galactose, sodium benzoate and flavourings. The granulated material is compressed into tablets using an alternative machine fitted with 20mm punches. A rotative machine fitted with 20mm punches may also be used for tabletting.
Example 6
Sterile Formulation for Intranasal Administration δ
3-[2-Dimethylamino)ethyl]-N-methyl-1H-indole-δ- methanesulphonamide 100mg
D-glucose δOOmg
Sulphuric Acid (concentrated) 21.2mg 0 Sodium Hydroxide BP qs to pH δ.4-δ.6
Water for Injections B.P. to 1 ml
The active compound and D-glucose is dissolved in the sulphuric acid previously diluted with water. The solution is made up to approximately 90% volume. The 5 solution pH is adjusted to δ.δ with sodium hydroxide solution and the solution finally made up to volume. The solution pH is remeasured and adjusted if necessary.
The solution may be packaged for intranasal administration, for example by filling 0 into vials, sealing and sterilising the vials by autoclaving at 121 *C for not less than 1 δ minutes.
Example 7
Preserved Formulation for Intranasal Administration δ
3-[2-Dimethylamino)ethyl]-N-methyl-1H-indole-5- methanesulphonamide 100mg
D-glucose 500mg
Sulphuric Acid (concentrated) 21.2mg 1 δ
Phenylethyl Alcohol USP 4mg
Benzalkonium Chloride USNF 0.2mg
Sodium Hydroxide BP qs to pH δ.4-δ.6
Purified Water BP to 1ml δ
The active compound and D-glucose is dissolved in the sulphuric acid previously diluted with water. Phenylethyl alcohol and benzalkonium chloride are added and the solution is made up to approximately 90% of volume. The solution pH is adjusted to δ.δ with sodium hydroxide solution and the solution finally made up to 0 volume. The solution pH is remeasured and adjusted if necessary.
In a similar manner further preserved formulations are prepared containing δ, 10, δO, 100, 200 and 400 mgml"1 of the active compound.
δ Formulations are administered in unit dose volumes of 100μl to either one or both nostrils of patients suffering from a moderate or severe migraine attack to deliver a dose of 1 , δ, 10, 20 or 40mg of the active compound.
Example 8 0 Sterile Formulation for Intranasal Administration
1 or 2.δ or
N-Methyl-3-(1 -methyl-4-piperidinyl)-1 H-indole-δ- δ or 10mg ethanesulphonamide hydrochloride
D-glucose δOmg 5 Purified Water B.P. To 1ml
100 microlitres of the above solution is administered to provide a 0.1 , 0.25, 0.5 and 1mg dose respectively. The glucose level may be used in the range from 10-1 OOmg (1-10% w/v). Example 9
Solution for Intranasal Administration
N-methal-3-(1 -methyl-4-piperidinyl)-1 H- 168.71 mg indole-δ-ethane sulphonamide to lmL δ% (w/v) D-glucose solution
100 microlitres of the above solution is administered to provide a 12mg dose of the free base.
Biological Examples
The rate of absoφtion of naratriptan in an intranasal formulation containing a δ paracellular absorption enhancer was compared with the rate of absoφtion of an aqueous formulation of naratriptan in dogs.
Test Formulations:
0 A B
Naratriptan maieate 168.71 mg Naratriptan maieate 168.71 mg
Water to 1 ml δ% (w/v) D-glucose solution to 1 ml
Method δ
Four male dogs were placed in individual cages. Each dog was given an intranasal dose of 100μL of Formulation A. Blood samples were taken from each dog by venepuncture of the cephalic or jugular vein into heparinised tubes at approximately 5, 10, 15, 20, 30 and 40 minutes and 1 , 1.5, 2, 3, 4, 6, 8, 12, 24, 32 and 48 hours after dosing. Each sample was centrifuged within 1 hour after collection and the plasma obtained was stored frozen prior to analysis. After a period of 14 days the procedure was repeated, giving each dog a 100μL dose of Formulation B.
The plasma samples were analysed for the presence of naratriptan and T^ and the absoφtion half-life were calculated for Formulation A and Formulation B.
Results
The results are shown in Tables I and II below:
Table I
Figure imgf000019_0001
Table II
Absorption half-life (h) Mean ± SD Animal No.
1 2 3 4
Formulation A 0.26 0.20 0.13 0.14 0.18 + 0.06
Formulation B 0.17 0.12 0.04 0.05 0.10 + 0.06 These results indicate that the rate of absoφtion of naratriptan when administered intranasally as the maieate salt is increased in the presence of D- glucose.

Claims

1. The use of a δHT-j-like receptor agonist and one or more paracellular δ absoφtion enhancers in the manufacture of medicaments for simultaneous, separate or sequential use for the treatment of cephalic pain, eg migraine and elevated, intraocular pressure.
2. The use of a δHT«|-like receptor agonist and one or more paracellular 0 absoφtion enhancers in the manufacture of medicaments for simultaneous, separator sequential use for the treatment of cephalic pain, eg migraine and elevated, intraocular pressure characterised that the paracellular absoφtion enhancer significantly enhances the absoφtion of the δHT-|-like receptor agonist.
6 3. The use according to claim 1 or claim 2 wherein the δHTi-like receptor agonist is sumatriptan, naratriptan or 4-[3-(trans-3-dimethylaminocyclobutyl)-1 H- indol-δ-ylmethyn-(4S) oxazolidin-2-one or a physiologically acceptable salt thereof.
0 4. The use according to any of claims 1 to 3 wherein the 6HTπ-like receptor agonist is naratriptan or a physiologically acceptable salt thereof.
δ. The use according to any of claims 1 to 4 wherein the medicaments are administered intranasally. 6
6. The use according to any of claims 1 to δ wherein the paracellular absoφtion enhancer is D-glucose or D-galactose. 7. A method of treatment of cephalic pain, eg migraine and elevated intraocular pressure in a mammal comprising orally or intranasally administering an effective amount of a pharmaceutical composition comprising a 6HTη-like receptor agonist, or a physiologically acceptable salt thereof, and one or more paracellular δ absoφti on enhancers.
8. A method of enhancing the rate of absorption of a δHT-j-like receptor agonist or a physiologically acceptable salt thereof following oral or intranasal administration by simultaneous, separate or sequential administration of the 0 δHTη-like receptor agonist with one or more paracellular absoφtion enhancers.
9. A method according to claim 7 or claim 8 wherein the δHT-j-like receptor agonist and the paracellular absoφtion enhancer are administered simultaneously. δ
10. A method according to any of claims 7 to 9 wherein the δHT-j-like receptor agonist and the paracellular absorption enhancer are administered intranasally.
11. A method according to any of claims 7 to 10 wherein the δHT-|-like receptor 0 agonist is naratriptan or a physiologically acceptable salt thereof.
12. A pharmaceutical composition for oral or intranasal administration comprising a δHTη-like receptor agonist and one or more paracellular absorption enhancers.
5 13. A composition according to claim 12 wherein the δHT-|-like receptor agonist is sumatriptan, naratriptan or 4-[3-(trans-3-dimethylaminocyclobutyl)-1H-indol-5- ylmethyl]-(4S) oxazolidin-2-one. 14. A composition according to claim 12 or claim 13 wherein the δHTη--like receptor agonist is naratriptan in the form of its maieate or aspartate hydrochloride salt.
δ 1δ. A composition according to any of claims 12 to 14 for intranasal administration.
16. A composition according to any of claims 12 to 1 δ wherein the paracellular absoφtion enhancer is D-glucose for D-galactose. 0
17. A composition according to any of claims 12 to 16 wherein the ratio of δHT-j-like receptor agonist to paracellular absorption enhancer is in the range of 1 :1 to 1 :1000 by weight.
PCT/GB1997/000663 1996-03-13 1997-03-11 Medicaments comprising 5ht1-like receptor agonists with an increased absorption WO1997033579A1 (en)

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016761A3 (en) * 1998-09-18 2000-05-25 Alcon Lab Inc Serotonergic 5ht2 agonists for treating glaucoma
WO2004093917A3 (en) * 2003-04-22 2005-04-14 Nastech Pharm Co Intranasal administration of triptans
US6881749B2 (en) 2001-06-01 2005-04-19 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma
US6960608B2 (en) 2001-06-01 2005-11-01 Alcon, Inc. Fused indazoles and indoles and their use for the treatment of glaucoma
US7071225B2 (en) 2001-06-01 2006-07-04 Alcon, Inc. Arylaminopropane analogues and their use for the treatment of glaucoma
US11554229B2 (en) 2013-03-26 2023-01-17 OptiNose Inc. Nasal administration

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2162522A (en) * 1984-08-01 1986-02-05 Glaxo Group Ltd An indole derivative
EP0308181A1 (en) * 1987-09-14 1989-03-22 Novo Nordisk A/S Trans-mucosal delivery formulations and a method for preparation thereof
GB2208646A (en) * 1987-08-13 1989-04-12 Glaxo Group Ltd Indole derivatives
WO1995020588A1 (en) * 1994-01-26 1995-08-03 The Wellcome Foundation Limited Indole derivatives as 5-ht1 agonists

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB2162522A (en) * 1984-08-01 1986-02-05 Glaxo Group Ltd An indole derivative
GB2208646A (en) * 1987-08-13 1989-04-12 Glaxo Group Ltd Indole derivatives
EP0308181A1 (en) * 1987-09-14 1989-03-22 Novo Nordisk A/S Trans-mucosal delivery formulations and a method for preparation thereof
WO1995020588A1 (en) * 1994-01-26 1995-08-03 The Wellcome Foundation Limited Indole derivatives as 5-ht1 agonists

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MOUNIR MESIHA ET AL.: "increased oral absorption of insulin by medium viscosity hydroxypropyl cellulose", INTERNATIONAL JOURNAL OF PHARMACEUTICS, vol. 114, no. 2, 1995, pages 137 - 149, XP000673693 *

Cited By (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000016761A3 (en) * 1998-09-18 2000-05-25 Alcon Lab Inc Serotonergic 5ht2 agonists for treating glaucoma
US6664286B1 (en) 1998-09-18 2003-12-16 Alcon Manufacturing, Ltd. Serotonergic 5ht2 agonists for treating glaucoma
US6881749B2 (en) 2001-06-01 2005-04-19 Alcon, Inc. Pyranoindazoles and their use for the treatment of glaucoma
US6960608B2 (en) 2001-06-01 2005-11-01 Alcon, Inc. Fused indazoles and indoles and their use for the treatment of glaucoma
US7071225B2 (en) 2001-06-01 2006-07-04 Alcon, Inc. Arylaminopropane analogues and their use for the treatment of glaucoma
WO2004093917A3 (en) * 2003-04-22 2005-04-14 Nastech Pharm Co Intranasal administration of triptans
US11554229B2 (en) 2013-03-26 2023-01-17 OptiNose Inc. Nasal administration

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