NZ735338B2 - Compositions and methods for the treatment of mucositis - Google Patents
Compositions and methods for the treatment of mucositis Download PDFInfo
- Publication number
- NZ735338B2 NZ735338B2 NZ735338A NZ73533816A NZ735338B2 NZ 735338 B2 NZ735338 B2 NZ 735338B2 NZ 735338 A NZ735338 A NZ 735338A NZ 73533816 A NZ73533816 A NZ 73533816A NZ 735338 B2 NZ735338 B2 NZ 735338B2
- Authority
- NZ
- New Zealand
- Prior art keywords
- acid
- formula
- oral
- compositions
- administration
- Prior art date
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- 239000000203 mixture Substances 0.000 title claims abstract description 158
- 206010028116 Mucosal inflammation Diseases 0.000 title claims abstract description 26
- 201000010927 mucositis Diseases 0.000 title claims abstract description 26
- 150000001875 compounds Chemical class 0.000 claims abstract description 88
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract description 26
- 239000007924 injection Substances 0.000 claims abstract description 9
- 230000000699 topical Effects 0.000 claims abstract description 9
- 238000002347 injection Methods 0.000 claims abstract description 8
- 239000006188 syrup Substances 0.000 claims abstract description 7
- 235000020357 syrup Nutrition 0.000 claims abstract description 7
- 238000007911 parenteral administration Methods 0.000 claims abstract description 6
- 229940100688 Oral Solution Drugs 0.000 claims abstract description 5
- 239000003814 drug Substances 0.000 claims description 33
- -1 mucoadhesive Substances 0.000 claims description 19
- 239000000969 carrier Substances 0.000 claims description 11
- 230000003111 delayed Effects 0.000 claims description 9
- 238000009472 formulation Methods 0.000 claims description 5
- 239000007921 spray Substances 0.000 claims description 5
- 206010028034 Mouth ulceration Diseases 0.000 claims description 4
- 208000003265 Stomatitis Diseases 0.000 claims description 4
- 230000003232 mucoadhesive Effects 0.000 claims description 4
- 208000002399 Aphthous Stomatitis Diseases 0.000 claims description 3
- 208000005232 Glossitis Diseases 0.000 claims description 3
- 208000002193 Pain Diseases 0.000 claims description 3
- 201000007100 pharyngitis Diseases 0.000 claims description 3
- 238000002627 tracheal intubation Methods 0.000 claims description 3
- 208000007565 Gingivitis Diseases 0.000 claims description 2
- 238000004519 manufacturing process Methods 0.000 claims description 2
- 206010044008 Tonsillitis Diseases 0.000 claims 2
- 238000001356 surgical procedure Methods 0.000 claims 1
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- 238000002664 inhalation therapy Methods 0.000 description 1
- 230000000266 injurious Effects 0.000 description 1
- 239000000543 intermediate Substances 0.000 description 1
- 238000007913 intrathecal administration Methods 0.000 description 1
- 238000010030 laminating Methods 0.000 description 1
- 229940094522 laponite Drugs 0.000 description 1
- 150000002605 large molecules Chemical class 0.000 description 1
- 125000000400 lauroyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000003902 lesions Effects 0.000 description 1
- 235000010420 locust bean gum Nutrition 0.000 description 1
- 239000000711 locust bean gum Substances 0.000 description 1
- 150000004668 long chain fatty acids Chemical class 0.000 description 1
- 239000006210 lotion Substances 0.000 description 1
- 230000001050 lubricating Effects 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 230000001404 mediated Effects 0.000 description 1
- 230000037353 metabolic pathway Effects 0.000 description 1
- 150000002734 metacrylic acid derivatives Chemical class 0.000 description 1
- VKQFCGNPDRICFG-UHFFFAOYSA-N methyl 2-methylpropyl 2,6-dimethyl-4-(2-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate Chemical compound COC(=O)C1=C(C)NC(C)=C(C(=O)OCC(C)C)C1C1=CC=CC=C1[N+]([O-])=O VKQFCGNPDRICFG-UHFFFAOYSA-N 0.000 description 1
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 description 1
- 239000004530 micro-emulsion Substances 0.000 description 1
- 235000019813 microcrystalline cellulose Nutrition 0.000 description 1
- 239000008108 microcrystalline cellulose Substances 0.000 description 1
- 229940016286 microcrystalline cellulose Drugs 0.000 description 1
- 239000004200 microcrystalline wax Substances 0.000 description 1
- 235000019808 microcrystalline wax Nutrition 0.000 description 1
- 235000013336 milk Nutrition 0.000 description 1
- 239000008267 milk Substances 0.000 description 1
- 238000002156 mixing Methods 0.000 description 1
- 239000001788 mono and diglycerides of fatty acids Substances 0.000 description 1
- 238000000465 moulding Methods 0.000 description 1
- 239000002105 nanoparticle Substances 0.000 description 1
- PSZYNBSKGUBXEH-UHFFFAOYSA-N naphthalene-1-sulfonic acid Chemical compound C1=CC=C2C(S(=O)(=O)O)=CC=CC2=C1 PSZYNBSKGUBXEH-UHFFFAOYSA-N 0.000 description 1
- 239000002858 neurotransmitter agent Substances 0.000 description 1
- 230000001264 neutralization Effects 0.000 description 1
- 229930015196 nicotine Natural products 0.000 description 1
- 231100000344 non-irritating Toxicity 0.000 description 1
- 230000003000 nontoxic Effects 0.000 description 1
- 231100000252 nontoxic Toxicity 0.000 description 1
- 235000008390 olive oil Nutrition 0.000 description 1
- 239000003960 organic solvent Substances 0.000 description 1
- 230000000399 orthopedic Effects 0.000 description 1
- 230000003204 osmotic Effects 0.000 description 1
- 238000002638 palliative care Methods 0.000 description 1
- 239000003346 palm kernel oil Substances 0.000 description 1
- 235000019865 palm kernel oil Nutrition 0.000 description 1
- 230000037361 pathway Effects 0.000 description 1
- 235000020232 peanut Nutrition 0.000 description 1
- 230000002093 peripheral Effects 0.000 description 1
- 239000008177 pharmaceutical agent Substances 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920003023 plastic Polymers 0.000 description 1
- 239000004033 plastic Substances 0.000 description 1
- 229920003229 poly(methyl methacrylate) Polymers 0.000 description 1
- 229920002647 polyamide Polymers 0.000 description 1
- 239000011528 polyamide (building material) Substances 0.000 description 1
- 229920001610 polycaprolactone Polymers 0.000 description 1
- 229920000728 polyester Polymers 0.000 description 1
- 229920000573 polyethylene Polymers 0.000 description 1
- 239000004926 polymethyl methacrylate Substances 0.000 description 1
- 229920005862 polyol Polymers 0.000 description 1
- 150000003077 polyols Chemical class 0.000 description 1
- 229920001296 polysiloxane Polymers 0.000 description 1
- 229920002635 polyurethane Polymers 0.000 description 1
- 239000004814 polyurethane Substances 0.000 description 1
- 229920002689 polyvinyl acetate Polymers 0.000 description 1
- 239000011118 polyvinyl acetate Substances 0.000 description 1
- 229920002451 polyvinyl alcohol Polymers 0.000 description 1
- 235000019422 polyvinyl alcohol Nutrition 0.000 description 1
- 235000013809 polyvinylpolypyrrolidone Nutrition 0.000 description 1
- 229920000523 polyvinylpolypyrrolidone Polymers 0.000 description 1
- 239000011148 porous material Substances 0.000 description 1
- ZLMJMSJWJFRBEC-UHFFFAOYSA-N potassium Chemical compound [K] ZLMJMSJWJFRBEC-UHFFFAOYSA-N 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 229920001592 potato starch Polymers 0.000 description 1
- 230000002265 prevention Effects 0.000 description 1
- 230000002035 prolonged Effects 0.000 description 1
- ATUOYWHBWRKTHZ-UHFFFAOYSA-N propane Chemical compound CCC ATUOYWHBWRKTHZ-UHFFFAOYSA-N 0.000 description 1
- 239000001294 propane Substances 0.000 description 1
- 239000003380 propellant Substances 0.000 description 1
- 235000013772 propylene glycol Nutrition 0.000 description 1
- 235000018102 proteins Nutrition 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 230000001698 pyrogenic Effects 0.000 description 1
- VBICKXHEKHSIBG-UHFFFAOYSA-N rac-1-monostearoylglycerol Chemical compound CCCCCCCCCCCCCCCCCC(=O)OCC(O)CO VBICKXHEKHSIBG-UHFFFAOYSA-N 0.000 description 1
- 239000006215 rectal suppository Substances 0.000 description 1
- 230000000268 renotropic Effects 0.000 description 1
- 230000001846 repelling Effects 0.000 description 1
- 230000000241 respiratory Effects 0.000 description 1
- 239000003340 retarding agent Substances 0.000 description 1
- 239000012487 rinsing solution Substances 0.000 description 1
- YGSDEFSMJLZEOE-UHFFFAOYSA-M salicylate Chemical compound OC1=CC=CC=C1C([O-])=O YGSDEFSMJLZEOE-UHFFFAOYSA-M 0.000 description 1
- 229960001860 salicylate Drugs 0.000 description 1
- 230000028327 secretion Effects 0.000 description 1
- 238000007493 shaping process Methods 0.000 description 1
- 239000012176 shellac wax Substances 0.000 description 1
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 1
- 231100000245 skin permeability Toxicity 0.000 description 1
- 210000000813 small intestine Anatomy 0.000 description 1
- 150000003384 small molecules Chemical class 0.000 description 1
- 239000001187 sodium carbonate Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000001509 sodium citrate Substances 0.000 description 1
- 229940080313 sodium starch Drugs 0.000 description 1
- 239000004334 sorbic acid Substances 0.000 description 1
- 235000010199 sorbic acid Nutrition 0.000 description 1
- WSWCOQWTEOXDQX-UHFFFAOYSA-N sorbic acid Chemical compound CC=CC=CC(O)=O WSWCOQWTEOXDQX-UHFFFAOYSA-N 0.000 description 1
- 239000000600 sorbitol Substances 0.000 description 1
- 235000012424 soybean oil Nutrition 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 235000019385 spermaceti wax Nutrition 0.000 description 1
- 238000001694 spray drying Methods 0.000 description 1
- 239000003381 stabilizer Substances 0.000 description 1
- QIQXTHQIDYTFRH-UHFFFAOYSA-M stearate Chemical compound CCCCCCCCCCCCCCCCCC([O-])=O QIQXTHQIDYTFRH-UHFFFAOYSA-M 0.000 description 1
- 125000003696 stearoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 239000004094 surface-active agent Substances 0.000 description 1
- 239000003765 sweetening agent Substances 0.000 description 1
- KKEYFWRCBNTPAC-UHFFFAOYSA-L terephthalate(2-) Chemical compound [O-]C(=O)C1=CC=C(C([O-])=O)C=C1 KKEYFWRCBNTPAC-UHFFFAOYSA-L 0.000 description 1
- 238000002560 therapeutic procedure Methods 0.000 description 1
- 239000011732 tocopherol Substances 0.000 description 1
- 125000002640 tocopherol group Chemical group 0.000 description 1
- 235000019149 tocopherols Nutrition 0.000 description 1
- 229930003799 tocopherols Natural products 0.000 description 1
- 230000036346 tooth eruption Effects 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 230000032258 transport Effects 0.000 description 1
- 150000003626 triacylglycerols Chemical class 0.000 description 1
- 239000011778 trisodium citrate Substances 0.000 description 1
- 235000019263 trisodium citrate Nutrition 0.000 description 1
- 230000002792 vascular Effects 0.000 description 1
- 235000019871 vegetable fat Nutrition 0.000 description 1
- 229920002554 vinyl polymer Polymers 0.000 description 1
- 230000017613 viral reproduction Effects 0.000 description 1
- 229920003169 water-soluble polymer Polymers 0.000 description 1
- 239000000080 wetting agent Substances 0.000 description 1
- 235000010493 xanthan gum Nutrition 0.000 description 1
- 239000000230 xanthan gum Substances 0.000 description 1
- 229940082509 xanthan gum Drugs 0.000 description 1
- 239000011787 zinc oxide Substances 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
-
- 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
- A61P11/04—Drugs for disorders of the respiratory system for throat disorders
-
- 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
- A61P17/00—Drugs for dermatological disorders
- A61P17/04—Antipruritics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- 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
- A61P37/00—Drugs for immunological or allergic disorders
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D313/00—Heterocyclic compounds containing rings of more than six members having one oxygen atom as the only ring hetero atom
- C07D313/02—Seven-membered rings
- C07D313/06—Seven-membered rings condensed with carbocyclic rings or ring systems
- C07D313/10—Seven-membered rings condensed with carbocyclic rings or ring systems condensed with two six-membered rings
- C07D313/12—[b,e]-condensed
Abstract
The invention relates to the compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII and formula VIII, or its pharmaceutical acceptable polymorphs, solvates, enantiomers, stereoisomers and hydrates thereof. The pharmaceutical compositions comprising an effective amount of compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII and formula VIII, and methods for the treatment of mucositis may be formulated for oral, mouth wash, buccal, rectal, topical, transdermal, transmucosal, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of oral and gastrointestinal mucositis, mucosal inflammatory and oral infectious diseases. ve amount of compounds of formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII and formula VIII, and methods for the treatment of mucositis may be formulated for oral, mouth wash, buccal, rectal, topical, transdermal, transmucosal, intravenous, oral solution, buccal mucosal layer tablet, parenteral administration, syrup, or injection. Such compositions may be used to treatment of oral and gastrointestinal mucositis, mucosal inflammatory and oral infectious diseases.
Description
(12) Granted patent specificaon (19) NZ (11) 735338 (13) B2
(47) aon date: 2021.12.24
(54) COMPOSITIONS AND METHODS FOR THE TREATMENT OF MUCOSITIS
(51) Internaonal Patent Classificaon(s):
C07D 313/12 C07D 231/56 A61K 31/416 A61P 29/00 A61P 1/02 A61P 1/04
(22) Filing date: (73) Owner(s):
2016.01.19 CELLIX BIO E D
(23) Complete specificaon filing date: (74) Contact:
2016.01.19 Griffith Hack
(30) Internaonal Priority Data: (72) Inventor(s):
IN 622/CHE/2015 2015.02.09 KANDULA, Mahesh
(86) Internaonal Applicaon No.:
(87) Internaonal aon number:
WO/2016/128991
(57) Abstract:
The invenon relates to the compounds of formula I, formula II, formula III, formula IV, formula V,
formula VI, formula VII and formula VIII, or its pharmaceucal acceptable polymorphs, solvates,
enanomers, stereoisomers and hydrates f. The pharmaceucal composions comprising an
effecve amount of compounds of formula I, formula II, formula III, formula IV, formula V, formula
VI, a VII and formula VIII, and methods for the treatment of mucosis may be formulated
for oral, mouth wash, buccal, rectal, l, transdermal, transmucosal, intravenous, oral soluon,
buccal mucosal layer tablet, parenteral administraon, syrup, or injecon. Such composions
may be used to ent of oral and gastrointesnal mucosis, mucosal inflammatory and oral
infecous diseases.
NZ 735338 B2
TITLE: COMPOSITIONS AND METHODS FOR THE
ENT OF MUCOSITIS
COMPOSITIONS AND S FOR THE TREATMENT OF
PRIORITY
The t application claims the benefit of Indian Provisional Patent Application NO.
622/CHE/2015 filed on 09-February-2015, the entire disclosure of which is relied on for all
purposes and is incorporated into this ation by reference.
FIELD OF THE INVENTION
This disclosure generally relates to nds and compositions for the treatment of
mucositis. More particularly, this invention relates to treating subjects with a pharrnaceutically
acceptable dose of compounds, crystals, solvates, enantiomer, stereoisomer, esters, hydrates,
prodrugs, or mixtures thereof.
OUND OF THE INVENTION
Oral mucositis, also called stomatitis, is a common, debilitating complication of cancer
chemotherapy and radiotherapy, occurring in about 40% of patients. It s from the systemic
s of cytotoxic chemotherapy agents and from the local effects of radiation to the oral
mucosa. Oral mucositis is inflammation of the mucosa of the mouth which ranges from redness
to severe ulceration.
Symptoms of mucositis vary from pain and discomfort to an inability to tolerate food or,
fluids. Mucositis may also limit the patient’s ability to tolerate either chemotherapy or
radiotherapy. Mucositis may be so severe as to delay treatment and so limit the effectiveness of
cancer therapy. Patients with d oral mucosa and reduced immunity
. resulting from
chemotherapy and radiotherapy are also prone to opportunistic infections in the mouth. The
mucositis may affectpatients' gum and dental condition, speech and Self esteem are reduced,’
further compromising patients’ response to treatment and/or palliative care. It is therefore
extremely important that tis be prevented.
Some studies have also reported a distribution of these lesions on keratinized surfaces
such as the hard palate and upper surface of the tongue. If ulcerations are noted in these areas,
cultures and/or biopsies should be taken from the s to rule out viral infections or other
causes. Redness and/or ulcerations, ranging. from a few millimeters to a few centimeters long,
can appear. Bleeding from the ulcerations is common; however, bleeding often reflects a severe
reduction in a t's platelet count, a condition called thrombocytopenia.
Managing acute pathology of often relies on the addressing ying pathology and
symptoms of the disease. There is currently a need in the art for new compositions to treatment
or delay of the onset of mucositis and its associated cations progression.
SUMMARY OF THE INVENTION
The present ion provides compounds, compositions containing these compounds
and methods for using the same to treat, prevent and/or rate the effects of the conditions
such as mucositis.
[0007A] In one aspect, there is provided a compound of Formula 1A, n the compound
Formula IA
[0007B] In another aspect, there is provided a pharmaceutical composition sing a
compound as defined herein and a pharmaceutically a cceptable carrier.
[0007C] In another , there is provided use of a pharmaceutical composition as defined
herein for the cture of a medicament for the treatment of pain, mucositis, gingivitis,
stomatitis, glossitis, aphthous ulcers, oral ulceration, pharyngitis, litis, radiation or
intubation mucositis, wherein said pharmaceutical c omposition is administered to a patient in
need by oral administration, delayed release or sus tained release, transmucosal administration,
syrup, mucoadhesive, spray, buccal formulation, muc oadhesive tablet, topical administration,
68_1 (GHMatters) P109617.NZ
parenteral administration, injection, subdermal administration, oral solution, rectal
administration, buccal administration or erma l administration.
The invention herein provides compositions comprising of formula I or pharmaceutical
acceptable hydrates or solvates thereof. The invention also provides pharmaceutical compositions
comprising one or more compounds of formula I or intermediates f and one or more of
pharmaceutically acceptable carriers, vehicles or diluents. These compositions may be used in
the treatment of tis and its associated complications.
Formula 1
17307668_1 ters) P109617.NZ
and pharmaceutically acceptable hydrates, es, enantiomers, and stereoisomers thereof;
Wherein,
RH independently represents
0 * O
O ”°
/ \ - \
0H OH
O O
, ,
‘ l-hydroxy-Z-
naphthoic acid, 2,2-dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-
midobe'nzoic acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1),
aspartic acid (1), benzenesulfonic acid, benzoic acid, camphoric acid (it) camphor-lO-sulfonic
acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic
acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, caproic acid, caprilic acid,
capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic
acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid, arachidonic acid,
‘ dodecylsulfidric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric
acid, galactaric acid, gentisic acid, glucoheptonic acid ((1), gluconic acid (d), glucuronic acid
(‘1), glutamic acid, gluta‘ic ._?_°ida,§1Y°§{9Ph9§Ph9¥ic maid, gly091i9. acid, hippufio acid»
"hy'drcbrcmic acid, hydrochloric acid, yric acid, lactic acid (d1), lactobionic acid, lauric
acid, maleic acid, malic acid (- l), malonic acid, mandelic acid (d1), methanesulfonic acid,
naphthalene-1,5-disulfonic'acid, naphthalene-Z-sulfonic acid, nicotinic acid, ‘R-Lipoic acid,
nitric acid, oleic acid, oxalic acid, ic acid, pamoic acid, phosphoric acid, proprionic acid,
pyroglutamic acid (- 1), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid,
ic acid (+1), anjc acid, esulfonic acid (p), undecylenic acid, n—acetyl cysteine
(nae), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
The compositions are typically nds in the forms of salts, hydrates or solvates of
benzydamine and an acidic moiety [RH] ning compound selected [RH] in which the
benzydamine is protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is
at least in partially ionic form. In some instances, however, for example depending on the pH
of the environment, the composition may be in the form of a mixture of benzydamine and acid
components [RH]. The invention also provides pharmaceutical compositions sing
itions of formula I and pharmaceutically acceptable excipients.
In another aspect, the compounds offormula II are described:
wa/ WW/.- .
* a
Formula II
and pharmaceutically acceptable hydrates, es, prodrugs, enantiomers, and stereoisomers
thereof;
Wherein,
X independently ts
° 0
o -
I ‘H'OV
/ \. /o \
O O - O
9 I I
, l-hydroxy-Z-naphthoic acid, 2,2-dichloroacetic
> acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, amidobenzoic acid, 4-.
al'icylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (l),benzene‘sulfonic
acid, benzoic acid, camphoric acid (+) camphor-lO—sulfonic acid (+), capric acid (decanoic
acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, caproic acid,
caprilic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic
V PCT[IN2016/000024
acid, stearic acid, oleic acid, c acid, linoleic acid, linolenic acid, linolelaidic acid,
arachidonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-
onic acid, ethanesulfonic acid, formic acid, fumaric acid, aric acid, ic acid,
glucoheptonic acid (d), gluconic acid (d), glucuronic acid (d), glutamic acid, glutan'c acid,
glycerophosphon'c acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic
acid (d1), lactobionic acid, lauric acid, maleic acid, malic acid (- l), malonic acid, ic,
acid (d1), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-Z-sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (- l), salicylic acid, sebacic acid, stearic acid, ic acid,
sulfuric acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), lenic acid, n-
acetyl cysteine (nae), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
The compositions are typically compounds in the forms of salts of benzydamine,
aminocaproic acid and an acid, moiety [X] containing compound selected [X] in which the
benzydamine is in protonated form and aminocaproic acid is in d form and the acid
moiety [X] is at least in partially ionic form. In some instances, however, for example
depending on the pH of the environment, the composition may be in the form of a mixture of
benzydamine, aminocaproic acid and an acid moiety [X]. The invention also provides
pharmaceutical compositions comprising compositions of formula II and pharmaceutically
' acceptable
excipients.'
In certain embodiments, the compounds of formula III are described:‘
Formula 111
WO 28991
and pharmaceutically able hydrates, es, prodr‘ugs, enantiomers, and stereoisomers
thereof;
Wherein,
X independently presents
l/ 'Ho \
O O
I
Ml0H
, 1-hydroxynaphthoic acid, 2,2-dichloroacetic
acid, 2-hydroxyethanesulfonic‘ acid, 2-oxog1utaric acid, 4-ac'etamidobenzoic acid, 4-
aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (1), benzenesulfonic
acid, benzoic acid, Camphoric acid (+) camphor-lO-sulfonic acid (+), capric acid (decanoic
acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid,-cinnamic acid,
citric acid, 'nic acid, dodecylsulfuric acid, ethane-1,2—disulfonic acid, ethanesulfonic
acid, formic acid, fumaric acid, galactaric acid, ic acid, eptonic acid (d), gluconic
acid (d), glucuronic acid ((1), glutamic acid, glutaric acid, glycerophosphoric acid, caproic
acid, caprilic acid, capric acid, lauric acid,»myristic acid, myristoleic acid, palmitic acid,
palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic
acid, arachidonic acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic
acid (d1), ionic acid, lauric acid, maleic acid, malic acid (- l), malonic acid, mandelic
acid (d1), methanesulfonic acid, alene-1,54disulfonic acid, naphthalene—Z-sulfonic acid,
‘ nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (- 1), salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid, n-
acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
. The compositions are typically compounds in the forms of salts of benzydamine,‘
tranexamic acid and an acid moiety [X] containing compound selected [X] in which the
benzydamine is in protonated form and tranexamic acid is in charged form and the acid moiety
[X]-is at least in partially ionic form. In some ces, however, for example dependingon
the pH of the environment, the composition may be in the form of a miXture of benzydamine,
tranexamic acid and an acid moiety [X]. The invention also provides pharmaceutical
compositions comprising compositions of a III and pharmaceutically acceptable
excipients.
In an additional ,lthe compounds of formula IV are bed:
Formula IV
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and isomers
thereof;
Wherein,
X independently presents
WigH»,1-hydroxynaphthoic acid, 2,2-dichloroacetic
acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-
aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1),» aspartic acid (1), benzenesulfonic
acid, benzoic acid, camphoric acid (+) cainphor—lO-sulfonic acid (+), capric acid (decanoic
acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), ic acid, cinnamic acid,
citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (d), gluconic
acid (d), glucuronic acid (d), ic acid, glutaric acid, glycerophosphoric acid, glycolic
acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid (d1), lactobionic acid, lauric
acid, maleic acid, malic acid (- l),- malonic acid, mandelic acid (d1), methanesulfonic acid,
naphthalene-1,5-disulfonic acid, caproic acid, caprilic acid, capric acid, lauric acid, myristic
acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid,
linoleic acid, linolenic acid, laidic acid, arachidonic acid, naphthalene-Z—sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, oric acid,
proprionic acid, pyroglutamic acid (- l), salicylic acid, sebacic acid, stearic acid, ic acid,
sulfuric acid, tartaric acid (+ 1), thiocyanic acid, toluenesulfonic acid (p), lenic acid, n-
acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
The compositions are lly compounds in the forms lof salts of benzydamine,
GABA and an acid moiety [X] containing compound selected [X] in which the benzydamine is
min protonatedformandGABA is. in, chargediformiandthe acid moiety*[X-]*is atrleastin partially
ionic form. In some instances, however, for e ing on the pH of the environment,
the composition may be in the form of a mixtureof benzydamine, GABA and an acid moiety
[X]. The invention also provides pharmaceutical compositions comprising compositions of
formula IV and pharmaceutically acceptable excipients.
In an additional aspect, the compounds of formula V are described: .
Formula V
and pharmaceutically acceptable hydrates, solvates, enantiomers, and stereoisomers thereof;
Wherein,
RH ndently represents
, a , 1-hydroxy
naphthoic acid:2,2-dichloroaceticiacid,i2-hydroxyethanesulfonic"acid,"2:0xog'l'utariciacid,’ ’4'-
acetamidobenzoic acid, 4-aminosalicylic acid, acetic acid, Vadipic acid, ascorbic acid (1),
aspanic acid (1), benzenesulfOnic acid, benzoic acid, camphoric acid (+) r-lO-sulfonic
acid (+), capric acid (decanoic acid), caproic acid (hexanoic acid), ic acid (octanoic
acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, caproic acid, caprilic acid,
capric acid, lauric acid, myristic acid, oleic‘acid, pahnitic acid, palmitoleic acid, stearic
acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, laidic acid, arachidonic acid,
'dodecylsulfuric acid, ethane—1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric
acid, galactaric acid, gentisic acid, glucoheptonic acid ((1), gluconic acid (d), glucuronic acid
(d), Vglutamic acid, ic acid, glycerophosphoric acid, glycolic acid, hippuric acid,
hydrobromic acid, hydrochloric acid, isobutyric acid, lactic acid (d1), lactobionic acid, lauric
acid, maleic acid, malic acid (- l), malonic acid, mandelic acid (dl), methanesulfonic acid,
naphthalene-1,5-disulfonic acid, naphthalene-Z-sulfonic acid, nicotinic acid, R-Lipoic aCid,
nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, proprionic acid,
pyroglutamic acid (- l), salicylic acid, sebacic acid, stearic acid, ic acid, sulfuric acid,
tartaric acid (+ l), thiocyanic acid, toluenesulfonic p), undecylenic acid, n—acetyl cysteine
(nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
The itions aretypically compounds in the forms of salts, hydrates or solvates of
‘ doxepin and
an acidic moiety [RH] containing compound selected [RH] in which the n is
protonated and the acid moiety [RH] of the pharmaceutically acceptable salt is at least in
partially ionic form. In some instances, however, for example depending on the pH of the
environment, the composition may be in the form of a mixture of doxepin and acid ents
I k'
[RH]. The invention also provides pharmaceutical compositions comprising compositions of
formula V and pharmaceutically acceptable excipients.
In another aspect, the compounds of formula VI are described:
Formula VI
and pharmaceutically able hydrates, solvates, pr'odrugs, enantiomers, and stereoisomers '
Wherein,
X independently presents
o. 0
l' OH'Ho \ ‘o
/' -/. \
I OH
0 o o
’ l , )
/\/\/\/“\0H
, 1-hydroxynaphthoic acid, chloroacetic
acid, oxyethanesulfonic acid, lutaric acid, 4-acetamidobenzoic acid, 4-
aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (1), benzenesulfonic
. acid, benzoic acid, camphoric acid (+) camphor-lO-sulfonic acid (+), capfic acid (decanoic
acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, caproic acid,
caprilic acid, capric acid, lauric acid, myristic acid, oleic acid, palmitic acid, palmitoleic
acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid,
arachidonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfiuic acid, ethane-1,2-
onic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, gentisic acid,
eptonic acid ((1), ic acid ((1), glucuronic acid (d), glutamic acid, glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, yric acid, lactic
acid (d1), lactobionic acid, lauric acid, maleic acid, malic acid (- l), malonic acid, mandelic
acid (d1), methanesulfonic acid, naphthalene—1,5-disulfonic acid, naphthalene-Z—sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (- l), salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid, n-
acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
The compositions are typically compounds in the forms of salts of doxepin,
aminocaproic acid and an acid moiety [X] containing compound selected [X] in which the
doxepin is in protonated form and aminocaproic acid is in charged form and the acid- moiety [X]
is at least in partially ionic form. In some instances, however, for example depending on the pH
of the environment, the ition may be in the form of a mixture of doxepin, aminocaproic
acid and an acid moiety [X]. The invention also provides ceutical compositions
comprising compositions of formula VI and pharmaceutically able excipients.
In certain embodiments, the compounds of formula VII are described:
_ X-
\ NH O
Formula VII
and pharmaceutically acceptable‘hydrates, solvates, prodrugs, enantiomers, and stereoisomers
thereof; v
Wherein, ‘
X independently presents
0‘ O
l HO
/ \. o
OH / \
0 0 0
, . ,
, 1-hydroxynaphthoic acid, 2,2-dichloroacetic
acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-
alicylic acid, acetic acid, adipic acid, ascorbic acid (I), aspartic acid (1), benzenesulfonic
acid, c acid, camphoric acid (+) camphor-lO—sulfonic acid (+), capric acid .(decanoic
acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid,
citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, formic acid, fumaric acid, galactan'c acid, gentisic acid, glucoheptonic acid (d), gluconic
acid (d), glucuronic acid ((1), glutamic acid, glutaric acid, glycerophosphoric acid, caproic
acid, caprilic acid, capric acid, lauric acid, myristic acid, oleic acid, palmitic acid,
palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic
acid, arachidonic acid, glycolic acid, hippuric acid, hydrobromic acid, yric acid, lactic
acid (d1), lactobionic acid, lauric acid, maleic acid, malic acid (-' l), c acid, mandelic
acid (d1), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalenesulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (- l), salicylic acid, c acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid, n—
acetyl ne (nac), fiiroate, methyl furoate, ethyl furoate or aminocaproic acid.
The compositions are typically compounds in the forms of salts of doXepin, tranexamic
acid and an acid moiety [X] containing compound ed [X] in which the doxepin is in
protonated form and tranexamjc acid is in charged form and the acid moiety [X] is at least in
partially ionic-form. In some ces, however, for example depending on the= pH of the
environment, the composition may be in the form of a mixture of doxepin, tranexamic acid and
an acid moiety [X]. The invention also provides pharmaceutical compositions sing
cqmpositionspfformula7VII..and pharmaceutically-racceptable’excipients‘.’
In an additional aspect, the nds of formula VIII are described:
Formula VIII
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers
thereof; V
Wherein,
v X independently presents
I / -Ho. \ /O \
‘OH'
0 o
9 I I
, 1-hydroxy—2-naphthoic acid, chlor0acetic
acid, 2-hydr’oxyethanesulfonic acid, 2-oxoglutaric acid, amidobenzoic acid, 4-
aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (1), benzeneSulfonic
acid, benzoic acid, camphoric acid (+) camphor—lO-sulfonic acid (+), capric acid oic
acid), caproic acid (hexanoic acid), caprylic acid oic acid), carbonic acid, cinnamic acid,
citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic ’
acid, formic acid, furnan'c acid, galactaric acid, ic acid, glucoheptonic acid ((1), gluconic
acid (d), glncuronic acid (d), glutamic acid, glutan'c acid, glycerophosphoric acid, glycolic
acid, hippuric acid, hydrobromic acid, yric acid, lactic acid (d1), lactobionic acid, lauric
acid, maleic acid, malic acid (— l), malonic acid, mandelic acid (d1), methanesulfonic acid,
naphthalene-1,5~disulfonic acid, caproic acid, caprilic acid, capric acid, lauric acid, myristic
acid, myristoleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic acid,
linoleic acid, linolenic acid, linolelaidic acid, arachidonic acid, halene—Z-sulfonic acid,»
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (— l), salicylic acid, sebacic acid, stean'c acid, succinic acid,
sulfuric acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), lenic acid, n-
acetyl cysteine (nae), furoate, methyl furoate, ethyl e or aminocaproic acid.
The compositions are lly compounds in the forms of salts of doxepin, GABA and
an acid moiety [X] containing compound selected [X] in which the dOXepin is in protonated
form and GABA is in Charged form and the acid moiety [X] is at least in partially ionic form.
In some instances, however, for e depending on the pH of the environment, the
composition may be in the form of a mixture of doxepin, GABA and an acid moietyl[X]. The
invention also provides pharmaceutical compositions comprising compositions of formula VIII
and pharmaceutically acceptable excipients.
Herein the application also provides a kit comprising any of the pharmaceutical
compositions disclosed herein. The kit may comprise instructions for use in the treatment of
mucositis or its related complications.
The ation also discloses a comprising a
, pharmaceutical ition
pharmaceutically acceptable carrier and any of the compositions herein. In some aspects, the
ceutical composition is formulated for oral solution, oral rinsing solution, oral antiseptic
solution, systemic administration, oral administration, sustained e, parenteral
stration, injection, subdermal administration, or transdermal administration.
, the application additionally provides kits comprising the pharmaceutical
compositions described herein. The kits may further comprise instructions for use in the
treatment of mucositis or its related complications.
The compositions described herein have several uses. The present application provides,
for example, methods of treating a patient suffering from mucositis or its related complications
manifested from metabolic” or genetic conditions or disorders, 'metabolic diseases, chronic
diseases or disorders; neurodegenerative disorders, metabolic ion, Hepatology, Cancer, ,
Respiratory, Hematological, Orthopedic, vascular, Renal, Skin, ar or Ocular
complications.
In the illustrative embodiments, examples of compounds of formula I, formula II,
formula III, formula IV, formula V, formula VI, a VII, formula VIII are as set forth
below:
WO 28991
(6-1)
BRIEF DESCRIPTION OF FIGURES:
Example embodiments are illustrated by way of e and not limitation in the
figures ofthe accompanying drawings, in which like references indicate similar elements and in
which: '
FIGURE 1 shows the H-NMR, 13C-NlV1R results for Compound 1 ofFormula I.
FIGURE 2 shows the H-‘NMR, R results for Compound 2 ofFormula 1.
FIGURE 3 shows the H-NMR, VIR results for Compound 1 of a 1V.
FIGURE 4 shows the H-NMR, 13C-NMR results for Compound 1 of Formula V.
FIGURE 5 shows the H-NMR, 13C—NMR results for Compound 2 ofFormula V.
FIGURE 6 shows the H-NMR, R resultsforCompound l ofFormula VIII.- ~
DETAILED DESCRIPTION OF THE ION
Definitions
As used herein, the following terms and phrases shall have the meanings set forth below.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning
as commonly understood to one of ordinary skill in the art.
Compounds that have the same molecular formula but differ in the nature or sequence
of bonding of their atoms or the arrangement of their atoms in space are termed "isomers."
Isomers that differ in the arrangement of their atoms in space are termed "stereoisomers."
DiaStereom'ers are stereoisomers with opposite configuration at one or more chiral centers
which are not enantiomers. Stereoisomers g one or more asymmetric centers that are non-
superimposable mirror images of each other are termed iomers." When a compound. has
an asymmetric center, for example, if a carbon atom is bonded to four different groups, a pair of
enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its
asymmetric center or centers and is described by the R— and S-sequencing rules of Cahn, lngold
' and Prelog,
or by the manner in which the molecule rotates the plane of polarized light and
designated as 'dextrorotatory or levorotatory (i.e., as (+) or (—)-isomers respectively). A chiral ‘
compound can exist as either individual enantiomer or as a mixture thereof. A mixture
containing equal proponions ofthe enantiomers is called a ic mixture".
As used herein, theterm “metabolic condition” refers to an Inbom errors of metabolism
(or genetic lic conditions) are genetic disorders that result from a defect in one or more
metabolic pathways; cally, the function of an enzyme is affected and is either deficient or
completely absent.
The term "polymorp "
as used herein is art-recognized and refers to one crystal structure
Of a given compound.
The phrases “parenteral administration” and “administered parenterally” as used herein
refer to modes of administration other than enteral and topical administration, such as
injections, and include without limitation intravenous, intramuscular, leural, intravascular,
intrapericardial, intraarten'al, intrathecal, intracapsular, intraorbital, intracardiac, ennal,
intraperitoneal, transtracheal, subcutaneous, subcuticular, inira—articular, sular,
subarachnoid, pinal and intrastemal injection and infusion.
A “patient,” “subject,” or “host” to be treated by the subject method may mean either a
human or non-human animal, such as primates, mammals, and vertebrates.
The phrase “pharmaceutically acceptable” is art-recognized. In certain embodiments,
the term includes compositions, rs and other als and/or dosage forms which are,
within the scope of sound medical judgment, suitable for use in contact with the tissues of
mammals, human beings and animfls-without excessive toxicity, tion, allergic response, or
other problem or complication, commensurate with a reasonable benefit/risk ratio.
' [0046] The phrase “pharmaceutically acceptable carrier” is art-recognized, and includes, for
example, pharmaceutically acceptable materials, compositions or vehicles, such as a liquid or
solid filler, diluent, solvent or encapsulating material involved in carrying or transporting any
subject composition, from one organ, or portion of the body, to another organ, or portion of the
body. Each r must be “acceptable” in the sense of being compatible with the other
ingredients of a subject composition and not injurious to the t. In certain embodiments, a
pharmaceutically acceptable carrier is non-pyrogenic. Some es of als which may
serve as pharmaceutically able carriers include: (1) sugars, such as lactose, glucose and —
sucrose; (2) starches, such as corn starch and potato starch; (3) celluloSe, and its derivatives,
such as sodium carboxymethyl cellulose, ethyl cellulose and ose e; (4) powdered
tragacanth; (5) malt; (6) gelatin; (7) talc; (8) cocoa butter and itory waxes; (9) oils, sUch
as peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; (10)
glycols, such as propylene glycol; (11) polyols, such as glycerin, ol, mannitol and
polyethylene ; (12) esters, such as ethyl oleate and ethyl laurate; (13) agar; (14) buffering
agents, such as ium hydroxide and aluminum hydroxide; (15) alginic acid; (16) pyrogen-
free water; (17) isotonic saline; (18) Ringer’s solution; (19) ethyl l; (20) phosphate buffer
solutions; and (21) other non-toxic compatible substances employed in pharmaceutical
formulations.
[0047fThe ’t’errn "‘prodfig””i’s"intended—to encompass compounds that, under physiological
conditions, are converted into the therapeutically active agents of the present ion. A
common method for making a prodrug is to include selected moieties that are hydrolyzed under
physiological conditions to reveal the desired molecule. In other embodiments, the g is
converted by an enzymatic activity of the host animal.
The term “prophylactic or therapeutic” treatment is art-recognized and includes
administration to the host of one or more of the subject compositions. If it is administered prior
state of the
to clinical manifestation of the unwanted ion (e.g., disease or other unwanted
host animal) then the treatment is prophylactic, i.e., it protects the hoSt against developing the
unwanted condition, whereas if it is administered after manifestation of the unwanted condition,
the treatment is therapeutic, (i.e., it is intended to diminish, ameliorate, or stabilizethe existing
unwanted condition 0r side s thereof).
The term "predicting" as used herein refers to assessing the probability related diseases
t will suffer from abnormalities or complication and/or terminal platelet aggregation or
failure and/or death (i.e. mortality) within a defined time window (predictive window) in the
future. The mortality may be caused by the central nervous system or complication. The
predictive window is an interval in which the subject will p one or more of the said
complications according to the predicted probability. The tive window may be the entire
remaining lifespan ofthe subject upon analysis by the method ofthe present invention.
The term ing" is art -recognized and includes preventing a disease, disorder 0r
Condition from occurring in an animal which may be predisposed to the disease, disorder and/or
condition but has not yet been diagnosed as having it; inhibiting the e, disorder or
condition, e.g., impeding its progress; and relieving the e, disorder, or condition, e.g.,
causing regression of the disease, disorder and/or condition. Treating the disease or ion
includes ameliorating at least one symptom of the particular disease or condition, even if the
underlying pathophysiology is not affected, such as treating tis, painful inflammation
and ulceration of the mucous membranes lining the digestive tract and gastrointestinal tract,
salivary gland dysfunction, erythema, inflammatory condition of oral tissue, ing mucosa,
dentition/periapices, and periodontium, infections of oral tissues as well as mucositis and other
related diseases or any other medical condition, is well understood in the art, and includes
administration of a composition which reduces the frequency of, or delays the onset of,
receive the
Symptoms of a medical condition in a t relative to a subject which does not
composition.
The phrase "therapeutically ive amount" is an art-recognized term. In certain
embodiments, the term refers to an amount of a solvate or hydrate or ition disclosed
herein that produces some desired effect at a reasonable benefit/risk ratio applicable to any
medical treatment. In certain embodiments, the term refers to that amount necessary or
sufficient to eliminate or reduce medical ms for a period of time. The effective amount
may vary ing on such factors as the e or condition being treated, the particular
targeted constructs being administered, the size of the subject, or the severity of the disease 0r
condition. One of ry skill in the art may empirically determine the efi‘ective amount of a
particular composition without necessitating undue experimentation.
In certain embodiments, the pharmaceutical compositions described herein are
ated in a manner such that said compositions will be red to a patient in a
, therapeutically effective , as part of a prophylactic or therapeutic treatment. The desired
amount of the composition to be administered to a patient will depend on absorption,
inactivation, and excretion rates of the drug as well as the delivery rate of the hydrates or
solvates and compositions fi'om the subject compositions. It is to be noted that dosage values
may also vary with the ty of the condition to be ated. It is to be further understood
that for any particular subject, specific dosage regimens should be adjusted over time according
to the individual need and the professional judgment of the person administering or supervising
the administration of the compositions. Typically, dosing will be determined using techniques
known to one skilled in the art.
Additionally, the l concentration and/or quantities or amounts of any particular
solvate or hydrate or composition may be adjusted to accommodate variations in the treatment
parameters. Such ent parameters include the clinical use to which the preparation is put,
and the nature
‘e.g., the site treated, the type ofpatient, e.g., human or non-human, adult or child,
ofthe disease or condition.
In certain embodiments, the dosage of the subject compositions provided herein may be
inedby nce to the plasma conCentrations of the therapeutic composition or other
encapsulated materials. For example, the maximum plasma concentration (Cmax) and the area
under the plasma concentration-time curve from time 0 to infinity may be used.
When used with respect to a pharmaceutical composition or other material, the term
“sustained release” is art-recognized. For example, a subject composition which releases a
substance over time may exhibit sustained release characteristics, in contrast to a bolus type
administration in which the entire amount of the substance is made biologically available at one
time. For example, in particular ments, upon contact with body fluids including blood,
spinal fluid, mucus secretions, lymph or the like, one or more of the pharmaceutically
acceptable excipients may undergo l or delayed ation (e.g., through hydrolysis)
with concomitant release of any material incorporated therein, e.g., an therapeutic and/or
ically active solvate or hydrate and/or composition, for a sustained or extended period (as
compared to the release from a . This release may result in prolonged delivery of
therapeutically effective amounts of any of the therapeutic agents disclosed herein.
The phrases “systemic administration,“ “administered ically,” “peripheral
administration”. and “administered peripherally” are cognized, and e the
administration of a subject composition, therapeutic orother material at a site remote from the
disease being treated. Administration of an agent for the disease being treated, even if the agent
is subsequently distributed systemically, may be termed “local” or “topical” or “regional”
administration, other than directly into the central neWous system, e.g., by subcutaneous
administration, such that it enters the patient’s system and, thus, is subject to metabolism and
other like processes.
The-phrase peutically effective amount” is an art-recognized term. In certain
embodiments, the term refers to an amount of a solvate or hydrate or composition disclosed
herein that produces some desired effect at a reasonable benefit/risk ratio able to any
medical treatment. In certain embodiments, the term refers to that amount necessary or
sufficient to eliminate or reduce medical symptoms for a period of time. The effective amount
may vary depending on such factors as the disease or condition being treated, the particular
targeted constructs being administered, the size of the subject, or the severity of the disease or
condition. One nary skill in the art may empirically determine the effective amount of a
ular ition t necessitating undue experimentation.
The present disclosure also contemplates prodrugs of the compositions disclosed herein,
as Well as pharmaceutically acceptable hydrates or solvates of said salts.
This application also discloses a pharmaceutical composition comprising a
pharmaceutically acceptable carrier and the composition of a compound of a I, formula
II, formula III, formula IV, formula V, formula VI, formula VII or formula VIII may be
formulated for systemic or topical or oral administration. The ceutical composition may
be also ated for oral administration, oral on, injection, mal administration, or
transdermal administration. The pharmaceutical composition may further comprise at least one
of a pharmaceutically acceptable stabilizer, t, surfactant, filler, binder, and lubricant.
In many embodiments, the pharmaceutical compositions described herein will
orate the disclosed compounds and itions (Formula I, formula II, formula III or
formula IV) to be delivered in an arnOunt sufiicient to deliver to a patient a eutically
effective amount of a compound of formula I, formula II, formula III, formula IV, formula V,
formula VI, formula VI! or formula VIII or composition as part of a prophylactic or therapeutic
treatment. The desired concentration of formula I, formula II, formula III, formula IV, formula
V, formula VI, a VII 0r formula VIIIor its pharmaceutical acceptable hydrates or solvates
will depend on absorption, inactivation, and ion rates of the drug as well as the delivery
rate ofthe hydrates or solvates and compositions from the subject compositions. It is to be
noted that dosage values may also vary with the severity of the condition to be alleviated. It is
to be further understood that for any particular subject, specific dosage regimens should be
adjusted over time according to the individual need and the professional judgment of the person
administering or supervising the administration ofthe compositions. Typically, dosing will be
determined using techniques known to one skilled in the art.
Additionally, the optimal concentration and/or quantities or amounts of any particular
compound of formula I, formula II, formula III, formula IV, formda V, a VI, formula
VII or formula VIIImay be adjusted to accommodate variations in the ent parameters. _
Such treatment parameters e the clinical use to which the preparation is put, e.g., the site
treated, the type of patient, e.gi, human or non-human, adult or child, and the nature of the
disease or condition.
The concentration and/or amount of any compound of formula I, formula II, formula III,
a IV, formula V, a VI, formula VII or formula VIIImay be readily identified by
routine screening in animals, e.g., rats, by screening a range of concentration and/or amounts of
the material in question using appropriate assays. Known methods are also available to assay
local tissue concentrations, diffusion rates of the es or solvates or compositions, and local
blood flow before and after administration of therapeutic formulations disclosed herein. One
such method is microdialysis, as reviewed by T. E. Robinson et a1., 1991, microdialysis in the
neurosciences, ques, volume 7, Chapter 1. The methods reviewed by Robinson may be
applied, in brief, as follows. A microdialysis loop is placed in situ in a test animal. Dialysis
fluid is pumped through the loop. When compounds with formula I, formula II, formula III,
formula IV, formula V, formula VI, formula VII or formula VIIIsuch as those disclosed herein
are injected adjacent to the loop, released drugs are collected in the dialysate in proportion to
their local tissue concentrations.~ The progress of diffusion of the hydrates or solvates or
compositions may be ined y with suitable calibration procedures using known
concentrations ofhydrates or solvates or compositions.
In certain embodiments, the dosage of the subject compounds of formula I, formula II,
formula III, formula IV, formula V, formula VI, a VII or formula VIIIprovided herein
may be determined by nce to the plasma concentrations of the therapeutic composition or
" For exampleithe’maximmn‘plasma concentration (Cmax) and the
‘ “othe'r'encapsulated material’s.
,,,,7
area under the plasma concentration-time curve from time 0 to infinity may be used.
Generally, in ng out the methods detailed in this application, an effective dosage
for the compounds of Formula I, formula II, formula III or'formula IVis in the range of about
0.01 mg/kg/day to about 100 mg/kg/day in single or d doses, for ce 0.01 day
to about 50 day in single or divided doses. The compounds of Formulas I may be
administered at a dose of, for example, less than 0.2 mg/kg/day, 0.5 mg/kg/day, 1.0 mg/kg/day,
mg/kg/day, 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day, or 40 mg/kg/day. Compounds of
Formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII or formula
VIIImay also be administered to a human patient at a dose of, for example, between 0.1 mg and
1000 mg, between 5 mg and 80 mg, or less than 1.0, 9.0, 12.0, 20.0, 50.0, 75.0, 100, 300, 400,
WO 28991
500, 800, 1000, 2000, 5000. mg per day. In ceriain ments, the compositions herein are
administered at an amount that is less than 95%, 90%, 80%, 70%, 60%, 50%, 40%, 30%, 20%,
or 10% of the Compound of formula I, formula II, formula III, formula IV, formula V, formula
VI, formula VII or formula VIIIrequired for the same therapeutic benefit.
An effective amount ofthe compounds of formula I, formula II, formula III, formula IV,
formula V, formula VI, formula VII or formula VIIIdescribed herein refers to the amount of one
of said es or solvates or compositions which is capable of inhibiting or preventing a
disease.
An effective amount may be sufficient to prohibit, treat, alleviate, ameliorate, halt,
restrain, slow or reverse the progression, or reduce the severity of a complication resulting from
nerve damage or demyelization and/or ed reactive oxidative-nitrosative species and/or
abnormalities in neurotransmitter homeostasis’s, in patients who are at risk for such
complications. As such, these methods include both medical therapeutic (acute) and/or
prophylactic (prevention) administration as appropriate. The amount and timing of
compositions administeredwill, of course, be dependent on the subject being treated, on the
’ severity of the ion, on the manner of administration and on the judgment of the
prescribing physician. Thus, because of patient—to—patient variability, the s given above
areaguidelineandthephysician,mayJitratedosesofthedrugtaachievertheireatment,that,the
physician considers appropriate for the t. In considering the degree of ent desired,
theq physician must balanCe a y of factors such as age of the patient, presence of
preexisting diSease, as well as presence of other diseases.
The compositions provided by this application may be administered to a subject in need
of treatment by a variety of conventional routes of administration, ing , topically,
parenterally, e.g., intravenously, subcutaneously or intramedullary. Further, the itions
may be administered intranasally, as a rectal suppository, or using a "flash" formulation, i.e.,
allowing the medication to dissolve in the mouth t the need to use water. Furthermore,
the compositions may be administered to a subject in need of treatment by Controlled release
dosage forms, site specific. drug delivery, transdermal drug delivery, patch e/passive)
mediated drug ry, by stereotactic injection, or in nanoparticles.
The compositions may be administered alone or in combination with pharmaceutically
acceptable carriers, vehicles or diluents, in either e or multiple doses. Suitable
ceutical carriers, vehicles and diluents include inert solid diluents or fillers, e
aqueous solutions and various-organic solvents. The pharmaceutical itions formed by
combining the compositions and the pharmaceutically acceptable carriers, vehicles or diluents
are then readily administered in a variety of dosage forms such as tablets, powders, lozenges,
syrups, injectable solutions and the like. These pharmaceutical compositions can, if d,
Contain additional ingredients such as flavorings, binders, excipients "and the like. Thus, for
purposes of oral administration, tablets containing various ents such as L-arginine,
sodium citrate, calcium carbonate and calcium phosphate may be ed along with various
disintegrates such as starch, c acid and certain complex silicates, together with binding
agents such as polyvinylpyrrolidone, sucrose, gelatin and acacia. Additionally, lubricating
, agents such as magnesium te, sodium lauryl sulfate and talc are often useful for tabletting
es. Solid compositions of a similar type may also be employed as fillers in soft and hard
filled gelatin capsules. Appropriate materials for this include lactose or milk sugar and high
molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for
oral administration, the essential active ingredient therein may be combined with various
sweetening or flavoring agents, coloring matter or dyes and, if desired, fying or
suspending agents, together with diluents such as water, l, propylene glycol, glycerin and
combinations thereof. The compounds of fOrmula I, formula II, formula III, formula IV, formula
V, formula VI, formula VII or formula VIIImay also comprise enterically coated comprising of
various excipients, as is well known in the pharmaceutical amt.
For parenteral administration, solutions of the compositions may be prepared in (for
example) sesame or peanut oil, aqueous ene glycol, or in e aqueous solutions may be
employed. Such aqueous solutions should be suitably buffered if ary and the liquid
diluent first rendered isotonic with sufficient saline or glucose. These particular s
solutions are especially suitable for intravenous, intramuscular, subcutaneous and
intraperitoneal administration. In this connection, the sterile aqueous media ed are all
readily available by standard techniques known to those d in the art.
The formulations, for instance tablets, may contain e.g. 1 mierogram to'1-0 rams,
1) mg to 10 mg, 10 to 100, 50 to .250, 150 to 500 mg, or 350 to 800 mg e.g. 10, 50, 100, 300,
500, 700, 800 mg of the compounds of formula I, formula II, formula III, formula IV, formula
V, formula VI, forr’nula VII or formula VIII disclosed herein, for instance, compounds of
formula I, formula II, formula III, formula IV, formula V, formula VI, formula VII or formula
VIII or ceutical acceptable hydrates or solvates of a compounds of Formula I, formula
II, formula III, formula IV, formula V, formula VI, formula VII and formula VIII.
Generally, a composition as described herein may be stered orally, or parenterally
(e.g., intravenous, intramuscular, subcutaneous or intramedullary). Topical administration may
also be ted, for example, where the patient fering from gastrointestinal disorder that
prevent oral administration, or whenever the medication is best applied to the surface of a tissue
or organ as determined _by the attending physician. Localized administration may also be
indicated, for example, when a high dose is desired at the target-tissue or organ. For buccal
administration the active composition may take the form of s or lozenges formulated in a
conventional manner. '
The dosage administered will be dependent upon the identity of the ogical disease;
the type of host involved, including its age, health and ; the kind of Concurrent ent,
if any; the frequency of treatment and therapeutic ratio.
Illustrative'ly, dosage levels of the administered active ingredients are: enous, 0.1
to about 200 mg/kg; intramuscular, 1 to about 500 mg/kg; orally, 5 to about 1000 mg/kg;
intranasal instillation, 5 to about 1000 mg/kg; and aerosol, 5 to about 1000 mg/kg of hOSt body
weight.
Expressed in terms of concentration, an active ingredient can be present in the
compositions of the present invention for localized use abOut the mouth wash, cutis,
2016/000024
intranasally, golaryngeally, bronchially, intravaginally, rectally, or ly in a
concentration of from about 0.01 to about 50% w/w of the composition; preferably about 1 to
about 20% w/w of the composition; and for parenteral use in a concentration of from about 0.05
to about 50% w/v ofthe composition and preferably from about 5 to about 20% w/v.
The compositions Of the present ion are preferably presented for administration to
humans and animals in unit dosage forms, such as tablets, capsules, pills, powders, granules,
suppositories, sterile parenteral solutions or suspensions, sterile non—parenteral solutions of
suspensions, and oral solutions or suspensionsand the like, containing suitable quantities of an
active ingredient. For oral administration either solid or fluid unit dosage forms can be
prepared.
As discussed above, the tablet core contains one or more hydrophilic polymers. Suitable
hydrophilic polymers include, but are not limited to, water ble ose derivatives,
polyalkylene glycols, thermoplastic polyalkylene oxides, acrylic polymers, hydrocolloids, clays,
gelling starches, swelling cross-linked polymers, and mixtures thereof. Examples of Ie
water swellable cellulose derivatives include, but are not limited to, sodium
carboxymethylcellulose, cross-linked hydroxypropylcellulose, hydroxypropyl cellulose .(HPC),
hydroxypropylmethylcellulose (HPMC), hydroxyisopropylcellulose, hydroxybutylcellulose,
hydroxyphenylcellulose, yethylcellulose (HEC), hydroxypentylcellulose,
hydroxypropylethylcellulose, hydroxypropylbutylcellulose, and hydroxypropylethylcellulose,
and mixtures thereof. Examples of le polyalkylene glycols include, but are not limited to,
polyethylene glycol. Examples of suitable thermoplastic polyalkylene oxides include, but are
not limited to, thylene oxide). Examples of suitable acrylic polymers include, but are not
limited to, potassium methacrylatedivinylbenzene copolymer, polymethylmethacrylate, high-
molecular weight crosslinked acrylic acid homopolymers and copolymers such as those
Commercially available from Noveon Chemicals under the tradename OLTM.
Examples of suitable hydrocolloids include, but are not limited to, alginates, agar, guar gum,
locust bean gum, kappa carrageenan, iota carrageenan, tara, gum arabic, anth, pectin,
xanthan gum, gellan gum, maltodextn‘n, galactomannan, pusstulan, laminarin, scleroglucan,
gum , inulin, , gelatin, whelan, rhamsan, zooglan, methylan, , cyclodextrin, ‘
chitosan, and mixtures thereof. Examples of suitable clays include, but are not limited to,
smectites such as bentonite, kaolin, and laponite; magnesium icate; magnesium aluminum
silicate; and mixtures thereof. Examples of suitable gelling starches include, but are not limited
to, acid hydrolyzed starches, swelling starches such as sodium starch glycolate and derivatives
thereof, and mixtures thereof. es of suitable swelling linked polymers include, but
are not limited to, cross-linked polyvinyl pyrrolidone, linked agar, and cross-linked
carboxymethylcellulose sodium, and mixtures thereof.
.[0077] The carrier may n one or more suitable excipients for the formulation of tablets.
Examples of suitable excipients include, but are not d to, fillers, adsorbents, binders,
disintegrants, lubricants, glidants, release-modifying excipients, superdisintegrants,
antioxidants, and mixtures thereof.
le s include, but are not limited to, dry s such as polyvinyl,
idone and hydroxypropyhnethylcellulose; wet binders such as water-soluble polymers,
including hydrocolloids such as acacia, alginates, agar, guar gum, locust bean, carrageenan,
carboxymethylcellulose, tara, gum arabic, tragacanth, pectin; xanthan, gellan, gelatin,
maltodextr‘in, galactomannan, pusstulan, rin, scleroglucan, , whelan, rhamsan,
n, methylan, , cyclodextn'n, chitosan, polyvinyl pyrrolidone, cellulosics, sucrose,
and “starches; and mixtures thereof. “Suitable. disintegrants include, butiare notilimitedito,
sodium starch cross-linked cross-linked -
. ate, polyvinylpyrrolidone,
carboxymethylcellulose, starches, microcrystalline cellulose, and mixtures thereof.
Suitable lubricants include, but are not limited to, long chain fatty acids and their
hydrates or solvates such as magnesium stearate and stearic acid, talc, glycerides waxes, and
mixtures thereof. Suitable glidants include, but are not limited to, colloidal silicon dioxide.
Suitable release-modifying excipients e, but are not limited to, insoluble edible materials,
pH-dependent polymers, and mixtures thereof.
Suitable insoluble edible als for use as release-modifying excipients include, but
are not limited to, Water—insoluble polymers and low—melting hydrophobic materials,
WO 28991 2016/000024
mers thereof, and mixtures thereof. Examples of suitable water—insoluble polymers
e, but are not limited to, ethylcellulose, polyvinyl alcohols, polyvinyl acetate,
polycaprolactones, cellulose acetate and its derivatives, acrylates, methacrylates, acrylic acid
copolymers, copolymers thereof, and mixtures thereof. Suitable low-melting hydrophobic
materials include, but are not limited to, fats, fatty acid esters,'phospholipids, '
waxes, and
‘ mixtures thereof. Examples of Suitable fats include, but are not limited to, hydrogenated
vegetable oils such as for example cocoa butter, enated palm kernel oil, hydrogenated
cottonseed oil, hydrogenated sunflower oil, and hydrogenated soybean oil, free fatty acids and
their hydrates or solvates and es f. Examples of le fatty acid esters include,
but are not limited to, sucrose fatty acid esters, mono-, di-, and triglycerides, glyceryl behenate,
glyceryl palmitostearate, glyceryl monostearate, glyceryl arate, glyceryl trilaurylate,
glyceryl myristate, GlycoWax-932, lauroyl macrogol-32 glycerides, stearoyl maerogol-32t
glycerides, and mixtures thereof. Examples of suitable phospholipids include phosphotidyl
choline, phosphotidyl serene, phosphotidyl enositol, phosphotidic acid, and mixtures thereof.
Examples of suitable waxes include, but are not limited to, carnauba wax, spermaceti wax,
beeswax, candelilla wax, shellac wax, microcrystalline wax, and paraffin wax; fat-containing
mixtures such as chocolate, and mixtures thereof. Examples of super disintegrants include, but
are not limited to, croscarmellose sodium, sodium starch glycolate and linked povidone
(crospovidone). In one embodiment the tablet core contains up to about 5 percent by weight of
such super disintegrant.
Examples of antioxidants include, but are not d to, tocopherols, ascorbic acid,
m pyrosulfite, butylhydroxytoluene, butylated hydroxyanisole, edetic acid, and edetate
hydrates or solvates of preservatives
, and mixtures thereof. es include, but are not
limited to, citric acid, ic acid, lactic acid, malic acid, acetic acid, benzoic acid, and sorbic
acid, and mixtures thereof.
In one embodiment, the immediate release coating has an average thickness of at least
50 microns, such as from about 50 microns to about 2500 microns; e.g., fi'om about 250 microns
to about 1000 microns. In embodiment, the immediate release coating is typically compressed
at a density of more than about 0.9 g/cc, as measured by the weight and volume of that specific
layer.
In one ment, the immediate release coating contains a first portion and a second
portion, wherein at least one of the portions contains the second pharmaceutically active agent.
In one ment, the portions contact each other at a center axis of the tablet. In one
embodiment, the first portion includes the first pharmaceutically active agent and the second
portion includes the second pharmaceutically active agent.
In one embodiment, the first portion contains the first phannaceutically active agent and
the second portion contains the second pharrnaceutically active agent. In one embodiment, one
of the ns contains a third pharmaceutically active agent.‘ In one embodiment one of the
portions contains a second immediate release portion of the same pharmaceutically active agent
as that contained in the tablet core.
In one embodiment, the outer coating’portion is prepared as a dry blend of materials
prior to addition to the coated tablet core. In another embodiment the outer coating portion is
included of a dried granulation ing the ceutically active agent.
Formulations with different drug e mechanisms bed above could be
combined in a final dosage form containing'single or multiple units. es of le units
include‘multilayer tablets, capsules containing tablets, beads, or granules in a solid or liquid
form. .Typical, immediate release formulatiOns include compressed tablets, gels, films, coatings,
liquids and particles that can be encapsulated, fer example, in a gelatin capsule. Many methods
for preparing coatings, covering or orating drugs, are known in the art.
The immediate release dosage, unit of the dosage form, i.e., a tablet, a plurality of drug-
containing beads, granules or particles, or an outer layer of a coated core dosage form, contains
a therapeutically effective quantity of the active agent with conventional pharmaceutical
excipients. The immediate release dosage unit may or may not be coated, and may or may not
be admixed with the delayed release dosage unit or units (as in an encapsulated mixture of
immediate release drug-containing granules, les or beads and delayed release drug-
containing granules or heads). a
Extended release formulations are generally prepared as diffusion or osmotic s,
for example, as described in "Remington—The Science and Practice of Pharmacy", 20th. Ed.,
Lippincott Williams & Wilkins, Baltimore, Md., 2000). A diffusion system typically consists of
one of two types of devices, reservoir and matrix, which are wellknown and described in die art.
The matrix devices are generally prepared bycompressing the drug with a slowly dissolving
polymer carrier into a tablet form.
An ate release portion can be added to the extended release system by means of
either applying an immediate release layer on top of the extended release core; using coating or
ssion processes or in a multiple unit system such as a capsule containing ed and
ate release beads.
Delayed release dosage ations are created by coating a solid dosage form with a
film. of a polymer which is insoluble in the acid environment of the h, but soluble in the
neutral nment of small intestines. The delayed release dosage units can be prepared, for
example, by coating a drug or a drug-containing composition with a selected coating material.
The drug-containing composition may be a tablet for incorporation into a e, a tablet for
use as an inner core in a "coated core" dosage form, or alplurality of drug-containing'beads,
particles or granules, for incorporation into either a tablet-or capsule.
A pulsed release dosage form is one that mimics a multiple dosing profile t
repeated dosing and typically allows at least a twofold reduction in dosing frequency as
ed to-the drug presented as a conventional dosage form (e.g., as a solution or prompt
drug—releasing, conventional solid dosage form). A pulsed release profile is characterized by a
time period of no release (lag time) or reduced release followed by rapid drug release.
‘ Each
dosage form contains a therapeutically effective amount of active agent. In one
embodiment ofdosage forms that mimic a twice daily dosing profile, approximately 30 wt. % to
70 wt. %, preferably 40 wt. % to 60 wt. %, of the total amount of active agent in the dosage
form is released in the initial pulse, and, correspondingly approximately 70 wt. % to 3.0 wt. %,
preferably 60 wt; % to 40 wt. %, of the total amount of active agent in the dosage form is
released in the second pulse. For dosage forms mimicking the twice daily dosing profile, the
second pulsei’s,‘ preferably ed approximately 3 hours to less than 14 hours, and more
preferably approximately 5 hours to 12 hours, following administration.
Another dosage form contains a compressed tablet or a capsule having a drug-
containing immediate release dosage unit, a delayed release dosage unit and an optional second
delayed release dosage unit. In this dosage form, the immediate e dosage unit contains a
plurality of beads, granules particles that release .drug substantially immediately ing oral
administration to provide an initial dose. Thedelayed release dosage unit contains a plurality of
coated beadsor granules, which release drug approximately 3 hours to 14 hours following oral
. administration to provide a second dose.
For purposes of ermal (e.g., topical) adniinistration, dilute sterile, aqueous or,
partially aqueous solutions (usually in about 0.1% to 5% concentration), otherwise similar to the
above parenteral solutions, may be prepared.
s of preparing various pharmaceutical compositions with a certain amount of
- one'or more compounds of formula I, fermul'a II, formula III, a IV, formula V, formula
, VI, formula VII and formula VIII, or other active agents are known, or will be nt in light
of this sure, to those skilled, in this art. For examples of methods of preparing
pharmaceutical compositions, see ton's Pharmaceutical Sciences, Mack Publishing
Company, , Pa, 19th Edition (1995).
In addition, in certain embodiments, subject compositions of the present application
maybe lyophilized or subjected to another appropriate drying technique such as spray drying.
The subject itions may be administered once, or may be divided into a number of
smaller doses to be administered at varying intervals of time, depending in part on the release
rate ofthe compositions and the desired dosage.
Formulations useful in the methods provided herein include those suitable for oral,
nasal, l (including buccal and sublingual), , vaginal, aerosol and/or parenteral v
administration. The formulations may conveniently be presented in unit dosage form and may
be prepared by any methods well known in the art of pharmacy, The amount of a subject
composition which may be combined with a carrier material to e a single dose may vary
of administration.
, depending upon the subject being treated, and the particular mode
Methods of preparing these formulations or compositions include the step of bringing
into association subject itionswith the carrier and, optionally, one or more accessory
ingredients. In general, the formulations are ed by uniformly and intimately bringing into
association a subject compOsition with liquid carriers, or finely divided solid carriers, or both,
and then, if necessary, shaping the.product.
The compounds of formula I, formula II, formula III, formula IV, formula V, formula
VI, formula VII and a VIII, described herein may be administered in inhalant or aerosol
formulations. The inhalant or aerosol formulations may comprise one Or more agents, such as
adjuvants, diagnostic agents, imaging agents, or therapeutic agents useful in inhalation therapy.
The final aerosol ation may for example contain 0.005-90% w/w, for instance 0.005-
.50%, 0.005~5% w/w, or 0.01-1.0% w/w, of medicament relative to the total weight of the -
formulation.
In solid dosage forms for oral administration les, tablets, pills, dragees,
powders, granules and the like), the subject composition is mixed with one or more
pharmaceutically acceptable carriers and/or any of the following: (1) fillers or extenders, such
as starches, lactose, sucrose, e, ol, and/or silicic acid; (2) binders, such as, for
example, carboxymethylcellulose, tes, gelatin, polyvinyl pyrrolidone, sucrose and/or
acacia; (3) humectants, such as glycerol; (4) egrating agents, such as agar-agar, calcium
carbonate, potato or tapioca starch, alginic acid, n silicates, and sodium carbonate; (5)
solution retarding agents, such as paraffin; (6) absorption accelerators, such as quaternary
ammonium nds; (7) wetting agents, such as, for example, aCetyl alcohol and glycerol
monoStearate; (8) absorbents, such as kaOlin and bentonite clay; (9) ants, such a talc,
m stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and
mixtures f; and (10) coloring agents. In the case of capsules, tablets and pills, the
pharmaceutical compositions may also comprise ing agents; Solid compositions of a
similar’type may also be ed as fillers in soft and hard-filled gelatin capsules using
lactoseor milk sugars, as well as high molecular weight polyethylene glycols and the like.
Liquid dosage forms for oral administration include pharmaceutically acceptable
emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the t
compositions, the liquid dosage forms may contain inert diluents ly used in the art,
such as, for example, water or other. ts, solubilizing agents and emulsifiers, such as ethyl
alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate,
propylene glycol, 1,3-butylene glycol, oils (in particular, cottonseed, corn, peanut, er,
soybean, olive, castor, and sesame oils), glycerol, tetrahydrofiiryl alcohol, hylene glycols
and fatty acid esters of an, and mixtures thereof.
Suspensions, in addition to the subject itions, may contain suspending agents
such as, for example, ethoxylated isostearyl alcohols, polyoxyethylene sorbitol, and sorbitan
esters, rystalline cellulose, aluminum, metahydroxide, bentonite, agar-agar and
tragacanth, and mixtures thereof. ,
Formulations for rectal or vaginal administration may be presented as a suppository,
which [may be prepared by mixing a subject composition with. one or more suitable non-
irritating carriers comprising, for example, Cocoa butter, polyethylene glycol, a suppository
wax, or a salicylate, and Which is solid at room temperature, but liquid at body temperature and,
therefore, will melt in the appropriate body cavity and release the encapsulated compound(s)
and composition(s). ations which are suitable for vaginal administration also include
pessaries, tampons, creams, gels, pastes, foams, or spray formulations containing such rs
as are known in the art to be riate.
] Dosage forms for transdermal administration include s, , ointments,
pastes, creams, lotions, gels, solutions, patches, and inhalants. A subject composition may be
mixed under sterile conditiOns with a pharmaceutically acceptable carrier, and with any
preservatives, buffers, or lants that may be'required. For transdermal administration, the
complexes may include lipophilic and hydrophilic groups to achieve the desired water lity
and transport ties.
The ointments, pastes, creams and gels may contain, in addition to subject
compositions, other rs, such as animal and vegetable fats, oils, waxes, parafl'ms, starch,
tragacanth, cellulose derivatives, polyethylene glycols, silicones, bentonites, silicic acid, 'talc
and zinc oxide, or mixtures thereof. Powders and sprays may contain, in addition to a subject
composition, excipients such as lactose, talc, silicic acid, aluminum hydroxide, calcium silicates
and polyamide , or mixtures of such substances. Sprays may additionally contain
customary propellants, such as chlorofluorohydrocarbons and volatile unsubstituted
hydrocarbons, such as butane and propane.
Methods of delivering a composition or compositions via a transdermal patch are
known in the art. Exemplary patches-and methods of patch delivery are described in US Patent
Nos. 6,974,588, 6,564,093, 6,312,716, 6,440,454, 6,267,983, 180, and 6,103,275.
In another embodiment, a transdermal patch may comprise: a ate sheet
comprising a composite film formed of a resin composition comprising 100 parts by weight of a
nyl chloride-polyurethane composite and 2-10 parts by weight of a styrene-ethylene;
butylene-styrene copolymer, a first adhesive layer on the one side lof the composite film, and a
polyalkylene terephthalate film adhered to the one side of the composite film by means of the
first adhesive layer, a primer layer which comprises a saturated polyester resin and is formed on
the surface of the polyalkylene terephthalate film; and a second adhesive layer comprising a
styrene-diene-styrene block copolymer containing a pharmaceutical agent d on the primer
layer. A method for the manufacture of the above-mentioned sribstrate sheet comprises
ing the above resin composition molding the resin composition into a composite film by a
calendar process, and then adhering a polyalkylene terephthalate film on one side of the
composite film by means of an adhesive layer thereby forming the substrate sheet, and forming
a primer layer sing a saturated polyester resin on the outer surface of the kylene
terephthalate film.
Another type of patch comprises incorporating the drug directly in a pharmaceutically
acceptable adhesive and laminating the drug-containing adhesive onto a suitable backing
member, e.g. a polyester backing membrane. The drug sh0uld be present at a concentration
which will not affect the adhesive properties, and at the same time deliver the required clinical
dose. '
] Transdermal patches may be passive or active. Passive transdermal drug delivery
systems currently available, such as the nicotine, estrogen and nitroglycerine patches, deliver
small-molecule drugs. Many of the newly developed proteins and peptide-drugs are too large to
be delivered through passive transderrnal patches and may ivered using technology such
as electrical assist (iontophoresis) for large-molecule drugs.'
Iontophoresis is a que employed for ing the flux of ionized nces
through membranes by application of electric current. One example of an iontophoretic
membrane is given in US. Pat. 'No. 5,080,646 to. TheeuwesrThe principal mechanisms by
which iontophoresis enhances molecular ort across the skin are (a) repelling a charged ion
from an electrode of the same charge, an) oosmosis, the convective movement of solvent
that occurs through a charged pore in response the preferential passage of counter-ions when an
electric field is applied or (c) increase skin permeability due to application of electrical current.
In some cases, it may be desirable to administer in the form of a kit, it may se
a container for containing the separate itions such as a divided bettle- or a divided foil
packet. Typically the kit comprises directions for the administration of the separate ents.
The kit form is ularly advantageous when the separate components are preferably
administered in ent dosage forms (e.g., oral and eral), are administered at different.
, dosage intervals, or when ion of the individual components of the combination is desired
by the prescribing physician.
An example of such a kit is a so-called blister pack. Blister packs are well known in the
packaging industry and are widely used for the packaging of pharmaceutical unit dosage forms
(tablets, capsules, and the like). Blister packs generally consist of a sheet of relatively stiff
material covered with a ”foil of a plastic material that may be transparent.
] s and compositions for the treatment of mucositis. Among other things, herein
is ed a method of ng mucositis, comprising administering to a patient in need thereof
a therapeutically effective amount of compound of Formula I:
RH \NMO/kb7/ |
Formula I
and’pharmaceutically’acceptable’hydrates; 'solvates; enantiomersiand’stereoisomersthereof;
‘Wherein,
RH independently represents
0 o
0 HO
0 0
, , l-hydroxy-Z-naphthoic acid, 2,2-
dichloroacetic acid, 2-hydroxyethanesulfonic acid, 2-0Xoglutaric acid, 4-acetamidobenzoic
acid, 4-aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (1),
benzenesulfonic acid, benzoic acid, camphoric acid (+) camphor—lO-sulfonic acid (+), capric '
acid (decanoic acid), caproic acid (hexanoic acid), ic acid (octanoic acid), carbonic acid,
cinnamic acid, citric acid, cyclamic acid, caproic- acid, caprilic acid, capric acid, lauric acid,
myristic acid, myrist'oleic acid, palmitic acid, palmitoleic acid, stearic acid, oleic acid, elaidic
acid, linoleic acid, 'linolenic acid, linolelaidic acid, arachidonic acid, dodecylsulfiiric acid,
ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid,
gentisic acid, glucoheptonic acid ((1), gluconic‘ acid ((1), glucuronic acid (d), glutamic acid,
glutaric acid, 'glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid,
hydrochloric acid, isobutyric acid, lactic acid (d1), ionic acid, lauric acid, maleic acid,
malic acid (- l), malonic acid, ic acid (d1), methanesulfonic- acid, naphthalene-1,5-
disulfonic acid, naphthalene-Z-sulfonic acid, nicotinic acid, R-Lipoic acid, nitric acid, oleic
acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid, onic acid, pyroglutamic
acid (- l), salicylic acid, c acid, stearic acid, succinic acid, sulfuric acid, tartaric acid (+
l), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid, n-acetyl cysteine (nac), furoate,
methyl furoate, ethyl furoate or aminocaproic acid,
In another , the compounds of formula II are described:
+ _
. N‘N \/\/N/H +_O
NH3 X
Formula II
and pharmaceutically able hydrates, solvates, prodrugs, enantiomers, and stereoisomers
thereof;
] ‘ Wherein,
, . X independently presents
, 1-hydroxy—2-naphthoic acid, chloroacetic
acid, 2-hydroxyethanesulfonic‘ acid, 2-oxoglutaric acid, 4-acetamidobcnzoic acid, 4-
aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (1), benzenesulfonic
acid, benzoic acid,» camphoric acid (+) r-lO—sulfonic acid (+), capric acid (decanoic
acid), caproic acid (hexanoic acid), caprylic acid oic acid), carbonic acid, caproic acid,
caprilic acid, capric acid, lauric acid, myristic acid, myristoleic acid, 'palmitic acid, palmitoleic
acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic acid,
arachidonic acid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-
' disulfonic acid, ethanesulfonic acid, formic acid, fumaric acid, galactaric acid, ic acid,
eptonic acid ((1), glnconic acid ((1), glucuronic acid (d), glutamic acid, glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic
acid (d1), lactobionic acid, lauric acid, maleic acid, malic acid (- l), malonic acid, mandelic
acid (d1), methanesulfonic acid, naphthalene~1,5-disulfonic~ acid, alene-Z-sulfonic acid,-
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (- l), salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), hundecylenic acid, n-
acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
In certain embodiments, the compounds of a III are described:
@N‘“ \/\/N“\+ ’° x
Formula 111
and pharmaceutically acceptable es, solvates, prodrugs, enantiomers, and stereoisomers
Wherein,
X independently presents
I/ HO
O o o
9 I ,
/\/\/\/U\OH
, 1-hydroxynaphthoic acid, 2,2-dichloroacetic
acid, 2-hydr0xyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-
aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (I), aspartic acid (1), benzenesulfonic
acid, benzoic acid, camphoric acid (+) camphor-lO-sulfonic acid (+), capric acid (decanoic
acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid,
citric acid, cyclamic acid, dodecylsulfilric acid, ethane-1,2—disulfonic acid, ethanesulfonic
acid, formic acid, c acid, galactaric acid, gentisic acid, glucoheptonic acid ((1), gluconic
acid (d), glucuronic acid (d), glutamic acid, glutaric acid, glycerophosphoric acid, caproic
acid, caprilic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid,
palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, laidic
acid, arachidonic acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic
acid (d1), lactobionic acid, lauric acid, maleic acid, malic acid (- l), malonic acid, mandelic
acid (d1), methanesulfonic acid, naphthalene-1,5-disulfonic acid, naphthalene-2‘sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (- l), lic acid, c acid, stearic acid, succinic acid,
sulfuric acid, ic acid (+ 1), thiocyanic acid, toluenesulfonic acid‘(p), undecylenic acid, n-
acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
- In an additional aspect, the compounds of a IV are described:
O _
V / H + O X
Q/ +
N‘N NH
\ \u/\/\ 3
’ 0
Formula IV
and pharmaceutiCally acceptable es, solvates, prodrugs, enantiomers, and stereoisomers
thereof;
X independently presents
OH '
HO \ . o
OH / ‘ \
O O
3 I I
/W\/“\0H
, I-hydroxy—Z-naphthoic acid, 2,2;dichloroacetic
acid, 2—hydroxyethanesulfonic acid, 2-oxoglutaric acid, amidobenzoic acid, 4-
. aminosalicylic acid, acetic'acid,_adipic acid, ascorbic acid (1), aspartic acid (1), benzenesulfonic
- acid, benzoic acid, camphoric acid (+) camphor-lO-Sulfonic acid (+), capric acid (decanoic
acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid,
citric acid, cyclamic acid, 'dodecylsulfuric acid, ethane-1,2—disulfonic acid, ethanesulfonic
acid, formic acid, fi1m3ric acid, galactaric acid, gentisic acid, glucoheptonic acid (d), gluconic
acid (d), glucuronic acid (d), glutamic acid, ic acid, glycerophos‘phoric acid, glycolic
acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic acid (d1), lactobionic acid, lauric
acid, maleic acid, malic acid (- l), c acid, mandelic acid (d1), methanesulfonic acid,
naphthalene—1,5-disulfonic acid, caproic acid, caprilic acid, capric acid, lauric acid, myristic
acid, oleic acid, palmitic acid, palmitoleic acid, Steaiic acid, oleic acid, elaidic acid,
linoleic acid, ‘linolenic acid, linolelaidic acid, arachidonic acid, _ naphthalene-Z-sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (— l), salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), undeCylenic acid, n—
acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
In an additional aspect, the nds of formula V are described:
Formula V
and pharmaceutically acceptable.hydratesrsolvates, omers, ereoisomers thereof:
Wherein,
RH independently represents
0 0
/°, \. H0 \
OH OH
O 0 '
, ,
, 1-hydroxy-2—
naphthoic acid,'2,2-dichloroacetic acid, 2—hydroxyethanesu1fonic acid, 2-oxoglutaric acid, 4-
acetamidobenzoic acid, 4-aminosalicy1ic acid, acetic acid, adipic acid, ascorbic acid (1),
aspartic acid (1), benzenesulfonic acid, benzoic acid, camphoric acid (+) camphor-IO-sulfonic
acid (+), capric acid'(decanoic acid), caproic acid (hexanoic acid), caprylic acid (octanoic
acid), carbonic acid, cinnamic acid, citric acid, cyclamic acid, c acid, caprilic acid,
capric acid, lauric acid, ic acid, myristoleic acid, palmitic acid, palmitoleic acid, c
acid, oleic acid, elaidic acid, ic acid, linolenic acid, linolelaidic acid, arachidonic acid,
dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic acid, formic acid, fumaric
acid, galactaric acid, gentisic acid, glucoheptonic acid (d), gluconic acid (d), glucuronic'acid
(d), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic acid, hippuric acid,
romic acid, hydrochloric acid, yric acid, lactic acid (d1), lactobionic acid, lauric
acid, maleic acid, malic acid (- l), malonic acid, mande‘lic acid (d1), methanesulfonic acid,
naphthalene-1,5-disulfonic acid, alene-Z-sulfonic acid, nicotinic acid, R-Lipoic acid,
nitric acid, oleic acid, oxalic-acid, palmitic acid, ‘acid, phosphoric acid, proprionic acid,
pyroglutamic acid (— l), salicylic acid, sebacic acid, stearic acid, succinic acid, sulfuric acid,
' tartaric acid (+I 1),.thiocyanic acid, toluenesulfo‘nic acid (p), undecylenic acid, n-acetyl cysteine
(nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
In another aspect, the compounds of a VI are described:
Formula VI
and pharmaceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers
thereof;
Wherein,
X independently presents
HO \
9 I
/\/\/\/H\0H
, l-hydroxy-Z-naphthoic acid, 2,2-dichloroacetic
acid, 2-hydroxyethanesulfonic acid, lutaric acid, 4-acetamidobenzoic acid, 4-
aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (1), benzenesulfonic
acid, c acid, camphoric acid (+) camphor-lO-sulfonic acid (+), capric acid (decanoic
acid), caproic acid (hexanoic acid), ic acid oic acid), carbonic acid, caproic acid,
caprilic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid, palmitoleic
acid, stearic acid, oleic acid, elaidic acid, linoleic acid, nic acid, linolelaidic acid,
arachidonic acid,
‘ cinnamic acid, citric acid, cyclamic acid, dodecylsulfilric acid, ethane-1,2-
disulfonic acid, ethanesulfonic acid, formic acid, fuman'c acid, galactaric acid, gentisic acid,
glucoheptonic acid (d), gluconic acid ((1), onic acid ((1), glutamic acid, glutaric acid,
glycerophosphoric acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic
acid (d1), lactobionic acid, lauric acid, maleic acid, malic acid (- l), malonic acid, mandelic
acid (d1), methanesulfonic acid, naphthalene-1,5-disu1fonic acid, naphthalene-Z-sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, oric acid,
_ proprionic acid,-pyroglutamic-acid (- 1), salicylic acid, c acid, stearic acid, succinic acid,
sulfui'ic acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid, n—
acetyl cysteine (nac), furoate, methyl furoate, ethyl furoate or aminocaproic acid.
In certain embodiments, the compounds of formula VII are described:
Formula VII
and pharmaceutically able es, solvates, prodrugs, enantiomers, and stereoisomers
thereof;
]" Wherein,
X independently presents
o 0 0
l HO . \ O \ /
. / OH OH
O O O
9 I I
, 1-hydroxynaphthoic acid, 2,2—dichloroacetic
acid, 2=hydroxyethanesulfonic acid, lutaric acid, 4-acetamidobenzoic acid, 4—
aminosalicylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (1), benzene'sulfonic
aCid, benzoic acid, camphoric acid (+) camphor—lO-sulfonic acid (+), capric acid (decanoic
» acid), caproic acid (hexanoic acid), ic acid (octanoic acid), ic acid, cinnamic acid,
citric acid, Cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, formic acid, fumaric acid, galactaric acid, gentisic acid, glucoheptonic acid (d), gluconic
acid (d), glncuronic acid ((1), glutamic acid, glutaric acid, glyceropbosphoric acid, caproic
acid, caprilic acid, capric acid, lauric acid, myristic acid, myristoleic acid, palmitic acid,
palmitoleic acid, stearic acid, oleic acid, elaidic acid, linoleic acid, linolenic acid, linolelaidic
acid, arachidonic acid, glycolic acid, hippuric acid, hydrobromic acid, isobutyric acid, lactic
acid (d1), lactobionic acid, lauric acid, maleic acid, malic acid (- l), malonic acid, mandelic
acid (d1), methanesulfonic acid, alene-1,5-disulfonic acid, naphthalene-Z-sulfonic acid,
nicotinic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,
proprionic acid, pyroglutamic acid (- 1), salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid (+ l), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid, n-
acetyl cysteine (nae), furoate, methyl fiJroate, ethyl furoate or aminocaproic acid.
In an onal aspect, the Compounds of formula VIII are described:
Formula VIII
and ceutically acceptable hydrates, solvates, prodrugs, enantiomers, and stereoisomers
thereof;
Wherein,
X ndently presents
Wk0H
, l-hydroxy-Z-naphthoic acid, 2,2-dichloroacetic
acid, 2-hydroxyethanesulfonic acid, 2-oxoglutaric acid, 4-acetamidobenzoic acid, 4-'
alicylic acid, acetic acid, adipic acid, ascorbic acid (1), aspartic acid (1), benzenesulfonic
acid, benzoic acid, camphoric acid (+) camphor-lO-sulfonic acid (+), capric acid (decanoic
acid), caproic acid (hexanoic acid), caprylic acid (octanoic acid), carbonic acid, cinnamic acid,
citric acid, cyclamic acid, dodecylsulfuric acid, ethane-1,2-disulfonic acid, ethanesulfonic
acid, formic acid, fumaric acid, galactaric acid, ic acid, eptonic acid (d), ic
acid (d), .glucuronic acid ((1), glutamic acid, glutaric acid, glycerophosphoric acid, glycolic
acid, hippuric acid, hydrobromic acid, is‘obutyn'c acid, lactic acid (d1), lactobionic acid, lauric
acid, maleic acid, malic acid (- I), malonic acid, mandelic acid (d1), methanesulfonic acid,
naphthalene-1,5-disulfonic acid, caproic acid, caprilic acid, capric acid, lauric acid, myristic
acid, myristoleic acid, palmitic acid, oleic acid, stearic acid, oleic acid, elaidic acid,
linoleic acid, linolenic acid, linolelaidic acid, arachidonic acid, naphtlialene-Zésulfonic acid,
nic acid, nitric acid, oleic acid, oxalic acid, palmitic acid, pamoic acid, oric acid,
proprionic acid, pyroglutamic acid (- l), salicylic acid, sebacic acid, stearic acid, succinic acid,
sulfuric acid, tartaric acid (+ 1), thiocyanic acid, toluenesulfonic acid (p), undecylenic acid, n-
acetyl cysteine (nae), furoate, methyl furoate, ethyl e or aminocaproic acid.
METHODS OF MAKING
Examples of synthetic pathways useful for making compounds of formula I, a II,
formula III and formula IV are set forth in example below and are generalized in the following
methodology:
Formula I:
Compound 1 of formula I
1 [00130]
- Synthesis ofcompound 1 of formula I:
A solution of amine (prepared from Benzydamine HCl by neutralizing with aq.
NaOH, 5.0 g) and Linoleic acid (4.53 g) in THF (100 mL) was stirred at 40-50 °C for 5 h. The
solution was cooled to RT, solvent was evaporated in vacuo and co-evaporated with hexanes to
dryness to aflord compound 1 of formula I in tative yield.
‘ Synthesis of compound 2 of formula 1:
Compound 2 of formula I
A solution of Benzydamine (prepared from Benzydamine HCl by neutrazing with aq.
.NaOH, 5.0 g) and Caprylic acid (2.33 g) in THF. (100 mL) was stirred at 40-50 °C for 5 h. The
solutiOn was cooled to RT, solvent was evaporated in vacuo and porated with hexanes to
dryness to afford compound 2 of formula I in quantitative yield.
Farmula IV:
Synthesis of nd 1 of formula IV:
QJ 0'
V OMNH;
Compound 1 of formula IV
A solution of amine red from Benzydamine HCl by neutralizing with aq.
NaOH, 5.0 g) and Linoleic acid (4.53 g) in THF (100 mL) was stirred at 40-50 °C for 5 h, later
GABA (1.14 g) in MeOH was stirred at 50 °C for 1H and evaporated in vacuo and the obtained
residue was co—evaporated with THF to afford Compound 1 of formula IV in quantitative yieldr
] Synthesis of compound 1 of formula V:
Compound 1 of formula V
A solution of Doxepin (prepared from Doxepin HCI by neutrazing with aq. NaOH, 5.0
g) and Linoleic acid (5.0 g) in THF (100 mL) was stirred at 40-50 °C for 5 h. The solution was
cooled to RT, t was evaporated in vacuo and co-evaporated With hexanes to s to
afford Compound 1 of formula V in quantitative yield.
Synthesis of compound 2 of formula V:
Compound 2 of formula V
A. solution of Doxepin. (prepared from-Doxepin-HClby 'neutrazing’wi‘th aqTNa'OH,"5.0
g) and Caprylic acid (2.57 g) in THF (100 mL) was stirred at 40—50 °C for 5 h. The solution was
cooled to RT, solvent was evaporated in vacuo and co-evaporated with hexanes to s to
afford Compound 1 of formula V in quantitative yield.
{00140} ofcompound 1 of formula VIII:
, Synthesis
1+ 0
HN\0W
We,/
Compound 1 of formula VIII
A Solution of Dexepin (prepared from Doxepin HCl by zing with aq. NaOH, 5.0
g) and Linoleic acid (5.0 g) in THF (100 mL) was stirred at 40-50 °C for 5 h. GABA (0.92 g) in
MeOH was stirred at 50 C for 1 h and evaporated in vacuo. The residue was co—evaporated with
THF to dryness to afford Compound 1 of formula VIII in quantitative yield.
E NTS
The present disclosure provides among other things compositions and methods for
treating ogical diseases and their complications. While Specific embodiments Of the
t disclosure have been discussed, the above specification is illustratiVe and not restrictive.
Many variations of the systems and methods herein will become apparent to those skilled in the
art upon review ofthis specification. The fill] scope ofthe claimed systems and methods should
be determined by reference to the claims, along with their full scope of equivalents, and the
specification, along with such variations.
INCORPORATION BY REFERENCE
] All publications and patents mentioned herein, including those items listed above, are
hereby incorporated by reference in their entirety as if each individual publication or patent was
specifically and individually ted to be incorporated by reference. In case of conflict, the
present application, including any definitions , will control.
Claims (4)
1.A compound of Formula 1A, wherein the compound is: Formula IA
2. A pharmaceutical ition comprising a compou nd of claim 1 and a ceutically able carrier.
3. Use of a pharmaceutical composition of claim 2 for the manufacture of a medicament for the treatment of pain, mucositis, itis, stomatitis, glossitis, aphthous ulcers, oral ulceration, pharyngitis, tonsillitis, radiation or intubation mucositis, wherein said pharmaceutical composition is formulated for oral a dministration, delayed e or ned release, transmucosal stration, syrup, mucoadhesive, spray, buccal formulation, mucoadhesive tablet, topical administration, parent eral administration, injection, subdermal administration, oral solution, rectal administratio n, buccal administration or transdermal administration.
4. Use of a pharmaceutical composition of claim 3, wherein the pain is associated with mucositis, dental surgery, oral ulceration, post-to nsillectomy, odontostomatology, gingivitis, stomatitis, glossitis, aphthous ulcers, oral ulcera tion, pharyngitis, tonsillitis, radiation or intubation mucositis. 17853278_1 (GHMatters) P109617.NZ
Applications Claiming Priority (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
IN622/CHE/2015 | 2015-02-09 | ||
IN622CH2015 | 2015-02-09 | ||
PCT/IN2016/000024 WO2016128991A1 (en) | 2015-02-09 | 2016-01-19 | Compositions and methods for the treatment of mucositis |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ735338A NZ735338A (en) | 2021-08-27 |
NZ735338B2 true NZ735338B2 (en) | 2021-11-30 |
Family
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