US20130039881A1 - Combination for the treatment of radiation- or chemotherapy-induced mucositis - Google Patents

Combination for the treatment of radiation- or chemotherapy-induced mucositis Download PDF

Info

Publication number: US20130039881A1
Authority: US; United States
Prior art keywords: treatment; oral; mucositis; pain; chemotherapy
Prior art date: 2009-11-26
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.): Abandoned

Application number

US13/511,900

Other languages

English (en)

Inventor

Franco Conti

Francesco Saverio Dioguardi

Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)

Professional Dietetics SpA

Original Assignee

Professional Dietetics SpA

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

2009-11-26

Filing date

2010-11-25

Publication date

2013-02-14

Family has litigation

First worldwide family litigation filed litigation Critical https://patents.darts-ip.com/?family=42244328&utm_source=google_patent&utm_medium=platform_link&utm_campaign=public_patent_search&patent=US20130039881(A1) "Global patent litigation dataset” by Darts-ip is licensed under a Creative Commons Attribution 4.0 International License.

2010-11-25 Application filed by Professional Dietetics SpA filed Critical Professional Dietetics SpA

2012-06-28 Assigned to PROFESSIONAL DIETETICS S.R.L. reassignment PROFESSIONAL DIETETICS S.R.L. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: ARBORIO MELLA (LEGAL REPRESENTATIVE AND HEIRESS OF DECEASED INVENTOR FRANCO CONTI), ISABELLA, CONTI (DECEASED), FRANCO, CONTI (LEGAL REPRESENTATIVE AND HEIR OF DECEASED INVENTOR FRANCO CONTI), EDOARDO CARLO MARIA, CONTI (LEGAL REPRESENTATIVE AND HEIR OF DECEASED INVENTOR FRANCO CONTI), GIOVANNI FEDERICO MARIA, DIOGUARDI, FRANCESCO SAVERIO

2013-02-14 Publication of US20130039881A1 publication Critical patent/US20130039881A1/en

Status Abandoned legal-status Critical Current

Links

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Classifications

- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K9/00—Medicinal preparations characterised by special physical form
- A61K9/0012—Galenical forms characterised by the site of application
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
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- A61K31/726—Glycosaminoglycans, i.e. mucopolysaccharides
- A61K31/728—Hyaluronic acid
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/13—Amines
- A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
- A61K31/138—Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/185—Acids; Anhydrides, halides or salts thereof, e.g. sulfur acids, imidic, hydrazonic or hydroximic acids
- A61K31/19—Carboxylic acids, e.g. valproic acid
- A61K31/195—Carboxylic acids, e.g. valproic acid having an amino group
- A61K31/197—Carboxylic acids, e.g. valproic acid having an amino group the amino and the carboxyl groups being attached to the same acyclic carbon chain, e.g. gamma-aminobutyric acid [GABA], beta-alanine, epsilon-aminocaproic acid or pantothenic acid
- A61K31/198—Alpha-amino acids, e.g. alanine or edetic acid [EDTA]
- A—HUMAN NECESSITIES
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- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
- A61K31/401—Proline; Derivatives thereof, e.g. captopril
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
- A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- 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
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P1/02—Stomatological preparations, e.g. drugs for caries, aphtae, periodontitis
- A—HUMAN NECESSITIES
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- 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
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- 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]

Definitions

the present invention relates to a combination of glycine, proline and optionally a natural or synthetic film-forming polymer, and/or lysine and/or leucine, for the treatment of mucositis induced by radiation or chemotherapy.
Oral mucositis is one of the most frequent and potentially serious side effects of non-surgical antitumoral treatment (1,2). Clinically, it is characterised by erythema, formation of ulcers with or without pseudo-membranes, bleeding, formation of exudates, and/or infections located at the upper level (3), and can evolve into a debilitating form which adversely affects the patient's quality of life.
the damage to the mucous membranes can extend from the oral cavity to the pharynx; in this invention, therefore, the term “oral mucositis” includes mucositis of the pharynx.
OM can be associated with pain symptoms such as dysgeusia, dysphagia, and difficulty in speaking, chewing or swallowing, with consequent impairment of the ability to eat, weight loss, and the need for feeding through a nasogastric tube.
the treatment of OM and the pain caused by it comprises: basic topical anaesthetics, systemic analgesics, anti-inflammatories, mucosa- coating agents, mouthwashes, oral hygiene in general, and antimicrobials (5,12-15).
basic topical anaesthetics systemic analgesics
anti-inflammatories e.g., aspirin, aspirin, aspirin, aspirin, and pulmonary embolism, and others.
mucosa- coating agents e.g., a number of other agents have also been tested, such as growth factors and cytokines, biological compounds that protect the mucosa, cryotherapy, and low-level laser treatment (13,16).
Hyaluronic acid plays an important role in tissue healing, by means of various mechanisms (17-19); clinical trials have also confirmed that it improves the healing process of ulcers of the lower limbs (20) and the nasal mucosa after surgery (21) and reduces acute epithelitis in patients who undergo radiotherapy to treat head, neck, breast or pelvic cancer (22).
the research therefore focuses on new treatment strategies for oral mucositis and the corresponding formulations.
WO 2007/048524 describes wound-healing pharmaceutical compositions comprising a combination of glycine, lysine, leucine and proline and sodium hyaluronan, which is particularly effective in facilitating the process of cell renewal that forms the basis of rapid wound-healing, promoting connective tissue reconstruction and consequent regeneration of the epithelial cells.
WO 2008/027904 discloses formulations of viscous polymers such hyaluronates or PVPs for treating stomatitis or mucositis.
WO 02/39978 discloses enteral nutritional supplement for malnourished or chronically ill patients comprising glutamine, anti-oxidants and fatty acids.
Glycine can be optionally present as a calcium antagonist.
combinations comprising glycine, proline, and optionally a natural or synthetic film-forming polymer, lysine and/or leucine, are effective in the treatment of oral mucositis induced by radiation or chemotherapy, especially as regards pain management.
the combination of glycine and proline surprisingly increases the gene expression of e-NO Synthase and of VEGF.
said aminoacids control and enhance the production of TGF beta and controls the collagen synthesis by fibroblasts quantitatively.
compositions according to the present invention have a considerable accelerating effect on wound-healing, and above all a surprising effect on pain management, especially in terms of pain reduction and immediate relief (only 2 hours after administration).
the use of the compositions according to the invention therefore constitutes a practical aid to pain management, providing rapid, effective pain reduction.
the present invention therefore relates to a formulation for oral use comprising:
the natural or synthetic film-forming polymer is selected from hyaluronic acid or a salt thereof, polyvinylpyrrolidone, and cellulose derivatives.
the natural or synthetic film-forming polymer is hyaluronic acid or a salt thereof.
aminoacids are present in the L form.
compositions according to the invention will contain the various active constituents in the following proportions of the composition by weight:
compositions according to the invention could be formulated suitably for topical administration in the form of a spray, aerosol, mouthwash or gel, and will be prepared according to conventional methods well known in pharmaceutical technology, such as those described in Remington's Pharmaceutical Handbook, Mack Publishing Co., New York, USA, using excipients, solubilisers, emollients, stabilisers, emulsifiers, pH regulators and preservatives acceptable for their final use.
the trial was conducted on 27 patients with OM, who had been treated recently (within two weeks) with daily doses of radiotherapy or chemotherapy, who presented at least grade 1 OM as assessed on the World Health Organisation (WHO) mucositis scale, and whose pain was not alleviated by treatment with paracetamol/co-codamol/acetylsalicylic acid.
Each patient was treated 3-4 times a day for 14 days with the composition according to the invention in spray form, which had to be maintained in situ for at least 2 minutes. They were instructed not to eat, drink or rinse their mouths for at least 1 hour.
Table I shows the pain score at the various assessment stages.
T0 baseline—before start of treatment
the following parameters were assessed: pain (using a linear visual analog scale from 1 to 100) and gravity of OM (using the WHO mucositis scale).
the efficacy of the treatment was assessed on the basis of the pain score, the clinical resolution index and patients' compliance at times T01 (after 2 hours), T1 (after 24 hours), T2 (after 72 hours), T3 (after 7 days) and T4 (after 14 days).
Intra-group test in repeated measures Intra-group models Mean test (Friedman Pain score (mm) ⁇ SD (Wilcoxon test) test) Pain T0 (baseline) 74.1 ( ⁇ 17.6) Significant (p ⁇ 0.0001) Pain T01 (after 2 h) 49.3 ( ⁇ 18.2) differences at Pain T1 (after 24 h) 39.4 ( ⁇ 22) T01 (p ⁇ 0.0001) Pain T2 (after 72 h) 24.8 ( ⁇ 19) and after 24 h, Pain T3 (after 7 days) 11.8 ( ⁇ 15.5) 72 h, 7 and 14 Pain T4 (after 14 days) 6.2 ( ⁇ 10.8) days (p ⁇ 0.0001) compared with baseline
Table II shows the effect of the treatment on the clinical resolution index.
the Friedman test showed a significant clinical improvement (p ⁇ 0.0001) compared with baseline at the various stages of measurement.
all patients showed a significant improvement compared with baseline (p ⁇ 0.0001), and their ability to swallow solids and liquids gradually improved.

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ITMI2009A002080		2009-11-26
ITMI2009A002080A IT1396935B1 (it)	2009-11-26	2009-11-26	Uso di una combinazione per il trattamento delle mucositi indotte da radiazioni o da chemioterapici
PCT/EP2010/068216 WO2011064297A1 (en)	2009-11-26	2010-11-25	Combination for the treatment of radiation - or chemotherapy - induced mucositis

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IT1396935B1 (it)	2012-12-20
EP2504001B1 (en)	2015-03-04
ES2538349T3 (es)	2015-06-19
KR101767226B1 (ko)	2017-08-10
RS54014B1 (sr)	2015-10-30
DK2504001T4 (en)	2018-05-22
JP2013512220A (ja)	2013-04-11
ZA201203808B (en)	2013-08-28
US9220726B2 (en)	2015-12-29
RU2570754C2 (ru)	2015-12-10
ES2538349T5 (es)	2018-06-18
PL2504001T5 (pl)	2019-06-28
DK2504001T3 (en)	2015-05-11
US20150079009A1 (en)	2015-03-19
PL2504001T3 (pl)	2015-10-30
CA2781820A1 (en)	2011-06-03
PT2504001E (pt)	2015-07-07
SI2504001T1 (sl)	2015-06-30
KR20120105454A (ko)	2012-09-25
WO2011064297A1 (en)	2011-06-03
CN102655861A (zh)	2012-09-05
EP2504001B2 (en)	2018-03-21
HRP20150523T1 (hr)	2015-06-05
ITMI20092080A1 (it)	2011-05-27
EP2504001B8 (en)	2018-06-06
NO2504001T3 (it)	2015-08-01
CA2781820C (en)	2018-05-08
BR112012012486A2 (pt)	2016-04-12
RU2012121562A (ru)	2013-11-27
EP2504001A1 (en)	2012-10-03

Publication	Publication Date	Title
US9220726B2 (en)	2015-12-29	Combination for the treatment of radiation- or chemotherapy-induced mucositis
US12485175B2 (en)	2025-12-02	Hypertonic antimicrobial therapeutic compositions
Colella et al.	2010	Efficacy of a spray compound containing a pool of collagen precursor synthetic amino acids (L-Proline, L-Leucine, L-Lysine and Glycine) combined with sodium hyaluronate to manage chemo/radiotherapy-induced oral mucositis: preliminary data of an open clinical trial
AU2014318702A1 (en)	2016-03-31	Hypertonic antimicrobial therapeutic compositions
US20200289413A1 (en)	2020-09-17	Compositions useful in the prevention and/or treatment of disorders of the oral cavity, upper airways and esophagus
EP2859891B2 (en)	2021-10-06	Use of a combination for the prevention of radiation- or chemotherapy-induced mucositis
Schimmel et al.	2025	Integrating Oral Health in Palliative Medicine
Dios et al.	2020	Supportive and Palliative Care
Sourati et al.	2017	Oral Mucositis
POOL	0	Department of Head and Neck Surgery Second University of Naples, Naples; 1Department of Medical Oncology, University of Palermo, Palermo; 2Department of Oral Sciences, Unit of Oral Medicine, University of Palermo, Palermo, Italy
Aarti	2018	Comparision of Amnion Membrane and Hyaluronic Acid in Gingival Recession Coverage and Gain in Clinical Attachment Level Following Coronally Advanced Flap Procedure-a Clinical Study

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