WO2003037355A1 - Compositions de polyacrylate destinees a etre utilisees pour la protection de la muqueuse - Google Patents

Compositions de polyacrylate destinees a etre utilisees pour la protection de la muqueuse Download PDF

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Publication number
WO2003037355A1
WO2003037355A1 PCT/GB2002/004906 GB0204906W WO03037355A1 WO 2003037355 A1 WO2003037355 A1 WO 2003037355A1 GB 0204906 W GB0204906 W GB 0204906W WO 03037355 A1 WO03037355 A1 WO 03037355A1
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WO
WIPO (PCT)
Prior art keywords
biological response
response modifier
radiation
mucoadhesive
treatment
Prior art date
Application number
PCT/GB2002/004906
Other languages
English (en)
Inventor
Peter Dettmar
Ian Ronald Flockhart
Original Assignee
Reckitt Benckiser Healthcare (Uk) Limited
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Reckitt Benckiser Healthcare (Uk) Limited filed Critical Reckitt Benckiser Healthcare (Uk) Limited
Priority to EP02774957A priority Critical patent/EP1441745A1/fr
Publication of WO2003037355A1 publication Critical patent/WO2003037355A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/74—Synthetic polymeric materials
    • A61K31/765—Polymers containing oxygen
    • A61K31/78—Polymers containing oxygen of acrylic acid or derivatives thereof

Definitions

  • the present invention relates to the use of mucoadhesive agents for the prevention and treatment of radiation and chemotherapy induced damage to mucosal surfaces and to compositions therefore.
  • Damage to mucosal surfaces may lead to immediate symptoms (early damage) but also to symptoms which only appear months or even years after treatment (late damage) .
  • compositions for the treatment of oral mucositis have been proposed in the prior art.
  • Int. J. Radiation Oncology, 1998, 40(5), 1033-1037 (M. Oguchi et al.) describes a mucoadhesive water-soluble polymer film comprising hydroxypropyl cellulose dissolved in ethyl alcohol containing anaesthetic agents and antibiotics.
  • This paper addresses the roles of pain and secondary infections produced by damage to the mucosae and concomitant invasion into the damaged areas of micro organisms.
  • the paper does not disclose any treatment which is designed to accelerate the healing process (i.e. biological response modifiers) , although good protection of the mucosal surfaces will, in itself, allow the normal repair processes to occur.
  • the treatment disclosed is designed as a palliative (pain relief) and prophylactic (antibiotic) .
  • Medline Abstract Accession No. 90375985 discloses the use of sodium alginate on the treatment of oral mucositis associated with radiotherapy. This paper discloses the use only of sodium alginate as a protective film forming agent. No biological response modification is disclosed. Strahlenther. Onkol . 173 (1997), 247-252 (C.
  • Belka et al. discloses the use of polyaluminium- sucrose complex sucralfate compositions for the prevention and treatment of mucosal reactions.
  • Sucralfate does have biological response modifying activity as well as mucous-adhesive properties, the problems associated with its use are two-fold. The first is the quantity of compound required, certainly for head and neck and other oropharyngeal treatments where a slurry of 1+ gm sucralfate is required several times/day (together with only very modest benefits to these treatment areas) .
  • the second problem is associated with an aluminium- containing compound which may be considered to interact with continued radiation treatment, thereby ruling out this particular approach until after the cessation of radiotherapy.
  • WO 92/03124 discloses a polymeric complex composition formed by the interaction of a polycarbophil component with alginic acid or a salt thereof in the presence of a divalent cation and an active agent which is a medicinal or cosmetic agent.
  • the composition provides a suitable delivery system for the delivery of active agents to the oral, buccal or gingival skin or mucosa over a period of time. There is no disclosure of the use of such compositions for the prevention, reduction or treatment of radiation damage.
  • WO 96/13973 discloses compositions having high bioadhesion, mucoadhesion and viscoelasiticity containing mixtures of synthetic polymers, such as polyvinyl alcohol and polycarbophil, and of biopolymers such as alginic acid, hyaluronic acid and dermatan sulphate.
  • synthetic polymers such as polyvinyl alcohol and polycarbophil
  • biopolymers such as alginic acid, hyaluronic acid and dermatan sulphate.
  • the compositions are stated to be useful in the treatment of skin and mucosal tissue dryness and dehydration. There is no disclosure of the use of such compositions for the prevention, reduction or treatment of radiation damage .
  • US-A-5750136 discloses a bioadhesive composition that adheres to a mucosal surface and which is capable of delivering drugs in a sustained fashion.
  • the mucoadhesive composition is preferably provided as a patch for adhesion to mucosal surfaces, such as the oral mucose. There is no disclosure of the use of the compositions or patches for the prevention, reduction or treatment of radiation damage.
  • WO 97/47310 disclosed the use of glyceryl poly (meth) acrylate gel based pharmaceutical compositions locally applied for the treatment of various conditions, including the treatment of light burns and post-radiotherapy burns. There is no disclosure in this document of the incorporation of biological response modifiers into the compositions.
  • JP-A-7316038 discloses a sustained release composition which is based upon an acrylic acid- alkyl (meth) acrylate copolymer and which incorporates a drug such as an angiotonic agent, antiallergenic agent, antibiotic, antibacterial agent or anti- inflammatory agent therein.
  • EP-A-0516141 discloses a sustained release pharmaceutical composition which comprises a bioadhesive polymer and at least one active ingredient.
  • the bioadhesive polymer is preferably a mucoadhesive polymer.
  • a mucoadhesive agent which is a polyacrylate or a salt thereof and a biological response modifier for the preparation of a pharmaceutical composition for simultaneous or sequential use in the prevention or treatment of radiation and/or chemotherapy induced damage to mucosal surfaces.
  • compositions of the present invention possess the advantages that a known film-forming agent can be used which can bind reversibly to mucous thus offering some mechanical protection to areas of underlying tissue where a depleted supply of mucous exists.
  • Polyacrylate mucoadhesive agents are known to slow the rate of gastric transit, thereby maximising the efficiency of both the protective effect and the time required for delivery of repair agents into the underlying tissue.
  • the composition which is used in the present invention either comprises or is co-administered with a biological response modifier.
  • the polyacrylate mucoadhesive agents used in the present invention are considered to be those agents capable of reversible adhesion to mucus or a mucosal surface.
  • the polyacrylate compositions which are used in the present invention may contain low levels, e.g.. up to 10% by weight, preferably less that 1% by weight of a polyol, such as glycerol. Most preferably, however, the polyacrylate is used as the sole gelling agent in the composition of the present invention.
  • the polyacrylate mucoadhesive agent is a carbomer e.g.
  • the mucoadhesive agent is a pharmaceutically acceptable grade of carbomer (e.g. Carbopol 974PNF) or a salt thereof (e.g. sodium carbomer) . Mixtures of the above mucoadhesive agents may also be used.
  • carbomer for the preparation of a pharmaceutical composition for the prevention or treatment of radiation induced early damage to the mucosa surface of the gastro intestinal tract of a mammal.
  • the mammal is a human.
  • the mucoadhesive agents may be applied to the mucosal surfaces in doses ranging from 10 mg to lOg, preferably 100 mg to 4g, more preferably 200 mg to 2g and most preferably 400 mg to lg.
  • BRM's are those agents known to be active in the repair or regeneration of damage caused to normal tissue.
  • BRM's include any agent capable of inducing a modification of the biological response of normal mucosae to radiation and/or chemotherapy.
  • Suitable BRM's include vitamins (e.g. A, E,,B5 or C) and their esters and precursors; prostaglandins (e.g.
  • PG X and their fatty acid precursors and esters/salts thereof; sulphur containing amino acids; dimethyl sulphoxide; methyl sulphonylmethane and alkyl sulphoxides and sulphonyl compounds of the form R 1 R 2 SO or R 1 R 2 S0 2 (wherein R ⁇ and R 2 are independently selected from alkyl CI to C12, preferably CI, C8 or CIO) ; non steroidal anti flammatory agents (e.g. benzydamine) ; acetyl salicylic acid; growth factors (e.g.
  • BRM epidermal growth factor
  • tumour necrosing factors and evening primrose oil, borage oil, sea-buckthorn oil or extracts thereof, lanolin or derivatives thereof and other oils of vegetable, animal or marine origin either wholly natural or semi-synthetic in origin and containing single or multiple unsaturated carbon-carbon bonds.
  • the BRM is benzydamine.
  • BRM's may also be adduced from a miscellaneous group of natural compounds known to have wound healing or skin regenerating activities e.g. allantoin, bisabolol and oils or essences or active fractions prepared from plant tissue e.g. Aloa Vera, or andrographis; provided that they are acceptable for the specific purpose intended.
  • the biological response modifiers may preferably be selected for their ability to stimulate surviving clonogenic stem regrowth in the treated tissue. Mixtures of one or more BRM's may be used in the invention.
  • the preferred concentrations of the BRM's in the pharmaceutical compositions used in the present invention are between 0.001 and 20% by weight of the pharmaceutical composition, the actual concentration depending upon the intrinsic activity of the BRM and the tissue being treated.
  • growth factors and prostaglandins find their concentration in the range 0.001 to 2.0% of the pharmaceutical composition, whereas vegetable or marine oils are preferably in the range 5 - 20%.
  • Most other agents described herein as BRM's will find their concentration intermediate between these ranges.
  • a combination of BRM's and mucoadhesive agents of the invention may be particularly efficacious for the treatment of damage at mucosal surfaces, as the mucoadhesive agent will act to hold the BRM's at the surface (i.e. targeted delivery).
  • a method of preventing or treating radiation and/or chemotherapy induced damage to a mucosal surface which comprises administering a pharmaceutically effective amount of a mucoadhesive agent, which is a polyacrylate or a salt thereof, in combination with or sequentially with a biological response modifier, to the mucosal surface.
  • a method for the prevention or treatment of radiation induced early damage to a mucosal surface of the gastro intestinal tract comprising administering a pharmaceutically effective amount of carbomer, in combination with or sequentially with a biological response modifier, to the mucosal surface.
  • compositions used in the present invention may be in any conventional pharmaceutical form, depending upon the size of the dose required and the site to which it is to be administered.
  • the compositions may therefore include conventional formulation excipients according to the form of the composition.
  • compositions comprising up to 20% w/v mucoadhesive
  • gel compositions comprising up to 20% w/v mucoadhesive
  • buccal compositions comprising 10 to 500 mg mucoadhesive
  • enemas comprising 10 mg to 2 g per 100ml mucoadhesive
  • pessaries comprising 10 mg to 1 g mucoadhesive
  • suppositories comprising 20 mg to 2 g mucoadhesive
  • mousse compositions comprising up to 20% mucoadhes
  • compositions may be produced using conventional techniques well known in the art. it will be understood that multiple units of a particular composition may need to be administered (or mixtures of two or more compositions types may be used) to achieve very high mucoadhesive doses.
  • the mucoadhesive agent and the BRM are intended to be administered to a particular mucosal surface within the gastrointestinal tract
  • the composition containing the mucoadhesive agent and optionally the BRM may need to be modified to allow the mucoadhesive agent and BRM to reach that area.
  • oral tablets or capsules may be enterically coated so that the mucoadhesive and BRM are not released until the composition reaches the small intestine.
  • compositions may be designed to stay in the stomach and not to progress further along the gastrointestinal tract if protection or treatment is only needed in the stomach. If the whole gastrointestinal tract is to be protected or treated simple oral administration may suffice, as the mucoadhesive will adhere all along the tract. Furthermore mucoadhesive agents which bind to upper regions of the mucosal tract may be rebound at lower regions following the sloughing off from the mucosal surface of the upper regions. Dosing frequency of the pharmaceutical compositions may be up to 8 times daily during the first 48 hours following radiation therapy, or up to 4 times daily at other times.
  • Suitable mucosal surfaces include the gastro intestinal tract, oral, nasal, vaginal, rectal and oesophageal surfaces, plus the bladder and anus. Most particularly the mucoadhesive agents may be used for the treatment or prevention of radiation or chemotherapy induced damage to the mucosal surfaces of the gastro intestinal tract. All forms of radiation or chemotherapy induced damage to mucosal surfaces may be prevented or treated by the methods and/or compositions of the invention, most particularly early damage.
  • a mucoadhesive agent which is a. polyacrylate or a salt thereof; ii) a biological response modifier; and i ⁇ ) instructions for the use thereof in the prevention or treatment of radiation and/or chemotherapy induced damage to mucosal surfaces.
  • Carbopol 974PNF 100 Sodium bicarbonate 100 Calcium carbonate 100 Methyl paraben 30 Propyl paraben 4 . 5 Sodium Saccharin 5 Natural source Vitamin E 1 . 0 Dexpanthenol (85% w/v) 12 . 5 Flavour 5 ⁇ l Sodium hydroxide solution (20%) qs
  • the carbomer is dispersed in 2/3 of the deionised water in a first vessel and neutralised with the sodium hydroxide solution.
  • the sodium bicarbonate is dispersed in a small amount of deionised water in a separate vessel and then added to the neutralised carbomer and mixed (carbomer phase) .
  • the calcium carbonate, sodium saccharin, methyl paraben, propyl paraben, Vitamin E and dexpanthenol are dispersed in deionised water in a second vessel (dispersion phase) .
  • flavour is added and the volume adjusted with deionised water, and the final pH of the gel formulation adjusted to pH 8.2 with sodium hydroxide solution.
  • Groups of 40 female Sprague-Dawley rats were divided into five treatment groups. Each subgroup received a standardised dose of ⁇ -radiation from a 9 o Sr / 9 ⁇ ⁇ pi ague to the tip of the tongue. The time of application was varied to give a dose escalation of radiation and mucositis incidence as follows: Group No. Radiation Dose Incidence of
  • Aerosol delivery system 0.5mg Vitamin E in ethanol/diethylene glycol monoethyl ether solution, 50 l/delivery.
  • the application of each formulation commenced 24 hours after the irradiation and continued daily for two weeks. Scoring of the tissue response was carried out independently by two trained observers.
  • the saline controls exhibited a nil response to the treatment, each of the irradiation groups exhibiting a response in line with historic controls (ED50 14.8 Gy, historic control 14.9 ⁇ 0.6 Gy) .
  • the Vitamin E spray exhibited only a small and nonsignificant modification to the ED50 value (15.4 ⁇ 0.8 Gy) , whereas the gel-based formulation of the invention gave a highly significant alteration to the ED50 of 17.7 ⁇ 0.9 Gy - a dose modification factor of 1.25 ⁇ 0.08 (Observer 1) or 1.17 ⁇ 0.06 (Observer 2) .
  • the mucin-binding carbomer formulation of the invention containing Vitamin E and dexpanthenol exhibits a significant effect on the course of radiation- induced damage to mucous membranes/tissue.
  • the calcium carbonate, sodium bicarbonate, microcrystalline cellulose and mannitol are sieved through a 500 ⁇ a (30#) sieve, added to the carbomer and blended in a high speed food processor.
  • the granules are dried at 60°C in a fluid bed drier for 25 minutes before screening through an 850 ⁇ (18#) sieve. 4.
  • the xylitol, benzydamine hydrochloride citric acid and aspartame are screened through a 500 ⁇ m (30#) sieve, added to the dried granules and mixed in a high speed food processor.
  • the granules are dried at 600°C in a fluid bed drier for 25 minutes before screening through an 850 ⁇ m (18#) sieve.
  • the flavour and magnesium stearate are added to the dried granules and blended for 3 minutes.
  • the granules are formed into tablets by pressing on a tablet press to give tablets with a weight of Ig.
  • the carbomer is dispersed in 1/3 of the deionised water in a suitable mixing vessel . 2. A further 1/3 of the deionised water is added and the solution neutralised with the sodium hydroxide solution. 3. The sodium chloride and benzydamine hydrochloride, are dissolved in deionised water, added to the neutralised carbomer and the final volume adjusted with deionised water. 4. The final pH is adjusted using sodium hydroxide solution to within the range 7.45 - 7.55.
  • the sodium bicarbonate is dispersed in a small amount of deionised water in a separate vessel and then added to the neutralised carbomer and mixed (carbomer phase) .
  • the calcium carbonate, sodium saccharin, methyl paraben, propyl paraben and methyl sulphonylmethane are dispersed in deionised water in a second vessel (dispersion phase) .
  • Vitamin E adsorbate 250 1U The process of Example 3 is used except that the Vitamin E adsorbate is added at the same time as the sodium bicarbonate, citric acid, flavour, aspartame and acesulfame K.
  • the aqueous phase is slowly added to the oil phase, increasing the mixing speed until uniformity is achieved.
  • the final pH of the product is adjusted using sodium hydroxide solution to within the range 7.4 - 8.0.
  • Panthenol 12 The process of Example 6 is used adding Vitamin A and Vitamin E esters to the oil phase and adding panthenol to the aqueous phase.
  • Deionised water to 10ml 1.
  • the carbomer is dispersed in 2/3 of the deionised water in a first vessel and neutralised with the sodium hydroxide solution.
  • the sodium bicarbonate is dispersed in a small amount of deionised water in a separate vessel and then added to the neutralised carbomer and mixed (carbomer phase) .
  • the calcium carbonate, glycerol, methyl paraben, propyl paraben and deqlycerrhised liquorice extract are dispersed in deionised water in a second vessel (dispersion phase) .
  • flavour is added and the volume adjusted with deionised water.

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

Abstract

L'invention concerne l'utilisation d'un agent muco-adhésif, lequel est un polyacrylate ou un sel de celui-ci, ainsi que d'un modificateur de réponse biologique, pour la préparation d'une composition pharmaceutique destinée à une utilisation simultanée ou successive dans la prévention ou le traitement de dégâts des surfaces des muqueuses provoqués par des rayonnements et/ou la chimiothérapie.
PCT/GB2002/004906 2001-10-30 2002-10-30 Compositions de polyacrylate destinees a etre utilisees pour la protection de la muqueuse WO2003037355A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
EP02774957A EP1441745A1 (fr) 2001-10-30 2002-10-30 Compositions de polyacrylate destinees a etre utilisees pour la protection de la muqueuse

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0126064.5 2001-10-30
GB0126064A GB0126064D0 (en) 2001-10-30 2001-10-30 Improvements in or relating to organic compositions

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Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP1660101A1 (fr) * 2003-08-21 2006-05-31 Access Pharmaceuticals, Inc. Preparations liquides pour la prevention et le traitement de maladies et de troubles de muqueuses
US20110159089A1 (en) * 2007-08-13 2011-06-30 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
US9220584B2 (en) 2012-03-30 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a stent and locally administered adjunctive therapy
US9220759B2 (en) 2012-02-23 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a drug eluting stent and adjunctive therapy
WO2016023923A1 (fr) 2014-08-11 2016-02-18 Perora Gmbh Formulation comprenant des particules
WO2016023924A1 (fr) 2014-08-11 2016-02-18 Perora Gmbh Procédé d'induction de la satiété
WO2017005887A1 (fr) 2015-07-07 2017-01-12 Perora Gmbh Composition comprenant des particules induisant une satiété
US9789071B2 (en) 2012-06-27 2017-10-17 G2B Pharma, Inc. Intranasal formulation of epinephrine for the treatment of anaphylaxis
US11234935B2 (en) 2015-07-07 2022-02-01 Perora Gmbh Method of inducing satiety
US11617716B2 (en) 2021-06-10 2023-04-04 Belhaven BioPharma Inc. Dry powder formulations of epinephrine and associated methods
US12005185B2 (en) 2021-12-17 2024-06-11 Belhaven BioPharma Inc. Medical counter measures including dry powder formulations and associated methods

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EP0169684A2 (fr) * 1984-07-27 1986-01-29 Reckitt And Colman Products Limited Compositions pharmaceutiques
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US6239119B1 (en) * 1998-04-27 2001-05-29 Medimmune Oncology, Inc. Topical administration of amifostine and related compounds
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Publication number Priority date Publication date Assignee Title
DE2542158A1 (de) * 1974-09-24 1976-04-01 Nippon Kayaku Kk Pharmazeutisches mittel fuer die verabreichung in der mundhoehle und verfahren zu seiner herstellung
EP0169684A2 (fr) * 1984-07-27 1986-01-29 Reckitt And Colman Products Limited Compositions pharmaceutiques
EP0193400A2 (fr) * 1985-03-01 1986-09-03 Reckitt And Colman Products Limited Compositions pharmaceutiques
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Cited By (23)

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Publication number Priority date Publication date Assignee Title
EP1660101A4 (fr) * 2003-08-21 2010-02-24 Access Pharma Inc Preparations liquides pour la prevention et le traitement de maladies et de troubles de muqueuses
EP1660101A1 (fr) * 2003-08-21 2006-05-31 Access Pharmaceuticals, Inc. Preparations liquides pour la prevention et le traitement de maladies et de troubles de muqueuses
US10688054B2 (en) * 2007-08-13 2020-06-23 Inspirion Delivery Sciences Llc Abuse resistant forms of extended release morphine, method of use and method of making
US20110159089A1 (en) * 2007-08-13 2011-06-30 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
US20120156277A1 (en) * 2007-08-13 2012-06-21 Inspirion Delivery Technologies, Llc Abuse resistant drugs, method of use and method of making
US20120164209A1 (en) * 2007-08-13 2012-06-28 Inspirion Delivery Technologiies, Llc Abuse resistant drugs, method of use and method of making
US10736852B2 (en) * 2007-08-13 2020-08-11 OHEMO Life Sciences, Inc. Abuse resistant oral opioid formulations
US10729656B2 (en) * 2007-08-13 2020-08-04 Ohemo Life Sciences Inc. Abuse resistant forms of immediate release oxycodone, method of use and method of making
US9220759B2 (en) 2012-02-23 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a drug eluting stent and adjunctive therapy
US9220584B2 (en) 2012-03-30 2015-12-29 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a stent and locally administered adjunctive therapy
US9750627B2 (en) 2012-03-30 2017-09-05 Abbott Cardiovascular Systems Inc. Treatment of diabetic patients with a stent and locally administered adjunctive therapy
US9789071B2 (en) 2012-06-27 2017-10-17 G2B Pharma, Inc. Intranasal formulation of epinephrine for the treatment of anaphylaxis
US10806709B2 (en) 2012-06-27 2020-10-20 G2B Pharma, Inc. Intranasal formulation of epinephrine for the treatment of anaphylaxis
EP3679924A2 (fr) 2014-08-11 2020-07-15 perora GmbH Formulation comprenant des particules
WO2016023924A1 (fr) 2014-08-11 2016-02-18 Perora Gmbh Procédé d'induction de la satiété
WO2016023923A1 (fr) 2014-08-11 2016-02-18 Perora Gmbh Formulation comprenant des particules
US11311570B2 (en) 2014-08-11 2022-04-26 Perora Gmbh Method of inducing satiety
US11504330B2 (en) 2014-08-11 2022-11-22 Perora Gmbh Formulation comprising particles containing a water-swellable or water-soluble polymeric component and a lipid component
WO2017005887A1 (fr) 2015-07-07 2017-01-12 Perora Gmbh Composition comprenant des particules induisant une satiété
US11234935B2 (en) 2015-07-07 2022-02-01 Perora Gmbh Method of inducing satiety
US11617716B2 (en) 2021-06-10 2023-04-04 Belhaven BioPharma Inc. Dry powder formulations of epinephrine and associated methods
US11872308B2 (en) 2021-06-10 2024-01-16 Belhaven BioPharma Inc. Dry powder formulations of epinephrine and associated methods
US12005185B2 (en) 2021-12-17 2024-06-11 Belhaven BioPharma Inc. Medical counter measures including dry powder formulations and associated methods

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Publication number Publication date
GB0126064D0 (en) 2001-12-19
EP1441745A1 (fr) 2004-08-04

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