WO2010031519A1 - Transcutaneous compositions for specific immuno-modulatory treatment - Google Patents

Transcutaneous compositions for specific immuno-modulatory treatment Download PDF

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Publication number
WO2010031519A1
WO2010031519A1 PCT/EP2009/006597 EP2009006597W WO2010031519A1 WO 2010031519 A1 WO2010031519 A1 WO 2010031519A1 EP 2009006597 W EP2009006597 W EP 2009006597W WO 2010031519 A1 WO2010031519 A1 WO 2010031519A1
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WO
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Prior art keywords
transcutaneous
treatment
specific
compositions
salicylic acid
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PCT/EP2009/006597
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French (fr)
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WO2010031519A8 (en
Inventor
Luigi Di Berardino
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Societa' Antica Ritrovati Medicinali S.A.R.M. S.R.L.
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Publication of WO2010031519A1 publication Critical patent/WO2010031519A1/en
Publication of WO2010031519A8 publication Critical patent/WO2010031519A8/en

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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
    • 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
    • A61K31/192—Carboxylic acids, e.g. valproic acid having aromatic groups, e.g. sulindac, 2-aryl-propionic acids, ethacrynic 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/35—Allergens
    • A61K39/36—Allergens from pollen
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants

Definitions

  • This invention relates to the use of an antigen and salicylic acid in a hydrophobic excipient as adjuvant for the preparation of a transcutaneous medicament for specific immuno-modulatory treatment, option which is intended to generate persistent relief from allergy symptoms.
  • the medicament interacts with the immune system interfering with the immunopathogenetic mechanisms causing the allergic disease.
  • the medicament is preferably in form of a patch containing suitable concentrations of the antigen/allergen and of salicylic acid in an hydrophobic adjuvant.
  • the patch is usually applied on the intact skin of the allergic patient for several hours, typically 24 hours, once a week for a few months.
  • the adjuvant according to the invention opens a controlled skin (window which allows allergens to cross the skin without manifesting the mast-cell reaction) and reach the immune system, where they exercise their well-known desensitising activity.
  • an allergenic dose directly injected into the lymphatic system may be 1000-fold lower than that injected subcutaneously in order to induce the same immune response
  • the continuous low doses administered transcutaneously may induce not only immunization but the immuno-modulatory treatment, i.e., according to the present invention, the opposite of immunization, namely a decrease of the specific atopic response to the antigen/allergen contained in the patch.
  • transcutaneous compositions for specific immuno-modulatory treatment (IMT) to which the invention relates are useful for the treatment of allergic patients who present typical IgE-mediated disorders (oculorhinitis, asthma, dermatitis, urticaria and gastroenteritis).
  • IMT immuno-modulatory treatment
  • allergen vaccine as the only treatment able to change the natural history of the disorder.
  • Specific immunotherapy is currently administered mainly subcutaneously, sublingually/orally and intranasally. In the USA, subcutaneous specific immunotherapy is the only approved treatment.
  • Transcutaneous administration was also proposed in US 2007/0292445 using a device that generates micro-channels in the skin of the patient treated, and in WO 2007/059979, which involves a skin pre-treatment before the application of the allergen.
  • salicylic acid in a hydrophobic excipient such as vaseline is an advantageous adjuvant which opens a controlled skin window that allows adequate and continuous transcutaneous diffusion of the allergen (without causing the mast-cell reaction in the dermis).
  • the invention therefore discloses the use of an antigen and salicylic acid in a hydrophobic excipient as an adjuvant for the preparation of antiallergic medicaments, in particular transcutaneous compositions for specific IMT.
  • Asthma and oculorhinitis are specific diseases which may be advantageously treated according to the invention.
  • Said medicaments may be in form, for example, of a transcutaneous plaster or patch, prepared according to known techniques.
  • Any allergen can be used, in the appropriate quantity, which will usually be a few micrograms per plaster.
  • the salicylic acid concentration in the hydrophobic excipient will usually be between 1 and 5% by weight, preferably from 2 to 3%.
  • the precontact of the antigen/allergen with the adjuvant in suitable concentrations allows that many epitopes, including the pathogenic ones, may: a) directly reach the distrectual lymphatic system, b) reach the distrectual lymphatic system through the precontact with some cells of the immune system, c) reach the whole immune system and the other secondary systems through the blood diffusion. It is accordingly obtained the clinical benefit (specific and favourable IMT).
  • the therapeutic effects achievable by administration of the IMT currently marketed can also be obtained by administering the allergen by repeated application of a plaster to the skin.
  • Group A transcutaneous grass specific IMT
  • Group B placebo Total duration of treatment: 12 weekly doses
  • Examination 1 recruitment clinical examination with general data and specific allergy information, check on inclusion and exclusion criteria, earlier medications, date and informed consent, prick test.
  • Examination 2 start of treatment start of treatment and delivery of grass specific IMT to instructed patient.
  • Inclusion criteria patients of both sexes, aged 6- 14 years, with a diagnosis of oculorhinitis and/or asthma.
  • Exclusion criteria Patients with IgE-mediated hypersensitivity (positive prick test and/or presence of specific IgE in the serum) towards Fagaceae, Oleaceae and Urticaceae.
  • the active ingredient group reported low drug consumption (antihistamine at the start of the pollen season and topical corticosteroid at the end).
  • the active group reported a definite, significant reduction in both respiratory and eye symptoms.
  • the primary endpoint was achieved with the demonstration that grass specific IMT administered transcutaneously is therapeutically effective (reduction in symptoms and in symptomatic drug consumption during the period in which the patients were exposed to pollen).

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Medicinal Preparation (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Disclosed is the use of an antigen and salicylic acid in a hydrophobic excipient as adjuvant to prepare transcutaneous compositions for specific immuno-modulatory treatment, option which is intended to generate persistent relief from allergy symptoms.

Description

TRANSCUTANEOUS COMPOSITIONS FOR SPECIFIC IMMUNOMODULATORY TREATMENT
This invention relates to the use of an antigen and salicylic acid in a hydrophobic excipient as adjuvant for the preparation of a transcutaneous medicament for specific immuno-modulatory treatment, option which is intended to generate persistent relief from allergy symptoms. The medicament interacts with the immune system interfering with the immunopathogenetic mechanisms causing the allergic disease.
The medicament is preferably in form of a patch containing suitable concentrations of the antigen/allergen and of salicylic acid in an hydrophobic adjuvant. The patch is usually applied on the intact skin of the allergic patient for several hours, typically 24 hours, once a week for a few months.
The adjuvant according to the invention (salicylic acid in a hydrophobic excipient, preferably vaseline) opens a controlled skin (window which allows allergens to cross the skin without manifesting the mast-cell reaction) and reach the immune system, where they exercise their well-known desensitising activity.
Since it is known that an allergenic dose directly injected into the lymphatic system may be 1000-fold lower than that injected subcutaneously in order to induce the same immune response, it is expected that the continuous low doses administered transcutaneously may induce not only immunization but the immuno-modulatory treatment, i.e., according to the present invention, the opposite of immunization, namely a decrease of the specific atopic response to the antigen/allergen contained in the patch.
The transcutaneous compositions for specific immuno-modulatory treatment (IMT) to which the invention relates are useful for the treatment of allergic patients who present typical IgE-mediated disorders (oculorhinitis, asthma, dermatitis, urticaria and gastroenteritis).
Prior art
The scientific societies' guidelines describe specific immunotherapy
(allergen vaccine) as the only treatment able to change the natural history of the disorder. Specific immunotherapy is currently administered mainly subcutaneously, sublingually/orally and intranasally. In the USA, subcutaneous specific immunotherapy is the only approved treatment.
Transcutaneous administration was also proposed in US 2007/0292445 using a device that generates micro-channels in the skin of the patient treated, and in WO 2007/059979, which involves a skin pre-treatment before the application of the allergen.
Description of the invention
It has now been discovered that salicylic acid in a hydrophobic excipient such as vaseline is an advantageous adjuvant which opens a controlled skin window that allows adequate and continuous transcutaneous diffusion of the allergen (without causing the mast-cell reaction in the dermis).
The invention therefore discloses the use of an antigen and salicylic acid in a hydrophobic excipient as an adjuvant for the preparation of antiallergic medicaments, in particular transcutaneous compositions for specific IMT. Asthma and oculorhinitis are specific diseases which may be advantageously treated according to the invention.
Said medicaments may be in form, for example, of a transcutaneous plaster or patch, prepared according to known techniques.
Any allergen can be used, in the appropriate quantity, which will usually be a few micrograms per plaster. The salicylic acid concentration in the hydrophobic excipient will usually be between 1 and 5% by weight, preferably from 2 to 3%.
The precontact of the antigen/allergen with the adjuvant in suitable concentrations allows that many epitopes, including the pathogenic ones, may: a) directly reach the distrectual lymphatic system, b) reach the distrectual lymphatic system through the precontact with some cells of the immune system, c) reach the whole immune system and the other secondary systems through the blood diffusion. It is accordingly obtained the clinical benefit (specific and favourable IMT).
The efficacy of transcutaneous IMT with the compositions according to the invention has been evaluated in a randomised double-blind clinical trial with two arms (active ingredient vs. placebo), conducted on patients of paediatric age suffering from allergic oculorhinitis caused by graminaceae.
Allergen treatment through the skin window induced by the adjuvant demonstrated a significant reduction in symptoms and in symptomatic drug consumption in allergic patients during natural exposure of the allergen.
Specific IMT by affixing a simple plaster containing salicylic acid in vaseline proved able to control the kinetics of the transcutaneous passage of the allergens, as demonstrated in greater detail in the following Example.
Example
The therapeutic effects achievable by administration of the IMT currently marketed can also be obtained by administering the allergen by repeated application of a plaster to the skin.
Clinical examination
Single-centre parallel double-blind trial to evaluate the efficacy of specific transcutaneous IMT, administered pre-seasonally, in the treatment of allergic rhinoconjunctivitis caused by graminaceae at paediatric age. Trial design: double-blind, randomised, placebo-controlled trial with 2 parallel groups.
Treatment:
Specific IMT for graminaceae, administered once a week for 12 weeks before the start of pollination. The plaster was kept in situ for 24 hours.
Trial groups:
Group A: transcutaneous grass specific IMT
Group B: placebo Total duration of treatment: 12 weekly doses
Flow chart of clinical stages:
Examination 1 : recruitment clinical examination with general data and specific allergy information, check on inclusion and exclusion criteria, earlier medications, date and informed consent, prick test.
Examination 2: start of treatment start of treatment and delivery of grass specific IMT to instructed patient.
Examination 3 : end of treatment check on tolerability and other factors during treatment, delivery of diary.
Examination 4: final follow-up clinical examination, collection and checking of clinical diaries, prick test. Completion of RQLQ (rhinoconjunctivitis quality of life questionnaire).
Inclusion criteria: patients of both sexes, aged 6- 14 years, with a diagnosis of oculorhinitis and/or asthma.
Exclusion criteria: Patients with IgE-mediated hypersensitivity (positive prick test and/or presence of specific IgE in the serum) towards Fagaceae, Oleaceae and Urticaceae.
Patients with a major food allergy (especially molluscs and/or Crustacea) or latex allergy.
Patient already undergoing specific immunotherapy (allergen vaccine).
Lack of collaboration by patient.
Other conditions which make IMT inadvisable according to the SIAIC Memorandum and/or the EAACI Position Paper (1993).
Results
No patient has reported side effects during the grass specific IMT.
The results shown in the table below demonstrate the efficacy of the transcutaneous treatment; in fact, there are significant differences between the two groups (active ingredient vs placebo).
The active ingredient group reported low drug consumption (antihistamine at the start of the pollen season and topical corticosteroid at the end).
Figure imgf000006_0001
p < 0.05 = significant reduction
The active group reported a definite, significant reduction in both respiratory and eye symptoms.
running Itching nasal resp. itching red sneezing lacrimation nose nose congestion diff. eyes eyes
April 3rd 0.32 0.17 0.98 0.54 0.25 0.23 0.41 0.82
April 4th 0.05 0.76 0.54 0.10 0.04 0.12 0.05 0.04
May 1st 0.08 0.35 0.17 0.04 0.04 0.01 0.04 0.01
May 2nd 0.003 0.008 0.060 0.000 0.015 0.003 0.009 0.007
p < 0.05 = significant reduction
Seasonal trend of Graminaceae pollens in the area where the clinical examination was performed:
Figure imgf000007_0001
The primary endpoint was achieved with the demonstration that grass specific IMT administered transcutaneously is therapeutically effective (reduction in symptoms and in symptomatic drug consumption during the period in which the patients were exposed to pollen).
Both the preparation of the plaster and its methods of use were validated.
The absence of skin reactions during the treatment demonstrates that the appropriate concentration of salicylic acid in vaseline opened a skin window which allows the continuous passage of the allergenic dose that proved therapeutic without triggering the mast-cell reaction in the dermis.

Claims

1. Use of an antigen/allergen and salicylic acid in a hydrophobic excipient as adjuvant to prepare transcutaneous medicinal products for specific IMT or desensitising immunotherapy.
2. Use as claimed in claim 1, wherein the hydrophobic excipient is vaseline.
3. Use as claimed in claim 1 or 2, wherein the medicinal product is in the form of a transcutaneous plaster.
4. Use as claimed in any of claims 1 to 3, for the treatment of allergic disorders.
5. Method of treatment of allergic symptoms in allergic patients which comprises transcutaneous administration to said patients of an antigen responsible for allergic symptoms, and salicylic acid in a hydrophobic excipient as adjuvant.
PCT/EP2009/006597 2008-09-16 2009-09-11 Transcutaneous compositions for specific immuno-modulatory treatment WO2010031519A1 (en)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT001652A ITMI20081652A1 (en) 2008-09-16 2008-09-16 TRANSDERMIC COMPOSITIONS FOR HYPOSENSIBILIZING SPECIFIC IMMUNOTHERAPY
ITMI2008A001652 2008-09-16

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WO2010031519A1 true WO2010031519A1 (en) 2010-03-25
WO2010031519A8 WO2010031519A8 (en) 2010-05-27

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Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0304786A2 (en) * 1987-08-27 1989-03-01 Bayer Corporation Intranasal vaccination of horses with inactivated microorganisms or antigenic materials
EP0445581A1 (en) * 1990-03-06 1991-09-11 Berlin-Chemie Ag Stable immunostimulating preparation for parenteral application, preparation and use thereof
WO1999011247A1 (en) * 1997-08-29 1999-03-11 Pharmaderm Laboratories, Ltd. Biphasic lipid vesicle composition for transdermal administration of an immunogen
EP1201232A1 (en) * 1999-07-27 2002-05-02 Hisamitsu Pharmaceutical Co. Inc. Patches for external use
EP1340496A1 (en) * 2000-11-07 2003-09-03 Hisamitsu Pharmaceutical Co. Inc. Pharmaceutical preparation of percutaneous absorption type
US20040105898A1 (en) * 1994-02-21 2004-06-03 Aberdeen University, A Great Britain Corporation Acidified nitrite as an antimicrobial agent
WO2005077411A2 (en) * 2004-02-10 2005-08-25 Innate Pharma Composition and method for the treatment of carcinoma
US20060002959A1 (en) * 1996-11-14 2006-01-05 Government Of The United States Skin-sctive adjuvants for transcutaneous immuization
EP1849477A1 (en) * 1998-02-25 2007-10-31 THE GOVERNMENT OF THE UNITED STATES, as represented by THE SECRETARY OF THE ARMY Use of skin penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response induced by ADP-ribosylating exotoxin

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0304786A2 (en) * 1987-08-27 1989-03-01 Bayer Corporation Intranasal vaccination of horses with inactivated microorganisms or antigenic materials
EP0445581A1 (en) * 1990-03-06 1991-09-11 Berlin-Chemie Ag Stable immunostimulating preparation for parenteral application, preparation and use thereof
US20040105898A1 (en) * 1994-02-21 2004-06-03 Aberdeen University, A Great Britain Corporation Acidified nitrite as an antimicrobial agent
US20060002959A1 (en) * 1996-11-14 2006-01-05 Government Of The United States Skin-sctive adjuvants for transcutaneous immuization
WO1999011247A1 (en) * 1997-08-29 1999-03-11 Pharmaderm Laboratories, Ltd. Biphasic lipid vesicle composition for transdermal administration of an immunogen
EP1849477A1 (en) * 1998-02-25 2007-10-31 THE GOVERNMENT OF THE UNITED STATES, as represented by THE SECRETARY OF THE ARMY Use of skin penetration enhancers and barrier disruption agents to enhance the transcutaneous immune response induced by ADP-ribosylating exotoxin
EP1201232A1 (en) * 1999-07-27 2002-05-02 Hisamitsu Pharmaceutical Co. Inc. Patches for external use
EP1340496A1 (en) * 2000-11-07 2003-09-03 Hisamitsu Pharmaceutical Co. Inc. Pharmaceutical preparation of percutaneous absorption type
WO2005077411A2 (en) * 2004-02-10 2005-08-25 Innate Pharma Composition and method for the treatment of carcinoma

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ITMI20081652A1 (en) 2010-03-17

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